PAINWeek Abstract Book 2019

1 Expert Consensus on the Optimization of Cannabinoids and Opioids for Chronic Pain Control

Aaron Sihota¹, Brennan Smith², Mirela Baranci³, Tim Mason³, Mark Ware³, MJ Milloy¹

¹University of British Columbia, Vancouver, BC, Canada, ²CTC Communications, Mississauga, ON, Canada, ³Spectrum Therapeutics, Montreal, QC, Canada

Purpose

Opioids have been commonly prescribed for chronic non-cancer pain management, yet there is increasing awareness of significant health risks associated with this family of compounds. Cannabinoids are increasingly being considered for the management of chronic pain, and have a more favorable adverse event profile and lower risk for dependence compared with opioids.^1,2 In balancing the risks associated with opioids and the relatively favorable tolerability profile of cannabinoids, there is increasing clinical interest in the use of cannabinoids to treat chronic pain as well as reduce overall opioid use and therefore minimize opioid-related harms.

Observational studies and early clinical trials have shown that cannabinoids have a synergistic effect with opioids leading to improved pain management and may have an opioid-sparing effect.³ Considering the degree of opioid-related harm is directly linked to the dose of opioid, strategies to taper opioid doses may reduce the associated health risks.

Despite the potential for cannabinoids to impact prescription opioid use, there is a lack of clinical trial evidence to inform on how clinicians should approach the co-management of these medication classes. However, because cannabis is also used non-medically, there are reports of patients already co-administering the two medication classes. In addition, frontline clinicians are consistently faced with questions on how to effectively use cannabinoids to reduce pain and deprescribe concurrent opioid therapy. In other words, although there is a lack of clinical trial data, there is a need for clinical guidance around managing these two medication classes in concert.

To provide guidance on how to manage opioids and cannabinoids in patients with chronic non-cancer pain, we are developing a consensus program built by subject matter experts from Canada and the United States that will address the most pertinent clinical questions surrounding the initiation, titration, tapering, monitoring, and dosage adjustments of opioids and cannabinoids in patients with chronic non-cancer pain.

Ultimately, the purpose of this consensus program is to develop a report and a clinical practice tool that will provide guidance on the use of cannabinoids with opioids for chronic pain management and harm reduction.

Methods

A modified Delphi method will be used to develop this consensus program and the corresponding report.⁴ Briefly, a core scientific committee of cannabinoid subject matter experts from the United States and Canada will identify the key areas of focus and build a set of corresponding questions associated with the clinical management of opioids and cannabinoids. This initial set of consensus questions will be reviewed twice and then finalized with the support of additional subject matter experts. Following the finalization of the consensus questions, the scientific committee and the other subject matter experts will meet in-person in the Fall of 2019. During this meeting the questions will be discussed and debated followed by anonymous voting to elucidate where consensus may be found. A corresponding report will be generated to distribute the findings from this process and include a formal literature review of the evidence, the consensus questions and committee discussion of each question, and the key consensus statements surrounding management of cannabinoids and opioids in patients with chronic pain.

Results

The areas of focus being considered for this consensus report include: when to introduce cannabinoids in the pain management continuum; initiating and titrating cannabinoids in a patient taking opioids; tapering or deprescribing opioids after initiating cannabinoids; evaluating measurements of clinical success when using cannabinoids and opioids; and consideration of specialized patient populations and patient factors in clinical practice. Following the finalization of these topics, key questions and corresponding answers will be developed for consensus voting. A formal consensus report will be generated based on the voting and developed for publication.

Conclusions

A consensus report developed by subject matter experts will provide practicing physicians, pharmacists, and nurses, with critically needed management strategies of how and when cannabinoids should be considered for chronic pain control in the presence of opioids, how and when to reduce opioids in the presence of cannabinoids, how to evaluate clinical success, and which specialized patient populations are suitable for cannabinoids. This report will provide a foundation for practicing clinicians and help direct future research on the topic of pain control in the presence of cannabinoids and opioids.

References

• Health Canada. Information for Health Care Professionals: Cannabis (marihuana, marijuana) and the cannabinoids.
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• National Academies of Sciences, Engineering, and Medicine, Health and Medicine Division, Board on Population Health and Public Health Practice, Committee on the Health Effects of Marijuana: An Evidence Review and Research Agenda. The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research.
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• Nielsen S, Sabioni P, Trigo JM, et al. Opioid-sparing effect of cannabinoids: a systematic review and meta-analysis. Neuropsychopharmacology. 2017;42(9):1752–1765.
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• Dalkey N, Helmer O. An experimental application of the DELPHI method to the use of experts. Manage Sci. 1963;9(3):458–467.
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2 A Co-Crystal of Tramadol-Celecoxib in a 1:1 Molecular Ratio Produced Synergistic Antinociceptive Effects in a Postoperative Pain Model in Rats

Manuel Merlos, Enrique Portillo-Salido, Bertrand Aubel, Jordi Buxens, Angels Fisas, Xavier Codony, Luz Romero, Daniel Zamanillo, Adelaida Morte, Jose Miguel Vela

Esteve Pharmaceuticals S.A., Barcelona, Spain

Purpose

In the United States, access to adequate pain relief may be challenging due to the growing scope of restrictions on potent schedule II opioids. Poorly controlled acute pain may result in delays in functional recovery and hospital discharge, and an increased risk of development of chronic pain. Patients with moderate to severe acute pain require novel potent analgesic treatments such as efficacious opioids with lower abuse potential or non-opioids with novel mechanisms of action (MOAs) and opioid-like efficacy.

Multimodal analgesia (MMA) involves the use of multiple techniques, and/or medications with different MOAs in order to achieve optimal pain control. MMA has the potential to improve analgesic efficacy beyond a single agent, such as an opioid, while potentially minimizing dose requirements and dose-dependent adverse effects of an opioid that may complicate their use.

The novel co-crystal of tramadol and celecoxib (CTC) incorporates racemic tramadol and celecoxib bound in a supramolecular crystal network that gives CTC its unique physiochemical characteristics. CTC is a combination of 3 active therapeutic moieties that contribute complementary central and peripheral MOAs for multimodal analgesia. Tramadol is a Schedule IV analgesic indicated for the management of pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate. (+) tramadol acts centrally as a mu opioid agonist to block central pain receptors. Additionally, (+) tramadol also inhibits serotonin reuptake and (-) tramadol inhibits norepinephrine reuptake; these mechanisms interfere with central and peripheral pain sensory pathways. Finally, celecoxib, a nonsteroidal anti-inflammatory drug, inhibits cyclooxygenase-2, a critical enzyme involved in inflammatory pain pathways. Celecoxib is indicated for treatment of acute pain and pain associated with chronic inflammatory disorders such as rheumatoid arthritis. Through its unique pharmacokinetic and pharmacodynamic characteristics, the therapeutic benefit of CTC can be achieved at lower doses of the active components resulting in optimal pain relief and an enhanced benefit-to-risk ratio.

This study explored the pharmacodynamic efficacy and safety of CTC administered in a suspension in a rat postoperative pain model compared with that of tramadol and celecoxib given separately, in order to assess the pharmacodynamic profile of CTC and possible synergistic antinociceptive interactions.

Methods

Male Wistar Han rats (6–8 weeks-old) were randomly assigned to treatment groups (n = 8–10/group): CTC suspension, 0.625–320 mg/kg; tramadol, 2.5–141 mg/kg; celecoxib, 0.6–179 mg/kg; acetaminophen, 40–320 mg/kg; and a mixture of tramadol and acetaminophen at a mole ratio of 1:17 (1:8.7 weight ratio). Behavioral measurements of pain (mechanical allodynia and thermal hyperalgesia) were assessed 4 hours after surgical injury that includes superficial tissue, deep tissue and nerve injuries to the right hindpaw and 1 hour after drug administration. Mechanical allodynia was quantified by determining the pressure threshold eliciting withdrawal of the ipsilateral and contralateral hind paws in response to stimulation applied to the plantar surface. Hyperalgesia was assessed by measurement of response to a thermal stimulus using a Hargreaves apparatus. The thermal stimulus (85 mW/cm²) was applied to both paws in turn, with a minimum interval of one min between stimulations. Latency time to the withdrawal response for each paw was measured. The percentage of mechanical allodynia and thermal hyperalgesia were each calculated with respect to the corresponding contralateral paw, i.e. (contralateral–ipsilateral/contralateral) × 100.

Safety tests including motor coordination using a rotarod apparatus, locomotor activity using in-cage, infrared detection beams, were assessed in naïve, non-operated animals.

The median effective dose (ED₅₀) values of the drugs and combinations were determined using standard nonlinear regression analysis of log dose–response. To analyze the interaction between tramadol and celecoxib or tramadol and acetaminophen in each combination, isobolographic analysis was performed. Additive isoboles were obtained by connecting the ED₅₀ of celecoxib or acetaminophen plotted on the abscissa with the ED₅₀ of tramadol on the ordinate. The theoretical additive dose (Z_add) for a combination was calculated and compared with the experimental ED₅₀ (Z_t) of the combination. The interaction between two drugs was classified using the interaction index (γ = Z_t/_Zadd): (1) supra-additive or synergistic interaction (γ < 1), with significant differences between Z_t and Z_add; (2) sub-additive or antagonistic interaction (γ > 1), with significant differences between Z_t and Z_add; and (3) additive interaction (γ ≈ 1), without significant differences between Z_t and Z_add.

Results

Dose-response curves for tramadol, celecoxib, and CTC suspension revealed ED₅₀ (SEM) values for mechanical allodynia on the right, ipsilateral hindpaw of 5.4 (0.8), 3.0 (0.5), and 2.0 (0.5) mg/kg, respectively; values for thermal hyperalgesia were 8.3 (1.2), 2.6 (1.5), and 2.3 (0.5) mg/kg, respectively. Compounds demonstrated full efficacy, except for celecoxib for thermal hyperalgesia (E_max = 47%). Isobolographic analysis demonstrated significant differences (P < 0.05) between the experimental ED₅₀ Z_t [2.0 (0.5) mg/kg] and the theoretical Z_add [3.8 (0.4) mg/kg], with an interaction index γ = 0.5, indicating a synergistic/supra-additive effect on mechanical allodynia of tramadol and celecoxib when administered as CTC suspension. Similarly, significant differences were found (P < 0.001) between the experimental ED₅₀ Z_t [2.3 (0.5) mg/kg] and the theoretical Z_add [9.8 (0.8) mg/kg], with an interaction index γ = 0.2, indicating a synergistic/supra-additive effect on thermal hyperalgesia of tramadol and celecoxib when administered as CTC suspension.

Dose–response curves of tramadol, acetaminophen, and the combination of tramadol and acetaminophen revealed ED₅₀ values for mechanical allodynia when stimulated on the right, ipsilateral hindpaw of 4.0 (0.4), 112.4 (10.0), and 39.5 (4.1) mg/kg; values for thermal hyperalgesia were 3.3 (0.5), 87.2 (6.1), and 75.0 (5.9) mg/kg for tramadol, acetaminophen, and their combination, respectively. All compounds showed full efficacy. Antagonistic/sub-additive effects of tramadol and acetaminophen on mechanical allodynia and thermal hyperalgesia were observed for the combination, with significant differences between the experimental ED₅₀ Z_t [39.5 (4.1) and 75.0 (5.9) mg/kg] and the theoretical Z_add [27.6 (2.2) and 24.2 (1.6) for mechanical allodynia and thermal hyperalgesia, respectively with an interaction index γ = 1.4 and 3.1, respectively.

Dose–response curves of tramadol, celecoxib, and CTC suspension for motor coordination and locomotion revealed ED₅₀ values for motor coordination impairment of 74.5 (1.1) and 160.1 (1.9) mg/kg for tramadol, and CTC suspension; values for motor activity impairment were 35.1 (1.0) and 87.6 (1.9) mg/kg for tramadol and CTC suspension, respectively. Celecoxib did not show significant effects at doses up to 160 mg/kg. Isobolographic analysis showed additive effects of tramadol and celecoxib on motor coordination and locomotor activity with no significant difference between the experimental ED₅₀ Z_t of 160.1 (1.9) and 87.6 (1.9) mg/kg, for motor coordination and locomotor activity, respectively and the theoretical Z_add of 165.3 (13.3) and 81.5 (1.9) mg/kg, with an interaction index of γ = 1.0 and 1.1, respectively.

Conclusions

Isobolographic analyzes showed that CTC suspension exerted synergistic mechanical anti-allodynic and thermal anti-hyperalgesic effects in the postoperative pain model in rats. In contrast, the tramadol and acetaminophen combination showed antagonistic effects on both mechanical allodynia and thermal hyperalgesia. No synergies between tramadol and celecoxib on motor coordination or locomotor activity were observed after the administration of CTC suspension. Overall, pharmacodynamic efficacy and safety data revealed that CTC suspension provided synergistic analgesic effects compared with each agent alone, without enhancing adverse effects. CTC, a novel co-crystal of tramadol, a schedule IV opioid, and celecoxib, a cyclooxygenase-2 specific nonsteroidal anti-inflammatory drug is designed to provide multimodal analgesia with multiple, complementary mechanisms of action and central and peripheral sites of action. The active components of CTC were specifically chosen to capitalize on their synergistic efficacy, and the ability of the co-crystal technology to modulate their physicochemical characteristics resulting in the enhanced therapeutic benefit of CTC. This novel co-crystal that achieves MMA with optimized physicochemical characteristics and an improved benefit-to-risk profile can provide a unique therapeutic option with broad clinical utility in multiple settings of moderate to severe acute pain.

3 The Unique Physiochemical Profile of Co-Crystal of Tramadol-Celecoxib Optimizes Pharmacokinetic and Pharmacodynamic Synchronization: Structural Properties, Differential Dissolution Behavior and Pharmacokinetic Parameters

Carmen Almansa, Adriana Port, Anna Vaque, Mariano Sust, Marisol Escriche, Mercedes Encabo, Artur Sans, Neus Gascon, Gregorio Encina, Raquel Enrech, Magda Bordas, Jaume Tomas, Adelaida Morte, Carlos Plata-Salaman

Esteve Pharmaceuticals S.A., Barcelona, Spain

Purpose

The multimodal nature of pain results in challenging and often inadequate pain management. Due to the complex nature, etiology and pathophysiology of pain, single agents often fail to provide a complete response. Combining agents and therapies is a common clinical practice in pain management. Recruitment of multiple mechanisms of action, that may function additively or synergistically, can provide more effective analgesia. Coadministration of two different drugs, separately, is the simplest way to achieve multimodal analgesia (MMA), however this approach increases the number of dosage forms and costs and may result in more adverse events. Fixed-dose combinations may improve convenience by administering multiple agents in one dosage form but do not resolve the potential for safety and tolerability issues, especially when dosage increases are necessary.

Co-crystal drugs containing multiple active drugs may circumvent these problems by optimizing the physiochemical and pharmacokinetic (PK) profiles, allowing for lower doses of active drugs, potentially reducing the incidence and severity of side effects and improving the efficacy-to-safety profile.

A novel, first-in-class co-crystal of tramadol and celecoxib (CTC) incorporates racemic tramadol and celecoxib bound in a supramolecular crystal network that gives CTC its unique physiochemical characteristics. CTC is a combination of 3 active therapeutic moieties that contribute complementary central and peripheral MOAs for MMA. Tramadol is a Schedule IV analgesic indicated for pain severe enough to require an opioid analgesic and for which alternatives are inadequate. (+) tramadol acts as a mu opioid agonist to block central pain receptors; (+) tramadol also inhibits serotonin reuptake and (-) tramadol inhibits norepinephrine reuptake; these mechanisms interfere with central and peripheral pain sensory pathways. Finally, celecoxib, a nonsteroidal antiinflammatory drug, inhibits cyclooxygenase-2, a critical enzyme in inflammatory pain pathways. Celecoxib is indicated for treatment of acute pain and pain associated with chronic inflammatory disorders such as rheumatoid arthritis. Through CTC’s unique pharmacokinetic and pharmacodynamic characteristics, therapeutic benefit can be achieved at lower doses of the active components resulting in optimal pain relief and enhanced benefit-to-risk profile.

The current study reports on the identification, characterization, unique dissolution properties of CTC and its Phase 1 single-dose and multiple-dose PK profiles.

Methods

Identification, Characterization and Dissolution Profile: CTC was prepared by crystallization from isopropanol. CTC was characterized using multiple techniques including proton nuclear magnetic resonance, infrared spectroscopy, differential scanning calorimetry, thermogravimetric analysis, x-ray powder diffraction, and single-crystal x-ray diffraction. Intrinsic dissolution rate (IDR) of CTC in water was studied according to standard United States Pharmacopeial Convention procedures. The behavior of CTC was studied in 0.5% hydroxypropyl methyl cellulose (HPMC) and evaluated to ensure the physical integrity at the time of in vivo administration. The impact of gastrointestinal tract dissolution media on CTC dissolution rate and its thermodynamic solubility and hygroscopicity, as an indicator of the impact of atmospheric water on CTC structure, were assessed.

PK Studies: Single-dose and multiple-dose PK studies were performed in healthy male and female adults. Single-dose and multiple-dose studies were conducted in randomized, open-label, four-period, four-sequence, crossover study carried out in a single center in Canada. Adults aged 18–55 years were orally administered four treatments under fasted conditions (treatment order was randomly assigned and treatments were separated by 7-day wash-out period): 200 mg CTC (equivalent to 88 mg tramadol and 112 mg celecoxib; Treatment 1); 100 mg tramadol (Treatment 2); 100 mg celecoxib (Treatment 3); and 100 mg tramadol and 100 mg celecoxib (Treatment 4) as either single-doses or as fifteen twice-daily doses for multiple-dose studies.

Blood samples for measurement of plasma concentration of tramadol and celecoxib were collected pre-dose and from 0.5 hours to 48 hours after treatments. PK parameters were calculated using noncompartmental analysis with parameters for CTC adjusted according to reference product dose (100 mg). Safety assessments, including the reporting and recording of adverse events (AEs), measurement of standard clinical laboratory parameters, physical examination (including vital signs) and 12-lead ECG, were performed throughout the study.

Results

Identification, Characterization and Dissolution Profile: CTC was unambiguously characterized by proton nuclear magnetic resonance, infrared spectroscopy, differential scanning calorimetry, x-ray powder diffraction, and single-crystal x-ray diffraction. CTC is a unique structure with a supramolecular three-dimensional network; tramadol and celecoxib are linked via hydrogen bonding and chloride ions. CTC is an ionic co-crystal, defined as a crystal sustained by charge-assisted hydrogen bonds and formed by a positive moiety (tramadolium cation), a negatively charged counterion (chloride anion), and a neutral molecule (celecoxib). IDR of tramadol and celecoxib alone from aqueous solution were substantially different when compared with their release from CTC. The release of celecoxib was faster (3-fold) from CTC than from celecoxib alone and the release of tramadol was 7-fold slower from CTC than from tramadol alone. The kinetic dissolution profile of CTC in HPMC and representative buffered solutions confirmed the IDR findings and led to a supersaturation state of celecoxib, which was released significantly faster from CTC than from the free combination of tramadol and celecoxib or from celecoxib alone. Tramadol was released much more slowly from CTC than from the free combination or tramadol alone. Experimental and predicted solubility−pH curves showed that the thermodynamic solubility of CTC lies in between those of tramadol and celecoxib within the physiologically meaningful pH range.

PK Studies: Thirty-six subjects participated in single-dose studies. Tramadol PK parameters for Treatments 1, 2 and 4, respectively, were mean C_max of 263, 346 and 349 ng/ml; mean AUCτ of 3039, 2979 and 3119 ng.hr/ml; and median T_max of 2.7, 1.8 and 1.8 hr. For Treatments 1, 3 and 4, the respective celecoxib PK parameters were mean C_max of 313, 449 and 284 ng/ml; mean AUCτ of 2183, 3093 and 2856 ng.hr/ml; and median T_max of 1.5, 2.3 and 3.0 hr. Thirty subjects participated in multiple-dose studies. Multiple-dose tramadol PK parameters for treatments 1, 2 and 4, respectively, were mean C_max of 551, 632 and 661 ng/ml; mean AUCτ,ss of 4796, 4990 and 5284 ng.hr/ml; and median T_max of 3.0, 2.0 and 2.0 hr. For treatments 1, 3 and 4, multiple-dose celecoxib PK parameters were mean C_max of 445, 536 and 396 ng/ml; mean AUCτ,ss of 2803, 3366 and 2897 ng.hr/ml; and median T_max of 2.0, 2.0 and 3.0 hr.

No unexpected adverse events were reported in either single-dose or multiple-dose studies.

Conclusions

CTC demonstrated distinctive features versus tramadol and celecoxib alone or the free combination. CTC showed substantially different dissolution behavior versus the free combination in vehicles relevant to preclinical and clinical formulations. The modified dissolution profiles of CTC contributed to improved synchronization of celecoxib and tramadol exposure. Tramadol was released from CTC at a slower rate versus tramadol alone or the free combination resulting in lower and later peak concentrations. Administration of CTC resulted in improved absorption of celecoxib with faster peak concentrations and maintained concentrations versus the free combination. Lower peak concentration of tramadol after repeated dosing of CTC may contribute to lower incidence of opioid-related, dose-dependent adverse events. The faster absorption and time to peak celecoxib concentrations seen with CTC may contribute to earlier onset of analgesia and the unique synergistic relationship of tramadol and celecoxib seen in rodent pain models. Through a unique structure that confers a differentiated physicochemical profile, CTC optimizes the pharmacokinetic profiles of the components, tramadol and celecoxib. This novel co-crystal of agents that achieve MMA with synchronization of physiochemical characteristics and an improved benefit-to-risk profile can provide a unique therapeutic option with broad clinical utility in multiple settings of moderate to severe acute pain.

4 Co-Crystal of Tramadol-Celecoxib: Efficacy and Safety Results from a Dose-Finding, Randomized, Double-blind, Multicenter, Phase II Clinical Trial in Patients With Moderate-To-Severe Acute Pain Due To an Oral Surgical Procedure

Jose Lopez Cendrun¹, Sebastian Videla², Miguel Burgueno³, Inma Juarez⁴, Samir Aboul-Hosn⁵, Rafael Martin-Granizo⁶, Joan Grau⁷, Miguel Puche⁸, Jose-Luis Gil-Diez⁹, Jose-Antonio Hueto¹⁰, Anna Vaque², Mariano Sust², Adelaida Morte², Jesus Cebrecos², Esther Ortiz², Carlos Plata-Salaman², Antoni Monner¹¹

¹Complexo Hospitalario Universitario A Corunaa, A Coruna, Spain, ²Esteve Pharmaceuticals S.A., Barcelona, Spain, ³Hospital Universitario La Paz, Madrid, Spain, ⁴Hospital Universitari de Bellvitge, Barcelona, Spain, ⁵Hospital Plato, Barcelona, Spain, ⁶Hospital Clínico San Carlos, Madrid, Spain, ⁷Hospital General de Granollers, Granollers, Spain, ⁸Hospital Clınico de Valencia, Valencia, Spain, ⁹Hospital Universitario La Princesa, Madrid, Spain, ¹⁰Hospital Universitari Vall d’Hebron, Barcelona, Spain, ¹¹Bellvitge University Hospital/IDIBELL, Barcelona, Spain

Purpose

Many patients with acute pain will not achieve adequate analgesia with single agent pain management. Strategies to address this unmet medical need include multimodal analgesia (MMA), achieved via the use of multiple classes of pain-relieving drugs that have different mechanisms of action, with the aim of improving efficacy.

Co-crystal of tramadol and celecoxib (CTC) is a novel, first-in-class co-crystal that incorporates racemic tramadol HCl and celecoxib bound in a supramolecular crystal network that gives CTC unique characteristics. The crystalline structure in CTC changes the physicochemical properties of constituent tramadol and celecoxib, thereby optimizing the pharmacokinetics (PK) of each active molecule. CTC is a pain-relieving co-crystal containing equimolar quantities of tramadol and celecoxib. A 100-mg dose of CTC contains 44 mg of racemic tramadol and 56 mg of celecoxib. Tramadol is a Schedule IV analgesic indicated for the management of pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate. (+) tramadol acts centrally as a mu opioid agonist to block central pain receptors. Additionally, (+) tramadol also inhibits serotonin reuptake and (-) tramadol inhibits norepinephrine reuptake; these mechanisms interfere with central and peripheral pain sensory pathways. Finally, celecoxib, a nonsteroidal anti-inflammatory drug, inhibits cyclooxygenase-2, a critical enzyme involved in inflammatory pain pathways. Celecoxib is indicated for treatment of acute pain and pain associated with chronic inflammatory disorders such as rheumatoid arthritis. Through its unique pharmacokinetic and pharmacodynamic characteristics, the therapeutic benefit of CTC can be achieved at lower doses of the active components resulting in optimal pain relief and an enhanced benefit/risk ratio.

The aim of this study was to establish the effective dose of CTC for treating moderate-to-severe acute pain after extraction of ≥2 impacted third molar teeth requiring bone removal. This complex model of pain was chosen as it involves mechanical manipulation, tissue and nerve damage, inflammation, and interaction between pain and inflammatory mechanisms.

Methods

This was a double-blind, randomized, placebo- and active-controlled, dose-finding Phase II trial performed in nine centers in Spain. The study enrolled adult men and women (≥18 years of age and body weight <110 kg) who experienced moderate-to-severe pain, defined as pain that reached pain intensity ≥50 mm on the visual analogue scale (VAS), after oral surgery with extraction of ≥2 impacted third molars (at least one mandibular) requiring bone removal. Patients were randomly assigned to receive a single administration of one of six treatments (in identical encapsulated forms): 1. CTC 50 mg (equivalent to 22 mg tramadol + 28 mg celecoxib); 2. CTC 100 mg (equivalent to 44 mg tramadol + 56 mg celecoxib); 3. CTC 150 mg (equivalent to 66 mg tramadol + 84 mg celecoxib); 4. CTC 200 mg (equivalent to 88 mg tramadol + 112 mg celecoxib); 5. Tramadol 100 mg (2 x 50 mg); 6. Placebo. Patients who received study medication remained at the study site for 12 h thereafter; during this period, patients could choose to receive rescue medication (supplementary analgesic medication).

The primary efficacy endpoint was the sum of pain intensity difference (SPID) from 0–8 hr. Other efficacy assessments included pain intensity (PI) by VAS, pain intensity difference (PID), pain relief (PAR) assessed by a 5-point ordinal scale, total pain relief (TOTPAR), use of rescue medication, proportion of responders, and patients’ overall assessment of study medication. PI was recorded at baseline and, together with PAR, at different time points from 10 min through 24 hr after study treatment (or until rescue medication was taken). Safety assessments included adverse events (AEs), standard laboratory tests, oral and dental evaluation, general medical examination, vital signs and 12-lead electrocardiogram.

The primary population for efficacy was the per-protocol analysis set (all randomized and treated patients who had no relevant protocol deviations, provided ≥3 valid VAS measurements within 8 hr of study treatment, and did not take rescue medication during the first hour post-study treatment). Safety was assessed in the safety analysis set (all randomized patients who received study treatment).

Results

A total of 335 patients with moderate-to-severe pain within 4 hr of oral surgery were randomized and all but one of these received one of six study treatments. Patients were predominantly young (mean age 24.5 years), Caucasian (98%), and female (57%). The primary efficacy endpoint (SPID up to 8 hr post-dose) was lower, reflecting lower pain intensity, with CTC 100 mg, 150 mg, and 200 mg compared with placebo (P < 0.05) and tramadol 100 mg (P < 0.05). CTC 50 mg was also numerically lower than placebo and tramadol, although this difference did not reach statistical significance. The effect of CTC on SPID (0–8 hr) was dose-dependent. CTC doses ≥100 mg were more efficacious than placebo (P < 0.05) with respect to PID from 1 hr after study drug administration, SPID regardless of the time interval examined and for all other efficacy endpoints, including TOTPAR, PAR, median time to first intake of rescue medication, responder rates, and overall assessment of study medication. CTC 150 mg and 200 mg were also more efficacious than tramadol 100 mg for PID at 8 and 12 hr, TOTPAR from 0–8 and 0–12 hr, and PAR at 8 hr (P < 0.05). Fewer patients on ≥100 mg CTC required rescue medication vs. those on 100 mg tramadol or placebo. The time to intake of rescue medication, was significantly longer for CTC vs. tramadol and placebo. The proportion of patients who responded to treatment (i.e., patients experiencing 30% and 50% reductions in pain intensity from baseline) was higher for CTC doses ≥100 mg vs. both tramadol 100 mg and placebo. Patients’ overall assessment of treatment was significantly better for patients taking 100, 150 and 200 mg CTC vs. those on 100 mg tramadol or placebo.

A total of 80 TEAEs in 61 patients were reported in this study. Intake of 50, 100 and 150 mg of CTC led to markedly fewer AEs compared with 100 mg tramadol, whereas, the safety and tolerability of 200 mg CTC and 100 mg tramadol were similar as expected: 29.8% (n = 17) of patients in the 200 mg CTC group and 29.3% (n = 17) of the patients in the 100 mg tramadol group experienced at least one TEAE. The most common side effects were nausea, dizziness and vomiting. TEAEs were mostly mild or moderate, with the exception of one severe drug-related TEAE (an incident of vomiting in a patient who had received 100 mg tramadol).

Conclusions

CTC (100–200 mg) provided greater efficacy over tramadol 100 mg and placebo in the treatment of acute moderate-to-severe pain after oral surgery. Although tramadol 100 mg did not achieve statistically significant efficacy versus placebo, the magnitude of analgesia was consistent with prior published results in the same pain model. AEs were in line with those expected with tramadol and celecoxib administered separately in an acute setting. CTC produced dose-dependent pain relief that was associated with similar (200 mg dose) or better (50–150 mg doses) overall safety and tolerability than tramadol 100 mg alone. The lower dose of tramadol and the complementary mechanisms of action of tramadol and celecoxib contained within the co-crystal contribute to the improved efficacy and tolerability (at doses <200 mg) vs. equivalent doses of tramadol alone. Overall, CTC demonstrated statistically significant and clinically relevant analgesic activity, faster onset of action, longer duration of analgesia, and less need for rescue medication compared with tramadol. This novel co-crystal of agents that achieve MMA with optimized physiochemical characteristics and an improved benefit-to-risk profile can provide a unique therapeutic option with broad clinical utility in multiple settings of moderate-to-severe acute pain.

5 Implementation of Pragmatic Guidelines for Inpatient Opioid Management in a Regional Multi-Hospital System

Amy Durell, Jessica Geiger-Hayes, Nicholas Parkinson

OhioHealth, Columbus, OH, USA

Purpose

Pain management has become increasingly difficult in the light of the nationwide opioid epidemic. Practitioners are becoming more and more uncomfortable with pain management. Pain, both acute and chronic, is one of the most common issues brought to the attention of emergency medicine physicians, hospitalists, surgeons and other inpatient providers. Inpatient clinicians are often called on to make decisions about pain management without the benefit of a long-term relationship with their patients, these decisions can be further complicated by clinical concerns for opioid use disorder (OUD), malingering, and other psychiatric diagnoses. These clinical concerns commonly generate anxiety for inpatient providers regarding the correct use of potentially addictive medications – particularly opioids and benzodiazepines.

The difficulty faced by inpatient clinicians is compounded by regulatory and financial pressure to avoid undertreating pain and to generate high patient satisfaction scores. In this context, detailed guidance regarding inpatient opioid management from medical societies and regulatory organizations over the past few decades have been lacking as they have been directed mainly toward primary care physicians.

The opioid epidemic, along with stricter regulations and laws, has made it necessary for our hospital system to provide guidance to inpatient providers. This guidance included the development of acute and chronic pain management pathways that can be utilized by providers for safe pain control.

Methods

A set of pain management guidelines were developed as the result of a cross-campus, interdisciplinary work group, focused on improving prescriber comfort with pain management in patients with and without suspected OUD. Easy to follow guidelines with appropriate educational tips provided as endnotes were developed over the course of several weeks. The two guidelines are focused on managing inpatient acute and chronic pain. The guidelines were presented and approved by the hospital medicine clinical guidance council and then were made available to all prescribers. Desired outcomes from the guidelines are as follows: 1) increased utilization of opioid and non-opioid pain management focused order sets 2) utilization of developed pain pathways.

Effect on practice of pain management was measured by utilizing an electronic survey system. The survey questionnaire was developed by the same cross-campus workgroup based on prior literature. It was administered to inpatient hospitalists across 6 main campuses of the healthcare system from May through October 2017. The survey contained 8 questions regarding utilization of the guidelines, skill level with pain management, and utilization of current available opioid and non-opioid intermittent pain management focused order sets. Education regarding the newly developed pain management guidelines were provided to the hospitalists included in the survey group prior to survey being administered.

Changes in practice were measured by evaluating utilization of the current approved opioid and non-opioid intermittent pain management focused order sets with electronic medical record software. The data was collected anonymously, de-identified, compared and presented in the form of a percentage of orders from orders sets at baseline compared to follow-up analysis at one month and at 6 months.

Results

One hundred fifty-six surveys composed of 8 questions were distributed during the study time frame of May-October 2017. One hundred eight of the surveys were completed, this correlates to an approximate 69% response rate. Two of the survey questions were directed toward utilization of the developed pain guidelines in clinical practice.

Of the completed surveys, 61.32% of responses indicated the guidelines would induce change in clinical practice and nearly 88% of respondents were willing to follow the guidelines.

Change in practice was measured by utilization of currently available opioid and non-opioid intermittent pain management focused order sets. This data was collected at baseline (pre-survey), 1-month post survey and 6-month post survey. The data resulted in a slight increase in utilization of opioid order sets from baseline to 1-month follow up. Baseline usage was 15.56% and 1-month follow up was 16.55%. At the 6-month follow up, there was a decrease to 12.28% utilization. The non-opioid order set utilization showed a small uptrend from 0.31%, to 0.48%, to 0.57% respectively from baseline to 1-month follow-up and 6-month follow up post survey.

Conclusions

Development of new guidelines for inpatient pain management in a large regional multi-hospital system was perceived as helpful by healthcare providers and was associated with a short-term trend toward safer prescribing practices. The increase and subsequent decrease in order set utilization shows that education was effective but bears repeating to keep utilization at higher levels. We focus on increased use of order sets as the order sets available include guidance for what medications to choose and when to choose them, which will help guide future practice. This is just one-step toward providing optimal opioid prescribing for hospitalized patients and allowing hospitalist to safely and optimally prescribe opioids while maintaining current standards of efficiency. Further investigation into order set utilization, prescriber comfort and prescriber knowledge on pain management would be warranted.

6 Tolperisone, a Novel Muscle Relaxant, Does not Impair Driving, While Cyclobenzaprine Results in Driving Impairment Potentially Due to Effects on Drowsiness

Amy Halseth¹, Judy Caron¹, Thomas Wessel¹, Gary Kay²

¹Neurana Pharmaceuticals, La Jolla, CA, USA, ²Cognitive Research Corporation, St. Petersburg, FL, USA

Purpose

Tolperisone, a centrally-acting muscle relaxant in development in the United States for treatment of acute and painful muscle spasms, has a long history of use in countries outside the United States. Tolperisone is reported to be non-sedating and does not induce drowsiness, unlike commonly used muscle relaxants. Results from a blinded 3-way crossover driving simulation study previously reported that there was no difference in simulated driving performance with continued TID administration of tolperisone (assessed as mean Standard Deviation of Lateral Position [SDLP]) compared to placebo on Day 1 of dosing (as a measure of acute effects), on the morning of Day 2 prior to dosing (as a measure of the next-day residual effects), or on Day 3 of dosing (as a measure of effects at steady state), while TID administration of cyclobenzaprine resulted in significantly increased SDLP on both Day 1 of dosing (mean increase of 9.3 cm) and the morning of Day 2 (mean increase of 5.7 cm). In this study, intra-subject variability in the SDLP was observed in the placebo condition, and this variability was even greater in response to cyclobenzaprine.

The current analysis was performed to determine if changes in SDLP from placebo with cyclobenzaprine on Day 1 and Day 2 were occurring in the same subset of subjects. In addition, the relationship between drowsiness (captured by standard adverse event reporting) and change in SDLP from placebo on Day 1 with cyclobenzaprine and tolperisone was examined.

Methods

31 healthy volunteers were enrolled in this inpatient, 3-way, randomized, blinded, crossover study. Subjects received 150 mg tolperisone TID, 10 mg cyclobenzaprine TID, or placebo TID for 3 days, with a 4-day washout between randomized treatments; 29 subjects completed all 3 treatments and were included in the per protocol population for analysis. While in the research unit, subjects performed a 100 km (60 min) simulated driving test on Day 1 one hour post-dose (acute effects around tolperisone T_max), morning of Day 2 pre-dose, and Day 3 one hour post-dose. The main outcome measure was SDLP, with other secondary endpoints collected during the simulated driving test related to speed control, lane exceedance, speed in cornering, total collisions, and divided attention while driving. The change from placebo in SDLP with the two active medications was calculated for each day of the driving test. A pre-determined threshold of an increase of 4.4 cm was established as indicative of driving impairment, as a mean increase of this magnitude has been associated with blood alcohol content of 0.05% in this simulated driving test.

Results

The mean SDLP during the placebo driving simulations on Days 1, 2, and 3 was 29.7 cm, 29.9 cm, and 29.6 cm, respectively, demonstrating that driving performance was relatively unchanged by time of day or other experimental factors in subjects receiving placebo. As previously reported, SDLP with tolperisone was similar to placebo (p values for each day exceeded 0.75), whereas cyclobenzaprine significantly increased SDLP (p < 0.01 vs placebo on all days). The increase in SDLP with cyclobenzaprine was greatest on Days 1 (9.3 [5.91, 12.60] cm; p < 0.001) and 2 (5.7 [3.25, 8.08] cm; p < 0.001; data shown are LS mean increases [95% CI]).

On Day 1, 5/29 subjects receiving tolperisone had a 4.4 cm increase in SDLP and 4/29 subjects had a 4.4 cm reduction, suggesting that the increases were due to typical variability. In contrast, 18/29 subjects receiving cyclobenzaprine had a 4.4 cm increase in SDLP while only 1/29 subject had a 4.4 cm reduction.

On Day 2, 4/29 subjects receiving tolperisone had a 4.4 cm increase in SDLP and 3/29 subjects had a 4.4 cm reduction; only one subject had a 4.4 cm increase on both days of tolperisone treatment. For cyclobenzaprine, 15/29 subjects had a 4.4 cm increase in SDLP, while 1/29 subject had a 4.4 cm reduction. 12 of these 15 subjects also had an increase of >4.4 cm on Day 1. Comparing the 12 subjects who had an impairment in driving performance on both Day 1 and Day 2 with cyclobenzaprine with those who did not show impairment, the subjects with impairment were numerically more likely to be male (75% male) than without impairment (59% male); there were no significant differences in age, body weight, or body mass index.

Self-reported drowsiness was associated with change in SDLP with cyclobenzaprine on Day 1, with mean changes in SDLP of 14.2 and 6.8 cm in subjects who did (n = 9) and did not (n = 20) report drowsiness, respectively. The mean change in SDLP on Day 1 with tolperisone was less than the predefined threshold of 4.4 cm in subjects who did or did not report drowsiness.

Conclusions

Tolperisone 150 mg TID was found to be similar to placebo on measures of driving, in contrast to cyclobenzaprine which showed impact on driving performance both on Day 1 of dosing, and on Day 2, prior to the morning dose of medication. Looking at individual patient data, where there was a high degree of overlap between subjects who demonstrated impairment with cyclobenzaprine on Day 1 and Day 2, suggests that a subset of individuals exist who is more susceptible to these effects. In contrast, the lack of effect in these subjects with tolperisone suggests that tolperisone may have utility as a muscle relaxant, without an increase in drowsiness or impact on driving ability as seen with other muscle relaxants.

7 Ubrogepant Is Effective for the Acute Treatment of Migraine in Patients With an Insufficient Response to Triptans

Andrew M. Blumenfeld¹, Peter J. Goadsby², David W. Dodick³, Susan Hutchinson⁴, Chengcheng Liu⁵, Michelle Finnegan⁵, Joel M. Trugman⁵, Armin Szegedi⁵

¹Headache Center of Southern California, The Neurology Center, Carlsbad, CA, USA, ²NIHR-Wellcome Trust King’s Clinical Research Facility, King’s College, London, United Kingdom, ³Mayo Clinic, Phoenix, AZ, USA, ⁴Orange County Migraine & Headache Center, Irvine, CA, USA, ⁵Allergan plc, Madison, NJ, USA

Purpose

To examine the efficacy of ubrogepant versus placebo for the treatment of a migraine attack in patients based on historical response to triptans.

Methods

Multicenter, double-blind, single-attack, phase 3 trials (ACHIEVE I, NCT02828020; ACHIEVE II, NCT02867709). Adults with a history of migraine, with/without aura, were randomized 1:1:1 to placebo or ubrogepant (50 mg or 100 mg, ACHIEVE I; 25 mg or 50 mg, ACHIEVE II). At baseline, patients were categorized as ‘triptan-effective,’ ‘triptan-ineffective’ (including those contraindicated), or ‘triptan-naïve,’ based on historical experience. Co-primary efficacy endpoints in both trials were pain freedom and absence of most bothersome migraine-associated symptom (MBS) 2 hours after the initial dose.

Results

At baseline, patients in the modified intent-to-treat population (N = 1327, ACHIEVE-I; N = 1355, ACHIEVE-II) were categorized as triptan-effective (40%, ACHIEVE-I; 35%, ACHIEVE-II), triptan-ineffective (27%, ACHIEVE-I; 23%, ACHIEVE-II), and triptan-naïve (32%, ACHIEVE-I; 42%, ACHIEVE-II). Reasons for categorization as triptan-ineffective were insufficient efficacy (78%, ACHIEVE-I; 82%, ACHIEVE-II), insufficient tolerability (18%, ACHIEVE-I; 15%, ACHIEVE-II), and contraindications/warnings (3%, ACHIEVE-I; 2%, ACHIEVE-II). For both 2-hour pain freedom and absence of MBS, response rates were higher for ubrogepant than placebo across all triptan subpopulations. Magnitude of efficacy (ubrogepant versus placebo) was not significantly different among the 3 subpopulations for pain freedom (treatment-by-subgroup interaction: P = 0.2561, ACHIEVE-I; P = 0.5011, ACHIEVE II) or absence of MBS (P = 0.4938, ACHIEVE-I; P = 0.9251, ACHIEVE-II). Placebo response rates were lowest in triptan-ineffective patients and highest in triptan-naïve. Proportion of patients reporting adverse events was comparable across treatment groups; no safety concerns were identified.

Conclusions

Ubrogepant was safe and effective for the acute treatment of migraine in participants with a reported history of triptan-ineffectiveness. No differences were observed in the magnitude of treatment effect between the defined triptan subgroups.

8 The Effect of Food on the Pharmacokinetic Profile of a New Abuse-Deterrent Oxycodone IR Formulation Compared to a Marketed Reference Formulation

Anja Tündermann, Michael Gautrois, Jiří Letal, Jens Rengelshausen, Hans-Jürgen Stahlberg

Grünenthal GmbH, Aachen, NRW, Germany

Purpose

Immediate release (IR) opioids are commonly abused. Abuse-deterrent formulations (ADFs) aim to prevent abuse by non-oral routes, e.g., snorting or injecting. The development of such formulations cannot rely on abuse-deterrent properties alone: a previously developed ADF of IR oxycodone was not approved by the FDA owing to a clinically relevant food effect compared to a marketed non-ADF.¹

To explore whether a new ADF of IR oxycodone (GRT7030) is subject to a pronounced food effect, a Phase I trial was conducted.

Methods

Thirty-two healthy subjects were orally administered single 10 mg doses of GRT7030 (Test) and Oxycodon HCl Aristo® (Reference) under fasted and fed conditions, in a randomized, open-label, 4-period crossover design.

Results

The intake of food increased the AUC by 28% (test) and 24%(reference) and C_max by 8% (test) and 7% (reference) respectively. Under fasted conditions median t_max was 1.0 h (test) and 0.75 (reference), under fed conditions median t_max was 1.5 h, identical for both formulations.

Conclusions

The data indicate that GRT7030 has similar in-vivo performance to the reference formulation under fed and fasted conditions. The unacceptable prolonged t_max seen with Avridi ^TM1 under fed conditions was not observed with GRT7030.

1. Published during Avridi Advisory Committee Meeting, September 2015.

9 Evaluation of the Intranasal Abuse Potential of a New Abuse-Deterrent Oxycodone IR Formulation Compared to Oxycodone Powder

Stefan Buller, Jiří Letal, Michael Gautrois, Anja Tündermann, Jens Rengelshausen, Hans-Jürgen Stahlberg

Grünenthal GmbH, Aachen, NRW, Germany

Purpose

Prescription opioid abuse is a public health concern, especially for immediate-release (IR) opioids. Non-oral routes of abuse, in particular, are associated with serious health risks. Grünenthal has therefore expanded their abuse-deterrent formulation (ADF) technology (INTAC®) to abuse-deterrent IR pellet formulations.

The objective of this trial was to compare the intranasal abuse potential of manipulated INTAC® ADF oxycodone IR (GRT7030) and oxycodone powder.

Methods

Healthy, non-dependent recreational opioid users with intranasal drug use experience were enrolled. Following a Qualification Phase, subjects insufflated manipulated GRT7030 (containing 30 mg oxycodone-HCl), 30 mg oxycodone-HCl powder, and placebo in a randomized, double-blind, double-dummy, active-comparator, placebo-controlled, 3-way crossover design. 37 subjects completed the Trial.

Results

The primary endpoint was the peak effect (E_max) for Drug Liking ‘at this moment’ on a 0-100 visual analog scale. Mean E_max for GRT7030 [54.5] was significantly lower than for oxycodone powder [75.0], and similar to placebo [52.3]. GRT7030 also significantly separated from oxycodone powder in other secondary pharmacodynamic measures like Take Drug Again. Pharmacokinetic data indicated a delayed and reduced absorption of GRT7030 relative to oxycodone powder.

Conclusions

Based on the trial results, INTAC® ADF oxycodone IR can be expected to have a lower potential for intranasal abuse compared to oxycodone powder.

10 Medication overuse in a post-hoc analysis of phase 3 placebo-controlled studies of galcanezumab in the prevention of episodic and chronic migraine

Sheena Aurora, Dustin Ruff, Eric Pearlman, Ankur Patel

Eli Lilly and Company, Indianapolis, IN, USA

Purpose

Galcanezumab, a humanized monoclonal antibody that selectively binds to the calcitonin gene-related peptide, was superior to placebo in the prevention of episodic and chronic migraine in three phase 3 studies. Medication overuse is common among migraine patients. This study investigated medication overuse in a post-hoc analysis of phase 3 placebo-controlled studies of galcanezumab.

Methods

This post-hoc analysis comprised EVOLVE-1 and −2 (pooled), and REGAIN, which were phase 3, double-blind, randomized, placebo-controlled studies in patients with episodic migraine (4 to 14 monthly migraine headache days [MHDs]; EVOLVE-1 and −2) and chronic migraine (≥15monthly MHDs per month for >3 months; REGAIN). Patients in each study were randomized 2:1:1 to monthly subcutaneous injections of placebo or galcanezumab 120 or 240 mg/month for 3–6 months. Headache medication overuse was collected in the electronic patient-reported outcome diary and determined using criteria adapted from the International Classification of Headache Disorders third edition. Mean changes in MHDs and the proportion of patients with medication overuse after randomisation were estimated via mixed modeling.

Results

The number of patients with baseline medication overuse in the placebo, galcanezumab 120-mg or galcanezumab 240-mg groups, respectively, was: 169(19.3%), 74 (17.0%), and 82 (19.2%) for EVOLVE-1 and −2, and 353 (63.4%%), 178 (64.3%), and 177 (64.1%) for REGAIN. Both galcanezumab doses demonstrated a statistically significant improvement compared with placebo (p < 0.001) for overall least square mean change in monthly MHD in patients with baseline medication overuse (EVOLVE-1 and −2: placebo = – 2.71; galcanezumab 120 mg = −6.26; galcanezumab 240 mg = −5.77; REGAIN: placebo = −2.25; galcanezumab 120 mg = −4.78; galcanezumab 240 mg = −4.51). Patients with baseline medication overuse had significantly lower average monthly medication overuse rates for both galcanezumab doses relative to placebo (p < 0.001) in all three studies (EVOLVE-1 and −2: placebo = 15.9%; galcanezumab 120 mg = 6.2%; galcanezumab 240 mg = 7.9%; REGAIN: placebo = 40.6%; galcanezumab 120 mg = 24.3%; galcanezumab 240 mg = 23.1%). These findings were consistent with those in patients without baseline medication overuse, as well as in the overall intent-to-treat population in all three studies.

Conclusions

Both doses of galcanezumab significantly improved mean monthly MHDs compared with placebo in patients with baseline medication overuse. Average monthly medication overuse decreased with galcanezumab compared with placebo in patients with baseline medication overuse. Galcanezumab is at least as efficacious in patients who overuse acute medications as in those who do not.

11 The Burden of Pain Symptoms: A prototype for citizens of British Columbia

Bhairavi Warke¹, Ruoyu Li¹, Diane Gromala¹, Linda Li², Chris Shaw¹, Ankit Gupta¹, Alison Hoens³, Cheryl Koehn⁴, Leanne Currie⁵, Hussein Mamdani², Delia Cooper⁴, Sunny Loo⁶

¹Simon Fraser University, Burnaby, British Columbia, Canada, ²Arthritis Research Canada, Richmond, British Columbia, Canada, ³Providence Health Care, Vancouver, British Columbia, Canada, ⁴Arthritis Consumer Experts, Vancouver, British Columbia, Canada, ⁵University of British Columbia, Vancouver, British Columbia, Canada, ⁶Ontario Pharmacists Association, Toronto, Ontario, Canada

Purpose

Pain symptoms are usually seen as indicators of a disease or condition but we know less about how burdensome they may be for citizens in their day-to-day life. In order to capture this data, the Arthritis Research Center of Canada conducted a co-creation study in collaboration with patient-partners.

We know that pain can severely affect a person’s biopsychosocial reality, day-to-day activities and QoL. It can also significantly impact their work, family life, and social environment. Symptom information used to diagnose conditions is readily available, but it is difficult to understand how burdensome living with these symptoms may be, both before or after a diagnosis. The primary goal of this co-creation study was to identify a patient-centered approach to gathering data about the burden of pain symptoms from citizens of British Columbia through existing and new health data collection methods. The ‘burden’ of symptoms can be described as the multi-faceted impact on a person’s biopsychosocial states, ability to work and quality of life (QoL).

In this study, participants gathered information related to pain symptoms, including how pain was communicated by non-experts, and identified the benefits and drawbacks of each data collection method. British Columbia is home to people from diverse cultures, ethnic backgrounds and languages. As a result, such a system will need to address the multiple aspects of a citizen’s life and allow them to express their experience of living with pain in adequate detail using their own words. The main intention of the study was to explore varied methods and to identify the needs and motivations of citizens who may contribute information about their pain symptoms.

Methods

The study was facilitated by a team of three researchers in an effort to avoid bias, while three patient-partners, two researchers who suffer from chronic pain and three other health researchers participated in the role of citizen contributors. To anonymize the information gathered, each participant was assigned a random patient ID. The study was conducted in four phases: choosing medically classified symptoms; annotating the human figure from the McGill Pain Questionnaire (short form) with those symptoms; describing how their symptoms impacted work, family, life and social contexts; and choosing subjective ‘mood cards’ to articulate psychological contexts.

Phase 1: Choosing medically classified symptoms

Participants were given a list of symptoms based on the Canadian Burden of Symptoms Study (CBOSS). The participants were expected to select all symptoms that they experience, add any symptoms that may have been missing from the list and modify the terminology to more commonly used terms. Participants also added comments about the merits and demerits of using such a list to collect information about pain symptoms.

Phase 2: Annotating a human figure from the McGill Pain Questionnaire with symptoms

Participants were given a paper copy of a line drawing of the human body (front and rear view). They were asked to mark up to seven symptoms (where relevant) on the body diagram using colored dot-stickers. For each one of these symptoms, participants were then asked to indicate the duration of each symptom listing the year they first started experiencing it, its frequency of occurrence and triggers, if any.

Next, using the pain characteristics defined in the McGill Pain Questionnaire (MPQ), participants were asked to annotate the body diagram with the characteristics of each symptom using color-coded labels for bothersomeness, character of the symptom, how long it lasts and its effect their mood.

Phase 3: Describing the impact of symptoms on functionality: work, family life, and social contexts

To gauge the potential burdens of the symptoms on the individual’s life, the participants were asked to answer questions about their ability to perform day-to-day tasks in a questionnaire extracted from the Canadian Burden of Symptoms Study (CBOSS).

Phase 4: Selecting ‘mood cards’ to articulate psychological context

A series of photographs depicting a variety of emotions were given to each participant. They were asked to choose 1–2 photographs that best visually ‘described’ their mood, taking into account the symptoms they had experienced over the week leading up to the study. They were then asked to articulate the reason they selected specific photographs. This activity was intended to pose an open-ended question about the effect of the symptoms on the individual’s Quality of Life by empowering them with visuals that they could interpret and articulate in their own terms.

Results

Responses from all phases were carefully recorded by three researchers who facilitated the study. The data was analyzed by clustering observations into unique themes and identifying patterns. From this, four key principles were derived. The principles have been phrased in the voice of the patient.

Principle 1: Develop a personalized and personified way to talk about my pain symptoms and their duration.

Participants discussed the limitations of current data capture methods (i.e. MPQ-SF) because they lacked a way to contextualize their symptoms. Most could not relate to some proper medical terms.

The uniqueness of a symptom described by Patient H, ‘I started having facial swelling 3 years ago, probably after a spider bite. It is constant and gets worse and painful when it is hot, or when I have fever or at night.’

Principle 2: Explain the physical feeling of the symptoms and its effect on my abilities.

The severity of pain symptoms varied greatly and limited day-to-day activities because it caused/exacerbated pain, discomfort, physical dysfunction or cognitive impairment. Participants articulated a strong desire to find better ways to explain their symptoms and restrictions to performing daily tasks.

As Patient B explained, ‘I had a back injury 20 years ago which has led to constant back pain affecting my work and gardening.’

Principle 3: Understand how my symptoms might be related to each other.

A relationship between multiple symptoms experienced by one individual was apparent. Moreover, symptoms affecting one part or ability of one’s body might lead to other symptoms, and changes in lifestyle, work-life and/or environment may have meta effects.

As Patient D observed: ‘My chronic pain is constant and leads to insomnia making it difficult to fall asleep at night. The pain gets progressively worse every year and is often induced by stress and lack of rest.’

Principle 4: Combined effect of symptoms is emotionally wearisome affecting overall well-being.

When asked to select a ‘Mood Card’ depicting an emotional state resulting from their symptom(s), most participants selected the card depicting a woman slumped over a chair and described it as ‘exhaustion,’ ‘fatigue’ and ‘helplessness.’ It was observed that pain symptoms could affect an individual’s emotional and/or psychological state, which in turn may hamper their ability to manage their symptom(s).

According to Patient A, ‘Certain symptoms are minor but exhausting. I feel helpless or feel gray when the symptoms are bad.’

Conclusions

This patient-centered study provided valuable insights about the needs and requirements for both citizens and researchers when determining the burden of pain symptoms. The methods tested in the four phases uncovered what was most valuable to citizens to explain the burden of their pain symptoms in their own words; this helped researchers understand the level and depth of information that an online system created to solicit such data would offer.

The findings of this study were shared with all researchers and patient-partners. The derived principles guided the development of a prototype system currently being developed to gather information about the burden of pain symptoms from the citizens of British Columbia. The team is currently testing multiple approaches to ensure security, privacy, usability, compliance, and effectiveness of the system. This system promises to extend the way pain symptoms are considered and positively change perspectives on the impact of pain symptoms.

12 Role of Tapentadol in Central Pain Condition: A Case Report

Casey Fisher, Amber Mendes, Dennis Brodsky

Pain Relief Solutions, Poway, CA, USA

Purpose

The above patient presented to the outpatient pain clinic with arm pain over the biceps area and leg pain over the inner thigh area. She was diagnosed with Multiple Sclerosis 6 months prior to her presentation with known lesions in her brain and spinal cord at the cervical level. However, she started to have pain at the same time. Upon presentation to the clinic she also showed evidence of possible myofascial pain and cervical spondylosis with radiculopathy, as well as central pain given an exam showing upper motor neuron signs. After subsequent treatment with both trigger point injections and cervical epidurals gave no relief, the patient’s pain was found to be of true central origin. She was then started on a course of tapentadol which was titrated up to effect. After a couple months on the medication, the severity of her pain lessened by 67% of what was initially felt when first seen. The aching and burning sensation felt decreased and the associated symptom of fatigue were reduced. Tapentadol improved the patient’s overall function and muscle strength of her upper extremities because she was now able to do more thus reducing the effect of muscle atrophy due to misuse. In this case, Tapentadol, at the appropriate dose, played a drastic role in daily functional improvement and quality of life in a patient with true neuropathic pain of central origin.

Methods

Setting: Outpatient Clinic

Patient: 70 Year Old Female

Results

Central pain syndrome is a neurological condition caused by damage the central nervous system, which causes disabling chronic pain and suffering. The extent and severity of the pain is associated to the cause of the CNS injury and severity of destruction. In this case, Multiple Sclerosis, a demyelinating disease of the central nervous system, caused the destruction. In an effort to relieve the patient’s pain condition, Tapentadol was prescribed and titrated up to over 400 mg per day. Clinical trials have shown that Tapentadol effectively relieves true neuropathic pain due to its dual-acting central anodyne that has lower affinity for mu opioid receptors (MOR) than traditional agonists, but supplies supplemental pain suppression by increasing Norepinephrine and activating alpha-2-adrenergic receptors in the spinal cord and brain. Tapentadol is an opioid pain medication that is used to treat moderate to severe pain, whether that be acute, chronic, or neuropathic pain. It is accessible in immediate-release (IR) and extended release (ER) formulas. Tapentadol is an advanced, next generation, fundamentally acting analgesic with dual mechanism of action that provides analgesic potency through two mechanisms of action: MOR agonism and noradrenaline reuptake inhibition (NRI). It is a non-racemic molecule that is quickly absorbed and has low protein binding, so displacement reactions are very unlikely. When compared to opioids and other non-steroidal anti-inflammatory drugs, it has an improved side effect profile. This opioid is commonly used for cases of trauma in the spinal cord, but is not limited to a variety of differing cases of nerve damage and other pathologies.

Conclusions

Tapentadol has powerful evidence for high-level outcomes and can refine the profusion of deficits that occur due to neuropathic pain.

13 Exploratory in-vitro mastication to assess the potential accelerated release of Fentanyl from a transdermal patch

Paul Fort¹, Christopher Altomare², Eric Kinzler¹, Gregory Gironda¹, Anthony Costantino¹

¹DRUGSCAN, Horsham, PA, USA, ²DRUGSCAN, Horsham, PA, USA

Purpose

The illicit use of fentanyl, a synthetic opioid analgesic used for treatment of chronic pain, has increased significantly since 2012 as toxicology data from New York City shows fentanyl was identified in 2% of drug overdose deaths from 2000 to 2012, then in 2017, fentanyl was linked to 57% of drug related overdose deaths.² Access to fentanyl by abusers comes in a variety of forms, and while the largest illegal sources of fentanyl come from China and Mexico², acquiring fentanyl from prescription drugs (CPDs) is commonly achieved through diversion of fentanyl-containing transdermal patches. Fentanyl transdermal patches are designed to deliver the drug at a slow rate: a single 25 mcg-h fentanyl transdermal patch is intended to deliver 1.8 mg of fentanyl over 72 hours at a rate of 0.025 mg per hour. Due to absorption and pharmacokinetics, the same patch contains 4.2 mg of fentanyl, two times the intended deliverable dose. Thus, excess fentanyl is added to patches and remains in exhausted patches which may subject patches to intentional abuse.

Oral abuse of fentanyl transdermal patches by sucking or chewing may release high concentrations of fentanyl that are quickly absorbed into the buccal mucosa³. DRUGSCAN, an independent laboratory focused on abuse-deterrent testing of branded and generic pharmaceutical products, utilized an investigative approach similar to the methods recommended in FDA’s Guidance documents to simulate mastication (chewing) in vitro. A mastication apparatus was used to simulate chewing a fentanyl transdermal patch to evaluate the total release and rate of fentanyl release from a transdermal patch when abused by chewing.

Methods

All experiments were performed in duplicate in 10 mL of pre heated (37°C) synthetic negative oral fluid media with extraction buffer, and for each experiment, one quarter of a 25 mcg-h fentanyl transdermal patch was used. Control experiments were performed in a water bath shaker with agitation at 200 RPM and stationary. Mastication experiments were utilizing the DRT™ manufactured by ERWEKA GmBH (Heusenstamm, Germany) which can tightly regulate temperature, compression force and distance, torsion, and mastication frequency and duration⁴. Human bite forces can vary greatly, and the compression force (bite force) for these experiments was set not exceed 250 N which is lower than the maximum human bite force for persons between 12 to 60 years old, and characteristic human mastication parameters were used ^5,6,7,8. The mastication experiments were conducted for a total of 10-minutes and controls were run for 30 -minutes with aliquots taken at 30-seconds, 1, 2, 5, 10 and 30-minutes. All aliquots were analyzed by LC-MS/MS for fentanyl content.

Results

Results showed that the in vitro mastication of a quarter 25 mcg-h fentanyl transdermal patch released more fentanyl over all time points up to 10-minutes of mastication. The average percent recovery of fentanyl after 10-minutes of in vitro mastication was 49.34%. In contrast, at 10-minutes the average percent recoveries from the water bath extractions was 24.83% and 11.44% with and without agitation, respectively. Additionally, the average percent recovery of fentanyl after 10-minutes of in vitro mastication was higher than the average percent recoveries after 30-minutes of extraction in the water bath with and without agitation which were 46.88% and 22.79%

Conclusions

Based on these results, oral abuse by chewing a quarter 25 mcg-h fentanyl transdermal patch could result in the release of nearly 50% of the drug content in 10-minutes providing an abuser with approximately 0.5 mg of fentanyl from a quarter of a patch. This is nearly one third of the 72-hour dose of the entire patch. Additional experiments are needed to determine the maximum recovery of fentanyl achieved from repeated chewing of a single quarter 25 mcg-h fentanyl transdermal patch as the data trend of drug release was increasing to the end for all experiments. Overall, these data suggest that transdermal fentanyl patches are highly subject to abuse via mastication, potentially releasing fatal amounts of fentanyl to multiple abusers using a single patch.

14 Opioid Use among People with Migraine: Results of the OVERCOME Study (2017-6229-002)

Sait Ashina¹, Shonda Foster², Robert A. Nicholson², Andre B. Araujo², Michael L. Reed³, Robert E. Shapiro⁴, Dawn C. Buse⁵, Dena H. Jaffe⁶, Janelle Cameron-Mellott⁷, Vicky Li⁷, Anthony Zagar², Eric M. Pearlman², Richard B. Lipton⁵, Colin Zappone*²

¹Department of Neurology and Department of Anesthesia, Critical Care and Pain Medicine, and Harvard Medical School, Beth Israel Deaconess Medical Center, Bost, MA, USA, ²Eli Lilly and Company, Indianapolis, IN, USA, ³Vedanta Research, LLC, Chapel Hill, NC, USA, ⁴Department of Neurological Sciences, Larner College of Medicine, The University of Vermont, Burlington, VT, USA, ⁵Department of Neurology, Albert Einstein College of Medicine, Bronx, NY, USA, ⁶Kantar Health, Tel Aviv, Israel, ⁷Kantar Health, New York, NY, USA

Purpose

Opioid use in migraine is typically discouraged; however, previous population-based surveys have found it to be common. The purpose of this analysis was to evaluate opioid use in people with migraine and compare the demographic/clinical characteristics of current, former, and never users of opioids for migraine among people with ≥4 migraine headache days (MHDs) per month.

Methods

Data were obtained in the fall of 2018 from a web-based survey conducted in a representative US sample [ObserVational survey of the Epidemiology, tReatment and Care Of MigrainE (OVERCOME)]. The present sample included 21,143 people with migraine (identified based on ICHD-3 criteria using a validated migraine diagnostic screener and/or self-reported healthcare provider migraine diagnosis). To better understand those with the greatest care needs, people with ≥4 MHDs per month were oversampled. People with migraine were grouped according to their self-reported opioid use for migraine: current, former, or never used. For patients with ≥4 MHDs per month, several variables [pain comorbidities (past 12 months), anxiety/depression (Patient Health Questionnaire-4, PHQ-4), disability, and MHDs per month] were evaluated for differences by opioid use status (current, never, former). If the overall test was statistically significant (p < .05), pairwise statistical comparisons by opioid use status were performed.

Results

For the total sample, the mean (SD) age was 42 (15) years, 74% were female, and 72% Non-Hispanic white, 8% Non-Hispanic black, 10% Hispanic, 3% Asian, and 8% other. Among the 12,299 with 0–3 MHDs per month, 59.0% were never, 26.0% were former, and 15.0% were current opioid users. Among the 8,844 with ≥4 MHDs per month, 44.9% were never, 31.2% were former, and 23.9% were current opioid users. There were minimal differences in age across opioid use category but females had a lower representation in the currently using opioids category (TABLE). Current opioid users were more likely to have pain conditions than former opioid users, and former opioid users were more likely to have pain conditions and anxiety/depression compared with never users. Differences in MIDAS (never = 25.9; former = 37.2; current = 43.5) and MHDs per month (never = 10.6; former = 11.4; current = 12.1) were statistically significant in all pairwise comparisons.

Conclusions

Among those with ≥4 MHDs per month, current/former opioid users report more pain and psychological comorbidities, greater disability, and more MHDs per month. However, directionality cannot be established in this cross-sectional study. Current opioid use remains alarmingly high. Future research should consider additional influences on opioid use, such as associated migraine symptoms (e.g., allodynia), triptan use, and preventive medication use. There remains a major issue with opioid use for migraine in the US, which underscores the continued need for improvements in migraine care.

15 Cannabidiol: A Retrospective Review of Patient Outcomes for Pain, Sleep, Anxiety, Depression and Function.

Daniel Roth¹, Hary Ailinani¹, Thomas Straub¹, Brian Henriksen², Rene Alonzo²

¹Summit Pain Management, Fort Wayne, IN, USA, ²Fort Wayne Medical Education Program, Fort Wayne, IN, USA

Purpose

As States across the Nation have legalized and continue to legalize the use of CBD (cannabidiol) oil, the prevalence of patient use is gradually increasing. It is imperative that pain practitioners be able to discuss the risks and benefits of CBD oil intelligently. Patients are presenting to physicians’ offices asking questions about CBD and its use for them clinically. Clinicians must become familiar with the potential risks and clinical benefits of CBD oil as it relates to the recommendation of use, appropriate monitoring, and dosing. Moreover, clinicians must realize and understand the current preclinical/clinical indications such as pain, anxiety, depression, sleep disturbance, and substance abuse. As we are in an opioid epidemic and crisis, clinicians must be able to recognize the potential effect on total harm reduction as it relates to usage of opioids, benzodiazepines, cocaine and methamphetamine in the general population. In our study, we retrospectively examined our patent population to assess the overall patient perceived benefits and side effects of CBD oil.

Methods

The objective of this study was to examine the self-reported benefits that chronic pain patients perceived using a hemp-derived (less than 0.3% THC) CBD oil in 5 of the most common clinical conditions routinely encountered in this patient population. In making this assessment, no differentiation was made between various product brands. The inclusion criteria included patients currently using an orally administered CBD oil product across the practice. We assessed the self-reported benefits using a standard 11-point Likert scale. The scale was prefaced with the instruction that a 0 indicated no change in the clinical condition and a 10 indicated complete resolution of the clinical condition. Specifically, the 5 clinical conditions assessed were pain, insomnia, anxiety, depression and overall function. The questionnaire first assessed patient use. If patients were using CBD oil at the time of the questionnaire administration, they then proceeded with answering the remainder of the questionnaire. An ANOVA statistical analysis of data was performed to assess for statistically significant changes in outcomes based upon dosing frequency within each individual metric tested.

Results

Of 4,578 patients receiving a questionnaire, 648 patients reported current usage of some form CBD Oil for an average duration range of 122 ± 8 days. We analyzed the data collectively using an ANOVA model and derived mean perceived clinical improvements based upon dosing frequency (QD, BID, TID, QID). The total mean improvement range for each condition is as follows; pain 4.81–6.48, insomnia 5.56–6.15, anxiety 5.36–5.94, depression 5.08–5.93 and overall function 5.06–5.50. These retrospective data indicate that patients perceive significant relief with CBD oil usage in each metric examined. Insomnia, anxiety, depression and function, all respond statistically equally across all dosing frequency ranges. However, at QID dosing, pain has a statistically significant improvement compared to QD, BID or TID dosing. Thus, these data have dosing recommendation implications in the clinical setting.

Conclusions

To our knowledge this is the first robust study of its kind to assess patient reported outcomes for CBD Oil usage in a large, multidisciplinary pain management practice. The overall reduction of symptomatology was significant and the side effect rate was less than 10%throughout the cohorts. The most common side effect noted was somnolence. Cumulatively, these data support the potential safety and efficacy for the use of cannabidiol in the chronic pain population. These data represent a diverse swath of chronic pain patients and provide a springboard for pursuing further retrospective and prospective studies assessing clinical outcomes and adverse events. Large scale controlled and blinded studies should be created to further test cannabidiol for each of the clinical conditions assessed in this study.

16 Does Cognitive Behavioral Therapy Increase Acceptance of Chronic Pain? A Practice-Based Evaluation amongst Veterans

David Cosio¹, Aviva Ariel-Donges²

¹Jesse Brown VA Medical Center, Chicago, IL, USA, ²Rush University Medical Center, Chicago, IL, USA

Purpose

Cognitive Behavioral Therapy (CBT) and Acceptance and Commitment Therapy (ACT) are two evidence-based, psychological, mind-body treatments for adults with chronic pain. CBT for chronic pain is a present-focused treatment that aims to help patients modify dysfunctional thinking patterns and engage in adaptive behaviors so as to reduce pain-related distress and impairment. ACT for chronic pain aims to increase acceptance of pain and suffering such that patients learn to ‘make room’ for their pain, instead of hoping to eliminate or reduce pain, while continuing to engage in a meaningful life. Despite teaching patients to employ different strategies for managing chronic pain (e.g., challenging negative thoughts about pain versus increasing acceptance of pain), the goal of both ACT and CBT for chronic pain is to increase adaptive coping and improve quality of life. Limited existing literature suggest that ACT and CBT for chronic pain result in comparable improvements in distress and functional impairment, yet it is unclear whether CBT also inadvertently reinforces acceptance-based skills and beliefs. The current study aimed to fill a gap in the literature by evaluating whether group CBT for chronic pain results in clinically meaningful changes in pain-related acceptance in a population of Veterans. The current study also examined the effect of CBT on standardized outcomes (i.e., self-efficacy, health locus of control, quality of life, and illness perception). For our primary aim, we hypothesized that CBT for chronic pain in a Veteran population would result in increased pain-related acceptance despite not explicitly targeting this belief in treatment. For our secondary aim, we anticipated that CBT would significantly increase pain-related self-efficacy; increase internal health locus of control beliefs; improve quality of life; and decrease perceptions of chronic pain as a threatening illness. The results of this study will inform future clinical decision making when determining whether to provide CBT, ACT, or both types of treatments for Veterans with chronic pain, while further illuminating the underlying mechanisms of change in CBT treatment.

Methods

A total of 1204 Veterans with mixed, idiopathic (back, neck, extremity, head, and fibromyalgia), chronic pain voluntarily participated in a 12-week patient pain education program at a Midwestern VA Medical Center between 13 November 2012 and 23 October 2014. Veterans were then given the opportunity to sign-up for either the ACT and/or CBT groups for chronic pain upon learning about the interventions. A total of 84 (7%) Veterans self-selected to participate in the CBT for pain group intervention. Approximately 60% of the sample (N = 50) completed both the pre-and post-intervention assessments, and their responses were included in the current study. A limited medical records review was conducted to retrospectively determine the number of CBT sessions attended, age at time of treatment, sex, and race/ethnicity. The 12-week CBT group for chronic pain in the current study included psychoeducation about pain (e.g., Gate Control Theory), thinking skills (e.g., cognitive restructuring, identifying core beliefs, problem-solving), and behavioral skills (e.g., relaxation strategies, activity pacing, pleasant activities scheduling, goal-setting, exposure to avoided activities). The primary outcome was assessed using the Chronic Pain Acceptance Questionnaire – Revised (CPAQ-R), which provides an overall pain acceptance score as well as domain scores for activities engagement (i.e., willingness to engage in life activities despite pain) and pain willingness (i.e., acknowledgment that avoidance and control are ineffective strategies). Secondary outcome measures assessed pain-related self-efficacy (Pain Self Efficacy Questionnaire), health locus of control (Multidimensional Health Locus of Control – Form C), quality of life (World Health Organization Quality of Life – BREF), and illness perception (Brief Illness Perception Questionnaire). The current study used a quasi-experimental, one-group, pre/post-test design. One-way analyzes-of-variance identified differences on demographic and outcome variables at baseline. Paired-samples t-tests were conducted to evaluate the effect of the intervention on the outcome variables from baseline to post-treatment. Data were collected using paper measures and analyzed using PSPP.

Results

Of the 50 Veterans who completed assessments at both timepoints, 84% identified as African American, 14% as Caucasian, and 2% as Hispanic/Latino. The majority of Veterans were male (80%). Veterans were between the ages of 35–85 years old at the time of treatment, with a mean age (± SD) of 59.5 years (± 10.2). Veterans, on average, attended 82% (9.8 sessions ± 1.4) of the 12 CBT group sessions, and treatment attendance ranged from 7–12 sessions. There were no significant baseline differences in race or ethnicity in completers versus non-completers (ps >.065), but non-completers were slightly younger (53.3 years ± 11.8, p = 0.011) and attended fewer treatment sessions (6.5 sessions ± 3.4, p < .001). There were no significant differences in demographics or baseline scores for completers by age, gender, or race (ps >.151), but male participants were older than female participants (61.4 years ± 9.7 vs. 52.2 years ± 8.7, p = 0.01). Veterans reported a significant increase in overall pain-related acceptance from baseline (52.60 ± 12.60) to post-treatment (57.88 ± 13.90), t(49) = −4.18, p < .001, Cohen’s d = .398. Engagement in activities also increased significantly from baseline (33.94 ± 10.14) to post-treatment (37.62 ± 9.40), t(49) = −3.51, p = .001, Cohen’s d = .376. There was no significant change in pain-related willingness from baseline (18.66 ± 6.85) to post-treatment (20.26 ± 8.08), t(49) = −1.58, p = .120. There was a significant increase in pain-related self-efficacy from baseline (29.62 ± 10.74) to post-treatment (34.44 ± 10.58), t(49) = −4.13, p < .001, Cohen’s d = .452. There was a significant increase in internal locus of control from baseline (21.58 ± 6.01) to post-treatment (23.68 ± 5.46), t(49) = −3.23, p = .002, Cohen’s d = .366. There was no significant change in chance locus of control from baseline (14.04 ± 5.38) to post-treatment (15.20 ± 5.26), t(49) = −1.64, p = .108. There was no significant change in psychological quality of life from baseline (52.00 ± 15.61) to post-treatment (55.82 ± 13.49), t(49) = −2.19, p = .033, nor in environmental quality of life from baseline (57.26 ± 15.27) to post-treatment (60.26 ± 14.65), t(49) = −1.84, p = .072. There was no significant change in illness perception from baseline (50.64 ± 9.07) to post-treatment (48.26 ± 8.42), t(49) = 2.46, p = .017.

Conclusions

Given that both CBT and ACT are widely available evidence-based treatments for chronic pain offered to Veterans, the present study aimed to add to the limited extant literature by evaluating whether CBT increases acceptance-related behaviors and beliefs without explicitly addressing those factors in treatment. Results of the present study indicated that group CBT for chronic pain in Veterans increased pain-related acceptance, yet this increase was driven by greater engagement in activities (i.e., participating in everyday activities despite the presence of pain) and not by changes in willingness to experience pain (i.e., decreasing the cognitive fight against pain). These outcomes support the notion that CBT’s focus on modifying maladaptive behaviors may inadvertently increase acceptance of chronic pain by reducing behavioral avoidance, which is consistent with the goal of acceptance-focused treatments. Results further indicated that CBT increased both self-efficacy for pain management and internal health locus of control. Given that self-management of chronic pain is essential for recovery, these results reinforce the utility of CBT as part of interdisciplinary pain treatment for Veterans. Future studies should examine the impact of ACT treatment on pain-related acceptance in Veterans in order to compare the relative effect sizes and confirm the pattern of effects.

17 An Examination of the Impact of Acceptance & Commitment Therapy on Pain-Related Acceptance in Veterans

David Cosio

Jesse Brown VA Medical Center, Chicago, IL, USA

Purpose

The goal of Acceptance & Commitment Therapy (ACT) is acceptance of pain and suffering. Patients learn to ‘make room’ for their pain, instead of hoping to eliminate or reduce pain, while continuing to engage in a meaningful life. Broadly, ACT for chronic pain involves experiential exercises related to six core skills: willingness to accept a range of experiences, engagement with the present moment, observing of the self, defusion from thoughts, identifying values, and committing to values-aligned action. Although CBT has a longer history of evidence supporting its use to treat chronic pain, randomized controlled trials in adults suggest that ACT is an efficacious alternative treatment. Limited existing literature suggest that ACT and CBT for chronic pain result in comparable improvements in distress and functional impairment, yet it remains unclear how ACT may impact pain-related acceptance differently from CBT. The current study aimed to fill a gap in the literature by evaluating how an ACT for chronic pain group results in clinically meaningful changes in pain-related acceptance in a population of Veterans. The current study also examined the effect of ACT on standardized outcomes (i.e., self-efficacy, health locus of control, quality of life, and illness perception). For our primary aim, we hypothesized that ACT for chronic pain in a Veteran population would result in increased pain-related acceptance through pain willingness and activities engagement. For our secondary aim, we anticipated that ACT would significantly increase pain-related self-efficacy; increase internal health locus of control beliefs; and improve quality of life. The results of this study will inform future clinical decision making when determining whether to provide ACT, CBT, or both types of treatments for Veterans with chronic pain, while further illuminating the underlying mechanisms of change in ACT treatment.

Methods

A total of 1204 Veterans with mixed, idiopathic (back, neck, extremity, head, and fibromyalgia), chronic pain voluntarily participated in a 12-week patient pain education program at a Midwestern VA Medical Center between 13 November 2012 and 23 October 2014. Veterans were then given the opportunity to sign-up for either the ACT and/or CBT groups for chronic pain upon learning about the interventions. A total of 94 (8%) Veterans self-selected to participate in the ACT for chronic pain group intervention. Approximately 56% of the sample (N = 53) completed both the pre-and post-intervention assessments, and their responses were included in the current study. A limited medical records review was conducted to retrospectively determine the number of ACT sessions attended, age at time of treatment, sex, and race/ethnicity. The 10-week ACT for chronic pain group in the current study has been investigated in past research and has been found to make a significant difference in measures of pain interference, illness-focused coping, and global distress. The primary outcome was assessed using the Chronic Pain Acceptance Questionnaire – Revised (CPAQ-R), which provides an overall pain acceptance score as well as domain scores for activities engagement (i.e., willingness to engage in life activities despite pain) and pain willingness (i.e., acknowledgment that avoidance and control are ineffective strategies). Secondary outcome measures assessed pain-related self-efficacy (Pain Self Efficacy Questionnaire), health locus of control (Multidimensional Health Locus of Control – Form C), and quality of life (World Health Organization Quality of Life – BREF). The current study used a quasi-experimental, one-group, pre/post-test design. One-way analyses-of-variance identified differences on demographic and outcome variables at baseline. Paired-samples t-tests were conducted to evaluate the effect of the intervention on the outcome variables from baseline to post-treatment. Data were collected using paper measures and analyzed using PSPP.

Results

Of the 53 Veterans who completed assessments at both timepoints, 72% identified as African American, 23% as Caucasian, and 5% as Hispanic/Latino. The majority of Veterans were male (79%). Veterans were between the ages of 29–76 years old at the time of treatment, with a mean age (± SD) of 56.4 years (± 10.2). Veterans, on average, attended 85% (8.5 sessions ± 1.2) of the 10 ACT for chronic pain group sessions, and treatment attendance ranged from 5–10 sessions. There were no significant baseline differences in race, ethnicity, gender, or age (ps>0.52) in completers versus non-completers. Non-completers attended significantly fewer treatment sessions than completers (4.44 ± 2.63 vs. 8.47 ± 1.15 sessions, p < .001). Male participants were older than female participants (58.03 ± 10.46 vs. 49.76 ± 9.87, p = 0.002). Latino participants scored significantly lower than the other racial groups on internality at baseline (p < 0.039). The youngest and oldest age groups scored significantly lower on overall acceptance at baseline (p < 0.023). Veterans reported a significant increase in overall pain-related acceptance from baseline (48.98 ± 14.67) to post-treatment (57.45 ± 14.06), t(52) = −5.14, p < .001, Cohen’s d = .589. Engagement in activities increased significantly from baseline (32.25 ± 11.91) to post-treatment (38.02 ± 10.89), t(52) = −4.06, p = .001, Cohen’s d = .506. Pain willingness also increased significantly from baseline (16.74 ± 6.95) to post-treatment (19.43 ± 7.63), t(52) = −2.30, p = .025, Cohen’s d = .368. However, the effect was not significant once the Bonferroni correction was utilized (α/9 = .006). There was a significant increase in pain-related self-efficacy from baseline (29.21 ± 12.14) to post-treatment (35.13 ± 10.06), t(52) = −4.47, p < .001, Cohen’s d = .531. There was no significant change in internality from baseline (22.96 ± 7.15) to post-treatment (22.58 ± 6.29), t(52) = 0.48, p = .633. There was no significant change in chance locus of control from baseline (15.47 ± 6.18) to post-treatment (16.47 ± 5.91), t(52) = −1.23, p = .223. There was no significant change in psychological QOL from baseline (51.26 ± 17.57) to post-treatment (54.55 ± 15.14), t(52) = −1.68, p = .100; nor in social QOL from baseline (37.57 ± 21.46) to post-treatment (41.60 ± 21.35), t(52) = −1.38, p = .173; nor in environmental QOL from baseline (55.32 ± 17.76) to post-treatment (57.42 ± 17.07), t(52) = −1.14, p = .260.

Conclusions

The present study aimed to add to the limited extant literature by exploring how ACT may impact pain-related acceptance differently from CBT. Results of the present study indicated that the ACT for chronic pain group in Veterans increased pain-related acceptance, and this increase was mainly driven by greater engagement in activities alike CBT. However, it appears ACT showed a trend toward changes in willingness to experience pain, a concept that is unique to ACT. The intervention may not have made a significant difference in scores on this measure due to the small sample size, but showed to have a small to moderate effect. In addition, the ACT intervention did not make a significant change in internality, which is the belief one has control over one’s health. These outcomes support the goals of ACT, which is to advocate the willingness to accept unwanted private experiences that are out of personal control. Results further indicated that ACT increased self-efficacy for pain management. Subsequent studies may want to explore the implications of sequencing order and examine the efficacy of brief ACT and CBT interventions to address barriers due to access in primary care settings and waiting lists in secondary consultative services.

18 A Randomized Control Trial of Multimedia Interventions to Improve Pain Education among Veterans with Chronic, Non-cancer Pain

David Cosio

Jesse Brown VA Medical Center, Chicago, IL, USA

Purpose

Pain is one of the most common reasons Veterans consult with their primary care providers and is one of the most prevalent symptoms reported by returning Veterans (Gironda et al., 2006). Cosio and colleagues (2012) developed and implemented the ‘Pain Education School’ to address an identified need for patient pain education within the VA. Past findings indicate that Veterans who elected to complete the program reported a statistically significant difference in pain intensity, readiness to adopt a self-management approach, experience of pain, and depressive symptoms, but failed to show a change in knowledge acquisition (Cosio & Lin, 2013). Additional studies have found improvement in knowledge acquisition with audience response technology (Simmons et al., 2015); patient satisfaction (Watson et al., 2014); and provider satisfaction with this particular program (Watson et al., 2015). One of the earliest studies investigating multimedia for use in educating patients about patient-controlled analgesia found the intervention made a significant difference in pain knowledge, produced better outcomes in pain relief, and received the endorsement of patients on its usefulness (Chen, Yeh, & Yang, 2005). Several other studies in health education (fall prevention, Hill et al., 2009; laparoscopic cholecystectomy, Wilhelm et al., 2009; COPD, Stellefson et al., 2009; and cancer pain, Capewell et al., 2010) have been conducted which provide support for the use of DVD-based interventions. The most recent venture in multimedia-based education and non-cancer pain is its application to improve readiness to self-manage joint pain (Elander, Robinson, & Morris, 2011). The current study explored how a patient pain education intervention translated into multimedia, such as DVD, a booklet, or both, in a randomized control trial. Primary outcome measures of the current study were whether the use of multimedia promoted a decrease in pain intensity and an increase in readiness to adopt a self-management approach among Veterans with chronic, non-cancer pain. Secondary outcomes included whether Veterans who participated in a low-intensity pain education intervention would increase in factual pain knowledge; experience decreases in intractable pain; demonstrate positive changes in their attitudes or beliefs about their own pain problem; and demonstrate a decrease in depressive symptoms.

Methods

A total of 120 Veterans with mixed, idiopathic (back, neck, extremity, head, and fibromyalgia), chronic pain voluntarily participated in a multimedia-based, patient pain education program at a Midwestern VA Medical Center between 3 January 2017–1 October 2018. A third of the sample were given a DVD (N = 40), a third was given a booklet (N = 40), and a third was given both (N = 40). Veterans will be recruited from the pain clinic during the weekly patient intake orientations. Veterans must not have been able to attend the face-to-face intervention due to a conflict in their schedule and must have had access to a DVD player. The DVD was a 3-disc set which included the 13 edited classes filmed in the face-to-face Pain Education School. Each clip on the DVD from each discipline (30–45 minutes each) shared information about chronic, non-cancer pain from their perspective, what treatments are available in their service, and how to access their respective clinics. The booklet included the same written materials given to Veterans who participated in the face-to-face intervention. Participants were asked to complete the pre-intervention assessment, which included the Numeric Rating Scale, the Readiness Questionnaire, the Patient Pain Questionnaire, the Pain Information and Beliefs Questionnaire, and the Patient Health Questionnaire. Participants were then instructed to review the materials within the next three months’ time. After three months, the Veterans were mailed their post-intervention assessment which included the same battery of measures. Three follow-up reminder calls were made, duplicate questionnaires were mailed, and return envelopes were provided to improve response rate. Upon completion of each assessment, Veterans received a gift card. Veterans were allowed to keep the education materials given as part of the low-intensity intervention. The primary outcome analysis was a 3 × 2 repeated measures (RM) multivariate analyses of variance (MANOVA), with ‘Intervention Arm’ as the between-subjects factor and ‘Time’ as the within-subjects factor. The dependent variables were the primary outcome variables of pain intensity and readiness to adopt self-management approach, and the secondary variables of pain knowledge, pain experience, factual knowledge, attitudes and beliefs, and depressive symptoms. SPSS was used for all outcome analyses.

Results

Of the 120 Veterans who were enrolled in the study, twenty-one (17.5%) of the participants were female; and 99 (82.5%) were male. Fifty-nine (49.1%) were African American; 51 (42.5%) were Caucasian; 8 (6.7%) were Latino; and two (1.7%) were identified as Other races. About 63% returned the post-assessment via mail; while 37% did not. Response rates are approximately 60% for most research and is the goal of researchers and editors of journals (Fincham, 2008). Among completers versus non-completers, there were no significant baseline differences in arm of intervention (p = 0.491) or sex (p = 0.730), but African American participants (73%) were the most likely to complete both assessments and Other races were the least (p = 0.023). There were no significant differences in demographics or baseline scores among the arms of the intervention (ps > 0.127), except those who were given the DVD were in more agreement with strategies of conservative pain management when compared to those who were also given the book (p = 0.003). There were no significant differences in demographics or baseline scores between sexes (ps > 0.079) or among races (ps > 0.062).

There was no significant interaction effect of ‘Intervention Arm x Time,’ Wilks’ λ = 0.743, F(14,134) = 1.535, p = 0.107, which indicates that the three arms of multimedia were no significantly different on their impact on the dependent measures aforementioned. There was a significant main effect for ‘Time,’ Wilks’ λ = 0.726, F(7,67) = 3.608, p = 0.002, n² = 0.274. A significant univariate main effect was obtained for the primary measures of pain intensity (now) from baseline (5.24 ± 2.238) to post-treatment (5.82 ± 2.285), F(1,73) = 6.272, p = 0.014, n² = 0.079; but not for readiness to adopt self-management approach, F(1,73) = 1.519, p = 0.222. Significant univariate main effects were also achieved for secondary measures of factual knowledge from baseline (25.95 ± 2.196) to post-treatment (25.38 ± 2.148), F(1,73) = 4.868, p = 0.031, n² = 0.063; and depressive symptoms from baseline (1.59 ± 1.601) to post-treatment (2.25 ± 1.819), F(1,73) = 11.274, p = 0.001, n² = 0.134. There was no significant main effect found for pain knowledge, F(1,73) = 1.683, p = 0.199; pain experience, F(1,73) = 2.861, p = 0.095; and attitudes and beliefs, F(1,73) = 1.178, p = 0.281.

Conclusions

Healthcare organizations consider the expenses being saved when using multimedia versus face-to-face interventions, such as medical and resource costs, but also the value of pain, suffering, and loss in QOL of Veterans. It can also reduce costs due to absenteeism and lost work days (Chen et al., 2005). Other advantages of using multimedia include having no time or spatial limits and learning can occur according to individual needs and progress. The current study assessed the effects of multimedia used in pain education interventions on a wide range of pain measures among Veterans with chronic, non-cancer. The current findings suggest that the use of multimedia had significant, moderate negative effects on pain scores and factual knowledge, and a large negative effect on depressive symptoms. This is surprising since the materials used are based on a face-to-face intervention that made significant improvements on all the measures (Cosio & Lin, 2013; Simmons et al., 2015). The current study underlines the potential negative aspects to using multimedia, such as imprecision, confusion, boredom, tiredness, and feelings of excessive involvement (Antonietti & Giorgetti, 2006). Thus, the use of multimedia should not replace any personal interaction from providers and should only be considered to support additional learning.

19 Improved Functionality, Pain Relief, and Satisfaction in Patients Treated With Ubrogepant vs Placebo: Results from 2 Single-Attack Phase 3 Studies, ACHIEVE I and II

David W. Dodick¹, Richard B. Lipton², Jessica Ailani³, Rashmi Halker Singh⁴, Anand R. Shewale⁵, Sihui Zhao⁶, Joel M. Trugman⁶, Sung Yun Yu⁶, Hema N. Viswanathan⁵

¹Mayo Clinic, Phoenix, AZ, USA, ²Albert Einstein College of Medicine, Bronx, NY, USA, ³MedStar Georgetown University Hospital, Washington, DC, USA, ⁴Mayo Clinic, Scottsdale, AZ, USA, ⁵Allergan plc, Irvine, CA, USA, ⁶Allergan plc, Madison, NJ, USA

Purpose

To examine the impact of ubrogepant on patient-reported functional disability, satisfaction with study medication, and Patient Global Impression of Change in 2 pivotal phase 3 trials.

Methods

Adult patients with migraine were randomized to placebo, ubrogepant 50 mg, or ubrogepant 100 mg (ACHIEVE I), or placebo, ubrogepant 25 mg, or ubrogepant 50 mg (ACHIEVE II). The single-item functional disability scale measured patients’ ability to perform daily activities, with 4 response options. Patient-reported satisfaction with study medication and Patient Global Impression of Change were measured using single items with 7-point rating scales.

Results

In ACHIEVE I and II, 1672 and 1686 participants were randomized, respectively; of those, 1327 and 1355 treated a migraine attack with study medication and were evaluable for efficacy. At 2 hours post dose, a significantly higher proportion of ubrogepant-treated patients reported being able to function normally (ACHIEVE I: 50 mg: 41%, P = 0.0012; 100 mg: 43%, P < 0.0001; ACHIEVE II: 25 mg: 43%, P = 0.0015; 50 mg: 41%, P = 0.0118) versus placebo (ACHIEVE I: 30%; ACHIEVE II: 34%); were satisfied/extremely satisfied with study medication (ACHIEVE I: 50 mg: 36%, P < 0.0001; 100 mg: 36%, P = 0.0002; ACHIEVE II: 25 mg: 35%, P = 0.0018; 50 mg: 38%, P < 0.0001) versus placebo (ACHIEVE I: 24%; ACHIEVE II: 25%); and indicated their migraine was much/very much better (ACHIEVE I: 50 mg: 34%, P = 0.0006; 100 mg: 34%, P = 0.0009; ACHIEVE II: 25 mg: 34%, P < 0.0001; 50 mg: 33%, P = 0.0002) versus placebo (ACHIEVE I: 22%; ACHIEVE II: 21%).

Conclusions

In both trials, a higher proportion of ubrogepant- than placebo-treated patients reported normal function and overall satisfaction with treatment and indicated their migraine was much better. The results of these patient-centered outcomes were found to be clinically meaningful and reinforce the potential benefits of ubrogepant in the acute treatment of migraine.

20 Functionality Study of the Pill-Safe^TM Digital Health System to Assess Real Time Mechanical, Clinical Practicality, and Utility including Instantaneous Analytical Data on Drug Abuse Tendencies and Adherence: Alpha Usability Test

Jeffrey Fudin¹, Michael Schatman², Jeffrey Bettinger³, Jacqueline Cleary¹, Ronald Kulich⁴, David Zuleta⁵, David DiBenedetto^6,7, Kelly Wawrzyniak^6,8, Hannah Shapiro⁹

¹Albany College of Pharmacy and Health Sciences, Albany, NY, USA, ²Tufts University School of Medicine, Boston, MA, USA, ³Saratoga Hospital Medical Group, Saratoga, NY, USA, ⁴Massachusetts General Hospital, Boston, MA, USA, ⁵ModoScript, Boston, MA, USA, ⁶Boston PainCare, Waltham, MA, USA. ⁷Tufts School of Dental Medicine, Boston, MA, USA. ⁸Tufts School of Medicine, Boston, MA, USA. ⁹Tufts University, Boston, MA, USA

Purpose

Recent data trends from 2012 to 2017 show overall reductions in national opioid prescribing rates, but overdose death rates involving any opioid continues to increase, with specific peaks in deaths involving non-methadone synthetic opioids (heroin, illicit fentanyl analogues, etc) and heroin. Notwithstanding, opioid deaths associated with heroin and illicit synthetics, also include prescription medications that have been diverted to persons to whom they were not prescribed. Furthermore, studies continue to show extremely high rates of non-medical use of prescription pain relievers, indicating that there are still problems with non-adherence, misuse, and abuse of prescription opioids.

ModoScript’s patentable Pill-Safe™ Digital Health System incorporates cutting-edge technology to provide patients with mobile/online personalized multilingual general and prescription treatment plans (initially in English, and Spanish). This system involves the use of a locking-dispensing cap that requires fingerprint biometrics to dispense caplets inside, AI-enabled multilingual treatment voice and visual interaction, and color-coded LED strip for medication differentiation. The device is also designed with a novel platform that integrates hardware, AI, and block chain security to provide real-time treatment adherence, prescription flow, and behavioral data to relevant stakeholders (prescribers, pharmacists, government entities, etc) via backend data gathering dashboard (EMR integrable) compatible with smart phones.

The platform has the ability to significantly increase system-wide efficiency and reduce short term and long term health costs associated with patient non-adherence, prescription drug abuse, overdose, under-dose, drug adverse reactions, and prescription drug trafficking. As the healthcare industry shifts into value-based care, ModoScript’s platform aligns with the technological shift that the industry is undergoing, providing a high-end system wide solution to ensure prescription opioid compliance in a multilingual setting.

The ultimate goal of this alpha-usability test is to ensure that the software is working completely and accurately, and to increase awareness of this technology as a potential new, innovative way to combat the opioid epidemic and overall medication non-adherence by becoming the next generation of remote treatment care delivery.

Methods

We intend to recruit up to 28-volunteers of students and separate them into 3 fictitious groups: 20-prescription users, 4-prescribers, and 4-dispensing pharmacists. Our investigators will train all three groups on how to use the dispensing cap and the patient group will be ‘prescribed’ different medication regimens (once daily, twice daily, and three times daily). The medication used with be lactose caplets, however the patient group will be instructed NOT to ingest them. Once trained, they will go about their daily routines, and our group will collect real time, analytical data on patient, prescriber, and pharmacist behaviors over a period of 1 or more months to ensure platforms and data collection are working. During this time, the prescription user’s compliance will be measured against prescribed regimens. At the end of the study, all participants will be asked to complete a system usability scale to assess overall usability of both the dispensing cap and dashboard technology.

The following outcomes will be assessed:

Primary Outcomes:

Secondary outcomes include:

1. Mapping the concentrated areas.

Results

Still to be collected

Conclusions

To be determined

21 Exploration of Body Ownership, Agency and Heat Pain Perception in Virtual Reality (VR)

Xin Tong¹, Henan Diao², Diane Gromala¹, Kunlin Wei²

¹Simon Fraser University, Vancouver, BC, Canada, ²Peking University, Beijing, Beijing, China

Purpose

Prior studies suggest the representation and movement of a body in VR may modulate heat pain thresholds. For instance, a reddened arm significantly decreased pain thresholds compared to normal/blue skin color. Seeing one’s arm alone in VR has a significant analgesic effect and increased heat pain thresholds. We hypothesize compared to a still-hand in VR, synced-arm movements may increase pain thresholds. This top-down modulation of pain through visual and motor input may suggest potential uses of altering embodied virtual body representations for managing pain.

Methods

Ten subjects (8 females, 19–29, mean = 25.2, SD = 5.4) were recruited. All experienced the same three visual conditions and were asked to perform the same movement tasks: (1) no virtual body (2) a virtual body with the right arm still, and (3) a virtual body with synced arm movements. Heat pain and a self-reported sense of body ownership and agency were measured in a 0-to-10 VAS. The heat pain stimulus was generated by a TSA-II NeuroSensory Analyzer.

Results

Comparing the still-arm condition with the synced-arm group, significant differences (p < 0.01) were found: ‘I felt the virtual arm was my own arm’ and ‘I felt my real arm was becoming virtual.’ The conditions with hands in VR showed significantly higher pain thresholds than the no-hand condition (p < 0.05). Nonetheless, we did not find significant differences in pain thresholds between the still and synced movement conditions.

Conclusions

In conclusion, we provided a higher level of SoA in the experimental condition than the control group and our data suggest that a higher level of SoA in VR did not provide a significantly higher level of analgesic effect under heat pain stimuli condition in healthy participants. We speculate that the mechanism of the VR analgesic effects is not the same between induced pain in healthy subjects and neuropathic pain or other types of long-term pain in chronic pain patients. Nonetheless, this requires future exploration with chronic pain sufferers – particularly those who present intriguing and well-studied CRPS or phantom limb pain – to see if synchronous movement and an enhanced SoA affects their neuropathic pain.

22 A Serious Immersive Virtual Reality Game for Promoting Chronic Arthritis Pain Patients’ General Physical Activity and Range of Motion

Xin Tong¹, Diane Gromala¹, Squire Pam², Daehan Kim³

¹Simon Fraser University, Vancouver, BC, Canada, ²University of British Columbia, Vancouver, BC, Canada, ³University of Saskatchewan, Saskatoon, Saskatchewan, Canada

Purpose

Virtual Reality (VR) shows great promise in creating testing and treatment environments where virtual representations can be precisely controlled and guided according to therapy needs. Therefore, the goal of this pilot study was to explore how arthritis pain patients like our VR environment and how effective it was at promoting physical activity (PA).

Methods

A mixed-method study was conducted. The inclusion criteria are arthritis patients who are older than 19 years old. Five participants with limitations of physical movement were recruited via convenient sampling, including 3 females (M = 61.5 years old, SD = 11.01). First, the participants were given a tutorial and then they explored the VR game for 15–20 mins. The participants’ real-time Heart Rate (HR) was measured, and they were asked to fill in the Rating of Perceived Exertion Scale questionnaire.

Results

We found there was an increase in HR variation as participant’s age increases. Patients reported perceived physical exertion (M = 75.78, SD = 8.45) is lower than their real exertion (M = 82.25, SD = 7.05). This indicated that our VR game was able to immerse and distract the patients from the amount of PA without noticing they were in an aerobic state. Besides, all participants had their average HR above or close to their 50% threshold.

Conclusions

Results presented a great promise of using our VR game to promote patients’ movement and enlarge their RoM. Our future work includes a longitudinal study to measure the effect on chronic pain patients’ PA level and pain.

23 Does Immersive Virtual Reality Provide Modulate Chronic Pain: A Longitudinal Study Design

Ruoyu Li¹, Bhairavi Warke¹, Diane Gromala¹, Bernie Garrett², Tarnia Taverner^2,3

¹School of Interactive Arts and Technology, Simon Fraser University, Burnaby, BC, Canada, ²Faculty of Nursing, University of British Columbia, Vancouver, BC, Canada, ³BC Children’s Hospital, Vancouver, BC, Canada

Purpose

Immersive Virtual Reality (IVR, or VR) has been proven to be effective for acute pain alleviation, and ongoing research studies are trying to determine if VR may also be a useful intervention for chronic conditions. However, since the duration of analgesic effects seems to not persist beyond the VR intervention, and since VR research studies have typically been small and short-term, this is yet to be determined. Therefore, we have designed and implemented a longitudinal research study to assess the effectiveness of VR for chronic pain patients.

Methods

To get a better idea of the level and persistence of any analgesic effect from VR, we designed a longitudinal mixed-methods study to evaluate the impact of a VR intervention on reducing chronic pain. It included a comparative controlled interventional trial and a qualitative-interpreted descriptive exploration.

A non-probability convenience sample of 47 adults with chronic pain (patients) was recruited for this study, and a between-group experiment design pattern was practiced. Patients were randomly assigned to either an experiment group or a control group; the experiment group used a stereoscopic VR headset while the control group used a 2D computer screen (monitor) as the designated medium (independent variable) for delivering equivalent content to its participants. In other words, the VR ‘content’ (VR games and a VR form of meditation) had a non-immersive equivalent on a regular computer screen.

The study lasted for 8 weeks. Each week, patients in both groups were randomly assigned a VR title or a non-immersive equivalent as a control session in their own homes. Patients were directed to use the VR or its equivalent at a minimum of 30 minutes 3 times per week. It is worth noting that no duplicate title was used in any 2 of the 8 weeks (a Latin square was used), that the patients in the experiment group all had identical VR setups installed in their homes, and patients in the control group all had identical computers and software installed in their homes. Although technical support was provided, it was seldom used. In addition, a nurse practitioner was on call but was never contacted.

To participate, patients first granted informed consent as required by university ethics protocols, and agreed to use their assigned intervention for a minimum of 30 minutes per day, at least 3 times per week. At the beginning of the study (baseline) and each time before and after their exposure to the intervention, participants were asked to rate their pain levels using a 10 point Numerical Rating Scale (NRS) and Brief Pain Inventory (BPI) in the form of paper questionnaires.

Questionnaire results were recorded into N-Vivo (v11.0), a validated qualitative data analysis software, and then read, re-read and coded for thematic elements by the Principal Investigators (PIs). In addition, the VR and equivalent software were designed to automatically capture the actual times patients used the intervention.

Results

The study has just concluded and data, as well as thematic elements, are currently being processed. Although we initially sought 100 chronic pain patients, recruiting challenges resulted in 47 participants overall. By far, no major negative events (red flags) were reported.

Conclusions

Some of the biggest challenges of determining whether immersive VR can provide an analgesic effect for chronic pain patients are:

1. the nature of chronic pain is longitudinal;

2. few VR studies are repeated, longitudinal, or have a large enough scope;

3. the ‘dosage’ of VR (the duration and frequency of use) has never been determined.

While the results of this research study are not yet available, the design of the study itself addresses crucial aspects of the viability of VR interventions for chronic pain patients. Further, this study is the result of a systematic approach to assessing the potential of VR for chronic pain patients that has included systematic reviews and a pilot research study.

24 The Design and Evaluation of AS IF for Sharing Chronic Pain Patients’ Experience in Virtual Reality Settings

Xin Tong, Pegah Kiaei, Diane Gromala, Chris Shaw

Simon Fraser University, Surrey, BC, Canada

Purpose

Chronic Pain (CP) is a persistent disease affecting 20% of the population in developed countries. It is defined as ‘an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described regarding such damage.’ It is noteworthy that this definition includes both physiological and psychological aspects, and that many pain researchers use a biopsychosocial method; thus, implicitly, patients’ psychological and social contexts are meaningful. Unlike other medical conditions, the presence and identification of CP mainly rely on patients’ self-reports. Until now, no objective medical exams or biomarkers have been discovered for the diagnosis of CP. In this paper, we discuss AS IF, a VR game we created for non-patients. The primary goals of this ‘serious game’ are to raise awareness, gain empathy and understanding, and foster positive attitudes toward CP patients to the degree possible by a game. We hypothesized that an embodied VR game could contribute to raise awareness, gain empathy and understanding, and to foster positive attitudes. From the results of our study, we learned which game components and mechanics worked and were understood by participants and which did not. The main contributions of this paper are the quantitative and qualitative evaluation of the game’s effects on fostering empathy for patients, as well as the articulation of design implications that may inform similar or future research.

Methods

Participants were recruited through a convenience sampling method, with ads placed in university campus media and emails sent to faculty and student groups. The exclusion criterion was any reported history of a CP diagnosis. Nineteen people participated in the study, aged from 19 to 36 years old (M = 24.8, SD = 3.8); 27% were female (N = 4). Among all participants, 3 of them had contact with CP patients. Upon arrival at the lab, participants were briefly introduced to the study procedure and were instructed to read and sign the consent form. Before the gameplay, participants were asked to fill out the pre-intervention questionnaire, which included a revised Compassion Scale and the Willingness to Help Scale, and emotional wheel evaluation. Next, they were given instructions about the game’s rules and thereafter played AS IF for 5–10 minutes. After playing the game, players were asked to fill out the post-intervention questionnaire (the same as the pre-intervention), sense of embodiment ratings, and one question evaluating the relationship between the self in the real world and in VR. Finally, researchers conducted a 5 to 10 minutes semi-structured interview with players, which were audio-recorded. Afterward, the data were transcribed and coded.

Results

For the quantitative data, the pre- and post-test comparisons of the Empathy Scale and Willingness to Help Scale were analyzed using one-tailed paired-samples t-test. For the qualitative data, the in-person interviews were first transcribed into electronic textual data. The text data were then coded into categories based on pre-existing knowledge or hypotheses. Significant patterns were highlighted, summarized, and grouped into themes.

For the scores of Willingness to Help before and after the game intervention, a significant increase in the post-test score was observed (M = 8.33, SD = 2.03) compared to the pretest score (M = 7.17, SD = 2.28), p = 0.031. The effect size for this analysis was found to be a median effect according to Cohen’s (1988) convention. For the Empathy Scale, the total scores in the pre-test (M = 47.33, SD = 4.24) and the post-test score (M = 59.22, SD = 4.33) did not reach statistical significance, p = 0.076. For the Compassion Scale’s subscales of kindness, indifference, separation and disengagement, the kindness subscale showed a statistically significant decrease in the pre-test (M = 15.61, SD = 2.85) and the post-test scores (M = 17.86, SD = 2.65), p = 0.009. The indifference (p = 0.14), separation (p = 0.46), and disengagement (p = 0.83) subscales were found to be statistically non-significant between pre-test and post-test scores.

As for the ratings asking for the relationship between the virtual avatar and the real self, 13 said they felt the actual self overlapping with the virtual avatar, 4 said they felt completely distinctive, one said he could not feel any identity either inside or outside the game of himself, and one said she felt completely the same.

Conclusions

To put non-patients ‘in the shoes of’ patients, the players ‘inhabit’ a virtual body or avatar of a CP patient who attends to everyday tasks. It simulates a few experiences common to CP: physical limitations of movement and musings verbally articulated by a CP patient. The visual-motor synchronicity of a player’s full-body movements mirrored by the avatar appears to elicit identification with the avatar. Results from the mixed-method study revealed that the game was effective in improving the willingness to help CP patients and people’s kindness, but did not show a significant increase in the overall compassion scale ratings toward PWCP. In the future work, we will iterate AS IF game design according to participants’ feedback and will conduct a randomized, controlled study with a larger sample size that is more diverse in gender and age.

25 ‘I’ve Got the Power!’ People in Pain and their Journey through Coaching

Mark Nazemi¹, Dorota Hedzelek¹, Nicole Kern², Jen Hanson¹, Maria Hudspith¹

¹Pain BC, Vancouver, BC, Canada, ²UBC, Vancouver, BC, Canada

Purpose

Research has shown that chronic pain can shift a person toward living a pain-centered life. Health and wellness coaching is an emerging intervention that may help an individual move toward living a more balanced life by improving their quality of life through learning self-managing strategies and adopting supportive behaviors. The purpose of this study is to review the effectiveness of Pain BC’s Coaching for Health program designed to support people living with chronic pain. The Coaching for Health program is a free telephone coaching program designed to help people living with pain learn self-management skills, regain function, and improve their well-being. The program is accessed through a referral from any licensed medical professional, including primary care providers, physiotherapists, clinical counselors, and more. Coaches call clients once a week for up to 12 weeks to support and mentor clients to meet their health goals and make meaningful changes in their lives. The coaches receive more than 40 hours of training in pain education, facilitation, and coaching.

Methods

A qualitative approach was used to analyze 80 client files out of 150 clients. An open coding approach was used to organize the raw data and look for common themes and trends across sessions. Out of the 80 client files, 61 were female, 18 male, and one transgender person. The two largest age groups amongst female clients were 55–64 and 35–44 with only one female participant falling in the 18–24 age category and one over 75. The male clients were between the age of 55–74.

Based on the data, 33 clients had completed the program with one client still ongoing. Twenty-two did not complete the program, and out of those, 8 of the clients did not provide a reason for ending their sessions. Ten of the clients discontinued the program because they felt they were too overwhelmed by challenges or were not yet ready for coaching. Five of the clients had discontinued because they misunderstood the coaching process and expected something different from the program. Twice a client stopped due to a mismatch between the coach and client.

Seven open coding categories were identified and these included: motor vehicle accidents, mood, fears/worry, pain issues and medication, barriers to care (anything that prevented the client from doing what they needed to take care of themselves), and self-management. Sub-categories and themes were also captured to formulate a complete narrative of the client journey through the coaching program.

Results

Out of the 80 clients, 29 had been in an MVA, and 11 clients spoke about having PTSD and 6 of those were directly linked to an MVA. Mood was an important topic were 68 clients talked about difficulties with mood. In the category of mood, 26 clients spoke about depression (either diagnosed with depression or experienced depressive thoughts and feelings). Other sub-categories of mood that clients conversed about with coaches included anxiety (28 clients), isolation/loneliness (23), stress (24), mixed emotions (19), frustration (17), feelings of failure (12). Over half of the clients mentioned having to deal with multiple emotions. Forty-nine clients talked about fears or worries with the most common concern being employment or finances. Almost half of the clients (39) took medication for their pain which included opioids but also over the counter medicine like Tylenol. Many had experience with back pain (31), and sleep (22), and some of the clients had identified as having fibromyalgia (19).

The main barriers to care identified by the clients included pain preventing them from completing their tasks/goal and the cost of treatment. Finances prevented the clients from seeing a specialist, purchase equipment to help with pain management, and socializing with friends. Some clients (11) spoke about receiving income assistance through government disability program. Other barriers included clinic wait times, family doctors not believing their pain, and the lack of resources in their area.

The majority of the clients (57) were engaged in or had tried various self-management activities with the most common being some form of movement exercise (47). Other everyday activities included yoga, journaling, meditation, deep breathing, and engaging in a hobby.

Goal completion for the program was defined as having finished 12 or more sessions or upon mutual agreement between the coach and client that more sessions were not needed. The average number of sessions was 10.8, the mode 12, and the maximum was 18. The most common goals were to increase movement (34), create a care plan or feel more in control (23), set boundaries (17), and gain self-acceptance (15).

Interestingly what was deemed most important was not necessarily completing the goals but having the clients gain the confidence to manage themselves. Many of the clients, as identified, already had experience with self-management but needed motivation, confidence, and coaching to help them stay on track.

Conclusions

The results highlighted the effectiveness of the Coaching for Health program by providing an opportunity for clients to improve their quality of life, keep them accountable with pain management goals, improve confidence, and give them the autonomy to move toward a balanced life. Future improvements to the program include offering coaching clients an adjunct pain science course to enhance baseline knowledge and optimizing tracking of clients who stop using the program.

26 Impact of Galcanezumab on Total Pain Burden: Findings from a Phase 3 Randomized, Double-Blind, Placebo-Controlled Study in Patients with Episodic Cluster Headache

David Kudrow¹, J Scott Andrews², Mallikarjuna Rettiganti², Tina Oakes², Jennifer N Bardos², Richard Wenzel², Dulanji Kuruppu², Charly Gaul³, James Martinez², Sheena Aurora²

¹California Medical Clinic for Headache, Santa Monica, CA, USA, ²Eli Lilly and Company, Indianapolis, IN, USA, ³Migraine and Headache Clinic Konigstein, Konigstein, Germany

Purpose

A composite measure that incorporates multiple dimensions of pain (severity, duration, frequency) may better characterize the pain burden experienced during a cluster headache (CH) attack. Here, we describe the development and application of total pain burden in episodic CH.

Methods

Study CGAL (NCT02397473) was a Phase 3 randomized, double-blind episodic CH study of galcanezumab (GMB). Patients randomly (1:1) received placebo or GMB 300 mg once monthly for an 8-week (wk) treatment period. Total weekly pain burden was calculated by multiplying three attack quantities measured daily: average duration (hours; hr), number, average pain severity (0 = no pain, 1 = mild pain, 2 = moderate pain, 3 = severe pain, 4 = very severe pain); and summing these over the days in a wk. Attack pain severity and duration represents the patient’s average over 24 hr regardless of acute medication use. Least square (LS) mean change from baseline in total weekly pain burden across weeks 1–3 was compared using a post-hoc analysis. Average total weekly pain burden scores across Weeks 1–3 were stratified by the Wk-4 Patient Global Impression of Improvement (PGI-I) responses to explore construct validity.

Results

Baseline mean (standard deviation) total weekly pain burden scores were similar for GMB and placebo; 41.5 (39.3) vs. 43.3 (44.0) severity-weighted hr. The LS mean change (decrease) from baseline in weekly total pain burden across Weeks 1–3 was 11.18 severity-weighted hr larger for GMB than placebo (95% confidence interval: 0.83, 21.53). Median total pain burden scores across Weeks 1–3 increased across the range of PGI-I response options at Wk 4, from 5.0 severity-weighted hr for patients who responded as feeling ‘very much better’, to 33.6 severity-weighted hr for those who responded as ‘very much worse’.

Conclusions

Greater total pain burden reduction was seen with GMB treatment. Construct validity was demonstrated but requires further validation. Total pain burden may provide an approach to holistically describe the pain experienced in episodic CH.

27 Features of Episodic Cluster Headache in the Real World Setting: Clinical Characteristics from a Large, Multi-National, Cross-Sectional Survey

James Martinez¹, J Scott Andrews¹, James Jackson², Russell Nichols¹, Sarah Cotton², Antje Tockhorn-Heidenreich³, James Carroll², Zoe Phillips², Dulanji Kuruppu⁴

¹Eli Lilly and Company, Indianapolis, IN, USA, ²Adelphi Real World, Bollington, United Kingdom, ³Eli Lilly and Company Limited, Windlesham, United Kingdom, ⁴Eli Lilly and Company, Indianapolis, IN,USA

Purpose

To describe the clinical characteristics associated with episodic cluster headache. Cluster headache (CH) is a primary headache disorder composed of recurrent intense, unilateral headache ‘attacks’ with associated cranial autonomic symptoms and/or restlessness. Characterization of episodic CH patients in the real world remains limited.

Methods

Data were drawn from the Adelphi 2017 CH Disease Specific Programme, a cross sectional survey including physicians from Germany, UK and US and their consulting CH patients. Patients with episodic CH were segmented into those experiencing ≤1 (n = 388), >1-≤2 (n = 175), >2-≤3 (n = 112) and >3 (n = 201) attacks per day (APD), on average, and were analyzed descriptively.

Results

The majority of patients were male (67%) and the mean age was 40.9 years. The proportion who smoke increased as APD increased (27% ≤1 up to 33% >3) and patients with comorbid depression almost doubled (11% ≤1 to 20% >3 APD). Patients experienced a mean of 2.6 cluster periods per year which lasted an average of 30.8 days with a mean of 2.4 APD. Three in ten patients had their CH condition misdiagnosed at least once prior to a confirmed CH diagnosis, most commonly being mislabelled with migraine (70%) or tension headache (22%). Most frequent current symptoms were unilateral pain (69%), orbital pain (46%), lacrimation (46%), conjunctival injection (43%) and temporal pain (41%). Symptoms were similar vs. APD. Patients reported feelings of stress (46%), anxiety (45%) and agitation (45%) being most prevalent during a typical attack, which increased proportionally as APD increased, and 67% described the level of pain suffered during a typical CH attack as severe to very severe. Reported findings were generally consistent across geographies.

Conclusions

Patients with episodic CH experience multiple bouts per year marked by frequent, painful attacks and a constellation of distressing symptoms.

28 DFN-15 (Celecoxib Oral Solution, 25 mg/mL) in the acute treatment of episodic migraine: Efficacy results from two phase III randomized, double-blind, placebo-controlled studies

Richard Lipton¹, Sagar Munjal², Elimor Brand-Schieber², Daniel Serrano³, Charles Iaconangelo³, Stewart Tepper⁴, David Dodick⁵

¹Albert Einstein College of Medicine, Bronx, NY, USA, ²Dr. Reddy’s Laboratories, Princeton, NJ, USA, ³Pharmerit International, Bethesda, MD, USA, ⁴Geisel School of Medicine, Hanover, NH, USA, ⁵Mayo Clinic, Phoenix, AZ, USA

Purpose

Nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit prostaglandin synthesis by blocking two cyclooxygenase isoforms, COX-1 and COX-2. Although some NSAIDs have randomized controlled evidence for acute treatment of migraine, the efficacy of celecoxib, a selective COX-2 inhibitor, for episodic migraine has not been established. We assessed the efficacy and safety of a rapidly absorbed investigational liquid formulation of celecoxib (DFN-15), compared with placebo, in the acute treatment of episodic migraine.

Methods

Two identical multicenter, randomized, double-blind, placebo-controlled pivotal efficacy and safety studies of DFN-15 versus placebo were conducted in the acute treatment of episodic migraine in adults. The co-primary endpoints were the proportion of subjects with pain freedom (reduction from moderate or severe pain at baseline to no-pain 2 hours post-dose) and freedom from the MBS (most bothersome symptom, chosen from nausea, photophobia, or phonophobia) at 2 hours post-dose in the first double-blind period. Subjects were re-randomized into a second double-blind period (data on file). Safety and tolerability were also assessed.

Results

A total of 631 patients were randomized in Study 1 and 622 subjects were randomized in Study 2. 508 (80.5%) and 498 (80.1%) subjects completed the studies. Study 1 was not statistically significant for 2 hours pain freedom. One site in study 1 reported a 75% placebo response in the first DB period; this site met the statistical criteria for being an outlier during posthoc analysis. As shown below in Table 1, the proportion of subjects who were pain-free at 2 hours was significantly greater with DFN-15 than placebo for both Study 1 with outlier site’s all 27 subjects removed (32.8% vs. 23.5%; p = 0.02) and Study 2 (35.6% vs. 21.7%; p < 0.001). Similarly, more subjects on DFN-15 were free from their MBS at 2 hours compared to placebo (58.1% and vs. 43.9%; p = 0.003) and Study 2 (57.8% vs and 44.8%; p = 0.007). Similar trends were observed for pain relief (moderate or severe to mild or no pain) at 2 hours for both Study 1 and Study 2 (DFN-15, 67.9% and 74.5% vs. placebo, 55.3% and 60.5%; p = 0.004; p < 0.001). The treatment-emergent adverse events (TEAE) rates were below 14% across all studies and treatment periods. There were no serious TEAEs or deaths. There were no remarkable findings in laboratory tests, vital signs, ECGs, or in any other safety assessments.

Table 1. Risk of OUD in people over age 50

• 1.7% risk for men

• 1.7% risk for alcohol users

• 1.9% risk for those between ages of 60–64 years

• 2.9% risk for those with past-year depression

• 9.0% for Native Americans

• 10.7% for marijuana users

Conclusions

DFN-15 is effective for the acute treatment of migraine.

29 Safety and tolerability of DFN-15 (Celecoxib Oral Solution, 25 mg/mL) in the acute treatment of episodic migraine: Safety results from two phase III randomized, double-blind, placebo-controlled studies.

Richard LIpton¹, Sagar Munjal², Elimor Brand-Schieber², Stewart Tepper³, David Dodick⁴

¹Albert Einstein College of Medicine, Bronx, NY, USA, ²Dr. Reddy’s Laboratories, Princeton, NJ, USA, ³Geisel School of Medicine, Hanover, NH, USA, ⁴Mayo Clinic, Phoenix, AZ, USA

Purpose

DFN-15, a 120 mg oral celecoxib solution has demonstrated rapid absorption in healthy subjects but has not been evaluated for the acute treatment of migraine. Two Phase 3 studies were conducted to evaluate the tolerability, and safety of DFN-15 in the acute treatment of up to two migraine attacks. This abstract reports the safety and tolerability results from both trials.

Methods

These were two identically-designed, multicenter, randomized, double-blind, placebo-controlled efficacy and safety studies of DFN-15 in the acute treatment of adults with episodic migraine. Subjects were randomized 1:1 to DFN-15 or placebo to treat one migraine attack of moderate or severe pain intensity and were then re-randomized to DFN-15 or placebo to treat a second attack at any pain level. Tolerability was assessed by treatment-emergent adverse events (TEAEs) and safety was assessed by physical examinations, concomitant medication review, suicidality assessment, pregnancy tests, vital signs (sitting systolic and diastolic blood pressure, pulse rate, and body temperature), clinical laboratory tests (hematology, chemistry, and urinalysis) and 12-lead ECG.

Results

A total of 631 and 622 subjects were randomized in Study 1 and Study 2, 578 (91.6%) and 571 (91.8%) treated with study drug, and 508 (80.5%) and 498 (80.1%) subjects completed the study, respectively. No serious TEAEs or deaths were reported. In Study 1, 10.7% (31/289; 33 events) of DFN-15 subjects, and 9.9% (28/283; 33 events) of placebo subjects reported a TEAE. The most common TEAEs included nausea, 4 (1.4%) DFN-15 subjects versus 5 (1.8%) placebo subjects and dysgeusia, 5 (1.7%) DFN-15 subjects versus 3 (1.1%) placebo subjects. Three (1.1%) placebo subjects also reported TEAEs of vomiting versus 1 (0.3%) DFN-15 subject. The TEAEs in the second treatment period were generally similar but with lower incidence. Altogether, 1.1% (3/28) of subjects in the placebo group reported 4 TEAEs that led to study drug discontinuation. Overall, only 1 severe TEAE was noted, a subject in the placebo group who had nausea.

In Study 2, 13.3% (38/285; 44 events) of DFN-15 treated subjects and 8.9% (25/282; 32 events) of placebo treated subjects reported a TEAE. In 9.1% of DFN-15 subjects and in 6.0% of placebo subjects the TEAEs were considered related to the study drug. The most common TEAEs included nausea, 9 (3.2%) DFN-15 subjects versus 5 (1.8%) placebo subjects, and dysgeusia, 12 (4.2%) DFN-15 subjects versus 4 (1.4%) placebo subjects. The TEAEs in the second treatment period were generally similar but with lower incidence.

Altogether, only one subject (0.2%) had a TEAE that led to study drug discontinuation (placebo treated; vomiting). Only 1 severe TEAE was reported in Study 2, a subject in the placebo group who had diarrhea. There were no remarkable findings in laboratory evaluations, vital signs or ECGs, or in any other safety assessment.

Conclusions

In two phase III placebo-controlled studies, the safety and tolerability profile of DFN-15 was found to be generally unremarkable. DFN-15 may serve as an effective, well tolerated, acute migraine treatment option.

30 A Randomized, Controlled, Crossover Study to Assess the Abuse Potential of Lasmiditan

Darren Wilbraham¹, Paul H. Berg¹, Max Tsai¹, Emily Liffick¹, Erin G. Doty¹, Li Shen Loo¹, Edward Sellers^2,3

¹Eli Lilly and Company, Indianapolis, IN, USA, ²DL Global Partners Inc., Toronto, Ontario, Canada, ³Department of Pharmacology and Toxicology, Medicine, and Psychiatry, University of Toronto, Toronto, Ontario, Canada

Purpose

Lasmiditan is a highly selective serotonin 5-hydroxytryptamine (5-HT)_1F receptor agonist being developed for the acute treatment of migraine. As lasmiditan is centrally-penetrant and has resulted in adverse events that are consistent with central activity, the potential for abuse was evaluated in accordance with the FDA’s Guidance on the Assessment of Abuse Potential of Drugs (FDA 2017). The aim of the present study was to assess the abuse potential of lasmiditan in human subjects.

Methods

This was a Phase 1, randomized, subject- and investigator-blind, placebo- and positive-controlled, crossover study in healthy adult subjects who were recreational poly-drug users. The primary objective of this study was to assess the abuse potential of lasmiditan compared to placebo and alprazolam using the maximal effect score (E_max) of the at-the-moment 100-mm bipolar Drug Liking Visual Analog Scale (VAS). Alprazolam is an appropriate positive control since the pharmacokinetics (PK) and adverse event (AE) profiles are similar to those of lasmiditan.

Subjects must have demonstrated the ability to discriminate the alprazolam test dose (1 mg) from placebo using the 100-mm bipolar Drug Liking VAS during the qualification phase of the study in order to enter the treatment phase. Subjects who qualified were then randomized to a dosing sequence, consisting of 5 dosing periods that evaluated the abuse potential of 1 of the 5 study treatments: placebo, alprazolam 2 mg, lasmiditan 100 mg, 200 mg (expected therapeutic doses), and lasmiditan 400 mg (a supratherapeutic dose). The washout period between each dose was at least 72 hours. Pursuant to FDA guidance, the study had three primary hypotheses of interest which were each analyzed via non-inferiority tests of differences between mean E_max scores: alprazolam minus placebo, alprazolam minus lasmiditan, and lasmiditan minus placebo.

Results

A total of 58 out of 96 subjects between the ages of 19–50 years with a BMI 18–32 kg/m² who participated in the qualification phase entered the treatment phase. There was a dose-dependent increase in systemic exposure (C_max and AUC[0-∞]) to lasmiditan and in E_max of at-the-moment Drug Liking score with increasing dose from 100 mg to 400 mg of lasmiditan. Based on the primary statistical analyses of the mean E_max of at-the-moment Drug Liking scores, lasmiditan and alprazolam were each different from placebo. While lasmiditan 400 mg was not different from alprazolam 2 mg, the 100 mg and 200 mg doses of lasmiditan were different from alprazolam 2 mg. For all doses of lasmiditan, the mean Drug Liking score increased at a similar rate compared to that observed following administration of alprazolam 2 mg; however, the E_max values for lasmiditan were lower relative to alprazolam and the scores returned to baseline more quickly for lasmiditan (8 hours) than for alprazolam (24 hours). There was a direct relationship between lasmiditan dosage and the incidence of AEs, which were CNS-related and similar to those reported in phase 3 studies. Of note, the incidence of euphoric mood in the recreational drug users was comparable among subjects receiving alprazolam 2 mg and lasmiditan 200 and 400 mg, with 43.4%, 49.1%, and 45.5% of subjects reporting this event, respectively, but was less commonly reported with lasmiditan 100 mg or placebo treatment (25.5% and 10.9% of subjects, respectively).

Conclusions

This study demonstrated that all doses of lasmiditan had higher Drug Liking scores at E_max than placebo. At the expected clinical doses (100 mg and 200 mg), Drug Liking scores at E_max were lower than alprazolam 2 mg. For the supratherapeutic dose (400 mg), Drug Liking scores at E_max were similar to alprazolam. Notably, the time course curve of the Drug Liking VAS demonstrated that the duration of drug liking was shorter with all doses of lasmiditan than with alprazolam. In addition, the incidences of euphoria were similar in the alprazolam group and the lasmiditan 200 mg and 400 mg dose groups.

31 Safety and Efficacy of Lasmiditan in Patients with Cardiovascular Risk Factors: Results from Two Phase 3 Trials for Acute Treatment of Migraine

Helen M Hochstetler¹, Ellen B Dennehy^2,3, Rashna Khanna⁴, Erin Gautier Doty¹, Paul H Berg², Amaal J Starling⁵, Robert E Shapiro⁶

¹Lilly USA, LLC, Indianapolis, IN, USA, ²Eli Lilly and Company, Indianapolis, IN, USA, ³Department of Psychological Sciences, Purdue University, West Lafayette, IN, USA, ⁴Eli Lilly and Company, Lilly UK, Erl Wood Manor, Windlesham, Surrey, United Kingdom, ⁵Mayo Clinic, Phoenix, AZ, USA, ⁶The University of Vermont Medical Center, Burlington, Vermont, USA

Purpose

Migraine is an independent risk factor for cardiovascular (CV) disease and is associated with an increased risk of CV events. Lasmiditan, a serotonin 5-hydroxytryptamine receptor 1F (5-HT_1F) receptor agonist, lacks vasoconstrictive effects observed in other acute treatments for migraine. We report the safety and efficacy of oral lasmiditan in patients with cardiovascular risk factors (CVRFs).

Methods

SAMURAI and SPARTAN were 2 similarly designed Phase 3, randomized, double-blind, placebo-controlled trials in adults treating a single migraine attack with lasmiditan 50 mg, 100 mg, or 200 mg. Both studies included patients with CVRFs, and SPARTAN additionally allowed patients with coronary artery disease, clinically significant arrhythmia, or uncontrolled hypertension. Subgroups of patients with and without CVRFs were analyzed.

Results

Nearly 80% of patients had at least 1 CVRF, and more than 40% of patients had at least 2 CVRFs at baseline. In both trials, significantly more lasmiditan-treated patients were headache pain-free as well as most bothersome symptom-free at 2 hours, compared with placebo-treated patients. The presence of CVRFs did not impact efficacy results. There was no statistical difference in the frequency of likely CV treatment emergent adverse events (TEAEs) either in the absence or presence of any CVRFs. The only likely CV TEAE seen across patients with ≥1 CVRFs was palpitations.

Conclusions

When analyzed by the presence of CVRFs, there was no statistical difference in lasmiditan efficacy or the frequency of likely CV TEAEs. Lasmiditan could provide an effective acute migraine treatment for patients with CVRFs.

NCT02439320 and NCT02605174

32 Subcutaneous Tanezumab for Osteoarthritis: A 24-Week Phase 3 Study With A 24-Week Follow Up

Francis Berenbaum¹, Francisco Blanco², Ali Guermazi³, Kenji Miki⁴, Takaharu Yamabe⁵, Lars Viktrup⁶, Rod Junor⁷, William Carey⁷, Mark T Brown⁵, Christine R West⁵, Ken Verburg⁵

¹Sorbonne Université, INSERM, AP-HP Hospital Saint Antoine, Paris, France, ²INIBIC-Complexo Hospitalario Universitario de A Coruña, A Coruña, Spain, ³Boston University School of Medicine, Boston, USA, ⁴Osaka Yukioka College of Health Science, Hayaishi Hospital, Osaka, Japan, ⁵Pfizer Inc., Groton, USA, ⁶Eli Lilly & Company, Indianapolis, USA, ⁷Pfizer Ltd., Tadworth, United Kingdom

Purpose

Tanezumab, a monoclonal antibody against nerve growth factor, is in development for the management of osteoarthritis (OA). This study aimed to assess its efficacy and safety in patients from Europe and Japan with moderate-to-severe OA who have not responded to or cannot tolerate standard-of-care analgesics.

Methods

The patients in this randomized, double-blind, placebo-controlled study (24 week treatment; 24 week follow-up) had moderate-to-severe OA (knee or hip) and a history of insufficient pain relief or intolerance to acetaminophen, oral nonsteroidal anti-inflammatory drug, and either tramadol or opioids (or were unwilling to take opioids). Patients received subcutaneous tanezumab (2.5 or 5 mg) or placebo at Baseline, and Weeks 8 and 16. Co-primary endpoints were change from Baseline in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Pain, WOMAC Physical Function, and Patient Global Assessment of OA (PGA-OA) scores at Week 24. Safety assessments included independent adjudication of joint safety events. Clinicaltrials.gov:NCT02709486.

Results

A total of 849 patients were randomized, treated, and evaluated. Tanezumab 5 mg met all co-primary endpoints, with significant improvements in WOMAC Pain (least squares mean change from Baseline: tanezumab 5 mg −2.85 vs. placebo −2.24), WOMAC Physical Function (−2.82 vs. −2.11), and PGA-OA (−0.90 vs. −0.72) versus placebo (all p ≤ 0.01). Tanezumab 2.5 mg met the WOMAC Pain and Physical Function endpoints but not PGA-OA; thus, this dose did not meet pre-specified efficacy criteria. The occurrence of adverse events (AEs; 53.0–57.0%) and discontinuations due to AEs (0.4–1.8%) were similar across groups during the treatment period, although serious AEs occurred more frequently with tanezumab (2.8–3.2%) than placebo (1.1%). Total joint replacements (TJRs) occurred in 6.7% (placebo), 7.8% (tanezumab 2.5 mg), and 7.0% (tanezumab 5 mg) of patients. Joint safety events, including TJRs, were mostly adjudicated as normal progression of OA (58/79; 73.4%). Pre-specified joint safety events occurred in 0% and 2.5% (n = 14) of patients in the placebo and tanezumab (2.5 mg, 1.8%; 5 mg, 3.2%) groups, respectively. These 14 events in the tanezumab groups included rapidly progressive OA (2.5 mg n = 4; 5 mg n = 8), subchondral insufficiency fracture (2.5 mg n = 1), and primary osteonecrosis (5 mg n = 1).

Conclusions

Tanezumab 5 mg significantly improved all co-primary endpoints of pain, physical function, and PGA-OA. Tanezumab 2.5 mg significantly improved pain and physical function, but did not reach significance on PGA-OA. AEs were consistent with previous studies of tanezumab in OA. A similar number of TJRs were reported across groups, though overall pre-specified joint safety events were more frequent with tanezumab than placebo.

33 Facet Joint: A New Path for the Epidural Steroid Injection in the Patients Taking Antiplatelets and Anticoagulants

Francis Nahm, Jae-Sung Lee, Woong Ki Han, Eunjoo Choi, Pyung-Bok Lee

Seoul National University Bundang Hospital, Seongnam, Korea, Republic of

Purpose

The epidural steroid injection has been used for treating the back pain from spinal stenosis and disc herniation. Among the elderly patients who suffer from back pain, a large proportion of the patients are taking the antiplatelet agents and anticoagulants, making it difficult for them to receive epidural injection because of the high risk of the procedure-related bleeding complication. The facet joint injection is relatively safe from intra-spinal bleeding risk compared to the epidural injection. Therefore, we postulated that if the medications can be spread to the epidural space through the facet joint, the facet joint can be a new path for the epidural steroid injection. The purpose of this study was to evaluate whether the facet joint can be used as an alternative path to the epidural space.

Methods

The medical images of the patients who had received fluoroscopy guided facet joint injection from 2018 February to 2019 April were analyzed. The facet joint injections were performed using a contrast medium of up to 2 mL under the fluoroscopy guidance. After facet joint arthrogram was confirmed, 4 mL of 0.18% ropivacaine mixed with 20 mg triamcinolone acetonide was injected. Then the anteroposterior and lateral fluoroscopic images were obtained. From the fluoroscopic images, it was investigated whether the contrast medium was observed in the epidural space.

Results

The fluoroscopy images of 144 facet joint injections in the 88 patients were included in this study. In the 50.6% of the patients, the contrast medium was observed in the epidural space. There were no post-procedural complications in the patients, especially in the 33 patients who were taking antiplatelet agents or anticoagulant.

Conclusions

The facet joint injection is an alternative path to the epidural space. Therefore, the facet joint injections can be used as an alternative technic to the epidural injections in the patients who are taking antiplatelet agents or anticoagulant to reduce low back pain.

34 Assessing Conformance of Healthcare System Policies and Procedures with Generally Accepted Best Practice Guidelines on Preventing Diversion of Controlled Substances

Frank Breve^1,2, Len Lewis³

¹Mid Atlantic PharmaTech Consultants, LLC, Ventnor City, New Jersey, USA, ²Opioid Consulting Educational Solutions, Ventnor City, NJ, USA, ³University of Michigan Health System, Ann Arbor, MI, USA

Purpose

Drug diversion by healthcare staff is a significant problem that compromises safe medication practices, may adversely affect employees, and is an affront to patient safety. Every healthcare system should have systematic, coordinated, and continuous operations to ensure drug diversion can be readily identified, promptly addressed, and minimized to the fullest extent possible. In accordance with this regard, an evaluation mechanism was developed to measure the compliance rate of existing health system policies and procedures for controlled substances compared with generally accepted best practice guidelines on preventing diversion of controlled substances.

Methods

A literature review of generally accepted best practice guidelines from American and Canadian resources for preventing diversion of controlled substances served as the basis for development of an assessment tool. A template was created to address various categories dealing with drug diversion within the guidelines. There were fourteen categories, each containing a variable number of items. Each category was referenced with a section number where detailed information about each item could be found on the template. A comment section was included for each item so that specific information about the nature of a ‘yes’ or ‘no’ response could be clarified or explained, if needed. There was a total of 252 possible yes/no responses among items within the fourteen categories. A compliance rate was calculated for each category via a ratio of ‘yes’ responses to total number of items. An over-all compliance rate was calculated to determine how well healthcare system controlled substances practices, policies, and procedures compare with generally accepted best practice guidelines.

Results

Tabulation of ‘yes’ responses on the assessment template served as the basis for calculating a compliance rate. The greater the compliance rate with generally accepted Best Practices Guidelines, the greater the likelihood that controlled substance diversion may be minimized. Note that while the assessment template is based on best practice guidelines rather than codified regulations, evidence indicates that adherence is commensurate with an effective drug diversion detection, prevention and response program. Compliance with these best practice standards serve as validation that healthcare system policies and procedures are proactive, and that the organization is taking responsible action to prevent, detect and respond to drug diversion. An organizational goal of all healthcare systems should be to ensure that a high compliance rate with generally accepted guidelines remain consistent and verified with periodic assessments. In this way, the likelihood of protecting patients, employees and the community from drug diversion issues might best be realized.

Conclusions

Healthcare systems need a mechanism to ensure their controlled substance policies and procedures related to the prevention, detection and response to potential diversion are not only adequate, but also proactive. Consensus guidelines on preventing diversion of controlled substances are a compilation of basic and proactive measures gleaned from multiple sources and should serve as a model set of standards for all healthcare systems to emulate. By utilizing the assessment tool compiled from these guidelines, healthcare systems can identify gaps in existing policies and procedures, take appropriate corrective action, and modify accordingly. A compliance rate of 90% or better is an indication that a healthcare system is meeting the challenge toward preventing and reducing drug diversion activity. Additionally, for benchmarking purposes, calculated compliance rates from other healthcare systems can provide valuable aggregate data which can be incorporated into continuous quality improvement initiatives.

35 Counterfeiting of Alprazolam Tablets: A Growing Problem with Disastrous Consequences

Frank Breve^1,2, Len Lewis³

¹Mid Atlantic PharmaTech Consultants, LLC, Ventnor City, NJ, USA, ²Opioid Consulting Educational Solutions, Ventnor City, NJ, USA, ³University of Michigan Health System, Ann Arbor, MI, USA

Purpose

Sophisticated counterfeiting schemes for alprazolam tablets are on the rise and have dire implications owing to production methods that result in a product virtually indistinguishable from authentic alprazolam. The composition of the counterfeited drug can contain toxic amounts of fentanyl and/or analogs of fentanyl, with the potential to cause severe harm and even death to the unknowing user. Illicit fentanyl and fentanyl precursors originating from China are flowing into the United States, Mexico and Canada at alarming rates. These are mass-produced in clandestine labs in China and smuggled via traditional distribution routes directly or indirectly into the United States. Kilo packaged drugs are being used to mass produce fake alprazolam tablets with pill press dies and machines that can be easily obtained, and ranging in price from $150 to over $10,000. Large pill press machines are capable of producing 5,000 pills an hour.

Methods

A literature review of illicit drug production was used to identify the prevalence of fentanyl-laced alprazolam tablets. There have been dramatic increases of this practice over the last several years due to cheap raw material costs and the prospect for huge profit. Unscrupulous individuals are not concerned with merely duplicating product composition, they would rather create an identical looking product and use the cheapest, and most toxic components that would give the user a high under the guise of anticipated alprazolam efficacy. Because alprazolam is such a popular drug, along with a restricted controlled drug schedule classification, there is a huge market for acquiring this product through illegal means.

Results

Non-pharmaceutical grade fentanyl, and its’ analogs, are specially designed narcotics illegally produced and manufactured by chemists in secretive laboratories worldwide. In some instances, fentanyl analogs can be up to 10,000 times more potent than morphine. The lethal dose of fentanyl analogs is not known; however, it is suspected to be micrograms compared to the potency of pharmaceutical grade fentanyl. Fentanyl analog substances are believed to be extremely potent in which there is no pharmacology to determine a toxic level. It would not be an unrealistic assumption to say that a few picograms of a fentanyl analog could be fatal.

Conclusions

Counterfeit alprazolam tablets are readily available on the Internet and have been shipped in the mail to unknowing consumers who think they are buying a benzodiazepine product. Unfortunately, these fake drugs have been identified to contain fentanyl and fentanyl analogs. They’re composed of various fillers, and typically a potent dose of fentanyl and/or fentanyl analog, without a trace of any alprazolam. The danger of this horrific scenario is not only risk of harm and death to innocent individual users, but also the sobering and very real threat to entire populations if these counterfeit substances ever find their way into the drug supply chain.

36 Best Practices for Optimal Waste Segregation Management in the Healthcare System

Frank Breve^1,2, Len Lewis³

¹Mid Atlantic PharmaTech Consultants, LLC, Ventnor City, NJ, USA, ²Opioid Consulting Educational Solutions, Ventnor City, NJ, USA, ³University of Michigan Health System, Ann Arbor, MI, USA

Purpose

Waste generated by healthcare systems can be a significant problem if not properly handled. Poor management of health care waste potentially exposes health care workers, waste handlers, patients and the community at large to infection, toxic effects and injuries, and risks polluting the environment. It is absolutely essential that all medical waste materials be segregated at the point of generation, appropriately treated, and disposed of in a safe and efficacious manner. Healthcare waste is a by-product of providing healthcare services that includes sharps, non-sharps, blood, body parts, hazardous and non-hazardous pharmaceuticals and chemicals, medical devices, cytotoxic drugs, controlled substances, radioactive materials, and all substances disposed of during the course of providing patient care. Because handling of waste is highly variable among different healthcare entities, we sought to define best practice standards that would ensure optimal waste management.

Methods

We surveyed twenty large healthcare systems throughout the United States and Canada that have robust waste management programs. We compiled data from waste segregation charts posted at each facility and correlated their procedures and methods for separating waste at point of disposal. We developed a template illustrating eight broad categories, which included Pharmaceutical Waste, Regulated Medical Waste, Hazardous Waste, Controlled Substances, Cytotoxic Agents, Radioactive Drugs, Special Disposal and Recycling, and General Trash and Glass. Each category was compared with information posted at the various facilities. Inconsistent or omitted information was identified. We then used aggregate data compiled from this gap analysis to formulate an optimal waste segregation chart based on safety, efficacy, logistical considerations, and cost containment.

Results

An optimal waste segregation guide was developed to provide healthcare system employees with a resource that will ensure regulatory compliance with local, state, federal and accreditation organizations with respect to all waste generated in the healthcare system. The guide is applicable not only to hospitals and other healthcare establishments such as dialysis centers and surgical centers, but also to laboratories and research centers, mortuary and autopsy centers, animal research and testing laboratories, blood banks and collection services, and all areas of long term care, including nursing homes, assisted living facilities, and medical day care.

Conclusions

All healthcare systems should have optimal policies and procedures in place for waste segregation management. Due to the enormity and plethora of generated healthcare waste, it is vital that staff utilize the best practices available for safe, efficient disposal. Lack of awareness about the health hazards related to health-care waste, inadequate training in proper waste management, and absence of waste management and disposal systems are no excuse for compromising patient and staff safety, not to mention the environmental implications.

37 Ketamine Infusions: An Opioid Reduction Strategy in Trauma Patients with Rib Fractures

Heather Alban, Alyssa Green, Emily Du

St. Luke’s University Health Network, Bethlehem, PA, USA

Purpose

Millions of people suffer injuries as a result of trauma, motor vehicle accidents, and assault every year. Blunt chest injury with subsequent displaced or non-displaced rib fractures account for approximately 40% of patients admitted to hospitals secondary to trauma.¹ Severe pain is a predictable clinical manifestation of rib fractures causing impaired respiratory function and alterations in oxygenation, resulting in poor respiratory effort, insufficient lung expansion, and inadequate cough. Poor respiratory mechanics and inability to clear secretions increases the risk of pneumonia by 30% and may lead to hypoxia, acute respiratory distress syndrome (ARDS), transfer to intensive care, and mechanical ventilation; thus, prolonging hospitalization and increasing mortality.¹⁻³

Optimization of pain control is an essential medical treatment strategy in patients with isolated or multiple rib fractures to allow for increased chest wall expansion and adequate coughing and deep breathing.⁴ Opioid medications have been considered the mainstay for acute and chronic pain management across the United States for decades. As pain is a foreseeable manifestation of trauma or injury, managing acute pain with multimodal, non-opioid analgesics (i.e. acetaminophen, nonsteroidal anti-inflammatory drugs, alpha-2 agonists, antidepressants, antiepileptics, N-methyl-D-aspartate [NMDA] antagonists) reduces the risk of opioid misuse, abuse, and patient harm.⁵

Ketamine is a NMDA receptor antagonist that decreases pain through its effect on central sensitization and pain modulation in the second somatosensory cortex, insula, thalamus, and anterior cingulate cortex of the nervous system.⁶ Multimodal analgesia, including ketamine, has demonstrated effectiveness on pain reduction and decreasing opioid consumption.^{5, 7−10} Over utilization of opioid medication has led to an epidemic of chemical dependency, abuse, and addiction; therefore, the purpose of this research was to further explore the use of a non-opioid medication, ketamine, as an opioid reduction strategy in patients who experience rib fractures as a result of blunt chest trauma.

Methods

A non-experimental design was used to compare the combination of opioid plus ketamine infusion therapy versus standalone opioid therapy in patients with rib fractures. Institutional review board approval was obtained.

The study population was from a single academic teaching hospital/level one trauma center in the northeastern United States. The hospital’s 2017 trauma registry was filtered for patients admitted with any number of rib fractures (n = 428). Patients with an initial Glasgow Coma Scale (GCS) of less than or equal to eight, Injury Severity Score (ISS) greater than or equal to 25, and age less than or equal to 18 were excluded; total n = 376. These parameters were selected because a GCS score of less than eight indicates severe brain injury and ISS greater than or equal 25 have been shown to have a sensitivity and specificity of 75.00% and 98.64% in predicting mortality.¹¹

Data collected from the trauma registry included age, sex, race, BMI, length of stay, number of rib fractures, and mechanism of injury. Additionally, history of substance abuse, medication administration, and opiate use prior to hospitalization, was collected by review of the electronic medical record. All data was collected by three reviewers and stored securely in RedCap Software (Version 6.4.6), a secure web application. Opiate administration was determined by checking medication administration records for documentation. Doses administered were converted into an oral morphine equivalent (OME) using standard conversion rates. All OMEs for the admission were added together to obtain a total OME. An average daily OME was then calculated by dividing total OME by length of stay. Administration of ketamine infusion for analgesia was determined if patients received an infusion of ketamine at doses known to achieve analgesia, rather than sedation. These doses are within the range of 0.1–0.3 mg/kg.¹²⁻¹⁴

Data analysis was performed by a statistician using IBM SPSS Statistics, version 18. Opiate administration between groups was compared using a Mann-Whitney rank sums test. ISS and opiate administration was correlated using a Spearman’s rank test. A p-value of < 0.05 was considered significant.

Results

The sample consisted of a total of 376 patients with rib fractures aged 18 years to 90 years and older during the 2017 calendar year. Of the 376 patients, 216 were male and 160 were female (57% and 43% respectively). A majority of patients (362 patients; 96%) did not receive ketamine, the remaining 14 patients received ketamine (4%). In the ketamine group, a majority were male (10 patients; 72%) and the median age was 47 years of age with age range of 29–80. For patient who did not receive ketamine, a majority were male as well at 57% (206 patients). These patients had a median age higher than the ketamine group at 67 years of age (age range: 18–100). Both groups had similar BMI of 28.6 in ketamine group and 26.5 in non-ketamine group.

When analyzing the correlation between ketamine use and decreased OME, OME in the ketamine cohort were 124.5 (range: 36.9–288.7) while the non-ketamine group had a median OMEs of 30 (0–395). The difference was not statistically significant do to the small sample size seen in the ketamine group. There was no reduction in OMEs seen in patients who did not receive ketamine. Other key findings looking at opioid requirements in patients with chronic pain history versus those without; results indicated that higher OMEs existed in patients with a chronic pain history when compared to patients with no history of chronic pain prior to hospital admission (51.3 vs 30; p < 0.02) which was statistically significant. There was a similar trend when examining prior opioid use and substance abuse. OMEs were statistically significantly lower in patients who used opiates prior to admission (46.4 vs 30; p < 0.004) as well as patients with substance abuse issues when compared to those without (45 vs. 300; p < 0.001). In addition, a correlation between higher Injury Severity Score (ISS) using spearman’s rank test was examined and found a moderately positive and statistically significant correlation between higher ISS and increased OME requirements (0.25; p < 0.0001).

Conclusions

Pain is an inevitable manifestation of trauma or injury. Historically, opioids have been known to be the first line treatment strategy. In the presence of an opioid epidemic and increased incidence of substance abuse, opioid reduction strategies such as implementation of non-opioid, adjunct analgesics will promote safer prescribing practices, optimize patient care, and avoid harm. In addition, decreasing opioid consumption in patients with rib fractures will avoid unnecessary opioid adverse effects and hemodynamic instability while improving outcomes and decreasing length of stay in the geriatric population. Non-opioid treatment strategies, such as sub-anesthetic dosing of ketamine, have demonstrated effectiveness in reducing opioid consumption, diminishing postoperative pain, and decreasing hyperalgesia/opioid tolerance. By avoiding respiratory and cardiovascular compromise, ketamine may be a safer alternative treatment modality compared to opioids in managing pain associated with rib fractures secondary to blunt force traumatic injury.

38 The Beginning: Defining Quality Metrics to Support Safe and Effective Pain Management

Holly Ross

UCLA Health, Los Angeles, California, USA

Purpose

The purpose of our project is to develop metrics to evaluate our compliance by collecting and analyzing data to identify gaps in practice, to initiate the changes required to meet regulatory requirements, and to support continued quality improvement of pain management.

Methods

We began prioritizing our improvement by analyzing our current compliance with new regulatory requirements. Once we identified gaps in our care practices, we defined what we perceive to be quality features of an integrated pain-management system by consensus of our pain management experts. We developed 21 quantitative metrics with interest on system processes and outcomes. Process metrics include our surveillance of physician monitoring of opioid polypharmacy, assessing patients at risk of opioid abuse, developing a pain management with the patient prior to undergoing a surgical procedure, providing appropriate and timely pain management intervention and reassessment after intervention, monitoring for signs and symptoms of adverse events and preventing harm related to opioid administration, and providing patient education about pain management and opioids. Outcome metrics include monitoring pain management efficacy and reporting adverse events related to pain management.

Results

The baseline results of this project transparently identified opportunities for improvements related to pain assessment and management. Specifically, a critical metric we failed to meet target compliance on measured the relationship of administering pain medication matching to documented pain score (30.65% mismatch and 8.0% no score to dose) and second, performing a timely reassessment after pain management intervention (73.93% reassessment performed within 1 hour of receiving pain management intervention). Of the 21 identified metrics, five metrics were unobtainable as the data source could not be clearly identified at this time.

Conclusions

The next phase of this project involves putting the metrics into action through nursing education and empowerment of our medication administration policy. Upon investigating the contributing factors influencing our noncompliance with matching pain medication dose to a reported pain score in documentation, we identified that our current medication administration policy did not include the patient’s right to refuse a full dose of medication. Updating our policy to reflect the patient request to receive a dose less than the dose ordered dose is an opportunity to increase our compliance with this particular metric. To address the metrics that we were unable to identify measurable data, we are in progress of developing improvement plans to obtain the data.

39 Phase 1 Trial Results for NTM-001 (Novel Alcohol-free Formulation for Continuous 24h IV Infusion of Ketorolac from a Pre-Mixed Bag) Meet Predictions of PK/PD Modeling Preliminary Results for Elderly Subjects with/without Renal Impairment of a Randomized, Controlled Pharmacokinetic Study of NTM-001 Compared with an IV Bolus Regimen of Ketorolac

Ilona Steigerwald¹, Joseph V. Pergolizzi², Robert Colucci^3,2, Michael A. Eldon⁴, Carl Peck^4,5

¹Neumentum, Inc., Palo Alto, California, USA, ²NEMA Research, Naples, FL, USA, ³Colucci & Associates, LLC, Newtown, CO, USA, ⁴NDA Partners, LLC, Rochelle, VA, USA, ⁵University California at San Francisco (UCSF) Department of Bioengineering and Therapeutic Sciences, San Francisco, CA, USA

Purpose

The opioid crisis in the United States demands effective and safe alternatives to opioids.

NTM-001 is a novel, alcohol-free formulation of the well-established potent NSAID analgesic ketorolac tromethamine applied by continuous intravenous infusion for 24 h from a pre-mixed bag.

NTM-001 is in development for the short-term management of moderately severe acute pain that requires analgesia at the opioid level, usually in a postoperative setting, for up to 24 hours.

This paper reports results of a pharmacokinetic trial with NTM-001 related to cohorts with vulnerable populations (elderly, renally impaired) potentially at increased risk for NSAID use.

The approved IV ketorolac bolus regimen (15 mg q6h) for patients >/ = 65 y of age or renally impaired reflects a 50% reduction compared to doses in populations not at increased risk for NSAID use to mitigate safety risks in this vulnerable population.

The NTM-001 dosing regimen in adult patients >/ = 65 y of age with no, mild or moderate renal impairment (6.25 mg loading dose, followed by a continuous infusion of 1.75 mg/h) is administered by pre-programmed, regular infusion pumps for up to 24 h. In line with the bolus reference label doses are reduced by 50% compared to the regimen in younger patients with a normal renal function.

Based on a population PK/PD model describing analgesia after ketorolac injection (Mandema et al., 1996) exposure-response modeling and simulation were used to predict the time courses of drug exposure and analgesic effect for a 50% reduced regimen of NTM-001 comparing to a reference regimen of 15 mg bolus IV ketorolac q6h for 24 hours.

Preliminary results are reported for cohorts 2–4 (healthy elderly, elderly with mild and moderate renal impairment) of a phase 1, randomized, open-label, crossover, pharmacokinetic study of intravenous NTM-001 compared with a bolus regimen of ketorolac tromethamine (KETO-BOLUS) in healthy subjects and subjects with impaired renal function.

This first-in-man study aimed to explore pharmacokinetics and safety of NTM-001 in a data-informed, model-based investigation of a candidate dosage regimen in populations at risk, consistent with current ketorolac labeling, and to assess suitability for use in further development and practice.

Methods

General

The study comprised 4 cohorts of subjects:

Cohort 1 (healthy young), cohort 2–4 (elderly, 2-no, 3-mild, 4-moderate renal impairment).

Cohorts 1 and 2 were dosed sequentially followed by a parallel conduct of cohorts 3 and 4 informed by an independent DSMB evaluations of safety and exposure data of cohorts 1 and 2, respectively. Preliminary cohort 2–4 results are reported.

By cohort, the study consisted of a Screening Period (up to 28 days), Baseline Assessments (1 day), Treatment Periods (24h each), and a 7-day Washout Period. Blood sampling was continued for up to 96h post dosing.

Cohort 2/3/4 subjects were randomized to receive a half dose regimen of NTM-001 (6.25 mg loading dose, 1.75 mg/h continuous infusion) and an intravenous (IV) bolus regimen of KETO-BOLUS (15 mg q 6 h) over 24 h, in a cross-over design with a 7-day washout period between doses.

PK/PD

The overall goal of this exploratory assessment was to determine whether the reduced NTM-001 regimen is suitable for further clinical development in subjects 65+ years old with/without renal impairment, or if regimen adjustment is warranted.

A Graphical Overlay Comparisons:

Observed ketorolac concentration-time profiles from each treatment of each subject were plotted over the corresponding model-predicted ketorolac target profile according to the pharmacokinetic Base Model and inspected visually.

B Model-based Comparison:

Concentration-time data from the NTM-001 and KETO-BOLUS treatments of each cohort were fitted with the Base Model using NLME modeling implemented in Monolix 3.2. The resultant median predicted plasma ketorolac concentration vs. time profiles with associated 95% population prediction intervals, were plotted over the corresponding target median and prediction interval profiles established using the Base Model.

Safety

In the trial two systems of safety data reporting and assignment of severity were used in parallel:

Reporting and severity assessment by the principal investigator

The Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers (2007)

Events of special interest regarding NSAID use and continuous infusion as well as stopping criteria for individual subjects and the overall trial were pre-defined. An independent DSMB reviewed safety and exposure data with trial progress.

Results

Trial Population

Cohort 2: 5 enrolled. 7 male, 8 female, 13 White, 2 Black/African American

Cohort 3: 16 enrolled, 7 male, 9 female. 12 White, 3 Black/African American, 1 Pacific Islander

Cohort 4: 8 enrolled, 2 male, 6 female, 8 White

Discontinuations

Cohort 2: N = 2; mild cellulitis (NTM-001) rated as not related to IMP; withdrawal of consent (KETO-BOLUS)

Cohort 3: N = 1; subject pulled accidentally spike from infusion bag (NTM-001)

Cohort 4: None

Pharmacokinetics

(a) Graphical Overlay Comparison Results

Individual-subject plasma ketorolac concentration-time profiles displayed relatively low intersubject variability.

Median concentrations following administration of the reduced regimens for both KETO-BOLUS and NTM-001 (50% dose reductions) were approximately 50% (Cohort 2), 60% (Cohort 3), 75% (Cohort 4) of the corresponding median concentration targets predicted using the full dose regimens

Two subjects in Cohort 2 and 1 in Cohort 3 receiving KETO-BOLUS displayed obvious outlier values and were omitted from analyses.

(b) Model-Based Comparison Results

Fitting the pharmacokinetic Base Model to preliminary PK data from Cohort 1 for NTM-001 and KETO-BOLUS reduced regimens was successful; model equations were consistent with those used to construct the original model.

Plots of observed vs. predicted data were distributed symmetrically around the line of identity and the lack of systematic departure from the line indicated that the equations and error models used fit the data well. These findings were reinforced by inspection of additional modeling output for both treatments. No model updating was required.

The model-predicted concentration curves were approximately 50%, 40% and 25% (Cohorts 2/3/4) lower than the target curves (full dose) in line with increasing levels of renal impairment.

Pain relief scores were not imputed for preliminary analyses for subjects in Cohorts 2–4.

Safety

Exposure

Exposure profiles for a 50% reduced dosing regimen of NTM-001 did not show any signal for excessive exposure vs. KETO-BOLUS (AUC, Cmax) in elderly subjects, without/with mild or moderate renal impairment.

Adverse events

No stopping criteria for individuals or the trial overall were met.

No serious, unexpected events or deaths occurred.

Regarding events of special interest for NSAID or infusion use, no signals of an increased risk with NTM-001 were observed:

o Only few gastro-intestinal (GI) events, of mild intensity

o No signs of acute renal injury in this vulnerable population

o Infusion/injection site reactions were observed more frequently in the KETO-BOLUS group

More detailed analyses are anticipated with final trial results.

Conclusions

NTM-001 is a novel, alcohol-free continuous IV infusion product with ketorolac tromethamine administered from a pre-mixed bag in development for the treatment of moderately severe acute pain for up to 24 h.

Preliminary results from this first-in-man PK study (Cohorts 2–4 with elderly volunteers without/with mild and moderate renal impairment) confirm the scientific product concept (loading dose followed by continuous infusion) developed with the support of extensive PK/PD modeling.

Pharmacokinetic results in this vulnerable target population show a high degree of similarity to the modeling targets requiring no update to the Base Model.

The 50% dose reduction implied by the generic ketorolac label (IV bolus) in the elderly and renally impaired suggests an effective level of analgesia while elderly patients with no or mild renal impairment might benefit from a dose reduction less than 50% for monotherapy.

Administration with pre-programmed pumps went smoothly contributing to high data quality.

NTM-001 was well tolerated and safe without any signs of excessive exposure with increasing renal impairment and no signal for acute renal injury.

If confirmed in clinical trials, NTM-001 can be a suitable alternative to opioids in the management of postoperative pain, also in elderly and/or renally impaired patients.

40 Phase 1 Trial Results for NTM-001 (Novel Alcohol-free Formulation for Continuous 24h IV Infusion of Ketorolac from a Pre-Mixed Bag) Meet Targets of Model-Informed Development Preliminary Results for Healthy Young Volunteers of a Randomized, Controlled Pharmacokinetic Study of NTM-001 Compared with a Standard Bolus Regimen of IV Ketorolac

Ilona Steigerwald¹, Joseph V. Pergolizzi², Robert Colucci^3,2, Michael A. Eldon⁴, Carl Peck^4,5

¹Neumentum, Inc., Palo Alto, CA, USA, ²NEMA Research, Naples, FL, USA, ³Colucci&Associates, Newtown, CO, USA, ⁴NDA Partners LLC, Rochelle, VA, USA, ⁵University California at San Francisco (UCSF), San Francisco, CA, USA

Purpose

The opioid crisis in the United States demands effective and safe alternatives to opioids.

NTM-001 is a novel, alcohol-free formulation of the well-established potent NSAID analgesic ketorolac tromethamine administered by continuous intravenous infusion for 24 hours from a pre-mixed bag.

NTM-001 is in development for the short-term management of moderately severe acute pain that requires analgesia at the opioid level, usually in a postoperative setting, for up to 24 hours.

The regimen in adult patients < 65 y of age without hepatic/renal impairment comprises a 12.5 mg loading dose, and continuous infusion of 3.5 mg/h administered by pre-programmed, regular infusion pumps for 24 hours.

The approved IV ketorolac bolus regimen (30 mg q6h) yields high peak exposure (Cmax), with safety-related risks, no evidence of increased analgesic efficacy, while troughs (Cmin) between repeat IV doses may provide insufficient analgesia. NTM-001 mitigates those issues by providing a constant exposure to effective dose levels during 24 hr following surgery with a lower total daily dose (96.5 mg) compared to a generic ketorolac injection regimen (120 mg).

Based on a population PK/PD model describing analgesia after ketorolac injection (Mandema et al. 1996), exposure-response modeling and simulation were used to predict the time courses of drug exposure and analgesic effect for a series of candidate IV loading dose/24-hour constant-rate (LD/CR) infusion regimens, comparing to a reference regimen of 30 mg bolus IV ketorolac q6h for 24 hours. The current target dosing regimen of NTM-001 was selected to achieve comparable overall efficacy, avoiding ineffective trough exposures and, in the interest of safety, lower peak and overall 24-hour ketorolac exposure, compared to the standard 30 mg q6h bolus regimen.

Preliminary PK and safety results are reported for cohort 1 (healthy young volunteers) of a phase 1, randomized, open-label, crossover, pharmacokinetic study of Intravenous NTM-001 compared with a bolus regimen of ketorolac tromethamine (KETO-BOLUS) in healthy subjects and subjects with impaired renal function.

This first-in-man study aimed to explore a data-informed, model-based candidate dosage regimen and safety of NTM-001, according to the targeted product profile, assessing suitability for use in further clinical development and practice.

Methods

General

The study comprised 4 cohorts:

Cohort 1 (healthy young subjects), cohort 2 (healthy elderly subjects), cohort 3 (elderly subjects with mild renal impairment) and cohort 4 (elderly subjects with moderate renal impairment).

Cohorts 1 and 2 were dosed subsequently followed by a parallel conduct of cohorts 3 and 4 as determined by an independent DSMB evaluating safety and exposure data of cohorts 1 and 2, respectively. Preliminary cohort 1 results are reported.

Per cohort the study consisted of an up to 28-day Screening Period, Baseline Assessments (1 day), Treatment Periods (24 h each), and a 7-day Washout Period. Blood sampling was continued for up to 96h post dosing.

Cohort 1 healthy young subjects (age 18–55) were randomized to receive a full dose regimen of NTM-001 (12.5 mg loading dose, 3.5mg/h continuous infusion) and an intravenous (IV) bolus regimen of KETO-BOLUS (30 mg q 6 h) over 24 h, in a cross-over design with a 7-day washout period between doses.

PK/PD

Observed ketorolac concentration-time data were assessed using (a) graphical overlay comparisons and (b) model-based comparisons.

(a) Graphical Overlay Comparisons:

Observed ketorolac concentration-time profiles from each treatment of each subject were plotted over the corresponding stochastic ketorolac target profile predicted using the pharmacokinetic Base Model and inspected visually.

(b) Model-based Comparison:

Concentration-time data from the NTM-001 and KETO-BOLUS treatments of each cohort were fitted with the Base Model using NLME modeling implemented in Monolix 3.2 and the resultant median predicted plasma ketorolac concentration vs. time profiles with associated 95% population prediction intervals, were plotted over the corresponding target median and prediction interval profiles established using the Base Model.

Safety

In the trial, two systems of safety data reporting and assignment of severity were used in parallel:

• Reporting and severity assessment by the principal investigator

• The Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers (2007)

Events of special interest regarding NSAID use and continuous infusion as well as stopping criteria for individual subjects and the overall trial were pre-defined. An independent DSMB reviewed interim safety and exposure data after cohort 1 and 2 to determine trial progress.

Results

Trial Population

In Cohort 1, 28 subjects were randomized and received IMP – 14 males and 14 females.

Fourteen (50%) were White, 8 (28.6%) Black or African American, 2 (7.1%) Asian, 1 (3.6%) was Native Hawaiian or Pacific Islander and 3 (10.7%) were ‘Other’ race.

Three subjects discontinued early (1 NTM-001, 2 KETO-BOLUS) due to personal matters.

Pharmacokinetics

(a) Graphical Overlay Comparison Results

Plasma ketorolac concentration-time profiles displayed relatively low between-subject variability falling within their respective concentration-time targets (original modeling) with only a small proportion (for NTM-001) falling below. Initial plasma concentrations for the IV bolus loading dose were somewhat higher than predicted. No extreme concentrations and no ‘outlier’ subjects were observed.

(b) Model-Based Comparison Results

Fitting the original pharmacokinetic Base Model to PK data from both regimens was successful;

Plots of

• observed vs. predicted data were distributed symmetrically around the line of identity indicating good fit of equations and error models and actual data.

• median plasma ketorolac concentration-time profiles and 95% prediction limits fell within exposure targets created with the original model

NTM‐001 exposure based on median ketorolac AUC was approximately 13% below target.

(c) Prediction of Pain Relief based on Pharmacokinetic Results

Pain relief scores vs. time were imputed using the Cohort 1 predicted median plasma ketorolac concentration‐time profiles and 95% prediction limits and the effect compartment and pharmacodynamic models described by the original model. Results fell within the pain relief targets, consistent with observed ketorolac exposure patterns.

Predicted initial pain relief scores for the IV bolus loading dose of NTM‐001 were somewhat higher, consistent with observed somewhat higher initial plasma ketorolac concentrations.

NTM‐001-predicted 24‐hr pain relief based on AUC of the median ketorolac pain relief was approximately 6% less vs. original target.

Treatment with NTM-001 maintains plasma concentrations greater than trough values for KETO-BOLUS, always greater than the target EC50 value for pain relief

Safety

- Exposure

The target exposure profile for NTM-001 was confirmed without any signal for excessive exposure vs. KETO-BOLUS (AUC, Cmax)

- Adverse events

No stopping criteria for individuals or the trial overall were met (DSMB supervision).

• No serious, unexpected events or deaths occurred.

• Regarding events of special interest for NSAID or infusion use, no signals of an increased risk with NTM-001 were observed:

o Only few gastro-intestinal (GI) events were reported, all of mild intensity

o No signs of renal injury

Conclusions

NTM-001 is a novel, alcohol-free continuous IV infusion product with ketorolac tromethamine administered from a pre-mixed bag in development for the treatment of moderately severe acute pain for up to 24 h.

Preliminary results from this first-in-man PK study (Cohort 1 with healthy young volunteers) confirm the scientific product concept and dosing regimen (loading dose followed by continuous infusion) developed with the support of extensive PK/PD modeling:

Cohort 1 pharmacokinetic results for both NTM‐001 and the comparator KETO-BOLUS show a high degree of similarity to the previously established modeling targets requiring no update to the Base Model.

Results appear highly robust without extreme values or outliers.

Regarding predictions of pain relief, stable analgesia over 24h was confirmed while for the loading dose a somewhat better and possibly earlier onset of pain relief is anticipated.

Administration with pre-programmed infusion pumps went smoothly contributing to high data quality.

The NTM-001 dosing regimen as modeled and studied appears appropriate for use in the target population and further development.

NTM-001 was well tolerated and safe in this cohort of healthy young volunteers.

If confirmed in further clinical trials, NTM-001 can be a suitable alternative to opioids in the management of postoperative pain.

41 NTM-001: A Novel, Alcohol-free Formulation of Ketorolac Tromethamine in a Pre-Mixed Bag for Intravenous Continuous 24h Infusion; A Potential Alternative to Opioids to Treat Acute Moderately Severe Post-Operative Pain

Robert Raffa¹, William Schmidt², Frank Diana^1,3, Joseph V. Pergolizzi⁴, Ilona Steigerwald¹

¹Neumentum, Inc., Palo Alto, CA, USA, ²NorthStar Consulting, LLC, Sacramento, CA, USA, ³FJD-CMC Consulting, LLC, Ocean City, NJ, USA, ⁴NEMA Research, Naples, FL, USA

Purpose

Efforts to address issues related to inappropriate or excess use of opioid analgesics include restricting their use in the postoperative period. This has resulted in a pressing need for alternative effective options for the short-term management of moderately severe acute pain. Ketorolac tromethamine is a well-known and extensively-studied non-steroidal anti-inflammatory and analgesic drug which was approved by the FDA in 1989, ‘For short-term (up to 5 days) management of moderately severe acute pain that requires analgesia at the opioid level, usually in a post-operative setting.’ Considerable clinical experience has firmly established the potential efficacy of parenteral ketorolac across a large range of post-surgical acute pain indications in comparison to and in combination with opioids, leading to a considerable sparing of opioid exposure. However, no GCP/GMP clinical trials have been performed that standardize the dose and define the safety for continuous infusion analgesia. There is broad evidence that patients may benefit from a continuous infusion regimen of ketorolac, considering that several aspects of current bolus dosing regimens are suboptimal and may result in unnecessary drug exposure and consequent adverse effects. We addressed this deficit by: (1) establishment of an evidence-based selection of loading dose and infusion rate using modern PK/PD modeling that identified an improved exposure profile, reduced maximum daily dose, and a provided a 50% reduced-dosing regimen for at-risk populations in line with the generic reference label, and (2) designing an alcohol-free IV formulation of ketorolac at approximately pH 7.4 that is readily available for use without further dilution in a pre-mixed bag and applied by pre-programmed infusion pumps (as in regular hospital use). The product (NTM-001) is designed for 24 hours of continuous IV infusion following administration of an IV loading dose from the same pre-mixed bag. The target dosing regimen, confirmed by recent Phase 1 PK data, is proposed to be independent of dosing intervals, to avoid peaks and troughs in exposure, and to allow for stable efficacy over 24 hr with an almost 20% reduction of daily dose of ketorolac tromethamine vs. a standard q6h IM or IV bolus regimen.

Methods

Previous clinical studies and clinical experience have shown that parenteral ketorolac, perhaps uniquely among NSAIDs, is as effective as morphine in treating moderate-to-severe postoperative pain (Brown, Mazzulla et al. 1990). While it is often used as part of a multimodal analgesia and opioid-sparing strategy (White, Raeder et al. 2012), efficacy results have been mixed, perhaps due to insufficient control of dose exposure using products that rely on periodic parenteral injections. This could result from fluctuating peak and trough plasma exposures from an injected product that might be corrected with a product that provides more continuous levels of exposure.

PK/PD modeling was employed to design a product that delivers a continuous IV infusion of ketorolac tromethamine following controlled IV delivery of a loading dose delivered from the same pre-mixed bag. The Neumentum infusion product (NTM-001) was designed for no more than 24 hours of use, an important distinction vs. the marketed generic bolus formulation intended for up to 5 days of application. In addition, it was modeled to provide analgesic efficacy with 50% reduction in bolus and infusion doses. The proposed loading dose is lower than a generic ketorolac bolus single dose. In line with literature and modeling suggesting this, it is designed to ensure rapid achievement of therapeutic plasma concentrations and smooth (peak- and trough-free) establishment and maintenance of efficacious levels of analgesia. This has been confirmed in a Phase-1 trial in healthy human subjects. The selected loading dose also avoids excessive exposure within the initial six hours of application in combination with the infusion.

Unlike periodic dosing regimens that result in a high peak exposure (C_max) that from a pharmacological perspective increases safety-related risks without providing evidence of increased analgesic efficacy and trough (C_min) between repeat doses that might result in insufficient analgesia for many patients, the continuous infusion with NTM-001 provides a relatively constant exposure to effective dose levels of ketorolac tromethamine during the first 24 hr following surgery with a lower total daily dose compared to the indicated dosing with generic injection.

Results

Based on a population PK/PD model describing reduction in pain scores after ketorolac tromethamine injection (Mandema and Stanski 1996), Neumentum used deterministic and stochastic simulations to predict the time courses of drug exposure and the analgesic effect for a series of candidate IV loading dose/24-hour constant-rate (LD/CR) infusion regimens. These were compared to the exposure and effect time courses from a reference regimen of 30 mg bolus IV ketorolac q6h for 24 hours. The reference regimen was selected based on the FDA-approved ketorolac label. The candidate LD/CR infusion regimens were investigated via simulations according to the goals of achieving equal analgesic efficacy, fewer unsafe or ineffective ketorolac exposures, and lower 24-hour total ketorolac exposure. Regimens consisting of various combinations of ketorolac tromethamine loading doses and infusion rates were simulated and the predicted PK and PD vs. time profiles were compared to the reference regimen.

The proposed shorter duration of exposure (24 hr) for NTM-001 vs. much longer (up to 5 days) exposure of treatment with generic IV ketorolac tromethamine suggests an improved safety profile for NTM-001. In a recent publication evaluating two major safety databases and the off-label use of ketorolac in Italy the authors concluded that ‘this use increases the risk of serious ADR, especially in case of prolonged duration of treatment and in elderly patients’ (Viola, Trifirò et al. 2016). These results were supported in a recent review of ketorolac safety in comparison to other postoperative analgesics, e.g., oxymorphone, tramadol, or tapentadol (Vadivelu, Chang et al. 2017). The practical use of NTM-001 as a continuous 24-hr infusion restricted to a supervised setting with a limited, tailored dose per bag (clearly separated, also by different bag size for full or 50% reduced dosing) further provides protection vs. off-label use including prolonged use of ketorolac tromethamine and use of unrestricted doses of ketorolac in elderly subjects that may lead to serious adverse drug effects.

Conclusions

Neumentum has conducted extensive PK/PD modeling to define an optimal regimen for loading dose and infusion dose to rapidly reach and maintain an efficacious and safer regimen for 24 hr applied by pre-programmed infusion pumps. Extensive evidence shows continuous infusion of ketorolac provides postoperative pain control comparable to opioids (Schwinghammer, Isaacs et al. 2017). Modeling suggests a comparable level of analgesia for NTM-001 vs. the 30-mg bolus regimen at clearly lower maximum and without below-therapeutic trough exposure levels. C_max exposures of the bolus regimen are not exceeded by NTM-001 at any time. The target dosing regimen, confirmed by recent Phase 1 PK data, is proposed to be independent of dosing intervals, to avoid significant peaks and troughs in exposure, and to allow for stable efficacy over 24 hr with an almost 20% reduced daily dose of ketorolac tromethamine vs. a standard q6h bolus regimen.

Limiting the proposed treatment period to 24 hours is in line with clinical practice and may improve the risk profile of NTM-001 vs. a 5-day application regimen.

In conclusion, NTM-001 may offer a safe and effective alternative to opioids for moderately severe post-operative pain.

42 NTM-001 – Evidence-Based and Modeling-Supported Development of a Novel Alternative to Opioids for Moderately Severe Acute Post-Operative Pain; A Literature Review Related to Safety and Efficacy Studies of Continuous IV Infusion of Ketorolac Tromethamine and the Proposed Dosing Regimen of NTM-001

Ilona Steigerwald¹, William Schmidt², Robert Raffa¹, Frank Diana^1,3, Joseph V. Pergolizzi^1,4

¹Neumentum, Inc., Palo Alto, CA, USA, ²NorthStar Consulting, LLC, Sacramento, CA, USA, ³FJD-CMC Consulting, LLC, Ocean City, NJ, USA, ⁴NEMA Research, Naples, FL, USA

Purpose

NTM-001 (Neumentum, Inc.) is an innovative product consisting of a new formulation of ketorolac tromethamine in a pre-mixed bag for continuous IV infusion. NTM-001 is in development for the short-term management of moderately severe acute pain that requires analgesia at the opioid level, usually in a postoperative setting, for up to 24 hours.

The proposed formulation of NTM-001 is alcohol-free (vs. about 10% alcohol contained in currently available injectable formulations) aiming to reduce potential local irritation for the purpose of continuous infusion. It contains 1.0 mg/mL of ketorolac tromethamine, USP in saline solution (~0.9% NaCl) adjusted to a pH of ~7.4. NTM-001 is readily available for infusion and administered from pre-mixed polyolefin infusion bags via pre-programmed infusion pumps as in regular, daily hospital use.

The development of NTM-001 and its dosing regimen (in adult patients without specific risk factors for NSID use: 3.5 mg loading dose administered within 60 seconds, followed by a continuous infusion of 3.5 mg/h for 24h) has been strongly supported by PK/PD modeling. As in line with the generic IV ketorolac bolus reference label, a 50% dose reduction has been considered with NTM-001 for patient populations at special risk for NSAID use.

Predictions of PK/PD modeling have been recently confirmed by results of a first-in-man randomized, controlled PK study of NTM-001 vs a ketorolac bolus q6h regimen in cohorts of healthy young and older (>/ = 65y of age) adults with no and with different degrees of renal impairment.

Published literature describing use of infusions of diluted IV ketorolac tromethamine also strongly supports the regimen of a loading dose followed by continuous infusion for safe and effective post-operative analgesia.

In this paper, we performed a systematic review of available literature related to trials that evaluated the efficacy and/or safety of continuous infusion ketorolac tromethamine for a period of 24–48 hours with a focus on adult patients.

Methods

A PubMed literature search (2018) identified 100 potential references using the terms ‘ketorolac continuous infusion.’ Routes of administration included IV, SC, and IM for durations of generally 24 or 48 hours to treat postoperative pain. After sorting for relevance, 39 references were reviewed and evaluated with particular attention to potential toxicities involving gastrointestinal, cardiovascular, and renal systems as well as dosing regimens used or adjusted for elderly patients and/or those with other special risk factors for NSAID use.

Of particular interest was whether the continuous infusion was preceded by a single bolus injection of ketorolac tromethamine as a loading dose to achieve therapeutic concentrations as quickly as possible.

The final review included 23 adult studies, 2 pediatric studies, and 2 review articles of previous continuous infusion studies in adults or in pediatric patients. Additional literature is quoted to point out specific aspects linked to the rationale for selection of the loading dose for NTM-001.

One study concentrated on cardiovascular safety following coronary artery bypass graft (CABG) surgery (Howard et al., 2016), and another study focused on renal safety in patients undergoing laparoscopic donor nephrectomy (LDN) or percutaneous nephrolithotomy (PNL) (Grimsby et al., 2012). Another study evaluated the pharmacokinetics of continuous SC infusion of ketorolac for 24 hours (Burdick et al., 2017).

Evidence on ketorolac postoperative continuous infusions lasting 24 to 48+ hours was studied in 23 primary published papers involving adults (N = 3191) and in 2 primary published papers in infants or children (N = 122) for an overall total of 3313 subjects. The results in adult patients are summarized below.

Results

The following points summarize the literature review:

1. In adults, effective analgesia was reported in 21 studies with infusion rates of 1.3 to 5.8 mg/hr (median = 3.6 mg/hr). Two reports indicated that ketorolac infusion did not produce effective analgesia following infusion rates of 0.8 mg/hr or 1.75 mg/hr.

   1. Bolus doses of ketorolac (mean = 16.5 mg, median = 18 mg) were used in 18 of the 22 studies reporting favorable analgesia.

   2. Bolus doses were not used in either of the two studies reporting ineffective analgesia.

In non-infusion trials, bolus doses of 10/15/30 mg IV ketorolac provide adequate levels of analgesia for acute pain in the emergency room (Motov et al., 2017) without significant differences in efficacy.

According to the TORADOL Product Monograph (Roche, Canada 2015) ‘the greatest difference between large and small doses of TORADOL administered by either route is in the duration of analgesia.’

1. In 10 adult studies, ketorolac infusion was reported to decrease opioid use by a range of 22 to 89% (mean = 42%; median = 37%).

2. Ketorolac plasma levels ranged from 0.4 to 2.2 μg/mL at 2–4 hr after an initial 10 mg IV bolus dose followed by 48 hr continuous IV infusion of ketorolac at 3.75 mg/hr. This is modestly lower than C_max plasma levels of 2.2–3.0 μg/mL following a single 30 mg IM dose of ketorolac in healthy volunteers.

3. None of the reviewed 24 adult 24–48 hr continuous infusion references reported adverse GI, cardiovascular, or renal effects, nor clinically-significant bleeding.

4. Many studies reported reductions in postoperative nausea/vomiting for ketorolac infusion compared to placebo groups when combined with rescue opioid analgesics. Reductions in postoperative nausea/vomiting may have been a consequence of reduced opioid consumption.

5. Beattie et al. (1997) reported nonfatal myocardial infarctions in 1 ketorolac and 2 placebo subjects following total hip or knee replacement; 21 subjects in this study had a history of previous myocardial infarctions. However, there were no differences in the number of ischemic episodes between ketorolac and placebo groups, but ischemic episodes were shorter in subjects receiving ketorolac.

6. None of the studies reported dose reductions for elderly subjects or for those with renal dysfunction as required by current IV/IM ketorolac labeling. However, as a caveat, most studies excluded subjects with severe renal, and/or relevant cardiovascular or GI disease.

Conclusions

Published literature provides strong support for the efficacy of continuous infusion of ketorolac in adult postoperative patients for 24 to 48 hours following a variety of major surgical procedures.

Evidence supports PK/PD modeling results that an initial loading dose is required to ensure a fast onset of analgesia following surgery. The variety of ketorolac loading dose regimens reflected in our analysis and further supportive evidence on bolus dosing suggest that loading doses lower than 30 mg are sufficient to reach effective plasma levels while avoiding unnecessary overexposure.

Based on PK/PD modeling of different options for NTM-001 a loading dose of 12.5 mg has been selected as sufficiently effective, fast in onset, and safe for initiating analgesia in the postoperative setting.

The infusion rate of 3.5 mg/hr proposed by modeling to maintain stable plasma levels and efficacy for 24 hours with NTM-001 is supported by literature (3.6 mg/h median).

In line with published evidence, no increase but potentially a decrease of safety-related risks is anticipated with NTM-001 vs. a regular (30mg q6) IV ketorolac bolus regimen considering also lower overall (AUC/total daily dose) and peak (Cmax) exposure and a maximum duration of administration of 24 hours.

43 The Behavioral Health Alternative Pain Program and the Integration of Clinical Pharmacy

Danah Quasmieh, Jacob Northrup, Christopher Pavero

Sun Life Family Health Center, Casa Grande, AZ, USA

Purpose

In 2016, the Centers for Disease Control reported over 42,000 Americans died due to opioid overdose, which was an average of 115 a day. Prescription opioid medications precipitated about 40% of these overdose deaths. Pinal County, Arizona, the home of Sun Life Family Health Center (SLFHC), was impacted particularly hard during this epidemic. With the goal of reducing patient’s pain safely, but also preventing and treating opioid misuse disorder, SLFHC’s Integrated Behavioral Health department created the alternative pain program. The purpose of this program was to educate patients on alternative methods to cope with pain and to increase healthcare access to patients in a rural health care setting using an evidence based, multidisciplinary approach, involving the Integrated Behavioral Health (IBH) and Clinical Pharmacy teams.

Methods

The alternative pain program was offered to patients with chronic pain who presented at SLFHC for an appointment with their provider. Patients could also request the alternative pain program after exposure to the service through pamphlets, flyers, word of mouth, infomercials in waiting areas, and outreach to local agencies. Once enrolled, patients were offered either individual sessions, group sessions, and/or brief consults during appointments with medical providers. Regardless of the sessions, alternative pain management techniques taught included progressive muscle relaxation, herbal remedies, diaphragmatic breathing, mindfulness, pacing for pain, tai chi, meditation, chair yoga, thought diversion, and pain log. A member of the clinical pharmacy department counseled patients on understanding their pain levels, the use of medications on alleviating pain, and creating realistic pain goals. The Current Opioid Misuse Measure (COMM) was administered to patients on opioid therapy at the start of group sessions and once again after finishing the program. Patient satisfaction surveys were distributed to patients at the end of group classes. Data was collected over 18 months to assess the impact of the alternative pain program on reducing pain levels.

Results

From January to December 2018, there were 34,005 unique patient visits aged 18 + . Of those patients, 337 adult patients were enrolled in SLFHC’s alternative pain program, with 464 total encounters. Nine percent (N = 29/337) of patients had a morphine milligram equivalent (MME) dose of greater than 120. Five percent (N = 21/464) of patients participated via group session(s). Fifty-eight percent (N = 11/19) of patients who completed a pre and post COMM Assessment showed a decrease in their overall score, indicating a decrease in opioid misuse potential. Thirteen patients completed a patient satisfaction survey with an average score of 4.9 out of 5.0, with 5.0 being extremely satisfied.

From January through June 2019, there were 24,588 unique patient visits aged 18 + . Of those patients, 288 adult patients were enrolled in SLFHC’s alternative pain program, with 310 total encounters. 0.01% (N = 2/288) of patients had an MME of greater than 90. Seven percent (N = 21/310) of patients participated via group session(s). Fifty percent of patients (N = 2/4) who completed a pre and post COMM Assessment showed a decrease in their overall score, indicating a decrease in opioid use potential. Seven patients completed a patient satisfaction survey with an average score of 4.8 out of 5.0, with 5.0 being extremely satisfied.

Conclusions

Results of SLFHC’s alternative pain program suggest that patients were able to better manage their pain and reduce their use of pain medication after completion of the program. Furthermore, the interdisciplinary approach using integrated behavioral health and clinical pharmacy, alongside primary care providers, has shown benefit in all aspects of patient care.

44 TrkA Antagonists as a New Therapeutic Option for Post-Operative Pain

Min-Gwan Shin, Je-Ho Lee, Yoon Jin, Sung-Ha Jin

JC Pharma Inc., Daejeon, Korea, Republic of

Purpose

Post-operative pain management is vital in patient care and recovery, public health, and pharmacoeconomics. To manage pain, current post-operative pain management involves multimodal analgesia approach involving APAP and/or NSAIDS. This multimodal is specially designed to reduce the reliance of opioid use in pain management. Even with the multimodal pain treatment approach, the treatment care is limited to liver and kidney functions and dose limiting side effects of many opioid drugs (respiratory depression, sedation, etc.). Moreover, current post-operative pain management lacks underlying pain pathophysiology. Therefore, there are novel opportunities to improve current multimodal analgesia method and post-operative care by understanding different pathophysiology. TrkA (tropomyosin receptor kinase A) is a family of tyrosine kinases involved in pain signal pathway along with NGF (nerve growth factor). The TrkA has been one of many targets for novel analgesic due to its involvement in NGF and pain cascade pathway. Finding antagonistic entity for TrkA receptor, thereby inhibiting NGF at downstream signal cascade may potentially improve pain tolerance. We developed post-operative pain model in rodent to test our TrkA antagonists evaluating the pain tolerance efficacies and neurologic deficit effects.

Methods

All experimental protocol and animal handling procedures were approved by Institutional Animal care and Use Committee (IACUC) of JC Pharma Inc. (JCP-17–10–101), and were performed according to the guideline that consistent with the National Institutes of Health Guide for the Care and Use of Laboratory Animals. This study used male Sprague-Dawley rats weighting 200-250g (Orient Bio Inc., Korea). They were adapted for 1 week before experiment. Rats were housed in groups of 4 in clear plastic cages with soft bedding with a 12-hr light-dark cycle. All experiments were performed between 9:00 AM and 4:00 PM. The compounds dissolved in 30% PEG 400 (Polyethylene glycol 400) were administered orally to the rats fasted at least 2 hours before the test. Pregabalin that are versatile drugs prescribed for neuropathic pain enhancing the psychoactive effects of opioids was used as a positive drug in the study. For evaluating pain threshold of drugs, we have developed and characterized hind paw incisional postoperative pain rodent model using Brennan’s method (Pain, 1996). The Paw withdrawal threshold (PWT) was measured using Von-Frey Monofilament (VFM). Mechanical allodynia was evaluated in ascending order through specific behavior (bottoming, licking and avoidance) according to the bending force VFM (1, 2, 4, 6, 8 and 15g). 50% withdrawal threshold (g) was calculated of modified Dixon’s up-down method (J Neurosci Meth, 1994). Rotarod test was used to assess motor dysfunction and sedative effect. The preselected rats were placed on rod speed at 6 RPM for 1 min for an accurate assessment. The assessment was scored based on the number of rats dropped on rod for 1 min. All these measurements were evaluated based on highest paw withdrawal thresholds value and neurological deficits at interval 0, 0.5, 1, and 2 hr after drug treatment.

Results

The ED50 (Median Effective Dose) for JCP-0108, JCP-0111, JCP-0114, JCP-0115, and JCP-0117 were 18.51, 3.94, 11.43, 3.78, and 17.51 mg/kg, respectively. That of pregabalin was 19.75 mg/kg in post-operative rodent model. JCP-0108, JCP-0114, and JCP-0117 showed similar or better efficacy to pregabalin. Especially, the efficacy of JCP-0111 and JCP-0115 were at least five times better than that of pregabalin. The TD50 (Median Toxic Dose) for JCP-0111, JCP-0115, and JCP-0117 are > 16.0, < 5.0, and > 20.0 mg/kg, respectively. This means that the dose of JCP compounds does not cause serious neurologic deficit. In contrast, pregabalin showed a neurological deficit of less than 10 mg/kg.

Conclusions

Our pipeline TrkA antagonists are effective in increasing pain tolerance threshold in post-operative rodent model with reduction in neurologic deficit effects compare to that of pregabalin (Lyrica). To better understand the efficacy of TrkA antagonists in post-operative pain in rodent model, we are working to develop comparative test using gold-standard analgesic: morphine. In addition, therapy with TrkA antagonists shows to provide effective management of post-operative pain at lower cost compared to antibody targeted therapy. As more efficacy and safety data become available, these products could be valuable alternatives to the standard therapy of APAP/NASID and opioid family for the management of the post-operative pain and may expend to broad spectrum of pain.

45 Clinically Relevant Improvements in Knee Osteoarthritis Pain with Diclofenac Sodium Gel 1%

Jeff Gudin¹, Florilene Bouisset², Sandy Yacoub Garas³

¹Englewood Hospital and Medical Center, Englewood, NJ, USA, ²GSK Consumer Healthcare, Nyon, Switzerland, ³GSK Consumer Healthcare, Warren, NJ, USA

Purpose

Topical nonsteroidal anti-inflammatory drugs (NSAIDs) are gaining in popularity as both adjunctive and primary treatment for musculoskeletal conditions including osteoarthritis (OA), and are recommended for the treatment of pain in patients with OA (1,2). Reported benefits of topically applied NSAIDs include targeted analgesia with reduced systemic exposure compared to oral NSAIDs. Diclofenac sodium gel 1% (DSG 1%), a topical NSAID, demonstrated significant improvements in pain and measures of physical function in patients with OA in a randomized clinical trial (3). It is often challenging to translate efficacy data endpoints from clinical trials to degrees of patient interpreted response. The minimal clinically important improvement (MCII) is defined as the smallest change in measurement that represents patients’ perceptions of what they view as a meaningful improvement of symptoms. Thus, MCII enables us to present results from therapeutic trials at an individual level (4). This post hoc analysis aimed to determine the number and percentage of patients with OA of the knee achieving MCII for pain, function, and stiffness in a previously reported clinical study of DSG 1%.

Methods

The study was a 12-week, randomized, double-blind, multi-center, vehicle-controlled, parallel group study to assess the efficacy and safety of DSG 1% for OA of the knee. The MCII for knee OA recommended by Tubach F et al (5) was applied to this study. The percentage of patients meeting the criterion for an MCII response, a relative improvement of 20% or more from baseline on 0–100 scale, was computed for Western Ontario McMaster Universities Osteoarthritis Index (WOMAC) pain, WOMAC function, WOMAC stiffness, and pain on movement (POM). Treatments were compared using the Cochrane-Mantel-Haenszel (CMH) test stratified by center. Depending on MCII response in relation to vehicle, responder rate based on improvement of 30% or more was also analyzed. Time to first MCII response was analyzed using the log-rank test stratified by center and the hazard ratio (HR) and 95% confidence intervals (CIs) were presented based on the Cox proportional hazards model accounting for center.

Results

This analysis included 254 patients treated with DSG 1% and 238 treated with placebo 4 times daily for 12 weeks. As previously reported for this OA knee study, DSG 1% resulted in significantly greater reductions in WOMAC pain, WOMAC function, WOMAC stiffness, and POM vs vehicle. These statistically significant reductions were seen at week 1 and were maintained through week 12. In the current post hoc analysis, subjects achieving a MCII response with DSG 1% vs vehicle at Week 1 were: WOMAC pain, 66% vs 55%, P = 0.011; WOMAC function 56% vs 42%, P = 0.002; WOMAC stiffness, 62% vs 48%, P = 0.002; POM, 66% vs 50%, P = 0.0003. All DSG 1% responses remained significantly different from vehicle through Week 12 with the exception of WOMAC pain. There was a significant difference in WOMAC pain based on 30% improvement at Week 1 (55% vs 42%, P = 0.003) and Week 12 (66% vs 56%, P = 0.019). Time to first MCII response was significantly lower with DSG 1% vs vehicle for all 4 measures: WOMAC pain, (HR = 1.35, P = 0.0026); WOMAC function, (HR = 1.55, P = 0.0002); WOMAC stiffness, (HR = 1.37, P = 0.0049); POM, (HR = 1.5, P < 0.0001), with clear separation of the curves from day 9 or 10 (Week 1 is the first collected data point).

Conclusions

The MCII is an additional tool for understanding clinically meaningful improvement in OA signs and symptoms by taking the perspective of the patient into account. Using the MCII to express results in percentages is potentially more clinically relevant and understandable for those interpreting the results of clinical trials, including both patients and physicians (2). This post hoc analysis represents the first time that the MCII has been applied to these DSG 1% clinical trial results. A significantly higher percentage of patients had MCII responses with DSG 1% compared to vehicle, achieving clinically meaningful relief within 1 week which was sustained for 12 weeks. In the context of this specific study, the results would suggest that higher MCII response criteria may be relevant to consider for WOMAC pain. This provides additional evidence for the efficacy of DSG 1% in the treatment of OA of the knee.

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46 Efficacy and Safety Profile of a Topical Methyl Salicylate and Menthol Patch in Adult Patients With Mild to Moderate Muscle Strain: A Randomized, Double-Blind, Parallel-Group, Placebo-Controlled, Multicenter Study

Jeffrey Gudin^1,2, Srinivas Nalamachu³

¹Rutgers NJ Medical School, Newark, NJ, USA, ²Englewood Hospital and Medical Center, Englewood, NJ, USA, ³Mid-America Poly Clinic, Overland Park, KS, USA

Purpose

The purpose of this study was to support the hypothesis that topical application of counterirritants such as methyl salicylate and menthol has analgesic benefit in patients with musculoskeletal pain. This was done using a combination patch formulation. The main goal was to determine the efficacy and safety profile of a patch containing 10% methyl salicylate and 3% l-menthol compared with a placebo patch in adult patients with mild to moderate muscle strain.

Methods

Eligible patients age ≥18 years with a clinical diagnosis of mild to moderate muscle strain were included, with more than 70% meeting the criteria for moderate pain. Patients were randomly assigned to receive either 1 active patch or 1 placebo patch applied to the skin at the affected area (i.e., shoulder, upper back, upper arm, etc.). Pain intensity was assessed on a 100-mm visual analog scale while at rest and with movement. The primary efficacy end point was the summed pain intensity difference score through 8 hours (SPID8) with movement.

Results

A total of 208 patients were randomized to 1 of 2 study groups (105 in the active-patch group [mean age, 37.3 years], 103 in the placebo-patch group [mean age, 38.1 years]). The primary efficacy analysis (SPID8 with movement) indicated that patients receiving the active patch experienced significantly greater pain relief (~40%) than those patients receiving a placebo patch (mean [SD], 182.6 [131.2] vs 130.1 [144.1]; P = 0.005). Analysis of the per-protocol population also found significantly more relief (P = 0.024) in the active-patch group (176.2 [131.4]; n = 92) versus the placebo-patch group (130.2 [144.0]; n = 96). Statistical analysis of secondary efficacy measures supported the primary end-point results. The number of patients experiencing any type of adverse event was comparable between study groups (active patch, 6.7% [7 events]; placebo patch, 5.8% [6 events]). No serious adverse events were reported during the study.

Conclusions

Pain is one of the most common reasons for seeking medical care and a major cause of disability and suffering. With toxicity issues facing opioids and oral NSAIDs, clinicians need alternative options to treat pain. Numerous data sources support that topical analgesics are a potentially safer than systemic analgesics. As part of CDC’s guidance for prescribing opioids, their CME training module recommended topical agents as alternative first-line treatments. The benefits of topically applied analgesics include targeted delivery of medication to peripheral sites of pain, and a relative lack of systemic absorption compared to oral and transdermal agents.

A single, 8-hour application of a patch containing methyl salicylate and l-menthol provided significant relief of pain associated with mild to moderate muscle strain in these adult patients compared with patients receiving a placebo patch. Considering the significant adverse effects noted with many over-the-counter and prescription analgesics, clinicians should consider topical analgesic therapies as first-line agents for pain relief.

The combination patch formulation researched in this study was approved by the FDA and is currently available as the Salonpas Pain Relief Patch Large. It is the only OTC medicine that is indicated to treat moderate pain.

47 Shorter Drug Testing Intervals are Associated with Improved Drug Misuse Rates

Jeffrey Gudin^1,2, Neel Mehta³, F Leland McClure⁴, Justin Niles⁴, Harvey Kaufman⁴

¹Englewood Hospital and Medical Center, Englewood, NJ, USA, ²Rutgers NJ Medical School, Newark, NJ, USA, ³Weill-Cornell Pain Medicine Center, New York, NY, USA, ⁴Quest Diagnostics, Secaucus, NJ, USA

Purpose

Misuse, abuse and diversion of controlled substances has contributed to our nation’s opioid epidemic. Currently available prescribing guidelines lack specific instructions on how often to utilize drug testing as part of overall risk management strategies. The purpose of this study was to evaluate whether shorter intervals between repeat drug testing were associated with improved compliance in patients undergoing drug monitoring.

Methods

We retrospectively analyzed Quest Diagnostics 2016–2017 serial drug testing results from 148,803 specimens with clinician-provided prescribing data. We included three consecutive specimens from 49,601 de-identified patients being monitored for prescription drug adherence in our analysis. Drug misuse was defined as absence of a prescribed substance or presence of a non-prescribed or illicit substance.

Results

Declines in misuse between the first and second urine drug test (UDT) were highest for those tested at the shortest intervals: weekly, 19%; monthly, 15%; bimonthly, 12%; quarterly, 9%; semi-annually, 3%; misuse rates increased by 1% for patients tested annually (p < 0.01 for trend). These results were more pronounced for opioids than other drug groups and included substantial overall declines in positivity for heroin (32%) and non-prescribed fentanyl (10%). Declines in misuse between the second and third UDT followed a similar pattern.

Conclusions

Our data suggest treatment strategies that include shorter intervals between drug testing may improve compliance with prescribed controlled substances and may help deter non-prescribed use or other illicit drug use. Recommendations by prescribing / clinical guidelines, such as those issued by CDC, suggesting drug testing ‘at least annually’ may be less than ideal to detect and deter aberrant behaviors in pain patients.

48 Educating Patients Receiving Prescription Opioids About Opioid Withdrawal

Jeremy Adler¹, Theresa Mallick-Searle², Mark Pirner³

¹Pacific Pain Medicine Consultants, Encinitas, CA, USA, ²Division of Pain Medicine, Stanford Outpatient Medical Center, Redwood City, CA, USA, ³US WorldMeds, LLC, Louisville, KY, USA

Purpose

Opioid medications are commonly used for the management of acute and chronic pain. Treatment guidelines recommend that opioid therapy for acute pain should be time-limited, and that opioid medications for chronic pain should be prescribed at the lowest effective dosage and frequently evaluated to weigh benefit versus risk of continuing opioid therapy (Dowell D, et al. JAMA 2016;315[15]:1624–1645). This review aims to educate health care providers (HCPs) about the neurobiology and symptoms of opioid withdrawal syndrome (OWS) to improve patient education when opioids are initially prescribed and facilitate opioid dose reduction or discontinuation when appropriate.

Methods

PubMed was searched using the terms ‘opioid withdrawal syndrome’ and ‘opioid withdrawal symptoms’ to identify articles relevant to the management of patients receiving opioid medications.

Results

Guidelines define physical dependence as ‘a state of adaptation that is manifested by a drug class–specific withdrawal syndrome that can be produced by abrupt cessation, rapid dose reduction, decreasing blood level of the drug, and/or administration of an antagonist’ (AAPM/APS/ASAM. Consensus Statement. 2001). Physical dependence may develop in just 5 days and occurs even when opioids are taken as prescribed. Physical dependence is caused by changes in certain brain functions (primarily involving the neurotransmitter norepinephrine) that compensate for the effects of opioid use. Physical dependence reflects a neurobiological process distinct from addiction, which is characterized by pronounced craving, compulsive drug-seeking, and persistent use despite ongoing harm, and develops in a small percentage of opioid-treated patients. When opioids are abruptly discontinued or when opioid dosage is rapidly decreased over a few weeks, OWS may occur. Symptoms of opioid withdrawal are exceedingly unpleasant and include anxiety, restlessness, stomach cramps, nausea, vomiting, muscle spasms, bone/muscle aches, hot flashes, cold flashes, piloerection, shaking, perspiring, eyes tearing, runny nose, and yawning. Although opioid withdrawal is generally not life-threatening, acute withdrawal can lead to significant morbidity (cardiac complications, electrolyte imbalances, severe dehydration) in compromised individuals. In one study, more than half of the patients with opioid use disorder and chronic pain who initially took opioids for pain relief continued to take opioids primarily to avoid withdrawal symptoms. Some patients may have difficulty distinguishing certain OWS from the pain symptoms for which they received their opioid medication.

Conclusions

Explaining the potential for physical dependence and symptoms of OWS to patients when they are first prescribed an opioid may help set their expectations and improve subsequent patient–HCP communication regarding opioid therapy. It is particularly important to educate patients about OWS identification when opioid dose reduction or discontinuation is clinically indicated so an effective management plan can be developed.

Funding support: US WorldMeds, LLC, Louisville, KY.

49 Lofexidine for the Management of Opioid Withdrawal Syndrome in a Patient Discontinuing Opioid Therapy for Chronic Pain

Jeremy Adler

Pacific Pain Medicine Consultants, Encinitas, CA, USA

Purpose

Patients receiving chronic opioid therapy often develop physical dependence to opioids. Physical dependence occurs as a result of physiological adaptation to drug exposure and manifests as a withdrawal syndrome specific to the drug class. When opioids are discontinued, especially after a period of long-term therapy, opioid withdrawal syndrome (OWS) may occur. Even when opioid discontinuation is clinically indicated, the distress associated with symptoms of opioid withdrawal (e.g., nausea, vomiting, anxiety, restlessness, muscle spasms, bone/muscle aches, shaking, perspiring, eyes tearing, runny nose) may prevent patients from successfully discontinuing opioid use. Lofexidine, a central alpha-2 adrenergic agonist, has been approved by the US Food and Drug Administration for mitigation of opioid withdrawal symptoms to facilitate abrupt opioid discontinuation in adults. This case study describes the use of lofexidine to manage OWS in a patient discontinuing opioids after receiving long-term opioid therapy for chronic pain.

Methods

The patient is a 54-year-old female with chronic pain secondary to lumbar spondylosis and radiculopathy, cervical spondylosis, fibromyalgia, chronic migraine headache, type 2 diabetes, and posttraumatic stress disorder. She is married, has one child, and described her occupation as a homemaker. Her chronic pain began in the 1980s after a motor vehicle accident that resulted in a whiplash-type neck pain. She developed other pain conditions over the years. The patient has consulted practitioners from multiple specialties, including neurology, psychiatry, psychology, physical therapy, orthopedic surgery, and rheumatology. Upon presentation to our practice, she had already received extensive physical rehabilitation and followed an independent exercise program. She had tried biofeedback, transcutaneous electrical nerve stimulation (TENS), acupuncture, and interventional pain treatments including myofascial trigger point injections and radiofrequency neurotomy. She had taken medications from a variety of pharmacologic classes, including nonsteroidal anti-inflammatory drugs, muscle relaxants, antispasmodics, tricyclic antidepressants, selective serotonin and norepinephrine reuptake inhibitors, antiepileptics, and opioids. Headache management included pericranial botulinum toxin injections. She had experienced multiple medication failures secondary either to lack of efficacy or to intolerable adverse effects. The patient presented to our practice with a many year history of chronic opioid therapy primarily provided to manage intractable back pain. She denied a history of tobacco or illicit drug use but did note 14 years of sobriety from alcohol abuse without relapse. Her father had a history of alcohol abuse as well, but otherwise, there was no additional family history of substance use disorders. She actively participated in her diagnostic workup, including imaging and electrodiagnostic testing. Her prescription drug monitoring program data did not suggest “doctor shopping” or any aberrant pattern of acquiring controlled substances. Results from urine drug monitoring were consistent with what was to be expected from her prescribed opioid regimen, and she did not display aberrant drug-taking behaviors during treatment. At initial presentation to our practice, the patient was utilizing fentanyl transdermal patch 100 mcg/h, which was reportedly inadequate for pain relief (provided less than 30% reduction in pain) and did not provide significant improvements in functionality.

Results

A gradual opioid dose-reduction plan was discussed, and the patient was in agreement with utilizing this approach. The patient was advised to continue taking gabapentin and duloxetine, and was additionally started on diclofenac. She also received concomitant psychological therapy during treatment. The fentanyl-patch dose was reduced by 12 mcg/h per dose every 2 weeks, as the patient was very concerned about withdrawal symptoms. The patient reported a number of symptoms associated with dose reduction, necessitating a very slow taper. In particular, she reported nausea, vomiting, insomnia, and increased pain. Clonidine 0.1 mg up to 3 times daily was provided without adequate resolution of her reported opioid withdrawal symptoms. At a fentanyl-patch dosage of 62 mcg/h, the patient declined further dose reduction citing tolerability concerns; it was then recommended that she enter an inpatient supervised setting for further rapid opioid weaning. However, her insurance company denied authorization for coverage of inpatient treatment. Following a prolonged, unsuccessful insurance appeal process, ongoing outpatient opioid taper was reattempted. The patient was able to reduce the fentanyl dosage to 25 mcg/h despite significant withdrawal symptoms but did not tolerate further dose reductions. Lofexidine was recommended to aid in opioid discontinuation on an outpatient basis. At the time, her blood pressure was 123/87 and heart rate 112. The patient was started on lofexidine and the fentanyl dose was reduced from 25 mcg/h to 12 mcg/h simultaneously; after 14 days, the patient was instructed to discontinue the fentanyl patch. The patient was instructed to initiate lofexidine treatment at 12 tablets/day (3 tablets, 4x/day), beginning on the first day of the 12 mcg/h dosing of fentanyl. After 7 days on 12 mcg/h of fentanyl, the lofexidine prescription was refilled with instructions to decrease to 8 tablets/day (2 tablets, 4x/day) for the next 7 days of fentanyl 12 mcg/h, then lofexidine was to be continued for an additional 3 days after the fentanyl patch was discontinued. On the fourth day after fentanyl discontinuation, lofexidine was tapered and the patient instructed to take it as needed for withdrawal symptoms. The patient returned to the office after completely discontinuing opioid use and indicated that her withdrawal symptoms were minimal during weaning, and lofexidine was well tolerated. Her follow-up blood pressure was 138/84 and heart rate 80. Ongoing medication for pain management at that time consisted of gabapentin, duloxetine, and diclofenac.

Conclusions

This 54-year-old patient with long-standing history of chronic pain failed multiple attempts to discontinue chronic opioid therapy due to intolerable withdrawal symptoms. Lofexidine mitigated the symptoms of opioid withdrawal, allowing the patient to discontinue chronic opioid use and continue pain management using a non-opioid regimen.

Funding support: US WorldMeds, LLC, Louisville, KY, USA.

50 Long-term Safety Evaluation of Ubrogepant for the Acute Treatment of Migraine Attacks

Jessica Ailani¹, Susan Hutchinson², Richard B. Lipton³, Kerry Knievel⁴, Kaifeng Lu⁵, Sung Yun Yu⁵, Michelle Finnegan⁵, Lawrence Severt⁵, Armin Szegedi⁵, Joel M. Trugman⁵

¹MedStar Georgetown University Hospital, Washington, DC, USA, ²Orange County Migraine & Headache Center, Irvine, CA, USA, ³Albert Einstein College of Medicine, Bronx, NY, USA, ⁴Barrow Neurological Institute, Phoenix, AZ, USA, ⁵Allergan plc, Madison, NJ, USA

Purpose

To evaluate the long-term safety and tolerability of ubrogepant for the acute treatment of migraine.

Methods

Phase 3, multicenter, randomized, open-label, 52-week extension trial. Adults with migraine with or without aura were randomized 1:1 in a blinded fashion to ubrogepant 50 mg or 100 mg. Safety and tolerability were assessed.

Results

In total, 837 participants were randomized to ubrogepant; 813 composed the safety population. Mean age was 42 years for ubrogepant 50 mg and 41 for ubrogepant 100 mg; 91% were female, 84% White; mean BMI was 30 mg/kg². Throughout the study, 21,454 migraine attacks were treated with 31,968 doses of ubrogepant. Treatment-emergent adverse events (AEs) reported: ubrogepant 50 mg, 268/404 (66%); ubrogepant 100 mg, 297/409 (73%); most common was upper respiratory tract infection (92/813, 11%), with a similar incidence observed across treatments. Treatment-related AEs: ubrogepant 50 mg, 42/404 (10%); ubrogepant 100 mg, 43/409 (10%). Serious AEs: ubrogepant 50 mg, 9/404 (2%); ubrogepant 100 mg, 12/409 (3%); 1 considered related by the investigator (ubrogepant 50 mg; sinus tachycardia). Sixteen cases of ALT/AST ≥3x ULN were reported and adjudicated by an independent panel of liver experts blinded to treatment. Thirteen of 16 cases (ubrogepant 50 mg, 3; ubrogepant 100 mg, 10) were adjudicated as unlikely to be related based on plausible alternative etiology/confounding factor(s). Two cases (both ubrogepant 50 mg) were adjudicated as possibly related to study medication and 1 case (ubrogepant 100 mg) as probably related; however, confounding factors were noted. All cases were asymptomatic, with no concurrent bilirubin elevation. ALT/AST elevations resolved in those who continued dosing.

Conclusions

Intermittent use of ubrogepant for the acute treatment of migraine over 1 year was well tolerated, with no safety concerns identified.

51 Reversion from Chronic to Episodic Migraine in Patients with Documented Inadequate Response to 2–4 Classes of Migraine Preventive Treatments: Results of the Randomized, Placebo-Controlled FOCUS Study

Jessica Ailani¹, Verena Ramirez-Campos², Joshua M. Cohen², Ronghua Yang², Maja Galic³, Xiaoping Ning², Rashmi Halker Singh⁴

¹Medstar Georgetown University Hospital, Washington, DC, USA, ²Teva Pharmaceuticals Industries, Frazer, PA, USA, ³Teva Pharmaceuticals, Amsterdam, Netherlands, ⁴Mayo Clinic, Phoenix, AZ, USA

Purpose

The FOCUS study of fremanezumab, a fully-humanized monoclonal antibody (IgG2Δa) that selectively targets calcitonin gene-related peptide (CGRP), was the first and largest study of a migraine preventive treatment in adults with both episodic migraine (EM) and chronic migraine (CM) and documented inadequate response to 2 to 4 classes of migraine preventive treatments. Reversion from CM at baseline to EM during study treatment and reductions in headache days among patients reverting from CM (≥15 headache days/month at baseline) to EM (<15 headache days/month in all 3 months) were evaluated in this post-hoc analysis.

Methods

Patients were randomized (1:1:1) to quarterly fremanezumab (Month 1: 675 mg; Months 2 and 3: placebo), monthly fremanezumab (Month 1: EM, 225 mg; CM, 675 mg; Months 2 and 3: 225 mg), or matched monthly placebo for 12 weeks. Overall headache days at baseline and Month 3 and percent change in headache days from baseline in Month 3 were evaluated for patients with CM at baseline who reverted to EM in Months 1, 2, and 3.

Results

In the placebo, quarterly fremanezumab, and monthly fremanezumab groups, respectively, 167, 167, and 172 patients had CM at baseline; of those, 18 (11%), 59 (35%), and 59 (34%) reverted to EM in Months 1, 2, and 3. Among patients who reverted, the mean (standard deviation [SD]) monthly numbers of headache days at baseline were 16.9 (2.34), 17.4 (2.37), and 17.4 (2.57) days in the placebo, fremanezumab quarterly, and fremanezumab monthly groups, respectively; the mean (SD) numbers of headache days at Month 3 were 9.9 (3.70), 8.6 (3.60), and 8.3 (3.72) days, representing reductions of 39%, 50%, and 52% days from baseline. Similar reductions were observed at Months 1 and 2.

Conclusions

Higher proportions of patients with CM reverted to EM with fremanezumab treatment versus placebo in this population of patients with inadequate response to 2 to 4 classes of migraine preventive treatments. On average, patients in the fremanezumab groups reverting from CM to EM experienced clinically meaningful ≥50% reductions in monthly headache days during the 3-month, double-blind treatment period.

52 Buprenorphine Buccal Film Improves Patient Global Impression of Change and Reduces the Prevalence of Anxiety and Insomnia in Patients With Chronic Low Back Pain

Joseph Pergolizzi¹, Todd Kunkel²

¹NEMA Research, Inc., Naples, FL, USA, ²BioDelivery Sciences International, Inc., Raleigh, NC, USA

Purpose

Chronic low back pain is associated with negative quality of life outcomes, including activity limitations, anxiety, and sleep disorders.¹ The buccal formulation of buprenorphine, a Schedule III opioid, has demonstrated efficacy in significantly reducing average daily pain intensity scores in patients with chronic low back pain.^2,3 To determine the impact of buprenorphine on quality of life outcomes associated with chronic low back pain, the Patient Global Impression of Change (PGIC) and the prevalence of anxiety and insomnia were assessed from two 12-week phase 3 clinical studies of buprenorphine buccal film, one in opioid-naive² patients and the other in opioid-experienced³ patients.

Methods

Patients completed an electronic version of the PGIC questionnaire at baseline and the end of the double-blind treatment phase. The PGIC consisted of a single item that asked patients to assess their impression of change in activity limitations related to chronic low back pain using a 7-point scale [ranging from 1 (no change) to 7 (a great deal better)]. Anxiety and insomnia were considered treatment-emergent adverse events if the conditions were not present prior to treatment but appeared after receiving buprenorphine, were present at treatment initiation but worsened during treatment, or were present at treatment initiation, resolved, and reappeared during treatment.

Results

In opioid-naive patients, the mean (SD) PGIC score was 5.3 (1.22) in the buprenorphine group and 5.2 (1.28) in the placebo group at baseline (before randomization); at the end of the double-blind treatment phase, the mean (SD) PGIC score was 4.5 (1.75) in the buprenorphine group and 3.9 (1.99) in the placebo group, with a significant difference between the groups of 0.6 (95% confidence interval [CI], 0.2 to 1.0; p = 0.0011). In opioid-experienced patients, the mean (SD) PGIC score was 5.4 (1.14) in the buprenorphine group and 5.3 (1.25) in the placebo group at baseline (before randomization); at the end of the double-blind treatment phase, the mean (SD) PGIC score was 4.5 (1.86) in the buprenorphine group and 3.2 (1.98) in the placebo group, with a significant difference between the groups of 1.3 (95% CI, 0.9 to 1.6; p < 0.001).

In a pooled analysis of opioid-naive and opioid-experienced patients, 16.9% of patients had ongoing anxiety at study entry, whereas only 1.6% of patients experienced anxiety during the open-label dose titration with buprenorphine buccal film. A total of 24.9% of patients had ongoing insomnia at study entry, whereas only 1.6% of patients experienced insomnia during the open-label dose titration with buprenorphine buccal film. In the double-blind phase, 1% of patients in the buprenorphine group experienced anxiety compared with 2.5% in the placebo group, and 0.6% of patients in the buprenorphine group had insomnia compared with 1.8% in the placebo group.

Conclusions

Upon treatment with buprenorphine buccal film, opioid-naive and opioid-experienced patients with chronic low back pain experienced significant improvements in their activity limitations as measured by the PGIC and were less likely to have anxiety or insomnia compared with the placebo group. Thus, in addition to improving chronic low back pain, treatment with buprenorphine buccal film may also enhance quality of life outcomes related to activity limitations and reduce the prevalence of anxiety and in

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53 Consistent Efficacy of Buprenorphine Buccal Film in Opioid-Naive and Opioid-Experienced Patients With Moderate to Severe Chronic Low Back Pain

Joseph Pergolizzi¹, Gary Cutter²

¹NEMA Research, Inc., Naples, FL, USA, ²University of Alabama-Birmingham School of Public Health, Birmingham, AL, USA

Purpose

Chronic low back pain (CLBP) is a leading cause of disability.¹ Acetaminophen and nonsteroidal anti-inflammatory drugs are first-line options;² however, when patients with moderate to severe CLBP do not achieve adequate pain relief, opioids are considered. Unfortunately, most opioid analgesics have the potential for adverse effects, abuse, and diversion.³ Buprenorphine is a synthetic opioid analgesic classified as a Schedule III controlled substance in the United States. It is a partial μ-opioid receptor agonist, an antagonist at the δ-opioid and κ-opioid receptors, and a full agonist at the opioid receptor-like 1 receptor.⁴ There is interest in buprenorphine as an analgesic because it has a lower addiction potential⁴ and reduced likelihood for respiratory depression⁵ compared to Schedule II opioids. To improve bioavailability, a buprenorphine buccal film was developed and is approved by the US Food and Drug Administration for use in patients with chronic pain severe enough to require daily, around-the-clock, long-term opioid treatment and for whom alternative treatment options are inadequate.⁶

Two pivotal phase III clinical trials (Study 307, Clinical Trial ID NCT01675167, and Study 308, Clinical Trial ID NCT01633944) were conducted that established the efficacy and safety profiles of buprenorphine buccal film.^7,8 The studies were very similar except that participants in Study 307 were opioid experienced (30 to 160 mg/d morphine sulfate equivalents) and participants in Study 308 were opioid naive. The purpose of the present analysis was to compare results from these studies to better understand the impact of prior opioid experience on the efficacy of buprenorphine buccal film in patients with CLBP.

Methods

Both clinical trials were multicenter, double-blind, placebo-controlled, enriched-enrollment, randomized-withdrawal studies in patients with moderate to severe CLBP needing around-the-clock treatment. The primary efficacy measure was an 11-point numeric rating scale (NRS). For each study, after a 2-week screening period, an 8-week open-label titration period was used to optimize the dosage to a level that provided adequate analgesia (a score ≤4 on the NRS) and was well tolerated. After the titration period, only responders to buprenorphine buccal film (patients with a mean daily pain intensity score ≤4 on the NRS for the last 3 days before randomization and at least 2 points lower than the NRS score at screening) were eligible for randomization. Also, their buprenorphine dose had to be ≥150 µg twice daily and stable for at least 2 weeks and had to have taken no more than one dose per day of rescue acetaminophen during the last 7 days prior to randomization.

For the 12-week double-blind treatment phase, patients were randomized 1:1 to twice-daily buprenorphine buccal film or placebo buccal film. Opioid-experienced patients were provided with 5 mg/325 mg hydrocodone/acetaminophen tablets as rescue medication. Opioid-naive patients were provided with 5 mg/325 mg hydrocodone/acetaminophen tablets as rescue medication during the first 2 weeks after randomization, then only acetaminophen thereafter. Both studies evaluated change in NRS scores and the proportions of 30% and 50% responders (patients who experienced a ≥ 30% or ≥50% decrease in NRS score at week 12, respectively).

Statistical analyses were carried out in the intent-to-treat population. Analysis of covariance was used to assess change in NRS scores. Response rates were compared using the chi-square test.

Results

For Study 307 (opioid-experienced patients), a total of 815 patients were enrolled in the open-label titration phase, 511 of whom were randomized (254 received buprenorphine buccal film, 257 received placebo). From baseline (at randomization) to week 12, mean [SD] NRS pain scores increased significantly more for the placebo group (1.92 [1.87]) than for the buprenorphine group (0.88 [1.79]; p < 0.001). In addition, 156 (64.2%) of the buprenorphine patients were 30% responders compared with only 76 (30.6%) of the placebo patients (p < 0.001). Similarly, 96 (39.5%) of the buprenorphine patients were 50% responders compared with only 42 (16.9%) of the placebo patients (p < 0.001).

For Study 308 (opioid-naive patients), a total of 752 patients were enrolled in the open-label titration phase, 462 of whom were randomized (229 received buprenorphine buccal film, 232 received placebo). From baseline (at randomization) to week 12, mean [SD] NRS pain scores increased significantly more for the placebo group (1.59 [2.04]) than for the buprenorphine group (0.94 [1.85]; p = 0.0012). In addition, 131 (62.7%) of the buprenorphine patients were 30% responders compared with only 99 (46.9%) of the placebo patients (p = 0.0012). However, 86 (41.1%) of the buprenorphine patients were 50% responders, but 69 (32.7%) of the placebo patients were also 50% responders (p = 0.0754).

Thus, there was a substantial difference in responder rates for those randomized to placebo depending on previous opioid experience. In the buprenorphine-treated groups, there was not a statistically significant difference in response rates between the opioid-experienced and opioid-naive patients (30% responders, p = 0.7692; 50% responders, p = 0.7731). However, in the placebo-treated groups, the response rates were significantly higher in the opioid-naive groups than in the opioid-experienced groups (30% responders, p = 0.0004; 50% responders, p = 0.0001).

Conclusions

Buprenorphine buccal film was effective and well tolerated for most of the participants in these studies, regardless of opioid use prior to study participation. However, the response rates of patients assigned to placebo differed depending on prior opioid experience. The number of 30% responders in the placebo group was greater in opioid-naive patients than in opioid-experienced patients (46.9% vs. 30.6%; p = 0.0004), as was the percentage of 50% responders in the placebo group (32.7% vs. 16.9%; p = 0.0001). Overall, it appears there was a greater placebo response in the opioid-naive patients, demonstrating that studies using both opioid-naive and opioid-experienced patients may provide a better assessment of efficacy than studies using opioid-naive patients alone.

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54 Aging High: Geriatric Patients with Opioid Use Disorder

Joseph V. Pergolizzi, Jr^1,2, Giustino Varrassi^3,4, Antonella Paladini⁵, Jo Ann LeQuang¹

¹NEMA Research, Inc, Naples, FL, USA. ²Neumentum, Inc, Palo Alto, CA, USA. ³President, Paolo Procacci Foundation, Rome, Italy. ⁴World Institute of Pain (WIP), Rome, Italy. ⁵Associate Professor, Department of MESVA, University of L’Aquila, L’Aquila, Italy

Purpose

Opioid use disorder (OUD) increasingly is encountered in geriatric patients and can create formidable challenges to clinicians. While OUD is more common in younger people, it is not accurate to assume that clinicians will not encounter the largely unstudied population of recreational opioid users who have become senior citizens with their drug use largely unchanged. Although not well studied, this population is not trivial – a New York methadone maintenance clinic reported 13% of its patients were over age 60. Furthermore, this unique population is expected to increase and account for about 2.4% of all seniors by 2020. Of the 80 million baby boomers who came of age in the 1960s and 1970s and are not reaching Medicare status, all types of substance use disorder appear to occur at higher rates than previous generations. There is little guidance in the literature as to how to manage geriatric patients with active OUD, many of whom see no particular reason to give up drugs. Furthermore, there are issues with geriatric patients in terms of drug metabolism.

Opioids were legal in the United States up until the Harrison Narcotic Control Act of 1914. At that time, the American attitude was that pain should be managed with moral fortitude rather than potentially dangerous drugs. Over time, opioids were valued for their analgesic effect in cancer patients at the end of life with the Cancer Pain Monograph from the World Health Organization. Baby boomers grew up in a world where celebrities used (and glorified) drugs and experienced the aches and pains of middle age at a time when opioids were liberally prescribed, and pain control was seen as a fundamental human right. Thus, the baby boomers grew up with a tolerant attitude toward drugs, may have experimented with them over their lifetime, and view them with a more favorable attitude.

As lifespan increases and patients live longer, sometimes with managed diseases like cancer or chronic painful conditions, geriatric patients with OUD are likely to become an important, emerging patient population.

Methods

This report was based on a literature search, clinical observations, and the opportunity to interview a 64-year-old patient in a skilled nursing facility with lifelong drug addiction, including a preference for opioids and OUD of at least 20 years.

Results

Geriatric patients are more likely to overdose on prescription than street opioids. It is not known if there are specific interventions or rehabilitation programs that might work better in the geriatric population than younger patients. In many cases, geriatric people with OUD may require alternate pain control strategies even if they originally took opioids for psychoactive rather than analgesic effects. The authors are not aware of any specific treatment options designed for older individuals. Maintenance therapy is not contraindicated in this population. However, there are important considerations when treating geriatric opioid addicts: drug metabolism slows, brain changes and cognitive disorders can complicate care, concomitant untreated mental health disorders may be deeply entrenched, and patients are likely on polypharmacy, thus at risk for drug-drug interactions.

An interview was conducted with a 64-year-old man in long-term care for paraplegia (unrelated to drug use which preceded the disability) who was willing to discuss his lifelong drug use providing he could speak anonymously. Some of his remarks appear in Table 2.

Table 2. From the interview with a geriatric man with OUD.

• ‘I got high for the first time when I was about 15 or 16. Rapidly, within months, progressed using psychedelics, LSD, and so-called psilocybin mushrooms.’

• ‘I didn’t go to college till I was 26, and I had the misfortune to live next to amphetamine manufacturers.’

• ‘I’ve noticed that the dugs that caused the most behavioral problems and the most effect on your judgment were alcohol and amphetamines. Opioids did not have that much of an effect.’

• ‘Opioids are my drug of choice.’

• ‘Most of the people I know did opioids to get high, but they did not initially get them prescribed by a doctor.’

• ‘I don’t take street heroin anymore because it’s too dangerous. Heroin was always a gamble. You just don’t know what’s in that bag.’

• ‘There is no question that addiction damaged my life. It had terrible effects. On the other hand, maybe I wouldn’t be here if I couldn’t have medicated myself. I don’t know.’

Conclusions

There is an urgent need to better understand, identify, and treat geriatric patients with OUD. They represent a small but growing population for OUD who may have special risks (such as age-related slower drug metabolism, the likelihood of pain syndromes, and psychological stressors like loneliness) and need specific interventions. More and more clinicians encounter such patients who pose a real clinical challenge. There is an urgent need to study these patients and craft appropriate guidance for clinicians who treat them.

55 Treating Pain in Patients with Dementia and How It Might Relieve Agitation

Joseph V. Pergolizzi, Jr^1,2, Antonella Paladini³, Giustino Varrassi^4,5, Charles Wollmuth², Mate Kalapos², Jo Ann LeQuang²

¹Neumentum, Inc, Palo Alto, CA, USA, ²NEMA Research, Inc, Naples, FL, USA, ³Associate Professor, Department of MESVA, University of L’Aquila, L’Aquila, Italy, ⁴President, Paolo Procacci Foundation, Rome, Italy, ⁵World Institute of Pain (WIP), Rome, Italy

Purpose

Dementia is an irreversible and progressive disorder that affects memory, judgment, cognition, learning ability, communication skills, and executive function but does not impair consciousness. Pain prevalence is high among the elderly who are also at elevated risk for dementia. People with dementia may have difficulty expressing their desire for pain control or describing their painful symptoms. Cerebral changes in dementia may also affect how they process pain. Agitation frequently accompanies dementia and agitation symptoms may decrease when pain is treated. The purpose of our narrative review was to examine the challenges of treating pain in dementia patients with emphasis on how pain control might affect symptoms of agitation.

Methods

This narrative review is based on a literature search of the PubMed database. In May 2019, the authors searched keywords ‘opioid for agitation in dementia’ (22 results), ‘opioid dementia’ (399 results), and ‘opioid dementia safety’ (24 results). Articles had to be available in full text to the authors and in English and priority was given to articles published in the last 10 years. Bibliographies of particularly relevant articles were also searched. Altogether, 75 articles were used.

Results

Pain is typically self-reported and this can be challenging for patients with deficits in language and communication skills. Pain assessment tools are available for use in dementia patients. Emerging evidence suggests that people with dementia process and perceive pain differently in that the neuropathology of Alzheimer’s disease in particular appears to confer on patients greater pain tolerance while maintaining the same pain threshold, a shift that becomes increasingly more pronounced as the disease worsens. Dementia patients do not have a placebo effect for pain or other medications; the placebo effect is an important factor in analgesia and the absence of a placebo effect may means analgesia doses must be higher in dementia patients, although the elderly often have polypharmacy and slowed metabolisms that make prescribing challenging. Agitation is common in dementia patients and may be an adverse effect of medication(s), a product of institutionalized care, or a neuropsychiatric symptom of dementia. However, agitation may also be present or exacerbated by uncontrolled pain and the patient’s frustration at not obtaining analgesia. While there are few studies involving dementia patients, evidence suggests that analgesia can decrease agitation. This suggests that pain may be at the root of certain agitated behaviors in dementia patients.

Conclusions

Pain is likely under-treated in elderly patients with dementia because of obvious challenges in pain assessment, prescribing, and communication. Dementia patients perceive and process pain differently and much needs to be elucidated on this topic. There is some evidence that analgesia reduces symptoms of agitation in dementia patients, suggesting that symptoms of agitation might be related to unrelieved pain.

A variety of pain assessment tools may be helpful for evaluating pain in elderly patients with cognitive impairment and/or dementia, many of which rely on a caregiver observing and then assessing the patient. Some of these tools are used in a range of patients with and without cognitive impairment while others were specifically developed for use in patients with cognitive deficits or other conditions, such as limited ability to communicate.

56 Fentanyl and the Southwestern Border

Joseph V. Pergolizzi, Jr^1,2, Robert Raffa^1,3,4, Jo Ann LeQuang²

¹Neumentum, Inc, Palo Alto, CA, USA, ²NEMA Research, Inc, Naples, FL, USA, ³Adjunct Professor, University of Arizona College of Pharmacy, Tucson, AZ, USA, ⁴Associate Professor, Temple University, Philadelphia, PA, USA

Purpose

U.S. deaths associated with synthetic opioid overdose increased 45% in just one year from 2016 to 2017, and while the deaths attributed to heroin (without fentanyl adulteration) or prescription opioids remained relatively unchanged, the illicitly manufactured fentanyl (IMF) is driving the increased mortality. IMF, 50 to 100 times as potent as morphine, can be inexpensively manufactured in clandestine laboratories. IMF is not to be confused with prescription fentanyl, an approved opioid analgesic. IMF is used to mix in with filler materials and then cut into heroin to increase profits. Dealers and users may be unaware of these adulterants, but the practice is so common now that a product of heroin plus fillers and IMF is marketed as ‘gray death.’ Using pill presses, dealers can also produce counterfeit prescription opioids from filler material and a little IMF to provide psychoactive effects. The use of IMF in any product can be lethal as minute doses can be fatal. In April 2016, the first seizure of IMF occurred at the southern border between Mexico and the United States. Today, the Drug Enforcement Agency (DEA) has declared that, ‘fentanyl is the most prevalent and the most significant synthetic opioid threat to the U.S. and will very likely remain the most prevalent synthetic opioid threat in the near term.’ The DEA reports that there is evidence that transnational criminal organizations (TCOs) operating near America’s Southwestern border are trafficking large quantities of fentanyl mixed with other non-opioid drugs.

The authors sought to investigate what is currently known about IMF being smuggled over the Southwestern border and to determine if and how the incursion of this new illicit substance was changing opioid overdose fatalities.

Methods

The authors searched the PubMed database for terms such as ‘illicit fentanyl,’ ‘illicitly manufactured fentanyl,’ and ‘fentanyl smuggling’ and went to the government websites of the Food and Drug Administration, the Centers for Disease Control and Prevention, and the Drug Enforcement Agency to gather the latest official statistics and information. This is not a rigorous review but rather an update based on a new and largely unstudied field.

Results

IMF has radically transformed the business of illicit drugs in that it is a cheaply produced material typically sold to high and mid-level drug dealers who can use it with other filler materials to stretch heroin or they can use it to provide the psychoactive effects in counterfeit pills. Visually, it is difficult to distinguish IMF-laced product. Even experienced heroin users can unknowingly ingest IMF-adulterated product.

IMF enters the U.S. mainly from China or Mexico (and sometimes from China via Mexico). A quantity of IMF that sells to dealers for about $5,000 can be converted to other products with a street value of $1.5 million. This has increased the lethality of street drugs and caused an explosion in the profitability of drug smuggling and dealing.

It appears that the Mexican TCOs are aggressively adding IMF to their other product lines. Illicit activity runs both ways with IMF and other drugs being smuggled into the U.S. and cash going out. Los Angeles known to be one of the main money-smuggling hubs for this illicit activity due to its historic business ties with Mexico and China, strong economy, and a multiplicity of small banks and financial institutions. IMF is also smuggled into the U.S. by mail and parcel delivery services as even very small quantities can be lucrative. China and Mexico both produce and smuggle IMF but it is unclear the extent to which they work together.

Most drugs seized at the border are captured at recognized points of entry but it is suspected that drugs are often driven or carried over more open, inadequately patrolled areas of the border. It is impossible to estimate accurately the flow of drugs entering the U.S. in the Southwest. The data we have come from seizures, and it goes without saying that U.S. officials are not seizing all of the drugs smuggled in. About 90% of all of the heroin and 90% of illegal cocaine in the U.S. comes into the country over the Southwestern border with a negligible amount of IMF until 250 pounds of IMF was seized in February 2019. IMF coming over the border by land tends to be lower potency/higher volume than IMF arriving by courier, which is often >90% pure but in small amounts.

Conclusions

IMF is driving an increase in opioid overdose mortality and may be arriving in larger than appreciated quantities over the Southwestern border between Mexico and the United States. TCOs are marketing IMF to American dealers and may at times be working with Chinese counterparts who are also active in IMF smuggling. Because IMF is so potent, it can be fatal to those who ingest even very small quantities and many illicit drug users consume it unawares. IMF poses a new challenge to the American opioid epidemic during this time of stress at the Southwestern border.

57 Reversing Opioid-Induced Respiratory Depression and Stemming Opioid Overdose Deaths: What Do We Do When Naloxone (Narcan) Is Not Enough?

Joseph V. Pergolizzi, Jr^1,2, Robert Raffa^3,4,1, Jo Ann LeQuang²

¹Neumentum, Inc, Palo Alto, CA, USA, ²NEMA Research, Inc, Naples, FL, USA, ³Adjunct Professor, University of Arizona College of Pharmacy, Tucson, AZ, USA, ⁴Professor Emeritus, Temple University, Philadelphia, PA, USA

Purpose

About 4% of U.S. adults have some form of opioid use disorder (OUD), which is ‘severe’ in about 2.1 million citizens. While opioids can be effective analgesics at therapeutic doses, at high doses they can induce potentially life threatening respiratory depression. In 2016, 42,000 Americans died of an opioid overdose, which amounts to the equivalent of four 11 September 2001 terrorist attacks in a year. Opioid mortality rates for 2016–2017 may be understated³ and overdose deaths are changing with the influx of illicitly manufactured fentanyl (IMF) into our street drug supply. In addition, the demographics of those with OUD has shifted as well.

Illicitly manufactured fentanyl (IMF, to be distinguished from prescription pharmaceutical-grade fentanyl) has radically transformed opioid morbidity and mortality. IMF is 50 or more times more potent than morphine and is cheap to manufacture. For example, a kilogram of heroin costs roughly $65,000 but the same weight of vastly more potent IMF costs $3,500. Since the drug market has always been financially driven, the ability to cut filler and cheap IMF into heroin or other drugs can increase profits. IMF is difficult to detect and many drug dealers and users buy heroin laced with IMF unawares. The Drug Enforcement Agency (DEA) has said that it is the influx of IMF that is now driving the opioid overdose rates.

Respiratory depression can occur quite readily with IMF-laced products and the potency of these products may be more than the reversal agent, naloxone (Narcan) can overcome. Naloxone is a short-acting high-affinity opioid antagonist that can rapidly reverse overdose in some patients by competing with the opioid for the opioid receptors. Naloxone can be administered in the hospital, by emergency responders, and even by trained (or untrained) laypersons with the aid of a ‘naloxone kit.’ Naloxone dosing has been empirical but when a person ingests large doses of opioid, IMF, or polypharmacy, naloxone administration at one or several standard doses (0.4 mg) may be inadequate. Nalmefene is a long-acting opioid antagonist that has been used to treat alcohol use disorder and may play a role in reversing opioid overdose as well.

Methods

The authors searched the PubMed database for ‘nalmefene’ and ‘Narcan’ and ‘naloxone’ and included their own clinical and academic experiences to offer an overview of this new opioid reversal paradigm.

Results

Nalmefene is a long-acting antagonist at the mu-opioid receptor and a partial agonist at the kappa-opioid receptor compared to naloxone, a short-acting opioid antagonist at the mu-opioid receptors. Nalmfene has been described as an ‘opioid modulator’ rather than reversal agent. Its plasma half-life is around 11 hours and it has a rapid onset of action (about five minutes for injection).

Naloxone has a very rapid onset of action and a half-life of about one hour, such that patients may become re-intoxicated as the drug wears off. Naloxone is not effective against cocaine, benzodiazepines, alcohol, and other agents. Naloxone may not be effective when the patient has taken IMF or very large doses of other opioids.

The appropriate role of nalmefene is emerging as the opioid crisis changes. Nalmefene was shown in a murine study to be more effective than naloxone in inhibition of binding to central opioid receptors and is four times as potent as naloxone in antagonizing mu-opioid receptors. Nalmefene at doses of 0.4 mg/70 kg appears to be associated with more potent opioid antagonism than naloxone, even when naloxone is taken in multiple doses; in addition, the effects of nalmefene last longer. In a study of patients who underwent anesthesia and randomized to receive IV nalmefene 1.0 mg, IV naloxone 1 mg, or saline, naloxone effectively reversed sedation for about 15 minutes, while nalmefene effectively reduced sedation for 210 minutes.

The role of nalmefene in the opioid overdose crisis remains to be elucidated. It is an effective reversal agent, is longer-lasting, and may be able to reverse respiratory depression associated with polydrug or drug-alcohol abuse. As IMF continues to invade the illicit drug supply and very tolerant patients use increasingly large quantities of opioids, nalmefene may be an important new product in the opioid-reversal armamentarium.

Conclusions

The high overdose mortality associated with OUD can in part be addressed by harm reduction efforts such as broad distribution and training of opioid reversal agents. Naloxone has filled this role and is often used by first responders, family members, and even bystanders to help reverse opioid-induced respiratory depression. Its short half-life has limited its utility and as more people overdose on multiple drugs, IMF-laced products, and very high doses of opioids, naloxone may be inadequate. Multiple doses may be required, which are not always available. Nalmefene offers greater potency and longer effect but with the same ability to reverse overdose and act quickly. Nalmefene may be an important new product in the arsenal against opioid overdose.

58 Recovery from Plantar Heel Pain through the Fascial Distortion Model: A Pilot Study

Joshua Boucher¹, Thomas Dewey²

¹United States Military, Army, Fort Bliss, USA, ²Philedelphia, College of Osteopathic Medicine, Georgia, USA

Purpose

To assess feasibility of the Fascial Distortion Model (FDM) for treatment of plantar heel pain (PHP). The FDM is a hands on direct technique that is non-invasive and has been shown in preliminary studies to be effective in treating musculoskeletal (MSK) injuries.

Methods

Apply two treatments within 10 days of each other with the FDM on 50 feet of 28 active duty service members (SM) with PHP. Plantar fascia thickness (PFT) was measured before treatment and at a 4 month follow up. Pain and function were measured before treatment during each visit and at the 4 month follow up via 100-mm visual analogue pain scale (VAS) and the validated Foot Health Status Questionnaire (FHSQ) before treatment.

Results

The study consisted of 13 females and 15 males with mean age of 39. When comparing pre-treatment PFT for the left foot (mean: 0.40cm; 95% CI 0.27–0.64) and right foot (mean: 0.41cm; 95% CI 0.28–0.84) with the 4 month post-treatment thickness for the left (mean: 0.36cm; 95% CI 0.25–0.53) and the right (mean: 0.35cm; 95% CI 0.23–0.68) in the total sample of patients, statistically significant differences were found on the right (p = 0.001) and left (p = 0.003). When performing analysis on the FHSQ data statistically significant improvement was found in foot pain, foot function, and general foot health with 36.1, 26.7, and 20.4 percent improvement in each respective category, which is significant according to validated FHSQ studies. VAS scores showed statistically significant improvement going from 71.4 to 24.71 at the second visit and finally 18.0 at the final visit (p = <0.001). Per protocol and intention to treat analysis were convergent.

Conclusions

Patients with PHP who received the FDM treatment did improve on all clinical outcomes with results lasting up to 4 months. Larger studies need to be completed to further assess the feasibility of the FDM in treatment of PHP.

59 Study of the Effect of lavender and Rosemary Extracts on the Modulation of T-Type Calcium Channels in Neuropathic Pain

Mohamed amine ZKIM, Taoufiq Fechtali

Laboratory of Biosciences, Integrated and Molecular Functional Exploration, Hassan 2 university, Faculty of Science and Technology, Mohammedia, Morocco

Purpose

Current health priorities are to expand the range of drug substances based on natural compounds, medicinal plants represent a significant reservoir of unexplored substances for early-stage drug discovery. It is interesting to note that two flowering Mediterranean plants have been used for thousands of years for their beneficial effects on nervous disorders, we’re talking about Lavender and Rosemary. However, the therapeutic potential of these plants in terms of their ability to target ion channels and neuronal excitability remains largely unknown.

Methods

Patch clamp technique

Results

Studies using the patch clamp technique show that T-type calcium channels (TTCC) are a molecular target of lavender and rosemary compounds, as well as being able to modulate their electrophysiological properties by inhibiting the Cav3.2 current in a concentration-dependent manner. The Anterior Cingulate Cortex (ACC) is reported as a key cortical region involved in persistent neuropathic pain. Disrupting the long-term potentiation of CCA can relieve neuropathic pain. In the same way, studies have shown that neural activity in the ACC is positively regulated in an animal model of neuropathic pain.

Conclusions

These studies suggest that inhibition of neuronal activity of the ACC by modulation of TTCC may relieve neuropathic pain.

60 Addition of Fentanyl to Ropivacaine does not Improve Analgesic Effect of Ropivacaine During Continuous Thoracic Paravertebral Infusion In Modified Radical Mastectomy

Jyotsna Punj¹, Hem Kumar²

¹AIIMS, New Delhi, Delhi, India. ²AIIMS, New Delhi, India

Purpose

When combined with general anesthesia, a single injection TPVB with continuous TPV catheter performed prior to the induction of GA has shown to provide excellent intraoperative and postoperative analgesia, decrease postoperative analgesic requirement, PONV and earlier resumption of oral fluid intake. Together, these benefits may allow early ambulation and discharge from hospital. Previously addition of opioids to bupivacaine in continuous thoracic paravertebral block has been shown to increase analgesic efficacy of local anesthetics in modified radical mastectomy surgeries but with increased incidence of nausea and vomiting. To the best of our knowledge no similar studies have been done with ropivacaine.

Primary objective of the present study was to determine the difference in pain scores in continuous thoracic paravertebral block with ropivacaine with and without the addition of fentanyl in modified radical mastectomy surgeries.

Secondary objective was to determine opioid related side-effects, disturbance of sleep and patient satisfaction in both the groups.

Methods

This prospective, double blinded, two parallel arm randomized controlled trial included 40 females with carcinoma breast undergoing modified radical mastectomy and were randomized by computer generated random numbers into two groups of 20 each. Group R(Ropivacaine):- Paravertebral infusion of ropivacaine 0.2% at the rate of 0.1ml/kg/hr 2hr after the initial block for 24hrs post op. Group R + F(Ropivacaine Fentanyl):- Paravertebral infusion of ropivacaine 0.2% + fentanyl 2µg/ml at rate of 0.1ml/kg/hr 2hr after the initial block for 24hrs post op. Paravertebral injection was performed with the patient in the sitting position at least 30min prior to skin incision with a stimuplex needle. After negative aspiration, 20 ml ropivacaine 0.5% was slowly injected. Catheter was advanced 2–3 cm beyond the depth at which TPV space was attained. Decreased sensation to pin prick just before induction of general anesthesia was labeled as successful block and patients who did not demonstrate this were excluded from the study. Group R received a paravertebral infusion of 0.2% ropivacaine at the rate of 0.1ml/kg/hr, 2hr after the initial block till 8am next morning. Group RF received a paravertebral infusion of 0.2% ropivacaine + fentanyl 2µg/ml at rate of 0.1ml/kg/hr.

The patients received a standardized anesthetic technique. Analgesic treatment in the post anesthesia care unit (PACU) consisted of on-demand fentanyl IV by patient controlled analgesia [PCA] device in doses of 10µg with 6 minute lock out interval (ten doses per hour).

Discomfort during performance of block (VAS 0–10) and irritation at the injection sites (present: yes/no) was also noted. Any sleep disturbances were also inquired for.

Results

VAS score at rest was significantly less in group R + F at 8am on post-operative day 1 compared to group R; Group R vs Group R + F : 2(0–7) vs. 1(0–6) ; (p = 0.016). VAS score at rest was not statistically significant in all other study periods between both the groups.

VAS score on movement was significantly less in group R + F at 60 min 2(0–9) in group R vs. 2(1–8) in group R + F (p = 0.010) and at 8am on post-operative day 1 2.5 (1–8) in group R vs. 2(1–8) in group R + F. (p = 0.042) when compared to group R. VAS score on movement was not statistically significant in all other study period between both the groups.

The VAS score at rest and on movement in both the groups were < 3 at all time intervals.

Mean total fentanyl consumed via PCA by Group R was highly significant compared to Group R + F: 107.5µg vs. 26.5 µg (p < 0.001).

Mean total fentanyl consumed (PCA + TPV infusion) by group R was highly significant compared to Group R; 107 + 1.91 ug vs. 140 + 2.00 ug (p < 0.001).

There was no statistical difference between the groups in the incidence of opioid related side effects (nausea, vomiting, urinary retention and pruritis), sleep disturbance and patient satisfaction.

Irritation at injection site during the study period was present in 22 (55%) patients with a mean VAS of 5(2–8) during TPVB placement. Complications [local anesthetic toxicity, vascular puncture, pleural puncture or pneumothorax] were not encountered in any participants during the whole of study period.

Conclusions

An increase in plasma levels of fentanyl after TPVB infusion when given as an adjunct in TPV has been demonstrated which could explain better pain relief in the present study though the plasma concentrations were not determined.

There was no significant difference in the incidence of PONV, pruritus and urinary retention between both groups in comparison to previous studied probably because of higher concentration of fentanyl used in them and also due to similar total fentanyl consumption (PCA and TPV infusion) in both groups.

Limitations are non-confirming of catheter tip on chest x ray and no plasma fentanyl concentration from both groups was not obtained,

In conclusion overnight infusion of fentanyl and ropivacaine in thoracic paravertebral infusion for modified radical mastectomy results in reduced pain at 60min post-surgery, on rest and on movement the next morning and pain on movement. However, as VAS score remains less than 3 in both the groups at all time intervals, addition of fentanyl 2µg/ml to 0.2% ropivacaine at 0.1ml/kg/hour seems to offer no advantage over plain solution of 0.2% ropivacaine at same infusion rate.

61 Randomized controlled trial to compare ultrasound and extraoral glossopharyngeal nerve block

Jyotsna Punj¹, Shanmuga Sundaram², Ravinder Pandey², Vanlal Darlong², Renu Sinha²

¹AlIMS, New Delhi, Delhi, India, ²AIIMS, New Delhi, Delhi, India

Purpose

Glossopharyngeal nerve (GPn) exits the skull through jugular foramen and lies posterior to internal carotid artery (ICA) deep to styloid process. Ultrasound nerve blocks are safer and more effective than landmark techniques however ultrasound guided glossopharyngeal nerve block (UGPNB) is not described before. Stylohyoid ligament, styloid process and small caliber GPn are not visible on ultrasound. Thus ICA pulsations, easily confirmed on USG were taken as landmark in the present study.

The hypothesis of the present study was that UGPNB performed by depositing local anesthetic posterior to ICA in submandibular region would result in superior pain control compared to landmark technique due to anatomical location. Primary objective of the present study was to compare numerical pain score (NRS) between patients given UGPNB and landmark GPNB. Secondary objective was to compare quality of life by BPI scores, rescue medications, and satisfaction scores between the two groups and to determine ultrasound probe and needle trajectory best suited for the UGPNB.

Methods

Inclusion criteria was adult patients with eagles syndrome with ear pain. . Exclusion criteria included patient refusal and BMI > 30.

51 patients with NRS > 5 with medical treatment were randomly divided into group USG (n = 25) : three weekly UGPNB with 1.5 ml of 0.5% ropivacaine with 20mg methylprednisolone and group LM (n = 26) : three weekly landmark GPNB with similar drug. Follow up was at 4th, 6th and 8th week. If patients reported NRS > 5 rescue medication was given.

Ipsilateral neck was scanned (FUJIFILM SonoSite Edge, Linear probe 13–6 MHz) from base of neck. Common carotid artery was traced upwards till bifurcation to ICA and external carotid artery (ECA), ICA was traced till the submandibular region between mastoid process and angle of mandible and confirmed by doppler. If vessel delineation was difficult a high frequency curvilinear probe was used (FUJIFILM SonoSite Edgelow frequency 2–5 MHz. Shortest avascular path to posterior ICA devoid of vessels was selected as the needle trajectory. In OOP (out plane needle trajectory) needle was passed from caudad side of the probe. If vessels were found in both IP and OOP to reach posterior ICA, the needle tip was placed at, in the following order ; between IJV and ICA, medial to ICA and above ICA. For block a 26 gauze hypodermic needle, length 3.5 cm with 10 cm extension flushed with saline was used to inject 1.5ml of 0.5% bupivacaine 7.5mg with 20mg Depo-Medrol (methylprednisolone injectable suspension) after negative aspiration of blood. Extra oral landmark block was performed as previously described and similar drug injected.

Parameters of numerical rating score (NRS), quality of life by Brief Pain Inventory(BPI) and satisfaction scores (‘0’ not satisfied and ‘10’ very much satisfied were noted at baseline (when recruited for the study) and at, 2^nd,3^rd,4^th,6^thand 8^thweeks. Complications were noted.

Statistical analysis was carried out using ‘Stata 12.0 [college station, Texas, USA]’. P value <0.05 was considered statistically significant

Results

Both groups were comparable in demographics, duration of illness, length of styloid process, site of GPN and duration of illness. Baseline NRS was comparable between both groups (p – 0.548).

NRS before giving the second and third block was significantly decreased in group USG compared to group LM (p 0.011) (p 0.004). In follow up, NRS was significantly less at 4^thweek (p-0.034) in group USG compared to group LM and comparable at 6^thand 8^thweek (p − 0.136,p-0.202) respectively) between both groups. At each of the three blocks NRS thirty minutes after block decreased significantly from pre block NRS in both groups.(p 0.001) NRS (thirty minutes after block) was comparable between both groups at all three blocks. NRS at follow up before giving the second and third block and at 4^th, 5^th, 6^thweek was significantly decreased from initial reported baseline NRS (p < 0.001) in both groups. Rescue medications were comparable between both groups.

Least pain and worst pain assessed by brief pain inventory was comparable between both groups at 2 months. Average pain intensity was significantly reduced from mild pain to no pain in group USG at 2^nd, 3^rd, and 4^thweek compared to group LM (p = 0.002, p = 0.002, p = 0.035) respectively. Right now pain intensity significantly reduced from moderate to mild pain in group USG compared to group LM at 3^rdweek (p = 0.007. Pain relief from last visit was significantly reduced in group USG at 2^ndvisit compared to group LM p = 0.023

Quality of life assessment showed significant reduction from mild interference to no interference in general activity in group USG at 2^ndvisit and 3^rdvisiit compared to group LM. p = 0.017, p = 0.004 respectively. Mood was significantly better from mild interreference to no interference in group USG compared to group LM at 2^ndand 3^rdweek (p = 0.037, p = 0.023). All other parameters were comparable. Complications were comparable.

Curvilinear probe was used in 68% patients without plane needle trajectory in 64%. In 56% patients, the needle tip was placed posterior to ICA.

Overall satisfaction score at end of 8 weeks was statistically significant compared to baseline in each group.

Conclusions

Bedder et at in 1985 described UGPNB in a patient of carcinoma tongue with severe pain of GPN where phenol was injected posterior to ICA in submandibular region with good results.

Azman et al described UGPNB in cadavers, where nerve was blocked distally at level of hyoid citing it safer. However as auricular branches are given off high in the neck this would not be effective in patients of GPN with auricular. Symptoms.

In 56% patients drug was injected posterior to ICA due to presence of vessels posteriorly or in needle path but significant pain relief in these patients points to the effectiveness of this approach probably due to close location of GPn in this compact region.

Limitations of the present study were possible anatomic variation of GPN for which further cadaver studies are proposed. Secondly the patient and the operator were not blinded however NRS was recorded by a third observer.

To conclude UGPNB without plane curvilinear probe provides better pain relief for at least a week after each of the three consecutive weekly blocks however at end of 6 and 8 weeks pain relief is comparable. Mood and general activity is better with UGPNB.

62 ZTLido® (Lidocaine Topical System) 1.8% has Superior Adhesion Compared to Generic Mylan Lidocaine Topical Patch 5%

Lynn Webster¹, Theresa Mallick-Searle², Jeremey A. Adler³, Emileigh Greuber⁴, Kalpana Patel⁴, Kip Vought⁴

¹PRA Health Sciences, Salt Lake City, Utah, USA, ²Stanford Health Care, Division Pain Medicine, Redwood City, CA, USA, ³Pacific Pain Medicine Consultants, Encinitas, CA, USA, ⁴Scilex Pharmaceuticals Inc, Mountain View, CA, USA

Purpose

In general, skin adhesion is one of the most important properties of topical systems/patches as it contributes directly to the optimal efficacy, safety, and patient compliance. Because the drug is contained in the adhesive of these products, any area of the adhesive not maintaining contact with the skin compromises adequate delivery of the drug.¹ Furthermore, lack of proper adhesion can result in heightened need for more frequent product replacement, which can in turn increase the treatment cost for the patient.¹ ZTLido 1.8%, a thin, single-layer, anhydrous drug-in-adhesive topical delivery system, is a recent FDA-approved lidocaine topical system that demonstrated bioequivalence to Lidoderm® 5% in a pivotal clinical study. Further in a head-to-head adhesion study, ZTLido 1.8% demonstrated a statistically superior adhesion profile with 75% of subjects maintaining ≥90% adhesion compared to Lidoderm with 13.6% of subjects at 12-hours – the end of the labeled administration period.² Lidoderm® is a hydrogel and may therefore have different adhesive properties than anhydrous systems such as that of ZTLido 1.8% and generic Mylan lidocaine patch 5%. To evaluate and compare the clinical adhesion performance of ZTLido topical system 1.8% and generic Mylan Lidocaine Patch 5%, two anhydrous lidocaine topical patch/systems.

Methods

An open-label, randomized, two-treatment, two-period, single-dose, study in 24 healthy, adult, human subjects evaluated adhesion performance of ZTLido 1.8%, and generic Mylan lidocaine patch 5%. One topical system (ZTLido) or patch (Mylan generic) were placed on the back of each subject for a 12-hour dosing period. The product was evaluated by a trained study personnel for degree of adhesion (‘lift-off’ score) using a dot matrix method and recorded as percent adhesion at 0, 3, 6, 9, and 12 hours after application.

Results

Twenty-four (24) subjects completed the study. ZTLido demonstrated statistically significant superior percent adhesion for all time points compared to generic Mylan lidocaine patch 5%. All 24(100%) ZTLido subjects were able to maintain >90% adhesion over the 12-hour administration period compared to zero subjects in the generic Mylan lidocaine 5% group with mean percent adhesion score of 95% ± 5% and 37% ± 21% (p < 0.0001), respectively. At the end of 12 hours, none of the ZTLido 1.8% systems were completely detached compared to 7 detached for the generic Mylan lidocaine patch 5%. Mylan generic patch 5% fell below the 90% adhesion threshold (mean adhesion <80%) as early as 0 hr time point (immediately after application). There were two dermal adverse events reported for ZTLido as pruritus versus no dermal adverse events for the Mylan generic patch 5%.

Conclusions

ZTLido 1.8% was well-tolerated and demonstrated a statistically superior adhesion profile with 100% of subjects maintaining ≥90% adhesion compared to none in Mylan generic 5% patches over the 12-hour dosing period. While ZTLido 1.8% and Mylan generic patch 5% both have a nonaqueous drug in adhesive system/patches, there is a clear difference in their clinical adhesion profile. This result suggests that adhesion performance improvement is not conferred merely by incorporating a nonaqueous adhesion system. ZTLido’s superior adherence profile should contribute to consistent drug delivery, minimize inappropriate product replacements, and may have potential patient compliance and pharmacoeconomic benefits.

63 Understanding the Patient Perspective: Benefits and Risks of Pain Treatment for Osteoarthritis and Chronic Lower Back Pain

Kelly Gavigan¹, Laura Stradford¹, Kathleen Booth¹, Kelly Wang¹, Michael Fields¹, Jeffrey R. Curtis², Shilpa Venkatachalam¹, W. Benjamin Nowell¹

¹Global Healthy Living Foundation, Upper Nyack, NY, USA, ²University of Alabama at Birmingham, Birmingham, AL, USA

Purpose

Chronic pain, defined as pain lasting three or more months, may be triggered by an injury, inflammation, or underlying disease, such as a rheumatic or musculoskeletal condition. An estimated 50 million US adults live with chronic or severe pain, and chronic pain is the second-most cited reason for outpatient visits to hospitals. Chronic lower back pain (CLBP) remains one of the most commonly diagnosed conditions causing chronic pain. In addition, with an estimated 54.4 million US adults living with arthritis, or about 25% of the population, arthritis remains the leading cause of disability and cause of chronic pain, stiffness, and inflammation of joints. Of the different types of arthritis, osteoarthritis (OA) is the most common form of arthritis, affecting over 30 million adults in the US.

Research has consistently shown that chronic pain is a multi-faceted sensory and emotional experience, thus most chronic pain management guidelines suggest a multi-pronged approach of pharmacological and non-pharmacological strategies to combat chronic pain. Because chronic pain cannot be successfully managed without concurrently addressing its physical, mental, and emotional domains, its treatment often includes a combination of analgesics and antidepressants. When simple analgesics prove ineffective, opioids may be prescribed.

Treating chronic pain also involves management of medication side effects that may range from tolerable to intolerable. The objective of this study was to examine OA and CLBP patient satisfaction with current pain treatment options, perceptions of treatment side effects, and the trade-offs patients are willing to make when weighing the potential risks and benefits of various pain treatments in order to reduce or eliminate their pain.

Methods

A 53-item survey was developed in partnership with OA and CLBP patient partners and administered online via the CreakyJoints patient community and ArthritisPower, a patient-led research registry for individuals with rheumatic and musculoskeletal disease. Participants were eligible if they were ≥19 years of age, resided in the US and reported physician-diagnosed OA or CLBP. Participants reported current health status (PROMIS measures for Pain Interference, Pain Intensity, Sleep Disturbance, and Emotional Distress-Depression; assessments measured as t-scores, with a score of 50 being average for the general population and higher scores indicating a greater amount of what is being measured), current and past treatment, motivations behind treatment decision making, and participants’ experiences and perceptions of side effects. Participants were asked to assess the extent to which they experienced and were bothered by potential side effects of pain treatment, including dry mouth, drowsiness, constipation, headache, reflux/heartburn, heart palpitations, nightmares, trouble sleeping, muddled thinking, visual distortions, sweating, mood changes, sneezing, itching, dizziness, memory lapses, weakness, nausea, and weight gain. Additionally, participants were asked to assess whether they would be willing to tolerate each side effect for the reduction or elimination of pain. Non-concordant pair tolerability was evaluated with a repeated pairs reduction/elimination study design, in which each individual served as his or her own control. Non-concordant pairs were tested using the McNemar’s test and odds ratios were calculated to evaluate the odds of tolerating a given side effect for elimination but not reduction of pain. Statistical significance was calculated at an alpha of 0.05 and confidence intervals were calculated at 95%.

Results

A total of 416 participants completed the survey. Most participants were female (n = 374, 89.9%), white (n = 394, 94.7%) and the average age (SD) was 59.0 (9.7). A majority of participants (n = 369, 88.5%) reported a diagnosis of OA and three-quarters reported CLBP (n = 320, 76.9%), with two-thirds (n = 272, 65.4%) reporting both. The mean (SD) score for Pain Interference was 65.7 (6.0); Pain Intensity was 53.7 (5.3); Sleep Disturbance was 57.3 (7.8); and Emotional Distress-Depression was 57.6 (9.3). The majority of participants (73.6%) had been on their current pain medication regimen for >1 year. The prescription medications currently being used by participants to treat pain included antidepressants (49.5%), prescription non-steroidal anti-inflammatory drugs (NSAIDs) (49.0%), opioids (35.8%), and steroids (20.9%).

The most commonly reported pain medication side effects were drowsiness (83.4%), dry mouth (82.2%), and constipation (74.8%); these were considered very bothersome by 12.7%, 24.0%, and 23.5% of participants, respectively. Common side effects considered very bothersome by the largest proportion of participants were weight gain (42.1%) and trouble sleeping (39.3%), experienced by 70.2% and 73.3%, respectively.

Tolerability of the most common and bothersome side effects was analyzed among participants who reported their pain as severe or very severe (n = 290, 69.7%). Dry mouth was considered a tolerable side effect by 84.1% of these participants if the treatment would reduce or eliminate pain. While less than a third of participants reported they would refuse to tolerate constipation (29.3%) and drowsiness (20.3%) to reduce or eliminate pain, more than half reported they would refuse to tolerate weight gain (51.7%) and trouble sleeping (50.3%), despite the potential to reduce or eliminate pain. Among these same individuals, all side effects were significantly more likely to be tolerated to eliminate pain versus reduce pain among non-concordant pairs. Of the five side effects discussed, the odds (OR, CI) of participants tolerating a side effect to eliminate versus reduce pain were highest for weight gain (15.0, 5.5–41.3) and trouble sleeping (5.6, 3.0-10.7). Side effects not considered ‘intolerable’ by most participants had smaller odds (OR, CI) of being tolerated to eliminate versus reduce pain: constipation (3.8, 2.0–7.4), drowsiness (3.6, 2.1–6.2) and dry mouth (2.2, 1.0-4.9).

Notably, among participants who previously used opioids (n = 160, 38.5%), the main reasons for discontinuation were worries about addiction (22.5%), unwanted side effects (16.3%), and doctor’s advice (15.0%). Of these respondents, 12% stated in the write-in option that they stopped due to acquisition difficulties resulting from the opioid epidemic.

Conclusions

These findings shed light on the relative tolerability of pain medication side effects. Most OA and CLBP patients deem weight gain and trouble sleeping to be bothersome to the point of intolerability. However, the likelihood of participants tolerating these two symptoms for elimination of pain versus reduction of pain was much higher than the likelihood of their tolerating less bothersome side effects in order to achieve elimination versus reduction of pain.

Increased understanding of OA and CLBP patients’ risk-benefit tradeoffs may help patients and providers identify relevant pain treatment preferences that assist in shared decision making. Future research using a discrete choice experiment methodology would allow OA and CLBP patients to determine which level of potential benefit they would require in order to tolerate the most commonly experienced and bothersome side effects of pain treatment as identified in this study.

64 Effects of Adverse Childhood Experiences on Pain Interference and Anxiety in an Integrative Chronic Pain Clinic

Kerrin Doran Kunze, Elizabeth Morse

Belmont University, Nashville, Tennessee, USA

Purpose

The purpose was to compare the prevalence and magnitude of adverse childhood experiences in a chronic pain population to the general population and to explore the physical and psychological health-related quality of life, specifically pain interference and anxiety, of the sample.

Methods

A retrospective project design involving secondary analysis of primary data was used to establish the baseline prevalence of ACEs in a population of new patients enrolled in integrative care for chronic pain management. Additionally, the relationship between ACEs and health-related quality of life were explored in this population using data from the Adverse Childhood Experiences (ACEs) Questionnaire and the PROMIS-29 (Patient-Reported Outcomes Measurement Information System) tool. Data was extracted from de-identified clinical patient records between July 2015 and October 2017 and the sample population consisted of 162 complete patient records.

Results

The results showed that there was a higher risk of having an adverse childhood experiences score of four or more in the sample population. Data analysis also revealed that a history of childhood trauma correlated with anxiety in the sample population, meaning that the sample demonstrated higher baseline anxiety levels than individuals who had no history of childhood trauma.

Conclusions

Key findings add to existing knowledge that patients who suffer from complications related to chronic pain have a higher probability of having experienced childhood trauma than the general population. Chronic pain management should include a biopsychosocial approach that includes recognition and thoughtful consideration of the deleterious effects of childhood trauma on patient health outcomes. Exploring the complex relationship between biological, psychological, and social constructs supports the need for improved chronic pain management through a trauma-informed care model. Providers should advocate for the organizational implementation of a trauma-informed care model that can improve patient health outcomes.

65 Efficacy of Fremanezumab in Patients with Migraine and Documented Inadequate Response to 2, 3, or 4 Classes of Migraine Preventive Treatments: Results of the International, Multicenter, Randomized, Placebo-Controlled FOCUS Study

Ladislav Pazdera¹, Xiaoping Ning², Maja Galic³, Joshua M. Cohen², Ronghua Yang²

¹Vestra Clinics, Rychnov nad Kněžnou, Czech Republic, ²Teva Pharmaceuticals Industries, Frazer, PA, USA, ³Teva Pharmaceuticals, Amsterdam, Netherlands

Purpose

Fremanezumab, a fully-humanized monoclonal antibody (IgG2Δa) that selectively targets calcitonin gene-related peptide (CGRP), has proven efficacy for migraine preventive treatment in adults. The FOCUS study of fremanezumab was the first and largest study of a migraine preventive treatment in adults with both chronic migraine (CM) and episodic migraine (EM) and documented inadequate response to 2 to 4 classes of migraine preventive treatments.

Methods

For 12 weeks of double-blind treatment, patients were randomized (1:1:1) to quarterly fremanezumab (Month 1: 675mg; Months 2 and 3: placebo), monthly fremanezumab (Month 1: CM, 675mg; EM, 225mg; Months 2 and 3: 225mg), or matched monthly placebo. Changes from baseline in the monthly average number of migraine days and response rates (≥50% reduction in the mean monthly number of migraine days) at 12 weeks were evaluated.

Results

Of 838 randomized patients, 50%, 32%, and 18% had inadequate response to 2, 3, and 4 prior classes of migraine preventive treatments, respectively. Changes from baseline in the monthly average number of migraine days over 12 weeks were significantly greater with quarterly and monthly fremanezumab, respectively, compared with placebo among patients with inadequate response to 2 migraine preventive treatment classes (LSMD vs placebo: −2.9, −3.7), 3 migraine preventive treatment classes (−3.3, −2.9), or 4 migraine preventive treatment classes (−5.3, −5.4; all P < 0.0001). The proportions of patients who achieved ≥50% reductions in migraine days at 12 weeks were significantly greater with quarterly and monthly fremanezumab, respectively, versus placebo among patients with inadequate response to 2 migraine preventive treatment classes (39% and 41% vs 11%), 3 migraine preventive treatment classes (32% and 28% vs 7%), or 4 migraine preventive treatment classes (27% and 32% vs 4%; all P ≤ 0.002).

Conclusions

For patients with migraine and documented inadequate response to 2, 3, or 4 classes of prior migraine preventive treatments, reductions in the monthly average number of migraine days and clinically meaningful response rates were significantly greater with both dosing regimens of fremanezumab compared with placebo.

66 Kidney Stones: A Simple Fix or a Life-Threatening Situation?

Lauren Cuenant, Gabrielle McDermott, Arthur Strzepka

Kiran C. Patel College of Osteopathic Medicine at Nova Southeastern University, Davie, FL, USA

Purpose

Depending on the size and location, kidney stones can be managed a number of ways. Kidney stones 5 mm or less usually pass spontaneously while those 10 mm or greater and those in the proximal ureter are unlikely to pass without intervention. Percutaneous nephrolithotomy is considered for stones larger than 2 cm, in patients with atypical anatomy, cysteine stones in the cancel diverticula. Medial and distal ureter stones are typically managed by ureteroscopy as are those which have failed to respond to shock wave lithotripsy. Shock wave lithotripsy is an option for smaller stones unable to pass on their own. Open surgery is rarely performed, limited to obese patients, patients with atypical anatomy and those with staghorn calculi.

Methadone is a synthetic opioid commonly administered in the perioperative setting for pain management. It is also used to treat opioid addiction and prevent withdrawal symptoms. Studies have shown that methadone treatment during surgery can allow for less intravenous and oral opioid use for post-operative pain. However, patients receiving methadone are at risk for QT prolongation, torsades de pointes, ventricular arrhythmias and sudden death.

Currently, patients on chronic methadone regimens receive a baseline EKG prior to surgery. There are otherwise limited standards regarding their surgical candidacy. This case study aims to highlight the need for more stringent criteria for such patients.

Methods

Case Description:

A 67-year old male presented with an asymptomatic 1.4 cm left renal calculi. An elective left ureteroscopy, laser lithotripsy, stone basking, left retrograde pyelogram and left ureteral stenting were performed due to an elevated serum creatinine of 1.5 mg/dL and history of chronic kidney disease. A nephrostomy, pollack catheter and stent were placed to allow the ureter to heal. While at the hospital, the patient developed atrial fibrillation with rapid ventricular rate, two episodes of wide complex regular tachycardia and one episode of torsades de pointes. Cardiac catheterization demonstrated a structurally normal heart. Urine cultures were positive for pseudomonas aruginosa, citrobacter braakii and candida albicans. The nephrostomy tube was also positive for candida. The patient was treated with intravenous antibiotics and advised to reduced methadone, however, the patient refused and ultimately left the hospital against medical advice. He was scheduled for surgical repair at another facility several days later.

Past Medical History:

1.4 cm left renal Calculus, stage 3 chronic kidney disease, hepatitis C, heroin abuse, type 2 diabetes mellitus, diabetic neuropathy, hypertension and benign prostatic hyperplasia

Past Surgical History:

Appendix removed in 1971 and surgical rod placed/removed from left lower extremity in 1973.

Social History:

Tobacco: Currently uses a vape. Quit smoking 3 years ago. Smoked 1 pack a day for

40 years.

Alcohol: No alcohol for 20 years.

Drugs: Former IV heroin user. Used for 5 years. Has abstained from recreational

drug use for 20 years. Currently on daily methadone.

Living: Patient lives alone on a boat.

Family History:

Mother: Deceased. “Old age.”

Father: Deceased. Cancer/history of alcoholism.

Siblings: Brother is an alcoholic.

Medications (abbreviated):

HEPARIN FLUSH 10 UNITS/ML INJ,30 UNITS/3ML IV

HYDRALAZINE 50MG PO QID

HYDROCHLOROTHIAZIDE 12.5MG PO DAILY

INSULIN 70/30 HUMAN 12 UNITS SUBQ BID

ISOSORBIDE MONONITRATE 15MG PO DAILY

LISINOPRIL 40MG PO QHS

MAGNESIUM OXIDE 420MG PO DAILY

CEFTAZIDIME INJ in CEFTAZIDIME 2GM/D5W PREMIX PC 100

METHADONE 210MG PO DAILY

MICAFUNGIN INJ 100MG

SODIUM CHLORIDE 0.9% 100ML INFUSE OVER 60 MINUTES

NIFEDIPINE 30MG PO QHS

PROPRANOLOL 10MG PO TID

VANCOMYCIN INJ in 1GM PREMIX 200ML

Allergies:

Lisinopril

Losartan

Results

A 67-year old male on chronic methadone treatment presented with an asymptomatic 1.4 cm left renal calculi. An elective left ureteroscopy, laser lithotripsy, stone basking, left retrograde pyelogram and left ureteral stenting were performed due to an elevated serum creatinine of 1.5 mg/dL and history of chronic kidney disease. The procedure was complicated by left ureter perforation. Subsequently, a nephrostomy, pollack catheter and stent were placed to allow for the ureter to heal. The same day, the patient developed atrial fibrillation with rapid ventricular rate which was controlled via intravenous diltiazem. Per cardiology, the patient began 100 mg of flecainide twice daily and atenolol 25 mg daily. Several days later, the catheter was removed and the patient developed two episodes of wide complex regular tachycardia. Flecainide was discontinued and Amiodarone was started. Cardiac catheterization demonstrated a structurally normal heart and idiopathic ventricular tachycardia. Urine cultures demonstrated pseudomonas aeruginosa, citrobacter braakii and candida albicans. The patient was stabilized and discharged (at his request) with oral 500 mg ciprofloxacin and 100 mg fluconazole. The patient was instructed to follow-up for ureter repair surgery as outpatient. The patient returned to the hospital due to fear of another arrhythmia and the desire to resolve his infection before surgical ureter repair. The patient was admitted for intravenous antibiotic treatment and instructed by urology to complete the course before surgery. The patient developed an episode of torsades de points and was started on 420 mg daily of oral Magnesium Oxide. The patient refused to discontinue or reduce his methadone below 210 mg, and ultimately left the hospital against medical advice.

Conclusions

Given the risks of the procedure and the patient’s complex medical history it is arguable that attempts to remove the stone should not have been performed. Moreover, the use of methadone is known to prolong the QT interval and is associated with torsades de points. Despite the fact that this condition can lead to sudden cardiac death the patient was still deemed a surgical candidate. Given the patient’s complex history and subsequent complications, it is arguable that more stringent criteria should be established for such patients considering surgery.

67 Prescription Drug Monitoring Program (PDMP) Utilization and Outcomes Within the West Palm Beach Veterans Affairs (VA) Healthcare System

Lauren Shirley¹, Sandra DiScala², Christine M Vartan², Hiroko Forbes²

¹West Palm Beach VA Medical Center, West Palm Beach, FL, USA, ²West Palm Beach VA Medical Center, West Palm Beach, FL, USA

Purpose

The misuse of prescription drugs has become and continues to be an epidemic. Veterans are some of the most vulnerable when it comes to this crisis, as they are nearly twice as likely to have a fatal accidental poisoning compared to the general population in the United States. Among Veterans, pain and mental health conditions are common diagnoses, and it has been found that substance use disorders (SUDs) are more often seen in patients with mental health diagnoses than without such conditions. Florida’s Chapter No. 2018–13 (Ch. 2018–13), formerly known as House Bill 21, requires prescribers and dispensers to query the PDMP with each new prescription and renewal. This law went into effect 1 July 2018. The Joint Commission and the National Quality Forum both recommend evaluating the utilization of PDMP as a part of hospital quality improvement (QI) processes. The purpose of this QI project is to compile and analyze data related to utilization of the PDMP both before and after the enactment of Ch. 2018–13, to see how it has affected utilization of the database within our facility, to characterize outcomes associated with use, and to establish an inter-professional workflow to efficiently complete PDMP queries.

Methods

A retrospective, cross-sectional pre-post design review was conducted. Data was collected from the Computerized Patient Record System (CPRS) from 1 September 2017 to 30 November 2017 (pre-mandatory period) and 1 September 2018 to 30 November 2018 (post-mandatory period). All PDMP notes entered within the above date ranges were identified via a report and a 10% random sample of the PDMP notes were reviewed. This sample was selected using Microsoft Excel® random number generator. Demographics were collected, and chart entries were reviewed to determine each Veteran’s history and current use of alcohol, tobacco, and other substances. Data regarding controlled substance prescriptions, including active controlled substance prescriptions and morphine equivalent daily dose (MEDD) of any opioid medications were recorded. Outcomes of the PDMP queries were collected and a subgroup analysis was conducted on the positive findings. A positive finding was if there was a non-VA prescription found via the PDMP query. Descriptive statistics were utilized to analyze the results. Any protected health information remained confidential per VA policy and the Health Insurance Portability and Privacy Act (HIPAA).

Results

A total of 2,228 PDMP queries were completed from September 1 to 30 November 2017 and 7,899 were completed from September 1 to 30 November 2018, a 354% increase. The mean age of the patients reviewed was 65 years old for 2017 and 63 years old for 2018. About 59% (132/222) and 62% (489/790) of patients had a diagnosed mental health condition in 2017 and 2018, respectively. Most controlled substance prescribers were primary care providers, followed by mental health. Opioids were the most commonly prescribed class of controlled substances queried. In 2017, 99% (220/222) of PDMP queries were completed by a pharmacist, while in 2018 this number dropped to about 60% (473/790). In 2017 and 2018, 30.6% (95% confidence interval [CI] 24.6 to 37.1, n = 68) and 20.8% (95% CI 18.0 to 23.8, n = 164) of PDMP queries resulted in positive finding(s), respectively. A query was considered a positive finding if there were any non-VA controlled substance prescriptions found. Among the positive findings, demographics were similar to the larger population. In both years, opioids were the most common type of non-VA controlled substance identified via PDMP query. Via the PDMP query, providers were made aware of non-VA controlled substances, as prescribers were previously unaware of 66.2% (45/68) of the positive findings in 2017 and 62.2% (102/164) of the positive findings in 2018. None of the positive findings resulted in a violation of informed consent for long-term opioid use or benzodiazepine use in either 2017 or 2018. Positive findings resulted in discontinuation of the controlled substance for 3.6% (8/222) of queries in 2017 and 1% (8/790) of those in 2018. The decision was made not to initiate a controlled substance prescription due to a positive query 3.6% (8/222) of the time in 2017 and 1.3% (10/790) of the time in 2018. Within the positive findings, 7 findings in 2017 (3.2% of total queries) and 23 findings in 2018 (2.91% of total queries) were found to be overlapping with VA prescriptions of the same type or resulted in the unsafe combination of a benzodiazepine or sedative and opioid. About 42.8% (3/7) of the potentially problematic findings in 2017 resulted in discontinuation of the controlled substance, while in 2018 this occurred 21.7% (5/23) of the time.

Conclusions

Mandating PDMP queries on new and renewed controlled substance prescriptions resulted in an increase in the total number of queries as well as the number of positive findings, but with similar percentage of duplicate prescriptions found between 2017 and 2018. Utilization of the PDMP system has increased because of the mandate, including a variety of discipline, such as physicians, physician assistants, advanced registered nurse practitioners and dentists. The lack of knowledge of prescribers about positive findings prior to query was similar over the two years. Outcomes of PDMP queries impacted prescribing by discontinuation and avoidance of controlled substance initiation in a low percentage of patients. Since the mandate, the West Palm Beach VA Medical Center has worked to improve inter-professional workflow to efficiently complete PDMP queries, as seen by making changes to PDMP policies and procedures as well as hiring a clinical pharmacy technician as a prescriber delegate to assist in completing queries.

68 Anti-infective Prescribing Practices in Hospice Patients

Heather Wittkorn, Gina Migneco, Mary Lynn McPherson, Leah Sera

University of Maryland School of Pharmacy, Baltimore, MD, USA

Purpose

Hospice care is designed to assist a patient’s transition from conventional life-prolonging interventions to palliative care at the end of life. Patient comfort and palliative care are achieved holistically through both emotional and medical support. In practice, life-prolonging interventions are withheld unless they hold a palliative benefit. Anti-infective agents are frequently prescribed to hospice patients, but in many cases, it is uncertain whether their use relieves symptom burden and/or improves patient quality of life. The purpose of this study was to characterize the prescribing practices of anti-infective agents in the hospice patient population.

Methods

A retrospective review of a patient information database compiled by a national hospice organization was conducted. Electronic medical records provided by Seasons Hospice and Palliative Care, a national hospice and palliative care organization located in 19 states in 2016, were utilized. The study included all hospice patients prescribed an anti-infective agent while in hospice care. Included patients were admitted to hospice care on or after 1 January 2016 and were discharged by death on or before 31 December 2016. The following information was available and was analyzed: admitting diagnosis, admission date, date of discharge by death, and medication orders including name, strength, formulation and dose. Admitting diagnoses were recorded and categorized into a primary diagnosis (e.g. malignant neoplasm of the stomach was categorized as cancer). Medication orders were evaluated to determine anti-infectives prescribed during patient’s hospice admission and medications were categorized by pharmacologic class. Data was analyzed for anti-infective prescribing trends based on route of administration, class and admitting diagnosis. Medication indication information was not available.

Results

In a population of 18,040 hospice patients, 24.7% were prescribed one or more anti-infectives during their admission. In total, 4,464 patients were prescribed an anti-infective and 6,839 anti-infectives were prescribed overall. Of the patients receiving anti-infectives, many were prescribed more than one agent, with the average number of anti-infectives prescribed being 1.5 per patient. The most common admitting diagnosis for patients prescribed at least one anti-infective was cancer (37.3% of patients), while 15.7% had a neurologic admitting diagnosis and 4.2% had a primary admitting diagnosis of infectious disease. Of the anti-infectives prescribed, 74.6% were antibacterial, 22.1% were antifungal, 3.0% were antiviral and 0.2% were antiparasitic. The most commonly prescribed anti-infectives were nystatin, levofloxacin, ciprofloxacin, metronidazole and sulfamethoxazole/trimethoprim.

Conclusions

The focus of hospice care is symptom management, and while some anti-infectives have been shown to improve quality of life, they can also cause adverse effects and may prolong the dying process. Clinicians should carefully weigh the risks and benefits of anti-infectives before initiating therapy.

69 Psychological Pain in Transgender People: Understanding Suicide Risk and Prevalence

lore dickey

North Country HealthCare, Bullhead City, AZ, USA

Purpose

Transgender (trans) people have the highest rates of suicide attempts of any marginalized group with 40% of trans people having attempted suicide at least once in their lifetime. Understanding the pain that is associated with suicide attempts may help researchers and clinicians to develop interventions that will prevent trans people from attempting suicide.

According to Joiner (2005) there are three concerns that need to be addressed in preventing suicide. These are thwarted belongingness (a sense of isolation), perceived burdensomeness (the perception that one is a burden to others and that this will never change), and a person’s access to lethal means.

The type of psychological pain that leads a person to attempt to end their life is similar to physical pain in that the same area of the brain is triggered. Eisenberger and colleagues (2003) conducted a study that explored a type of thwarted belongingness using fMRI methodology. Results of the study indicate that the same area of the brain (anterior cingulate cortex or ACC) that is involved in physical pain is also seen in psychological pain.

Research also shows that trans people are likely to experience victimization, discrimination, and violence (James et al., 2016). This type of injury has the potential to lead to symptoms of post-traumatic stress disorder (PTSD), social isolation, and engagement in maladaptive coping strategies.

Methods

This poster is a review of literature exploring psychological pain including pain that leads up to attempted suicide by transgender people.

Minority Stress Theory

This section explores Minority Stress Theory (MST) which was first proposed by Ilan Meyer (1993, 2005). Hendricks and Testa (2012) later adapted the theory to trans people. MST posits that people experience proximal (internal) and distal (external) stressors. Additionally, there is the anticipation that these stressors will happen. The anticipation itself is cause for psychological pain.

Interpersonal Theory

Interpersonal Theory (IPT) is model for understanding suicidal thinking and behavior. In this model a person will experience thwarted belongingness, or a sense of isolation from others. Additionally, they will perceive that they are a burden on others and that this burdensomeness will not change. Finally, IPT states that a person has access to lethal means.

Demoralization

Demoralization is the profound sense of meaninglessness, hopelessness, and helplessness. In trans people demoralization is linked to depression and suicidality in a synergistic manner.

Results

Understanding that psychological pain is perceived in much the same way as physical pain in our brains helps to understand the depth at which this impacts people. Suicidal thoughts and behaviors may be driven by a type of psychological pain that triggers a response in the brain that is similar to how a person responds to physical pain.

Psychological pain, pain which no one can see, can be debilitating. The fact that others cannot see this pain makes it exceptionally troublesome for those who experience it. This is because other people have nothing to witness except for the reaction from the person they are with. Given that the reaction is likely negative, friends and family are left to wonder how they can support their loved one. This is further complicated by the fact that the trans person may not have a clear awareness and understanding of the source of the psychological pain they are experiencing.

This poster explores Minority Stress Theory, Interpersonal Theory, and Demoralization as causes psychological distress and pain. The author defines these theoretical concepts and applies them to trans people’s lives with a focus on suicidal thinking and behavior.

Conclusions

Understanding the sources of psychological pain can help us to better understand the ways that day-to-day challenges are experienced by trans people. Without this understanding, clinical interventions are likely to fall short thereby leaving the trans person to alone. This has the ability to create a situation in which the trans person feels they have no other option than to end their life.

70 Onset and Maintenance of Efficacy of Subcutaneous Tanezumab in Patients with Moderate to Severe Osteoarthritis of the Knee or Hip

Louis Bessette¹, Thomas J Schnitzer², Arifulla Khan³, Glenn Pixton⁴, Lars Viktrup⁵, Isabelle Davignon⁶, Leslie Tive⁷, Mark T Brown⁶, Christine R West⁶

¹Laval University, Quebec City, Canada, ²Northwestern University, Chicago, IL, USA, ³Northwest Clinical Research Center, Bellevue, WA, USA, ⁴Pfizer Inc., Morrisville, NC, USA, ⁵Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA, ⁶Pfizer Inc., Groton, CT, USA, ⁷Pfizer Inc., New York, NY, USA

Purpose

In a recent 16-week Phase 3 clinical trial of patients with moderate-to-severe osteoarthritis (OA) of the knee or hip, the nerve growth factor monoclonal antibody tanezumab demonstrated statistically significant improvements over placebo in the co-primary endpoints of Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Pain, WOMAC Physical Function, and Patient Global Assessment of OA (PGA-OA). The current analysis expands upon these findings by examining the onset and maintenance of this effect on pain and function.

Methods

This randomized, double-blind, parallel-group, placebo-controlled, dose-titration study (16-week double-blind treatment period and 24-week safety follow-up period) was conducted in patients with difficult-to-treat OA of the knee or hip (NCT02697773). Patients had radiographically confirmed OA, baseline WOMAC Pain and Physical Function scores of ≥5 (on an 11-point scale), baseline PGA-OA of ‘fair’, ‘poor’, or ‘very poor’, and a history of insufficient pain relief from or intolerance to acetaminophen, nonsteroidal anti-inflammatory drugs, and tramadol or opioids (or were unwilling to take opioids). Patients received either subcutaneous placebo at baseline and week 8 (placebo group), subcutaneous tanezumab 2.5 mg at baseline and week 8 (tanezumab 2.5 mg group), or subcutaneous tanezumab 2.5 mg at baseline and tanezumab 5 mg at week 8 (tanezumab 2.5/5 mg group). The current analyses assessed change from baseline through the 16-week treatment period between placebo and tanezumab treatment groups in average daily index joint pain (calculated from daily pain scores reported in an electronic diary, where patients rated pain in the index joint daily on a scale from 0 = no pain to 10 = worst possible pain: change from baseline was calculated daily for days 1 to 7 and as weekly means at weeks 1, 2, 3, 4, 6, 8, 10, 12, and 16) and WOMAC Pain and Physical Function (during clinic visits at weeks 2, 4, 8, 12, and 16). Treatment comparisons utilized an analysis of covariance model with a multiple imputation approach to missing data.

Results

A total of 696 patients received placebo (n = 232), tanezumab 2.5 mg (n = 231), or tanezumab 2.5/5 mg (n = 233); their mean age was 60.8 years, 65% were female, and 85% had a knee selected as their index joint. Both tanezumab groups demonstrated statistically significant improvements compared with placebo in average daily index joint pain within the first week (day 3–5) and WOMAC Pain and Physical Function at the first measured time point (week 2). Both tanezumab groups demonstrated statistically significant improvements compared with placebo in average daily index joint pain at all weekly time points, with the exception of both tanezumab groups at week 8. Both tanezumab groups demonstrated statistically significant improvements compared with placebo in WOMAC Pain and Physical Function at all measured time points through the 16-week treatment period, with the exception of the tanezumab 2.5/5 mg group at week 8 with respect to WOMAC Pain.

Conclusions

Subcutaneous tanezumab administered at baseline and week 8 provided statistically significant improvements compared with placebo in average daily index joint pain within the first week and WOMAC Pain and Physical Function scores at the first assessment (week 2) that were generally maintained throughout the 16-week treatment period.

71 Dangerous Bradycardia and QT Interval Elongation in a Patient on Buprenorphine-Naloxone Therapy: A Case Report.

Luc Frenette¹, David Hardin², J. Michael Hardin², Hector Toledo¹

¹Preferred Pain Associates, Birmingham, AL, USA, ²Samford University, Birmingham, AL, USA

Purpose

The purpose of this case report is to describe a significant QT prolongation and associated bradycardia in a patient without known cardiac disease receiving buprenorphine-naloxone therapy for treatment of opioid addiction. QT interval prolongation is a potentially life-threatening adverse effect of many medications, including those used in the treatment of opioid addiction and chronic pain. Some of these medications, such as methadone, have the well-established adverse effect of QT interval prolongation. However, in previous study, buprenorphine has been seen as a safe alternative to methadone with respect to QT prolongation.

Methods

Patient medical records were used to gather data and compile a comprehensive case report. Patient consent was obtained with agreements put in place consistent with all HIPPA regulations. No patient specific identifiers were used in the creation of this case report.

Results

A 58-year old Caucasian female with a past surgical history of multi-level cervical and lumbar spinal fusions and medical history of hypertension on beta-blocker therapy presented to clinic and began buprenorphine-naloxone therapy at a dose of 8mg/2mg BID. Initial EKG showed QT of 392 msec with subsequent EKGs taken every six months. Buprenorphine dose was increased to 12mg BID at month 9 due to opioid cravings with QT of 391 msec on EKG after dose increase. 6 months following dose change, QT was measured at 402 msec with next routine EKG approximately 1 year from dose change measuring absolute QT 500 msec with a HR of 44 bpm. After findings of bradycardia and QT prolongation, patient stopped previously stable metoprolol tartrate 25mg BID and buprenorphine-naloxone was decreased to 8mg/2mg BID. Follow-up EKG one month later showed resolution of both bradycardia and QT prolongation with HR 68 bpm and QT 411 msec. A second follow-up EKG 1 month after resolution measured HR 62 bpm and QT interval of 415 msec.

Conclusions

This case report suggests a possible need for routine EKG monitoring in patients on buprenorphine therapy. Contrary to current study and common insurance policy, these patients require regular EKG monitoring with buprenorphine dose adjustments based on QT interval, similar to ongoing practice in patients receiving methadone. Given a high relative incidence of sudden death due to presumed overdose or other undetermined cause, fatal arrhythmia secondary to dangerous QT prolongation may be more prevalent in buprenorphine therapy patients as a cause of death. We recommend further study of this adverse effect with possible need for black box warning for life-threatening QT prolongation.

72 Evaluation of the Number of Migraine Headache Days and Hours in a Multicenter, Open-Label, Long-Term, Safety Study of DFN-02 (Tosymra™; an Intranasal Spray of Sumatriptan 10 mg Plus Permeation Enhancer DDM) for the Acute Treatment of Migraine

Mark B. Halvorsen¹, Michelle B. Zachman¹, Sagar Munjal², Alan M. Rapoport³

¹Upsher-Smith Laboratories, LLC, Maple Grove, MN, USA, ²Promius Pharma, a subsidiary of Dr. Reddy’s Laboratories Inc., Princeton, NJ, USA, ³The David Geffen School of Medicine at UCLA, Los Angeles, CA, USA

Purpose

DFN-02 [Tosymra™ (sumatriptan) nasal spray] was recently approved by the FDA for the acute treatment of migraine with or without aura in adults. DFN-02 is a novel intranasal spray formulation composed of sumatriptan 10 mg and 0.2% of the permeation-enhancer Intravail® (1-O-n-Dodecyl-β-D-Maltopyranoside [DDM]). This composition of DFN-02 allows for rapid absorption at a rate comparable to subcutaneously administered sumatriptan. DFN-02 was shown to be well tolerated when used over 6 months in an open-label study to treat multiple episodes of migraine. The objective of this post hoc analysis was to evaluate whether there was a change in the number of migraine headache days and hours at month 6 as compared to month 1 with continued intermittent DFN-02 use for acute treatment.

Methods

This multi-center, open-label safety study enrolled subjects diagnosed with migraine with or without aura, according to International Classification of Headache Disorders (ICHD)-2 criteria, who experienced 2 to 6 migraine attacks per month with fewer than 15 headache days per month and at least 48 headache-free hours between attacks. Subjects used DFN-02 to treat their migraine attacks acutely over the course of 6 months. During the study, subjects recorded the dates and the start and stop times of their migraine headaches plus details of the DFN-02 dosing in a paper diary. Post hoc analysis using Wilcoxon Signed-Rank test compared the number of migraine headache days and hours between the first and last month of the study.

Results

Enrolled subjects totaled 173, with 134 (77.5%) completing the 6-month study. Subjects had a mean (standard deviation [SD]) age of 43.4 (11.4) years, and the majority were female (81.4%) and white (81.4%). The mean number of migraine headache days (ie, the sum of the number of days from each migraine headache start to end) in month 6 was 3.2 ± 2.17 (SD), a statistically significant decrease of 2.3 days from month 1 (P < 0.0001). The mean number of migraine hours in month 6 was 10.6 ± 16.43 (SD), a 10.9-hour reduction from month 1, which was also statistically significant (P < 0.0001). Migraine recurrence also decreased over time, with 52.2% of subjects reporting migraine recurrence in month 1 compared with 37.1% reporting recurrence in month 6.

Conclusions

In subjects using DFN-02 to treat their migraine headaches acutely during a 6-month study, statistically significant reductions in the number of both migraine headache days and hours from month 1 to month 6 were reported. Together, these data indicate that DFN-02 leads to continued improvements over time in the treatment of acute migraine. Additional prospective studies are required to evaluate if DFN-02 can play a role in slowing the progression of migraine and prevent the development of chronic migraine.

73 Triptan-Related Adverse Events in a Multicenter, Open-Label, Long-Term, Safety Study of DFN-02 (Tosymra™; an Intranasal Spray of Sumatriptan 10 mg Plus Permeation Enhancer DDM) for the Acute Treatment of Migraine

Mark B. Halvorsen¹, Michelle B. Zachman¹, Sagar Munjal², Alan M. Rapoport³

¹Upsher-Smith Laboratories, LLC, Maple Grove, MN, USA, ²Promius Pharma, a subsidiary of Dr. Reddy’s Laboratories, Princeton, NJ, USA, ³The David Geffen School of Medicine at UCLA, Los Angeles, CA, USA

Purpose

A number of delivery methods are used to administer triptans, the most common migraine-specific treatment for acute migraine. Although subcutaneous (SC) sumatriptan is fast-acting, triptan-related adverse events (AEs) are highest with SC sumatriptan compared to oral or nasal formulations. DFN-02 [Tosymra™ (sumatriptan) nasal spray] is a novel intranasal spray formulation composed of sumatriptan 10 mg and 0.2% of the permeation-enhancer Intravail® (1-O-n-Dodecyl-β-D-Maltopyranoside [DDM]). This novel formulation exhibits pharmacokinetics comparable to subcutaneously administered sumatriptan – including a rapid time to maximum plasma concentration – with better tolerability. Herein we report triptan-related AE rates by incidence and by DFN-02 doses taken over a 6-month treatment period.

Methods

This was a multi-center, open-label, repeat-dose, safety study in adults diagnosed with episodic migraine with and without aura, according to International Classification of Headache Disorders (ICHD)-2 criteria. Subjects who experienced 2 to 6 migraine attacks per month with fewer than 15 headache days per month and at least 48 headache-free hours between attacks used DFN-02 to treat their migraine headaches acutely over the course of 6 months. A total of 24 triptan-related adverse events were pre-identified for analysis (anxiety, asthenia, chest discomfort, diarrhea, dizziness, dyspnea, fatigue, feeling hot, feeling jittery, flushing, headache, lacrimation increased, lethargy, muscle tightness, musculoskeletal stiffness, nausea, pain in jaw, palpitations, paresthesia, peripheral edema, sensation of heaviness, throat tightness, tooth disorder, and vomiting).

Results

Enrolled subjects totaled 173, 167 (96.5%) of whom used at least 1 dose of study medication and were evaluable for safety, and 134 (77.5%) of whom completed the 6-month study. Subjects had a mean age of 43.4 years and were mostly female (81.4%) and white (81.4%). A total of 2,211 migraine headaches were reported, and 3,292 doses of DFN-02 were administered; the mean per subject monthly use of DFN-02 was 3.6 doses. Overall, 32 subjects (19.2%) reported 94 triptan-related treatment emergent AEs (TEAEs) over the 6-month period. Of those TEAEs, 14 were of moderate severity and 80 were mild; none were severe. After analyzing the number of DFN-02 doses taken, the adjusted triptan-related TEAE rate was 2.9% (94 events/3,292 doses taken). The most common triptan-related TEAEs (occurring in at least 1% of patients) were dizziness and nausea (each reported by 6 subjects; 3.6%); chest discomfort and paresthesia (3 subjects each; 1.8%) and feeling hot, feeling jittery, muscle tightness, and vomiting (2 subjects each; 1.2%). Five subjects (3.0%) discontinued from the study due to adverse events. Three of these 5 subjects discontinued due to experiencing triptan-related TEAEs: one with dizziness, another with nausea and vomiting, and a third with dizziness and feeling jittery.

Conclusions

Overall, DFN-02 was well tolerated in this long-term safety study in which subjects were treating multiple migraine headaches for up to 6 months. Low rates of triptan-related TEAEs were reported, and few patients discontinued due to triptan-related TEAEs.

74 Randomized, Double-Blind, Pilot Study Comparing 3 mg Subcutaneous Sumatriptan With 6 mg Subcutaneous Sumatriptan Using DFN-11 Autoinjector (Zembrace® SymTouch®) for the Acute Treatment of Rapidly Escalating Migraine Attacks

Mark B. Halvorsen¹, Sagar Munjal², Michelle B. Zachman¹

¹Upsher-Smith Laboratories, LLC, Maple Grove, MN, USA, ²Promius Pharma, a subsidiary of Dr. Reddy’s Laboratories Inc., Princeton, NJ, USA

Purpose

Migraine, a common episodic disorder, is characterized by a disabling headache that can be associated with nausea, vomiting, and sensitivity to light and sound. Triptans are a class of drugs effective for the acute treatment of migraine and can be administered as subcutaneous injection, nasal spray, or orally. Subcutaneous (SC) sumatriptan has a fast onset of action and is more effective than oral sumatriptan but is associated with more adverse events. The maximum single recommended adult dose of SC sumatriptan is 6 mg, though this dose is not tolerated by all patients. As such, a 3 mg dose of SC sumatriptan [DFN-11; Zembrace® SymTouch® (sumatriptan injection) 3 mg] may provide improved tolerability while maintaining efficacy. The objective of this study was to compare 3 mg and 6 mg SC sumatriptan using the DFN-11 autoinjector for the acute treatment of rapidly escalating migraine attacks.

Methods

This randomized, double-blind, crossover study compared the efficacy and tolerability of 3 mg SC sumatriptan with 6 mg SC sumatriptan in adults with a history of moderate-to-severe migraine attacks. Subjects were randomized (1:1) to treat each of two attacks with either a DFN-11 plus matching placebo autoinjector (total 3 mg sumatriptan dose) or two DFN-11 autoinjectors (total 6 mg sumatriptan dose). The primary endpoint was pain freedom at 60 minutes. Triptan-related adverse events (AEs) – referred to herein as ‘triptan sensations’ – were defined as one of the following: paresthesia, neck pain, flushing, muscle contractions, chest pain, disorientation, dizziness, myalgia, tinnitus, vomiting, hyperhidrosis, and malaise.

Results

A total of 20 adults were enrolled in this study. The proportion of subjects pain free at 60 minutes postdose was similar with 3 mg and 6 mg SC sumatriptan (50% and 52.6%, respectively; P = .87). Pain freedom at 90 minutes and 120 minutes was also not significantly different between the 3 mg and 6 mg sumatriptan doses. Other efficacy outcome measures were comparable for 3 mg and 6 mg SC sumatriptan, including pain relief; reductions in migraine pain intensity; and relief from nausea, photophobia, or phonophobia (P > .45 for all). For the 3 mg and 6 mg sumatriptan doses, mean patient treatment satisfaction ratings (2.6 and 2.4; P = .81) and the mean number of rescue medications (0.11 and 0.26; P = .32) were also similar. Triptan sensations were reported by 12 subjects: 1 subject following the 3 mg dose only, 4 subjects following the 6 mg dose only, and 7 subjects following both doses. Of the 32 triptan sensations reported in these subjects, 14 occurred following 3 mg sumatriptan and 18 following 6 mg sumatriptan (P = .60); the most common was paresthesia (5 events with 3 mg and 4 events with 6 mg). Mean duration for triptan sensations was 27 minutes with 3 mg and 64 minutes with 6 mg SC sumatriptan (P = .43). Chest pain affected 2 subjects (10%) treated with 6 mg and no subjects (0%) treated with 3 mg SC sumatriptan.

Conclusions

A single dose of DFN-11 [Zembrace® SymTouch® (sumatriptan injection) 3 mg] provided relief of migraine pain and associated symptoms similar to 6 mg of SC sumatriptan. Though the triptan-related AEs in the two dose groups were similar, the 3 mg dose showed a numerical advantage in duration of triptan sensations and may provide an important migraine treatment option to achieve the optimal balance of efficacy and safety in individual patients.

75 Breaking barriers to care: learnings from Pain BC’s Pain Support Line

Mark Nazemi, Dorota Hedzelek, Jen Hanson, Maria Hudspith

Pain BC, Vancouver, BC, Canada

Purpose

In a recent Canada wide poll, one in three Canadians (34%) reported experiencing pain that has lasted longer than three months. The complexities of pain impact many aspects of a person’s life including employment, personal relationships, sleep, mood, physical, and behavioral health. For many facing such challenges, access to social services and support whether in urban or rural regions, are often difficult and impacts recovery.

In this study, we examine longitudinal data collected from Pain BC’s Pain Support Line to identify the social determinants of health needs of people living with pain in British Columbia (BC), Canada. This free telephone-and-email based pain support service is unique in Canada offering a safe space for people to talk about pain and its impact on their life. The service also provides information on self-management tools, connections to community resources, help navigating the health system, and information about Pain BC’s other services and resources. The Pain Support Line also aims to attend to each caller using empowering language applying compassionate, trauma-informed, strength-based, and person-centered approach. The data from the support line provides a snapshot of the specific determinants. This data also illustrates the need for individualized support for people in pain by creating a low barrier service that provides social support, concrete resources, and connects people with appropriate local community-based health services.

Methods

A quantitative analysis was conducted based on caller data collected from 1,652 clients who used Pain BC’s free volunteer-run phone and email Pain Support Line service over a span of four years. Clients calling the service were identified as people living with chronic pain and of those who used the service 65% were female, 31% male, 1% transgender, and 3% did not disclose. Social determinants of health were categorized as access to specific allied health providers (Physiotherapists (PT), Occupational Therapists (OT), Registered Massage Therapist (RMT), Acupuncture,) income support, access to health services (physician, counseling, dental care, pain clinic, pain management groups, home health service,) social services (education, employment, support groups, working conditions, leisure/recreational program,) housing, food security, transportation, and advocacy/legal service. In addition, living situation, income variables, the primary support person, and housing situation were identified. A comparative analysis was used to identify the relationship between gender and the needs of the Pain Support Line clients to highlight the gaps in services and drive the development of Pain BC’s future support services.

Results

Of the total number of callers, the majority were female 65 or older (66%) while males (45%) ranked highest between the age of 55–64. The youngest callers were between the age of 13 and 17. Demand for accessing information regarding physicians accepting new patients was highest amongst both female (57%) and male (42%) followed by information regarding pain management groups (female 55%, male 44%) and pain clinics (female 61%, male 35%, Transgender (3%).

Requests for a physiotherapists ranked highest (female 70%, male 19%) followed by a registered massage therapist (female 70%, male 27%), acupuncture (female 72%, male 28%) and occupational therapist (female 80%, male 20%).

Clients requesting information to join or learn about support groups was most significant amongst female callers in the social services category (female 81%, male 18%) followed by employment opportunities (female 67%, male 33%), education (female 69%, male 31%), and leisure/recreation programs (female 57%, male 43%).

Callers who identified as living alone utilized the service most and were predominantly female callers (70%) compared to male (28%) and transgender (2%) callers. This result was also consistent with callers (female 58%, male 42%) indicating that they do not have anyone to support them with their experience of living with pain. Other determinants included requests for requiring transportation assistance which ranked low; however, obtaining information regarding housing was highest amongst female callers (80%) in comparison to male callers (45%). Lastly, seeking legal advice/advocacy was requested more frequently by female callers (77%) compared to male callers (20%).

Conclusions

The findings from the data show that people in pain living in BC, Canada face many challenges when attempting to find specific health and social services. Although many of the callers were situated in urban areas of Vancouver with a wide range of services available, people in pain find it hard navigating such an extensive network. The data also shows that finding a physician accepting new patients was identified as the top need. Many of the callers identified themselves as living alone, which may add to the challenge of finding appropriate support groups, pain management groups, information on housing, and employment opportunities. Access to low-cost medical care is identified as a barrier to care. Furthermore, a significant number of callers requested information regarding self-management tools and availability of social support groups.

The study suggests that an innovative and specialized person-centered service utilizing a social work approach on a large scale like the Pain Support Line is integral to supporting people living with chronic pain.

76 Incidence and Severity of Constipation in Patients Treated for Chronic Pain With Buprenorphine Buccal Film

Martin Hale¹, Joseph Pergolizzi, Jr.²

¹Gold Coast Research, Plantation, FL, USA, ²NEMA Research, Naples, FL, USA

Purpose

Constipation is one of the most common adverse events associated with long-term use of opioids in patients with chronic pain. Buprenorphine is a Schedule III opioid with partial agonist activity at the µ-opioid receptor that is approved by the United States Food and Drug Administration for the management of chronic pain. Here, we report the frequency and severity of constipation in 3 clinical studies evaluating the safety and efficacy of buprenorphine buccal film in opioid-naive and opioid-experienced patients with moderate to severe chronic low back pain.

Methods

Adults ≥18 years of age with moderate to severe chronic low back pain were enrolled in each of the 3 studies. Patients enrolled in the 2 randomized placebo-controlled studies (Study 1,¹ using opioid-experienced patients; Study 2,² using opioid-naive patients) underwent an open-label dose-titration period of ≤8 weeks. Those whose dose was successfully titrated to an optimal level (Study 1, 150 to 900 μg; Study 2, 150 to 450 μg) were subsequently randomized 1:1 to receive either buprenorphine buccal film or placebo buccal film every 12 hours for a 12-week double-blind period. In Study 3,³ a long-term open-label study of patients from Study 1 and Study 2 (and a third cohort of newly recruited de novo patients), patients underwent a dose-titration period of ≤6 weeks; those receiving an optimal dose (300 to 900 μg) every 12 hours for ≥7 days continued treatment for a long-term period of ≤48 weeks. Frequency and severity of constipation were evaluated for all patients in each study who received ≥1 dose of study medication.

Results

Patients in the safety population for Study 1 (n = 810) had a constipation rate of 18.4% at study entry, which decreased to 8.3% during the buprenorphine open-label dose-titration period. Following double-blind treatment with either buprenorphine buccal film (n = 254) or placebo buccal film (n = 256), constipation rates were 2.8% and 0.8%, respectively. Of the 749 opioid-naive patients assessed in the safety population for Study 2, the 5.3% constipation rate at study entry increased to 13% during the open-label dose-titration period. With continued treatment during the double-blind period, rates were 3.9% (9/229) in the buprenorphine group and 2.6% (6/232) in the placebo group. At Study 3 entry, 15.8% of patients in the safety population reported a medical history of constipation (80/506), and 5.9% (30/506) reported constipation during the open-label dose-titration period. After subsequent long-term open-label treatment of ≤48 weeks, only 3.9% (17/435) of patients reported constipation.

For all 3 studies, the overall mean constipation rate among buprenorphine-treated patients at study conclusion was 3.6% (33/918). Of the 2065 total patients assessed in the open-label dose-titration phases of these studies, only 0.2% experienced severe constipation. During the 12-week double-blind treatment periods of Study 1 and Study 2, only 0.2% (1/483) of buprenorphine-treated patients reported severe constipation, and no cases of severe constipation were reported in the ≤48-week long-term treatment period of Study 3.

Conclusions

Overall, constipation rates decreased with continued use of buprenorphine buccal film, a finding observed in the randomized placebo-controlled studies and in the long-term open-label study. Opioid-naive and opioid-experienced patients reported low overall rates of constipation while being treated at their optimal therapeutic dose of buprenorphine buccal film, and most of those reporting constipation described it as mild or moderate. Long-term use of buprenorphine buccal film for up to 54 weeks did not increase the frequency of constipation in patients with chronic moderate to severe low back pain. Compared with a systematic review of 34 clinical trials using several other commonly prescribed opioids (morphine, oxycodone, tramadol, etc.) with an average constipation rate of 15%,⁴ these 3 studies of buprenorphine buccal film use demonstrated an average constipation rate of 3.6%, suggesting that it may be a preferred option to avoid opioid-induced constipation in the treatment of chronic pain.

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77 Efficacy and Safety of Naldemedine for Opioid-Induced Constipation in Patients With Chronic Non-cancer Pain: Subgroup Analyses by Opioid Dose

Martin Hale¹, Mancia Ko²

¹Gold Coast Research, Plantation, Fl, USA, ²BioDelivery Sciences International, Inc., Raleigh, NC, USA

Purpose

Opioid analgesics are an important therapeutic option for treating moderate to severe pain, but their use is often associated with adverse events such as opioid-induced constipation (OIC).¹ Naldemedine is a μ-opioid receptor antagonist that acts primarily in the gastrointestinal tract and is indicated for the treatment of OIC in adult patients with chronic non-cancer pain, including patients with chronic pain related to prior cancer or its treatment who do not require frequent opioid dosage escalation.² The safety and efficacy of naldemedine was established by the phase 3 randomized, double-blind, placebo-controlled COMPOSE-1 and COMPOSE-2 studies, in which subjects received either 0.2 mg naldemedine or placebo once daily for 12 weeks.¹ The purpose of this analysis was to assess the consistency of naldemedine’s efficacy and safety based on opioid dose using pooled COMPOSE-1 and COMPOSE-2 study data.

Methods

Data from the COMPOSE-1 and COMPOSE-2 studies were pooled for calculation of spontaneous bowel movement (SBM) responder rates and overall incidence of treatment-emergent adverse events (TEAEs) among naldemedine- and placebo-treated subjects based on opioid morphine milligram equivalent (MME) doses. An SBM responder was defined as a subject with a positive response-week in at least 9 of the 12 weeks (including at least 3 of the last 4 weeks) during the COMPOSE-1 and COMPOSE-2 treatment periods.¹ A positive response-week was defined as a week with ≥3 SBMs and an increase of ≥1 SBM from baseline. The analysis subgroups were defined by opioid dose strata (30 to ≤100 MME and >100 MME) and opioid average total daily dose (TDD) at baseline (30 to ≤100 MME, >100 to ≤200 MME, >200 to ≤400 MME, and >400 MME). Each subgroup analysis evaluated the percentage of SBM responders in the naldemedine and placebo groups for the COMPOSE-1 and COMPOSE-2 studies and the pooled population. For the pooled population, the differences in the percentage of responders between treatment groups were calculated along with 95% confidence intervals (CIs). The incidence of TEAEs among naldemedine- and placebo-treated subjects in each MME dosing subgroup was calculated for the pooled population.

Results

Data from 1095 subjects (naldemedine, n = 549; placebo, n = 546) in the COMPOSE-1 and COMPOSE-2 studies were included in the efficacy analysis. In the individual studies and the pooled population, the proportion of SBM responders was greater in the naldemedine group than in the placebo group for the 30 to ≤100 MME (difference, 15.9%; 95% CI, 8.3%-23.5%) and >100 MME (difference, 16.1%; 95% CI, 7.3%-25.0%) opioid dose strata subgroups. Across both individual studies and in the pooled population, the proportion of SBM responders was higher in the naldemedine group than in the placebo group for all opioid average TDD subgroups. The percentage increases in responders for the naldemedine groups compared with the placebo groups (95% CI) in the pooled population were as follows: 30 to ≤100 MME, 14.7% (7.0%-22.5%); >100 to ≤200 MME, 14.9% (3.7%-26.1%); >200 to ≤400 MME, 18.5% (3.0%-34.0%); and >400 MME, 37.1% (8.7%-65.4%). Data from 1088 subjects (naldemedine, n = 542; placebo, n = 546) were included in the safety analysis. In the 30 to ≤100 MME opioid dose strata subgroup, the overall incidence of TEAEs was similar among naldemedine-treated (44.9%, 144/321) and placebo-treated (43.8%, 140/320) subjects. In the >100 MME opioid dose strata subgroup, the overall incidence of TEAEs was higher with naldemedine (47.1%, 104/221) than placebo (39.8%, 90/226). The incidences of TEAEs in the opioid average TDD subgroups were as follows: 30 to ≤100 MME, 45.0% (139/309) for naldemedine and 43.7% (135/309) for placebo; >100 to ≤200 MME, 46.0% (63/137) for naldemedine and 40.7% (55/135) for placebo; >200 to ≤400 MME, 52.9% (37/70) for naldemedine and 42.5% (31/73) for placebo; and >400 MME, 30.0% (6/20) for naldemedine and 30.8% (8/26) for placebo.

Conclusions

The pooled data analysis from the COMPOSE-1 and COMPOSE-2 studies suggest that the efficacy of naldemedine is superior to that of placebo across a wide range of opioid doses. The incidence of TEAEs was similar among naldemedine- and placebo-treated subjects receiving lower opioid doses (≤100 MME), but was on average somewhat higher with naldemedine than with placebo among those receiving opioid doses >100 MME. Current guidelines from the Centers for Disease Control and Prevention (CDC) recommend avoidance of daily opioid doses ≥90 MME for patients with chronic pain.³ Thus, these findings suggest that the efficacy of naldemedine is consistent across lower and higher opioid doses and that naldemedine is as safe as placebo when used with opioid doses aligned with current CDC recommendations.

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78 PMHNPs and Pain: A Call for Precepting the Psychiatric Mental Health Nurse Practitioner Student in Interdisciplinary Pain Management Teams

Melissa Garno, Stephanie Broxton, Hedly “Lee” Broxton

Georgia Southern University, Statesboro, GA, USA

Purpose

The purpose of this research is to provide evidence that encourages qualified providers working in pain management to precept PMHNP students, especially in interdisciplinary settings.

Interdisciplinary treatment teams are widely accepted as evidence-based practice with positive patient outcomes. While the number of accredited interdisciplinary pain programs in the United States is dwindling, the demand for pain management care is not. To keep up with the growing number of Americans experiencing chronic pain, PMHNPs could be utilized in several settings for treatment, along with other commonly-recognized pain management professions. While the practice authority of the PMHNP varies from state to state, The American Psychiatric Nurses Association (APNA) defines the role of a PMHNP as a masters-level or doctorally-prepared person that provides primary care to persons with mental health and co-occurring disorders. These nurse practitioners are uniquely qualified to provide integrated care to patients both as an independent practitioner and in partnership with disciplines like psychiatry, social work, counseling, and internal medicine.

For PMHNP graduates to be qualified providers to patients with chronic pain, they must first undergo clinical training for a minimum of 500 hours (many schools requiring more) with a qualified preceptor and faculty oversight, along with didactic courses. Securing a preceptor can be an immense challenge for nurse practitioner students as there are few providers qualified to serve as preceptors, and even fewer willing to commit to the task of educating students. In the interest of rectifying the shortage of preceptors, this research seeks to answer the questions: Are interdisciplinary treatment teams including PMHNPs a viable asset to pain management care?; and Are students exposed to interdisciplinary care models in their clinical training more successful?

Methods

This research will primarily include evidence from the outcomes of a Health Resources and Services Administration (HRSA) Behavioral Health Workforce Education and Training (BHWET) funded PMHNP track. Students who receive a BHWET stipend are required to complete all clinical training hours in an interdisciplinary setting. Students are surveyed about their interdisciplinary experiences, stipend funding, and program administration at two points in the clinical track. Students are surveyed halfway through the PMHNP program, and again at the end. The full surveys will be included in the poster presentation. BHWET student scores on the Barkley Diagnostic Readiness Test (DRT) are also recorded as outcomes of their interdisciplinary education. The results from two cohorts will be provided. Cohort One includes four students who completed the mid-point survey, the end of program survey, and the DRT. Cohort Two currently has eleven students, who have not yet completed the program. For Cohort Two students have only completed the mid-point survey.

This research will also provide a review of relevant literature from 2009 to 2019, covering sources in support of interdisciplinary treatment teams, interdisciplinary training, and PMHNPs in pain management.

Results

The results of the mid-point surveys, end of program surveys, and DRT scores indicate that interdisciplinary education has a positive effect on PMHNP students.

In the mid-point survey for Cohort One, one hundred percent of respondents indicated that they were extremely satisfied completing their clinical hours in an interdisciplinary site. One hundred percent of respondents indicated that they would recommend completing clinical hours in an interdisciplinary site to other Nurse Practitioner students. When given the chance to describe how interdisciplinary education helped them grow as practitioners students gave responses such as: ‘The ability to observe multiple disciplines work together to care for patients has allowed me to think outside of my box and take tools from the other professionals, such as how they communicate with patients, what is important to them in their practice, etc. and incorporate it into my thinking’.

In the end of program survey for Cohort One, one hundred percent of students indicated they were extremely satisfied completing their clinical hours in an interdisciplinary setting. One hundred percent recommended completing clinical hours in an interdisciplinary site to fellow nurse practitioner students.

On the Diagnostic Readiness Test given to students as a measure of their preparedness for the certification exam, the students in Cohort One had an average score of 74.5. This was 16.5 points higher than the score of non-BHWET students of whom interdisciplinary sites were not required.

In the mid-point survey for Cohort Two, eighty percent of respondents indicated they were extremely satisfied completing their clinical hours in an interdisciplinary site, while twenty percent indicated they were somewhat satisfied. One hundred percent of respondents indicated that they would recommend interdisciplinary training to fellow nurse practitioner students. Seventy percent of students indicated they would be extremely likely to seek employment in an interdisciplinary site following certification, and thirty percent indicated they would be somewhat likely to do so. When given the opportunity to describe how interdisciplinary education helped them to grow as practitioners they gave responses such as: ‘I got experience working with different populations, which will help me better care for them in future encounters’.

The relevant literature indicates that interdisciplinary training and practice are an essential part of pain management care, and beneficial to PMHNP students.

Conclusions

The intention of presenting this evidence is to serve as a call to action for pain management practitioners of all disciplines to include PMHNP students on their treatment teams. With the right training, PMHNPs could be the bridge to integrating behavioral health and primary care services, a relevant cross section in pain management. Students who have interdisciplinary training appear to be more successful based on the data in this research, and literature indicates the value of PMHNPs as an asset to pain management care. The positive effect that interdisciplinary education has on students that received a BHWET stipend indicates that interdisciplinary training is a key to creating both well-rounded providers and providers prepared to work on treatment teams after certification.

79 Reversion from chronic to episodic migraine and clinically meaningful responses to fremanezumab in patients with inadequate response to 2–4 classes of migraine preventive medications

Messoud Ashina¹, Xiaoping Ning², Maja Galic³, Joshua M. Cohen², Verena Ramirez-Campos², Ronghua Yang², Jessica Ailani⁴

¹Danish Headache Center, Department of Neurology Rigshospitalet, Glostrup, Denmark, ²Teva Pharmaceuticals Industries, Frazer, PA, USA, ³Teva Pharmaceuticals, Amsterdam, Netherlands, ⁴Medstar Georgetown University Hospital, Washington, DC, USA

Purpose

Fremanezumab, a fully-humanized monoclonal antibody (IgG2Δa) that selectively targets calcitonin gene-related peptide (CGRP), has proven efficacy for migraine preventive treatment in adults. The FOCUS phase 3b study demonstrated the effectiveness of fremanezumab for the preventive treatment of episodic migraine (EM) and chronic migraine (CM) and documented inadequate response to 2 to 4 classes of migraine preventive medications. This post-hoc analysis evaluated response rates in patients reverting from CM to EM during the FOCUS study.

Methods

CM patients were randomized (1:1:1) to quarterly fremanezumab (Month 1: 675 mg; Months 2 and 3: placebo), monthly fremanezumab (Month 1: 675 mg; Months 2 and 3: 225mg), or matched monthly placebo for 12 weeks of double-blind treatment. Reversion rates from CM to EM were defined as: A) ≥15 headache days at baseline but <15 headache days at all 3 months or B) ≥15 headache days at baseline but <15 headache days on average over 12 weeks. Proportions of responders (≥50% reduction in migraine days) were calculated using both reversion definitions.

Results

Of the CM patients, 18/167 (11%) reverted to EM based on definition A with placebo, 59/167 (35%) reverted to EM based on definition A with quarterly fremanezumab, and 59/172 (34%) reverted to EM based on definition A with monthly fremanezumab; 50/167 (30%), 81/167 (49%), and 91/172 (53%), respectively, reverted based on definition B. Among patients reverting based on definition A, higher proportions of patients achieved ≥50% reductions in the monthly number of migraine days with fremanezumab versus placebo within 4 weeks (quarterly fremanezumab, 31/59 [53%]; monthly fremanezumab, 38/59 [64%] vs placebo, 6/18 [33%]) and during 12 weeks of treatment (quarterly fremanezumab, 34/59 [58%]; monthly fremanezumab, 37/59 [63%] vs placebo, 6/18 [33%]). Higher proportions of patients reverting based on definition A also achieved ≥50% reductions in the weekly number of migraine days within 1 week with fremanezumab (quarterly fremanezumab, 36/59 [61%]; monthly fremanezumab, 36/59 [61%]) versus placebo (5/18 [28%]). Similarly, among patients reverting based on definition B, higher proportions of patients receiving fremanezumab versus placebo achieved ≥50% reductions in the weekly number of migraine days within 1 week and ≥50% reductions in the monthly number of migraine days over 4 and 12 weeks.

Conclusions

Reversion was common (~35%) at all 3 months of double-blind treatment with both fremanezumab dosing regimens in patients with documented inadequate response to 2 to 4 classes of migraine preventive treatments. Clinically meaningful response rates within 1 and 4 weeks and sustained ≥50% response rates over 12 weeks were higher with both dosing regimens of fremanezumab than with placebo.

80 Virtual Embodiment in Virtual Reality Reveals Mirror Visual Feedback Influences on Pain-Free Range of Motion

Michael Trujilo¹, Anthony Alvarez¹, Daven Crossland², James Petros^1,3, Lincoln Nguyen¹

¹Karuna Labs, Inc, San Francisco, CA, USA, ²Pitzer College, Claremont, CA, USA, ³Allied Pain & Spine Institute, Los Gatos, CA, USA

Purpose

Karuna Labs Inc. has created virtual reality (VR) software for the treatment of movement-related chronic pain, combining virtual embodiment with graded motor imagery (GMI) and mirror therapy principles. GMI is a biopsychosocial approach to physical therapy that uses imagery, rehearsal, and simulation to re-learn associations to pain and improve function. Using off the shelf VR hardware (HTC Vive headset and Vive hand trackers), Virtual Embodiment Therapy (VET™) incorporates accurate and precise virtual avatar representation of both gross and fine motor movements along with embodiment concepts. Virtual embodiment is a phenomenon where a person perceives the movements of a virtual avatar as their own and the benefits are similar to mirror box therapy as described by Ramachandran^[1]. The purpose of the present mechanistic pilot study was to gain insight into the effects of mirroring in VET™ on pain-free range of motion (ROM) in patients with chronic shoulder pain. We hypothesized that mirroring a nonaffected shoulder motion onto an affected painful shoulder would increase ROM of the painful shoulder. Furthermore, we hypothesized that mirroring movements of a painful shoulder onto a nonaffected shoulder would decrease the range of motion of the nonaffected shoulder. The rationale for our hypothesis is based on principles of mirror visual feedback (MVF) where a patient’s visual perception of motion exerts a strong influence over sensory-motor pathways^[2]. If patients perceive that movement of a painful limb is occurring in a non-painful limb, then pain-free range of motion should increase in the painful limb. Conversely, we further investigated if the opposite effect would also be true, that the perception of a painful limb moving would decrease ROM in a nonaffected limb.

Methods

This study was approved by an Institutional Review Board (Advarra). Fifteen chronic shoulder pain patients were recruited to participate in this study. Mean age was 56.3 years, 8 were female and 7 were male, 8 presented with left side chronic shoulder pain and 7 presented with right side chronic shoulder pain. Following written informed consent, patients donned a head-mount-display (HTC Vive) and were familiarized into the VR experience. Once patients felt comfortable, range of motion was measured on three planes for each arm (shoulder flexion, shoulder scaption, and shoulder abduction). Joint angles were calculated based on inverse kinematics of the position of HTC Vive hand controllers as tracked by HTC Vive infrared motion tracking lighthouses. The order of measurements were flexion, scaption, and abduction of the right arm followed by flexion, scaption, and abduction of the left arm. Patients first saw the ipsilateral arm moving for each plane (i.e. move right arm, see right virtual avatar arm move) followed by seeing the contralateral mirrored side moving (i.e. move the right arm, see left virtual avatar arm move). Patients were instructed to move their arm in each plane within their comfort zone and to not extend beyond the position that induced pain. A paired t-test for each condition (painful mirrored onto nonaffected and nonaffected mirrored onto painful) was used to determine if mirroring of painful limb onto nonaffected limb increased ROM for each plane and whether mirroring of nonaffected limb onto the painful limb decreased ROM of the nonaffected limb.

Results

A paired T-test revealed a significant decrease in ROM when the nonaffected arm was mirrored onto the painful arm (moving the nonaffected arm but seeing painful side move) for shoulder flexion (t = 2.761, P = 0.019) and for shoulder scaption (t = 3.182, P = 0.009). No significant effect was observed for shoulder abduction when the nonaffected arm is mirrored onto painful arm (t = −0.04, P = 0.96). These results indicate that range of motion for flexion and scaption is reduced in a nonaffected limb when patients perceive the movement as occurring in their painful limb.

No significant effect was observed when the painful arm is moving and mirrored onto the nonaffected limb for flexion (t = −0.6, P = 0.56), scaption (t = 0.16, P = 0.86), nor abduction (t = 1.4, P = 0.18).

The magnitude of reduction in shoulder flexion when the nonaffected limb is mirrored to the painful limb ranged from 2 to 22-degrees reduction. The magnitude of reduction in shoulder scaption when the nonaffected limb is mirrored to the painful limb ranged from 1.4–25.5-degrees. These results indicate that mirroring can exhibit a large effect on pain-free range of motion on a nonaffected limb when a patient perceives the motion as occurring in a painful limb.

Conclusions

This mechanistic pilot study provides evidence that MVF in VR can influence the function of a nonaffected limb if a patient perceives that function as occurring in a painful limb. These results have implications for rehabilitation strategy in patients suffering from chronic pain. MVF and GMI have been shown to improve ROM in patients with pain limitations. With the recent advances in motion-sensing technology used in VR applications, clinicians are now able to measure improvements in ROM within millimeter accuracy. This pilot study provides a framework for future studies to investigate whether training MVF in VR can improve function in chronic pain patients whose ROM is limited by pain. Furthermore, these results may lead to greater knowledge of the mechanisms by which MVF can be used to treat chronic pain.

References

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81 Efficacy and safety of fremanezumab in patients with migraine and documented inadequate response to 2–4 classes of migraine preventive medications: results of the multicenter, randomized, placebo-controlled FOCUS study

Michel D. Ferrari¹, Hans-Christoph Diener², Xiaoping Ning³, Maja Galic⁴, Joshua M. Cohen³, Ronghua Yang³, Messoud Ashina⁵

¹Leiden University Medical Center, Leiden, Netherlands, ²Universitätsklinikum Essen, Essen, Germany, ³Teva Pharmaceuticals Industries, Frazer, PA, USA, ⁴Teva Pharmaceuticals, Amsterdam, Netherlands, ⁵Danish Headache Center, Department of Neurology, Glostrup, Denmark

Purpose

Migraine is associated with substantial symptom burden and is the second leading global cause of years lived with disability. Fremanezumab, a fully-humanized monoclonal antibody (IgG2Δa) that selectively targets calcitonin gene-related peptide (CGRP), has proven efficacy for migraine prevention in adults. The FOCUS study of fremanezumab was the first and largest study of a migraine preventive treatment in a population of adults with difficult-to-treat chronic and episodic migraine (CM and EM) who had documented inadequate response to 2–4 classes of migraine preventive medications.

Methods

The FOCUS study was an international, multicenter, randomized, double-blind, parallel-group, placebo-controlled, phase 3 study. At baseline, patients were randomized (1:1:1) to quarterly subcutaneous (SC) fremanezumab (CM or EM: Month 1, 675 mg; Months 2 and 3, placebo), monthly SC fremanezumab (CM: Month 1 [baseline], 675 mg; Months 2 and 3, 225 mg; EM: Months 1, 2, and 3: 225 mg), or matched monthly placebo over 12 weeks of double-blind treatment. The primary efficacy endpoint was the mean change from baseline in the monthly average number of migraine days during the 12 weeks after the first dose of study drug, compared between treatment groups using an analysis of covariance model. Adverse events (AEs) and serious adverse events (SAEs) were summarized by treatment group.

Results

A total of 838 patients (placebo, n = 279; monthly fremanezumab, n = 283; quarterly fremanezumab, n = 276) were randomized and received at least 1 dose of study drug. The mean (SD) age was 46.2 (11.04) years, and the majority of patients were women (84%). For the primary endpoint, significantly greater reductions from baseline in the monthly average number of migraine days were observed with both fremanezumab regimens (least-squares mean [standard error (SE)] change: quarterly fremanezumab, −3.7 [0.34]; monthly fremanezumab, −4.1 [0.34]) compared with placebo (−0.6 [0.34]) during the 12-week, double-blind treatment period in the overall population (both P < 0.0001). When the primary endpoint was evaluated by type of migraine, reductions from baseline in the monthly average number of migraine days over 12 weeks of treatment were significantly greater with both fremanezumab regimens compared with placebo in patients with EM (least-squares mean [SE] change: quarterly fremanezumab, −3.7 [0.44]; monthly fremanezumab, −3.8 [0.45]; placebo, −0.7 [0.43]) and in patients with CM (quarterly fremanezumab, −3.9 [0.46]; monthly fremanezumab, −4.5 [0.45]; placebo, −0.7 [0.47]; all P < 0.0001). AEs were reported for similar proportions of patients across treatment groups (placebo, 48%; all fremanezumab groups, 50%). The most common AE (incidence ≥5% in the placebo or all fremanezumab groups) was injection-site erythema (placebo, 5%; all fremanezumab groups, 6%). Incidences of AEs leading to discontinuation (placebo, 1%; all fremanezumab groups, <1%) and SAEs (placebo, 1%; all fremanezumab groups, 1%) were low and comparable with placebo and fremanezumab. No SAEs were considered to be treatment-related by investigators, and no safety signals were identified.

Conclusions

Compared with placebo, quarterly or monthly fremanezumab treatment was associated with significant improvements in efficacy, based on reductions in the monthly average number of migraine days, and was well tolerated over 3 months of double-blind treatment in patients with EM or CM and documented inadequate response to 2–4 classes of migraine preventive medications.

82 Dysgeusia Rates in a Multicenter, Open-Label, Long-Term, Safety Study of DFN-02 (Tosymra™; an Intranasal Spray of Sumatriptan 10 mg Plus Permeation Enhancer DDM) for the Acute Treatment of Migraine

Michelle B. Zachman¹, Mark B. Halvorsen¹, Sagar Munjal², Alan M. Rapoport³

¹Upsher-Smith Laboratories, LLC, Maple Grove, MN, USA, ²Promius Pharma, a subsidiary of Dr. Reddy’s Laboratories, Princeton, NJ, USA, ³The David Geffen School of Medicine at UCLA, Los Angeles, CA, USA

Purpose

Migraine is a common, disabling disease, and many patients remain dissatisfied with available therapies. Intranasal administration of triptans is effective for the treatment of acute migraine. However, currently marketed intranasal formulations are associated with frequent reports of dysgeusia, a distortion of the sense of taste, likely due to poor nasal absorption and medication dripping down the throat. Dysgeusia is also reported as an important reason for patients to avoid using triptan nasal sprays. DFN-02 [Tosymra™ (sumatriptan) nasal spray] is a novel intranasal spray formulation composed of sumatriptan 10 mg and 0.2% of the permeation-enhancer Intravail® (1-O-n-Dodecyl-β-D-Maltopyranoside [DDM]). This allows sumatriptan to be rapidly absorbed from the nose into the systemic circulation. DFN-02 exhibits pharmacokinetics comparable to subcutaneously (SC) administered sumatriptan, including a rapid time to maximum plasma concentration. A 6-month, open-label study was conducted to evaluate the long-term safety of DFN-02. Here we report dysgeusia rates over the 6-month treatment period.

Methods

This was a multi-center, open-label, repeat-dose safety study in adults with episodic migraine with and without aura according to International Classification of Headache Disorders (ICHD)-2 criteria. Subjects, who experienced 2 to 6 migraine attacks per month and who had fewer than 15 headache days per month and at least 48 headache-free hours between attacks, used DFN-02 to treat their migraine headaches acutely over the course of 6 months. Dysgeusia rates by incidence and per DFN-02 doses taken over the 6-month treatment period were evaluated.

Results

Enrolled subjects totaled 173, 167 (96.5%) of whom used at least 1 dose of study medication and were evaluable for safety, and 134 (77.5%) of whom completed the 6-month study. A total of 2,211 migraine headaches were reported, and 3,292 doses of DFN-02 were administered; mean per-subject monthly use of DFN-02 was 3.6 doses. Overall, 35 subjects (21%) reported 232 events of dysgeusia over the 6-month treatment period. After analysis per the total number of doses taken in the study, the dysgeusia rate was 7.0% (232 events/3,292 doses taken). Severity of dysgeusia was mild in 30 (18%) subjects; moderate in 5 subjects (3%), and no subject reported severe dysgeusia. In addition, no subjects discontinued the study due to dysgeusia.

Conclusions

DFN-02 was well tolerated in this long-term safety study with subjects treating multiple migraine headaches acutely. Low incidence of dysgeusia per dose was observed, and no subjects withdrew from the study due to dysgeusia. The low rates of dysgeusia observed in the study may be due to increased sumatriptan nasal absorption with Intravail®.

83 The Effect of Migraine Headache Intensity on the Efficacy of Low-Dose (3 mg) Sumatriptan Injection (DFN-11; Zembrace® SymTouch®) in the Acute Treatment of Episodic Migraine Attacks: The RESTOR Study

Stephen Landy¹, Mark B. Halvorsen², Michelle B. Zachman², Sagar Munjal³, Alan M. Rapoport⁴

¹Baptist Medical Group, Memphis, TN, USA, ²Upsher-Smith Laboratories, Maple Grove, MN, USA, ³Promius Pharma, a subsidiary of Dr. Reddy’s Laboratories Inc., Princeton, NJ, USA, ⁴The David Geffen School of Medicine at UCLA, Los Angeles, CA, USA

Purpose

Triptans are a class of migraine-specific medications effective for the acute treatment of migraine and can be administered as subcutaneous injection, nasal spray, or orally. Subcutaneous (SC) sumatriptan, which has the fastest onset of action of all the routes of administration, has a maximum single recommended adult dose of 6 mg. Efficacy of a low-dose (3 mg) SC sumatriptan injection [DFN-11; Zembrace® SymTouch® (sumatriptan injection) 3 mg] was established in a large, phase 3, US, multicenter, randomized, double-blind (DB), placebo-controlled study of episodic migraine subjects treating a migraine attack of moderate or severe headache intensity (NCT02569853). The objective of this analysis was to assess whether the pre-dose pain intensity level (moderate versus severe) impacted DFN-11 efficacy.

Methods

Subjects with at least 12 months of episodic migraine (2 to 6 attacks per month on average), with no more than 14 headache days per month, and at least 48 headache-free hours between attacks, were randomized 1:1 to DFN-11 or placebo in the 4-week DB period. Subjects were instructed to self-administer the study medication to treat a migraine attack at moderate or severe pain intensity (2 or 3, respectively, on a rating scale of 0 to 3). Pain intensity and symptoms were recorded pre-dose and post-dose in a real-time eDiary; symptoms recorded included selection of their most bothersome symptom [MBS] among nausea, photophobia, phonophobia. The primary efficacy endpoint, the proportion of subjects who were pain free (rating of 0) at 2 hours post-dose in the DB period, and secondary endpoints of pain relief (rating of 0 or 1) and MBS freedom, were analyzed using 1-sided Fisher’s Exact test (alpha set at 2.5%) and with last observation carried forward (LOCF) imputation. Post hoc assessment of subject subsets by pre-dose pain intensity (moderate vs severe) was also performed using descriptive statistics.

Results

Of 268 subjects randomized at 16 sites, 208 had DB data post-dose (n = 104 in each treatment arm). Overall, DFN-11 subjects had significantly higher 2-hour pain free rates compared with placebo (primary endpoint; 51.0% vs 30.8%, P = .002) and 2-hour pain relief rates (76.0% vs 61.5%, P = .018). DFN-11 2-hour MBS freedom was numerically higher (64.1% vs 48.1%; P = .031); post hoc analysis using observed cases was significant for DFN-11 compared with placebo (65.3% vs 47.4%; P = .021) for MBS. In the DFN-11 group, pain intensity pre-dose was recorded as moderate by 68 subjects (78%) and severe by 19 subjects (22%), with a similar distribution in the placebo group. For DFN-11 subjects who had moderate vs severe pain intensity pre-dose, 52.9% vs 47.4% reported pain freedom at 2 hours post-dose, respectively. Rates of MBS freedom at 2 hours post-dose were 62.3% vs 70.6% for DFN-11 subjects who reported moderate vs severe pain intensity pre-dose. Rates of pain relief were: 77.9% vs 68.4%, respectively, for DFN-11 subjects who reported moderate pain intensity vs severe intensity pre-dose. Placebo response rates at 2 hours post-dose for subjects with moderate pain pre-dose were higher vs subjects with severe pre-dose pain intensity for all three measures.

Conclusions

DFN-11, a low dose (3 mg) SC sumatriptan injection, relieved pain and the most bothersome symptom similarly when migraine attacks were treated acutely at moderate or severe pain intensity. These data suggest that patients with severe headaches may be treated with a lower dose of SC sumatriptan.

84 Pharmacokinetics of DFN-02 (Tosymra™; an Intranasal Spray of Sumatriptan 10 mg Plus Permeation Enhancer DDM) Compared With Intranasal Sumatriptan 20 mg in Healthy Adults

Michelle B. Zachman¹, Sagar Munjal², Mark B. Halvorsen¹

¹Upsher-Smith Laboratories, LLC, Maple Grove, MN, USA, ²Promius Pharma, a subsidiary of Dr. Reddy’s Laboratories, Princeton, NJ, USA

Purpose

Intranasal sumatriptan (Imitrex®) may be an alternative for migraine patients who refuse injections and cannot tolerate oral agents. However, poor bioavailability and slow absorption of intranasal sumatriptan limit the clinical utility of the currently marketed formulation, highlighting an unmet need for an effective, non-oral/non-injectable migraine medication with a rapid onset of action. To overcome the slow absorption profile associated with intranasal administration, we evaluated the impact of the permeation enhancer Intravail® (1-O-n-Dodecyl-β-D-Maltopyranoside [DDM]) on sumatriptan’s pharmacokinetic (PK) profile. The objective of this study was to compare, in healthy adults, the PK of commercial intranasal sumatriptan (Imitrex®) 20 mg with DFN-02 [Tosymra™ (sumatriptan) nasal spray], a novel intranasal product composed of sumatriptan 10 mg and 0.2% of the permeation enhancer Intravail® (DDM).

Methods

This was an open-label, randomized, single-dose, crossover bioavailability study in healthy, fasted adults. The study compared single doses of intranasal DFN-02 (10 mg sumatriptan and 0.2% DDM) with intranasal Imitrex (20 mg sumatriptan). Subjects received a single dose of each treatment with at least three days in between. Blood was sampled for PK evaluation of sumatriptan and DDM up to 24-hours post-dose. PK parameters included area under the curve from time zero to 2 hours and to infinity (AUC_0-2 and AUC_0-∞), maximum plasma concentration (C_max), and time to C_max (T_max).

Results

A total of 18 healthy adults were included in the study. Sumatriptan absorption was faster with intranasal DFN-02 than with intranasal Imitrex 20 mg (T_max: 15 minutes vs 120 minutes, respectively). Sumatriptan C_max was greater with DFN-02 (63.9 ng/mL) compared with Imitrex (21.4 ng/mL). Sumatriptan AUC_0-2 was also greater for DFN-02 (48.4 ng*hr/mL) than Imitrex (24.7 ng*hr/mL), though AUC_0-∞ values were similar (DFN-02, 84.2 ng*hr/mL; Imitrex, 87.3 ng*hr/mL). For DFN-02, the PK profile of DDM reflected minimal absorption (plasma level of 2 ng/mL) and short-lived systemic exposure (half-life of 0.84 hours).

Conclusions

Plasma sumatriptan levels peaked earlier with intranasal DFN-02 (10 mg sumatriptan and 0.2% DDM) than intranasal Imitrex (20 mg sumatriptan). DFN-02 also had higher levels of sumatriptan C_max and AUC_0-2 compared with Imitrex. Systemic exposure to the permeation enhancer DDM was short-lived. Together, these data suggest that the addition of the permeation enhancer DDM (Intravail®) improved the absorption profile of sumatriptan compared with intranasal Imitrex.

85 Medication Use Evaluation of Opioid Prescribing Patterns at Eskenazi Health

Michelle Busch¹, Todd Walroth¹, Palmer MacKie^1,2, Rebecca Gerske^3,1, Morgan Ragsdale^3,1

¹Eskenazi Health, Indianapolis, IN, USA, ²Indiana University School of Medicine, Indianapolis, IN, USA, ³Butler University, Indianapolis, IN, USA

Purpose

JAMA Surgery published a retrospective, multi-site, population-based analysis in 2019 that demonstrated excessive opioid prescribing in comparison to consumption patterns for patients undergoing 12 different surgical procedures. In April 2019, the data gathered from this survey prompted the Michigan Surgical Quality Collaborative (MSQH) and the Opioid Prescribing Engagement Network (OPEN) to publish a set of recommendations for the number of oxycodone tablets (or equivalent) to be prescribed after specific surgical procedures. For example, the OPEN guidelines recommend patients to receive 15 tablets after cesarean section, 30 tablets after total hip arthroplasty (THA), and 50 tablets after total knee arthroplasty (TKA). The objective of our study was to evaluate Eskenazi Health’s opioid prescribing patterns following these three surgical procedures compared to the published recommendations. The primary endpoint was the number of tablet equivalents prescribed against OPEN recommendations. Secondary outcomes included total dose equivalents prescribed over OPEN recommendations and dose equivalents prescribed per day over 5 days. A post-hoc analysis was conducted in the THA and TKA populations comparing prescribing differences between opioid-naive and opioid-tolerant patients.

Methods

This was a retrospective chart review of patients selected from a report generated by the electronic health record (EHR). Patients were identified based on surgery type and date of surgery. Cesarean section was pulled using “cesarean delivery only’ procedure code from March 1, 2019 to June 6, 2019. THA patients were identified using ‘arthroplasty, acetabular and proximal femoral prosthetic replacement (total hip arthroplasty), with or without autograft or allograft’ procedure code from December 1, 2018 to June 6, 2019. TKA patients were identified using ‘arthroplasty, knee, condyle and plateau; medial and lateral compartments with or without patella resurfacing (total knee arthroplasty)’ procedure code from December 1, 2018 to June 6, 2019. Patients were excluded if they were not prescribed opioids post-surgery (n = 2). Patient medical record numbers were used to search the EHR for demographic information and the opioid prescription. INSPECT, Indiana’s prescription drug monitoring program, was used to obtain fill data and determine if the patient was opioid-naïve or opioid-tolerant. An opioid-tolerant patient was defined as a patient who filled an opioid within the last 90 days according to INSPECT records. The prescribing patterns were analyzed using tablet equivalents and dose equivalents. The tablet equivalents were converted to dose equivalents based on the Centers for Disease Control and Prevention’s opioid conversion standards which equated to 112.5 MME (morphine milligram equivalents) for cesarean section, 225 MME for THA, and 375 MME for TKA. Statistical analysis was performed using MiniTab 16.0. All continuous, non-parametric data were analyzed using Mann-Whitney U and dichotomous variables were analyzed using Fisher’s exact or Chi-square tests.

Results

A total of 127 cesarean section, 43 THA, and 58 TKA patients were included for review. For discharge prescriptions following cesarean sections, the OPEN recommendation is 15 tablets of oxycodone 5 mg or hydrocodone/APAP 5/325 mg or 112.5 MME. Eskenazi Health physicians prescribed a median (IQR) of 5 (5–6) tablets over OPEN recommendations after cesarean sections. The median (IQR) dose equivalents over OPEN recommendations was 37.5 (16–56) MME. The median (IQR) dose equivalents prescribed over 5 days was 30 (25.8–33.8) MME/day. Only 2 patients were considered opioid-tolerant so a post-hoc analysis was not performed. For discharge prescriptions following THA and TKA procedures, Eskenazi Health providers prescribed a median (IQR) of 54 (14–54) and 34 (34–34) additional tablets over the OPEN recommendations for THA and TKA, respectively. The median (IQR) dose equivalents prescribed over the OPEN recommendations was 405 (405–405) MME for THA and 255 (255–255) MME for TKA. The median (IQR) dose equivalents prescribed per day over 5 days was 126 (126–126) MME for both THA and TKA. Over 80% of patients received more tablet equivalents and dose equivalents than recommended for these procedures. In the post-hoc analysis, a total of 51% and 36% of patients in the THA and TKA groups, respectively, were considered opioid tolerant. There was no significant difference between the median tablet equivalents prescribed for opioid-naive and opioid-tolerant patients after both THA and TKA (p > 0.050). THA opioid-tolerant patients received 84 (75–84) median (IQR) tablet equivalents compared to opioid-naive patients who received 84 (39–84) median (IQR) tablet equivalents (p = 0.054). TKA opioid-tolerant patients received 84 (84–126) median (IQR) tablet equivalents compared to opioid-naive patients who received 84 (84–84) median (IQR) tablet equivalents (p = 0.063). THA opioid-tolerant patients received a median (IQR) of 126 (126–126) MME per day over 5 days compared to opioid-naive patients who received 126 (84–126) MME per day over 5 days (p = 0.063). TKA opioid-tolerant patients received a median (IQR) of 126 (126–189) MME per day over 5 days compared to opioid-naive patients who received 126 (126–126) MME per day over 5 days (p = 0.036).

Conclusions

Our results support the need for opioid prescribing restrictions. The cesarean section data identified prescribing habits for this procedure are in line with goal recommendations; however, the THA and TKA post-procedure prescribing have room for improvement. Opioid-naive and opioid-tolerant patient comparisons showed no significant difference between the total number of tablet equivalents prescribed indicating the potential for over-prescribing opioids depending on the patient’s history. The median dose equivalents prescribed per day over 5 days was not significantly different post-THA; however, a statistically significant difference was seen between opioid-tolerant and opioid-naive patients post-TKA. Perioperative pain management is essential for discharge, rehabilitation, and overall patient well-being. Published data has shown that the number of tablets prescribed has a greater impact on the number of tablets consumed than a patient’s pain score; therefore, prescribers should consider a multimodal approach by adding non-opioids and/or non-pharmacological alternatives to a patient’s pain regimen to decrease the amount of opioids prescribed while maintaining sufficient pain control. Next steps will be to use these results to guide interventions, direct changes to the EHR, and promote educational initiatives to improve our outcomes and follow published recommendations.

86 A Call for diligent Cannabidiol Research: Discrepancies between Knowledge and Beliefs of Healthcare Professionals

Jan M Schilling¹, Chloe G Hughes¹, Brielle N Leon¹, Jasminne E Parkinson¹, Miroslav Backonja^1,2, Tobias Moeller-Bertram¹

¹Vitamed Research LLC, Rancho Mirage, CA, USA, ²University of Washington, Seattle, WA, USA

Purpose

Public demand for the legalization of cannabis resulted in the availability of medical cannabis in the United States beginning in California in 1996. As of 2019, thirty-three states have legalized the use of marijuana for medical purposes, creating a new treatment option for patients seeking alternative therapies. Perceived health benefits of marijuana use have been reported, leading to an increased interest in cannabinoid research. In particular, there has been a focus on the phytocannabinoid cannabidiol (CBD) because it is thought to have minimal psychoactive effects. However, the evidence available is considered inconclusive at best and emphasizes the need for scientifically valid information about this compound. Patients have utilized CBD as a treatment for childhood epilepsy, chronic pain, and anxiety disorders, with more studies currently being performed. The number of published research studies on PubMed that investigate the effects of CBD have doubled since the year 2015. This growing interest in CBD as a potential treatment option produces a need for healthcare individuals to elucidate the potential of CBD in medicine through personal and scientific evaluation. This study aims to assess Healthcare Professionals about their knowledge, attitude, beliefs, and personal experience towards CBD products.

Methods

Healthcare Professionals (N = 106) of undisclosed backgrounds were asked about their knowledge, beliefs, and personal experience surrounding CBD products. After IRB review (exempt status), the internet survey platform, SurveyMonkey, was utilized to administer the survey online between February 19th, 2019 and July 14th, 2019. Additionally, the survey was handed out as a paper version during PAINWeekEnd regional conferences in Anaheim, Scottsdale, Atlanta, Denver, and San Diego, with all events occurring in 2019. Data was analyzed utilizing IBM SPSS Statistics Subscription and presented as descriptive statistics. Data is presented as N and percentage of responses, Mean (SD), Median (IQR), Range, and Missing (N).

Results

Participants were 57.2 ± 13.2 (Mean±SD) years old, and females (52.0%) and males (49.0%) were equally distributed. The majority identified as white (58.5%) and non-Hispanic (91.3%), are either ‘Employed for wages’ or ‘Self-employed’, have an annual household income of more than $125,000, and participated in post-college (master’s or higher) education. The majority of participants work in the fields of Family Medicine (29.2%), Internal Medicine (12.3%) and Pain Management (23.6%) in a Private Practice environment (64.1%). The majority deny that their school provided education about medical cannabis and CBD products (95.9%). Nonetheless, the majority also stated that they have read literature about CBD (79.4%) and have informed themselves through lay media (81.6%). About half of the participants (49.5%) have read a peer-reviewed article about CBD, of which the majority were reviews (83.3%). Participants have previously recommended CBD products (41.7%) such as tinctures, edibles, and capsules for conditions such as back pain, nerve pain, anxiety, joint pain, insomnia, neck pain, etc., while 58.3% have not recommended CBD products. Of the healthcare professionals, 30.2% report that they have tried a CBD product. When asked about their patients, 68.8% report that their patients have proclaimed favorable benefits when using CBD products, while 18.9% report that patients have attributed adverse effects directly to CBD. When asked about familiarity with using CBD as a treatment option, the majority state that they are either ‘not at all familiar’ or only ‘slightly familiar’ with the use of CBD as a treatment option, the regulations in their state, CBD’s mechanism of action, dosing ranges, and concentration ranges. The majority believe that CBD is a good treatment option (68.5%) and that a CBD/THC combination is more effective than CBD alone, yet, they do not feel that they have an adequate amount of knowledge about CBD as a treatment option. About half of the participants believe that CBD does not have addictive potential and does not get you ‘high’. The majority concede new evidence is integral to support the efficacy of CBD, specifically clinical, preclinical, and pharmacokinetic/pharmacodynamic data. Participants also believe that it would be better if patients could receive CBD from a medical professional as opposed to other sources, and that patients are also more likely to purchase a CBD product from them.

Conclusions

In conclusion, the data shows that the majority of healthcare providers conceive CBD to be a good treatment option. Patients of the participants have reportedly experienced positive effects concerning their health conditions, and about 40% of participants have previously recommended CBD products to their patients. Yet, overall familiarity with details such as dosing ranges, concentration ranges, mechanism of action, regulations of CBD treatment and overall perceived knowledge about CBD is low and education about the topics in this cohort currently stems more from lay media than controlled-studies and peer-reviewed publications. Additionally, about one fifth reported that their patients experienced adverse effects directly attributed to CBD. The majority of Healthcare Professionals in our survey believe that new evidence to uphold the efficacy of CBD is necessary. Taken together, our survey shows that healthcare professionals have heard positive patient reports and believe CBD is a viable treatment option. Still, the overall perceived knowledge about this treatment is low and additional evidence and education is pertinent for providers to be more comfortable with CBD as a therapeutic. Study limitations lie in the voluntary nature of survey designs. Nonetheless, studies like this can help identify areas that warrant further, more controlled research.

87 Characterization of Individuals With Osteoarthritis in the United States and Their Use of Prescription and Over-the-Counter Treatments

Nancy Lane¹, Jasmina Ivanova², Birol Emir², Ali Mobasheri^3,4,5, Morten Jensen⁶

¹University of California at Davis School of Medicine, San Francisco, California, USA, ²Pfizer Inc., New York, New York, USA, ³State Research Institute Centre for Innovative Medicine, Vilnius, Lithuania, ⁴University of Oulu, Oulu, Finland, ⁵Queen’s Medical Centre, Nottingham, United Kingdom, ⁶Pfizer Consumer Healthcare, Søborg, Denmark

Purpose

Osteoarthritis (OA) is a frequently occurring, chronic condition associated with symptoms such as pain and stiffness that reduce both function and quality of life. There are limited reports available that describe the demographic and clinical characteristics of individuals with OA and the treatments they use to manage their joint symptoms. The current analyses were conducted to characterize the OA population in the United States and describe the prescription (Rx) and over-the-counter (OTC) treatments used by this population based on consumer research data collected through an online survey.

Methods

Data from the 2017 US National Health and Wellness Survey (NHWS) for adults ≥35 years of age were used to evaluate the relation between OA and a number of demographic and clinical characteristics and identify most commonly used treatment options. NHWS data were collected through a survey of individuals drawn from the Internet panel maintained by Lightspeed Research (Bridgewater, New Jersey) in 2017. Results were projected for the total population using known population incidences for key subgroups. The following variables were weighted in the model: sex, age, race/ethnicity, and education. The Current Population Survey (Annual Demographic File) from the US Census Bureau was utilized to generate the weighted estimates based on the NHWS. Comparisons between the general and OA populations were made based on normal (19–24 kg/m²) and high (≥25 kg/m²) body mass index (BMI), regular exercise (≥12 days/month) and less frequent exercise (<12 days/month), and comorbid diagnoses of hypertension or diabetes. Dietary supplement use, Rx or OTC treatment use with chondroitin with/without glucosamine (Ch±Gl), Rx treatment use by length of OA diagnosis, and utilization of a physical therapist among the OA population were described.

Results

The overall prevalence of OA in this population was 17.6% and was higher in individuals with high BMI (21.9%) versus those with normal BMI (10.8%). Compared with the non-OA general population where the proportion of individuals with high BMI was 61.6%, there was a higher proportion of elevated BMI in the total OA population (79.0%) and in males (83.3%) and females (76.5%) with OA individually. The prevalence of OA was also higher among those who did not exercise regularly (19.0%) compared with those who regularly exercised (14.5%). The mean number of days with exercise per month was higher among the general non-OA population (8.3 days) compared with the OA population (6.3 days overall; men: 6.7 days; women: 6.1 days). Among patients diagnosed with hypertension or diabetes, the prevalence of OA (36.2%) was higher than in the general population (9.7%). Ch±Gl (6.0%) was the most commonly used OTC dietary supplement in the OA population, followed by omega-3 fatty acids (2.8%), vitamin D (1.9%), calcium (1.1%), and multivitamins (0.7%). Approximately 32% of individuals with OA reported using Rx treatments, and the likelihood of using an Rx treatment increased as number of years since OA diagnosis increased (<3 years: 27.5%; ≥21 years: 32.5%). Among individuals with OA, those who were using Ch±Gl were less likely to use only Rx treatments (0.0%) than those who did not use Ch±Gl (19.4%). Individuals using Ch±Gl were more likely to use Rx+OTC (24.6% vs 13.0%) or OTC (75.4% vs 37.2%) products only. Tramadol (16.2%), ibuprofen (15.6%), meloxicam (15.5%), gabapentin (12.3%), and hydrocodone (11.4%) were the most common Rx treatments used in the total OA population. Approximately 13% of patients with OA had visited a physical therapist in the past 6 months.

Conclusions

The prevalence of OA was higher in those with a high BMI and those who were less likely to exercise regularly. Individuals with comorbid diabetes or hypertension had higher prevalence of OA than the general population. Individuals with OA using Ch±Gl were more likely to report use of OTC products only or to use them combined with Rx products, while those not using Ch±Gl were more likely to be untreated or use Rx products only. The likelihood of using Rx products increased with the length of OA history. These data provide valuable new information about demographics, clinical characteristics, and commonly used Rx and OTC treatments and dietary supplements in the OA population.

88 Concordance of Baseline Pain Measures (Across Two Reporting Instruments) Influences Treatment Effect of Extended-Release Triamcinolone: Phase 3 Post-Hoc Sensitivity Analysis

Nathaniel Katz¹, Edgar Ross², Dennis Turk³, Amy Cinar⁴, Joelle Lufkin⁵, Scott Kelley⁴

¹Analgesic Solutions, Natick, MA, USA, ²Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA, ³University of Washington School of Medicine, Seattle, WA, USA, ⁴Flexion Therapeutics, Inc., Burlington, MA, USA, ⁵Independent Consultant, Beverly, MA, USA

Purpose

Baseline score inflation, where patients inflate their scores on a clinical assessment for which a minimum score is required for entry, has been documented in clinical trials, and this biases studies toward a reduced estimate of treatment effect. In a Phase 3 randomized controlled study, differing efficacy results were observed when triamcinolone acetonide extended-release (TA-ER) was compared to conventional TA crystalline suspension (TAcs) with two different pain measures, average daily pain (ADP) using a 0–10 numeric rating scale (NRS) and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC-A subscale). Trial enrollment criteria may have contributed to this discrepancy, as a moderate-to-severe ADP score of ≥5 to ≤9 (NRS) was required at baseline whereas no limitations were placed on WOMAC-A average score (0–4 Likert). This allowed for randomization of patients who reported knee pain as mild via WOMAC-A criteria (average score <2). We conducted a post hoc sensitivity analysis to assess treatment effects in patients who reported moderate-to-severe osteoarthritis (OA) pain on both ADP and WOMAC-A scales (ie, concordant pain reporters, where baseline score inflation was less likely).

Methods

This post hoc analysis included adults (≥40 years) with knee OA (Kellgren-Lawrence Grade 2–3) who reported moderate-to-severe OA pain at baseline using both instruments (ADP ≥5 to ≤9 and WOMAC-A ≥ 2). Patients received a single intra-articular injection of TA-ER 32 mg (n = 95), TAcs 40 mg (n = 100), or Saline-placebo (n = 97). Patient-reported ADP‐intensity (including area-under-the-effect [AUE] curves), WOMAC-A (pain), rescue medication usage, and adverse events (AEs) were assessed throughout the study.

Results

60.3% (292/484) of patients in the full analysis population had concordant moderate-to-severe knee OA pain. Baseline characteristics and AE profiles were consistent with the full analysis population. TA-ER significantly (P < 0.05) improved ADP scores compared with TAcs (Weeks 5–19) and Saline-placebo (Weeks 1–20). AUE_Weeks1-12 and AUE_Weeks1–24 were statistically significantly greater for TA-ER compared with TAcs (least-squares mean [LSM] difference [95% CI]: −47.7 [−94.4, −1.0] and −98.4 [−194.5, −2.3], respectively; P < 0.05 for both) and Saline-placebo (LSM difference [95% CI]: −136.1 [−184.2, −88.0] and −212.1 [−311.1, −113.1], respectively; P < 0.0001 for both). At Week 12, the proportion of patients who reported they had no knee pain (ADP score = 0) was higher with TA-ER (~28%) compared with TAcs (~8%). TA-ER significantly improved WOMAC-A compared with TAcs at Weeks 4, 8, and 12 and Saline-placebo at Weeks 4, 8, 12, and 16. Significance was observed from Weeks 2–20 (TA-ER vs TAcs) and Weeks 1–24 (TA-ER vs Saline-placebo) for rescue medication.

Conclusions

In patients with knee OA who reported concordant moderate-to-severe pain at baseline across two different reporting instruments, TA-ER provided statistically significant and clinically meaningful pain relief compared with conventional TAcs and Saline-placebo. Concordant pain reporters were better able to discern treatment effect; results of this post hoc analysis have implications for study design and patient recruitment of future trials evaluating efficacy of intra-articular interventions for OA knee pain.

89 Attrition of Treatment-Emergent Adverse Events by Methylnaltrexone in Patients With Chronic Noncancer Pain and Opioid-Induced Constipation

Neel Mehta¹, Neal Slatkin^2,3, Nancy Stambler⁴, Robert Israel⁵

¹Weill Cornell Medicine, New York, NY, USA, ²University of California Riverside, School of Medicine, Riverside, CA, USA, ³Salix Pharmaceuticals, Bridgewater, NJ, USA, ⁴Progenics Pharmaceuticals, Inc., New York, NY, USA, ⁵Bausch Health US, LLC, Bridgewater, NJ, USA

Purpose

Opioids, often prescribed to treat chronic noncancer pain (CNCP), may be associated with nausea, vomiting, and constipation. Constipation, in particular, has been associated with a negative impact on quality of life and often leads to dose reduction or discontinuation of opioid therapy. Preventive measures often provide limited relief of opioid-induced constipation (OIC), and tolerance to OIC is uncommon. Methylnaltrexone is a peripherally acting µ-opioid receptor antagonist that reverses opioid-induced effects in the gastrointestinal tract, such as delayed gastric emptying and prolonged oral-cecal transit time, without reversing the opioid central effects on pain. Clinical trials of methylnaltrexone have shown that the majority of adverse events are gastrointestinal in nature (eg, abdominal pain, nausea, diarrhea), all of which are also common during laxation. This analysis assessed the reduction of adverse events after the first and second dose of methylnaltrexone in adults with CNCP and OIC.

Methods

Two randomized, double-blind trials were pooled to include adult patients diagnosed with OIC and receiving opioids regularly for CNCP. The presence of OIC was confirmed during screening and defined as fewer than 3 rescue-free bowel movements (RFBMs; no laxative use within 24 hours prior to the bowel movement) per week on average and 1 or more of the following: hard or lumpy stools, straining during bowel movements, or a sensation of incomplete evacuation after bowel movements. Patients received subcutaneous methylnaltrexone 12 mg once daily, 12 mg once every other day, or placebo for 4 weeks (study 3200K1–3356, NCT00529087) or oral methylnaltrexone 150, 300, or 450 mg or placebo daily for 12 weeks (study 3201, NCT01186770). Rescue laxative use (1 dose of up to 3 or 4 bisacodyl tablets) was permitted if the patient had no bowel movements for 3 consecutive days. Treatment-emergent adverse events and adverse event intensity (mild, moderate or severe) were evaluated on study days 1 and 2. Opioid withdrawal was assessed using the Subjective Opiate Withdrawal Scale and the Objective Opiate Withdrawal Scale data pooled from day 1 and weeks 2, 4, 6, 8, and 12. Opioid analgesia was measured using a pain scale of 0 (none) to 10 (severe). RFBMs within 4 hours of the first study drug dose (ie, RFBM responders) were assessed to evaluate efficacy.

Results

The pooled analysis included 1263 patients; 900 received methylnaltrexone (subcutaneous, n = 298; oral, n = 602) and 363 received placebo. The analysis population mean age was 50.6 years, and the majority of patients were women (61.9%). Patients in the oral methylnaltrexone treatment group reported modestly lower rates of baseline laxative use and a slightly greater mean number of RFBMs per week compared with patients who received subcutaneous methylnaltrexone. The baseline median (range) daily morphine-equivalent dose was 152.54 (7.1–2289.0) mg/d for methylnaltrexone and 145.33 (13.6–1287.0) mg/d for placebo. A total of 219 (17.3%) patients (178 [19.8%] methylnaltrexone, 41 [11.3%] placebo) experienced an adverse event during the first 2 days of treatment. Treatment-emergent adverse events declined from day 1 to day 2 (methylnaltrexone: 16.2%–5.6%; placebo: 6.6%−5.2%). The greatest decrease occurred in gastrointestinal adverse events. A significantly greater proportion of RFBM responders receiving methylnaltrexone reported abdominal pain on day 1 compared with nonresponders (10.6% and 4.2%, respectively; P = 0.0008). No association was observed between RFBM response and symptom presence in the placebo group. No meaningful changes occurred in opioid withdrawal symptoms or pain intensity.

Conclusions

This pooled analysis of methylnaltrexone use for OIC supports previous findings suggesting that treatment-emergent adverse events were generally gastrointestinal-related and decreased from day 1 to 2. The association between gastrointestinal adverse events and laxation response support the hypothesis that early-onset adverse events with methylnaltrexone, particularly gastrointestinal adverse events are, at least in part, a consequence of laxation. Methylnaltrexone effectively minimized peripherally mediated OIC without compromising the centrally mediated analgesic effect of opioids.

90 Treatment With Methylnaltrexone in Patients With Opioid-Induced Constipation With or Without Active Cancer: Effects of the Initial Dose Based on 3 Pooled Clinical Studies

Bruce Chamberlain¹, Michelle Rhiner², Neal Slatkin^3,4, Nancy Stambler⁵, Robert Israel⁶

¹Genesis Healthcare, Davenport, IA, USA, ²Loma Linda University Health, Loma Linda, CA, USA, ³University of California Riverside, School of Medicine, Riverside, CA, USA, ⁴Salix Pharmaceuticals, Bridgewater, NJ, USA, ⁵Progenics Pharmaceuticals, Inc., New York, NY, USA, ⁶Bausch Health US, LLC, Bridgewater, NJ, USA

Purpose

Opioid-induced constipation (OIC) is a common and bothersome side effect in patients receiving opioid therapy for cancer and noncancer pain. Despite laxative use, OIC often persists during opioid therapy. Methylnaltrexone (MNTX), a peripherally acting μ-opioid receptor antagonist, has demonstrated efficacy in the treatment of OIC. Subcutaneous (SC) MNTX is approved for OIC in adults with chronic noncancer pain and for OIC in adults with advanced illness or with active cancer who require opioid dosage escalation for palliative care. Results from 3 clinical trials were analyzed to characterize the response to an initial MNTX dose in patients with and without cancer, most of whom had not had an adequate response to laxative therapy.

Methods

This post hoc analysis pooled results from 3 randomized, placebo-controlled studies of MNTX for the treatment of OIC (N = 518). Patients with advanced illness received single doses of SC MNTX 0.15 or 0.30 mg/kg or placebo (study 301, NCT00401362); SC MNTX 0.15 mg/kg or placebo every other day for 2 weeks (study 302, NCT00402038); or SC MNTX 8 or 12 mg in patients 38–<62 or ≥62 kg, respectively, or placebo every other day for 2 weeks (study 4000, NCT00672477). Data were generated to analyze the proportion of patients with rescue-free laxation (RFL, defined as laxation without the use of other laxatives) response ≤4 hours and ≤24 hours postdose, time to RFL, effects on opioid analgesia 4 hours postdose (assessed via pain scores based on an 11-point rating scale), and treatment-emergent adverse events (TEAEs), stratified by the presence/absence of cancer and by treatment

Results

The pooled intent-to-treat population included 355 patients with cancer (MNTX n = 198, placebo n = 157) and 163 without active cancer (MNTX n = 83, placebo n = 80). The analysis population represented patients with a mean age of 64 to 73 years, most of whom were white. More men were represented in the cancer cohort while more women were represented the noncancer cohort. Although the cancer and noncancer groups were similar with respect to current and worst pain scores and use of laxatives, median baseline opioid use was higher in cancer (MNTX: 190 mg/d, n = 198; placebo: 200 mg/d, n = 157) versus noncancer patients (MNTX: 120 mg/d, n = 82; placebo: 80 mg/d, n = 80). MNTX significantly increased the percentage of patients with an RFL response ≤4 hours and ≤24 hours after the first dose in cancer (MNTX: 61.1% and 71.2%, placebo: 15.3% and 41.4%, respectively; P < 0.0001 for all MNTX/placebo comparisons) and noncancer patients (MNTX: 62.2% and 74.4%, placebo: 17.5% and 37.5%, respectively; P < 0.0001 for all MNTX/placebo comparisons). Time to RFL was similar in cancer and noncancer patients, but faster among those receiving MNTX with most patients responding by the 1-hour time point. Postdose mean pain scores declined similarly in all groups, with no evidence of MNTX-induced compromise of opioid analgesia. The most common gastrointestinal adverse events in both cancer and noncancer patients were abdominal pain, flatulence, nausea, and vomiting. Abdominal pain, a common symptom associated with laxation, was the most frequently reported TEAE in the MNTX group (38.6% vs 28.3% in the cancer and noncancer cohorts, respectively) compared with the placebo group (11.5% vs 13.8% in the noncancer cohorts, respectively).

Conclusions

When administered to severely ill patients with OIC receiving chronic opioid therapy with an inadequate response to conventional laxatives, a single dose of MNTX was associated with an effective and rapid laxation response in the majority of patients regardless of whether they had a cancer diagnosis, suggesting that the presence of cancer does not impact the effectiveness of MNTX. Use of MNTX with a cancer diagnosis did not compromise opioid-induced analgesia, and the gastrointestinal adverse events observed were similar to those that occur during effective laxation (eg, abdominal pain, flatulence, nausea). Further studies are needed to assess if these findings translate into reducing treatment costs and hospitalization rates.

91 Evaluation of a Pharmacist-Led Pain Care Management Pilot Program

Olivia Letzkus¹, Holly Little¹, Ranna Ardebili¹, Mariah Pettapiece-Phillips¹, Meridith Blevins Peratikos^1,2, Stacey Grant¹, Elizabeth Ann Stringer¹

¹axialHealthcare, Nashville, Tennessee, USA, ²Vanderbilt University Medical Center, Department of Biostatistics, Nashville, Tennessee, USA

Purpose

Pain is the leading cause of disability in America, a major contributor to health care costs, and the most common reason Americans access care. As the healthcare system moves towards value-based care, a patient-centered approach to pain management will be necessary to improve outcomes for individuals experiencing acute and chronic pain. Patient Support Programs (PSPs) have emerged to meet this need and can include education and counseling, health coaching, home visits, care coordination, and medication management. PSPs have shown potential to improve medication adherence, clinical outcomes, and lowered healthcare costs. Further research is needed to establish the associated improvements in care specifically for pain care management, along with which delivery methods and program components offer the greatest value.

Modeled after PSPs, a pharmacist-led pain care management program (PCMP) was piloted in partnership with a Pennsylvania-based Medical Assistance Managed Care Organization (MCO). Objectives of this patient outreach program included supporting coordinated care with appropriate clinicians, providing clinical guidance on medication and alternative management of pain and comorbidities, improving patient self-efficacy in managing pain and function in daily life, and providing general health coaching.

This analysis describes the PCMP workflow, patient demographics for those enrolled in the program, and results for patient-reported pain intensity and interference, self-efficacy in managing pain, change in quality of life, and satisfaction with the program. Characterization of patient outreach, including methods, duration, frequency, and days between outreach attempts is also described. Findings will highlight the impact of a pharmacist-led PCMP and opportunities for improvement in future program iterations.

Methods

Patient eligibility for the PCMP was determined by a Pennsylvania-based MCO and included patients that have been on opioids for at least 30 consecutive days with greater than or equal to 90 morphine milligram equivalents (MME) per day prior to November 2017. This provided a list of 1,348 patients with MCO coverage meeting eligibility requirements, and 374 of those patients were ultimately enrolled in the program.

The PCMP was facilitated by a team of engagement specialists, health coaches, and clinical pharmacy specialists that provided patient support via telephonic, video messaging, and in-person outreach from January through December 2018. PCMP clinical content was designed using guidelines for pain management, and patient support was modeled after an evidence-based health and wellness program for patients with chronic pain. Upon conclusion of the program, we reviewed the distribution of outreach methods (telephonic, video, in-person) as well as mean and median duration of outreach, time between outreach attempts, and frequency of successful outreach. Successful outreach included only attempts where a team member and patient had meaningful interaction based on program goals, either telephonically, over video-chat, or in-person (scheduling, pending callbacks, and voicemails not included).

Patient demographics and access to remote communication methods were collected upon enrollment. The Pain, Enjoyment, and General Activity (PEG) scale was administered throughout the program to assess trends in patient-perceived pain intensity and interference. Patients with at least two PEG values (N = 76) were included in subsequent PEG analyses. In a response feature analysis, individual slopes summarizing change in PEG scores per quarter of engagement were averaged and compared to the null hypothesis of no change using a one-sample t-test. We further evaluated the comparative effectiveness of telephonic versus face-to-face (video or in-person) outreach using a two-sample t-test comparing each group’s mean change in PEG per quarter of engagement.

Near the end of the program, a survey including the Patient-Perceived Self-Efficacy (PSEQ) scale and Perceived Global Impression of Change (PGIC) scale was administered to a convenience sample of patients to evaluate self-efficacy in managing pain and function in daily life and patient-perceived change in quality of life, respectively, and to assess overall program satisfaction. Kendall’s tau was used to estimate correlation between patient self-efficacy and perceived change in quality of life scores.

Results

Of the 374 patients initially enrolled, only patients with at least one successful outreach after enrollment were included in analyses (N = 142). The majority (57%) of patients were female with a mean age of 50 years (median: 50). 81% were Caucasian; 43% single; 76% had achieved an education level of high school or less; and 91% were unemployed at the time of enrollment. 49% of patients reported access to the Internet. 76% owned a cellphone: 50% with smartphone application capability, 40% video messaging, 66% short message service (SMS), and 22% with unlimited minutes.

12% of patients received video and/or in-person outreach. Mean outreach duration was 32 minutes (median: 15); mean days between successful outreach was 20 (median: 13); and mean successful outreach frequency was 12 sessions (median: 8).

76 patients reported at least two PEG values and were included in response feature analyses. Patients saw a mean average improvement in PEG score equal to −0.33 during one quarter of engagement. This improvement was statistically different from zero at alpha = 0.05 level of significance (95% CI = -Inf to −0.33). Patients who received video or in-person outreach (N = 11) had greater improvement in PEG scores (median change of −0.66 points per quarter of engagement) compared to patients who received telephonic outreach only (N = 60, median change of −0.25 per quarter of engagement). This difference was not statistically significant at the alpha = 0.05 level of significance, potentially limited by the small sample size.

Among the convenience sample (N = 35), we found a significant positive association between patient self-efficacy and patient-perceived global impression of change. Patients who scored higher on self-efficacy at the end of the program were more likely to report an improved difference in managing their pain and in their overall quality of life (τb = 0.37, p = 0.004). Of survey respondents, most (N = 27, 77%) reported they would refer the program to a friend or family member; the PCMP net promoter score among survey respondents was 74.

Conclusions

Patients enrolled in this pharmacist-led PCMP demonstrated quarterly improvement in PEG scores over one year of engagement. Patients who received face-to-face outreach via video or in-person communication experienced better PEG improvements compared to those with only telephonic outreach. However, these results may be confounded by clinical pharmacists being largely responsible for face-to-face outreach versus other members of the PCMP team. Future analyses could examine whether a clinical or face-to-face outreach component is most important for improving pain intensity scores.

The positive correlation between self-efficacy and patient-perceived change in quality of life indicates that the program had a positive impact on patient lives, regardless of pain reduction. Patient-perceived measures provide valuable non-clinical insight into the behavioral health challenges of complex pain care management. Future programs may include a mixed-methods design, utilizing both clinical and non-clinical indicators to support and determine effectiveness among patients who live with acute or chronic pain.

Lack of access to remote communication methods was a main barrier for patient outreach; less than half of enrolled patients had internet access, and one-fourth did not own a cellphone. Future programs should strive to overcome communication challenges by accommodating patient communication method preferences or providing access to telehealth communication resources.

92 Long-term efficacy of fremanezumab in patients with chronic migraine with concomitant preventive medication use

Peter J. Goadsby¹, Joshua M. Cohen², Ronghua Yang², Xiaoping Ning², Adelene E. Jann³

¹NIHR-Wellcome Trust King’s Clinical Research Facility, King’s College London, London, United Kingdom, ²Teva Pharmaceuticals, Frazer, PA, USA. ³Department of Neurology, NYU Langone Health, New York, NY, USA

Purpose

Migraine preventive treatment is intended to reduce the frequency, severity, and disability associated with migraine attacks. Fremanezumab, a fully humanized monoclonal antibody (IgG2Δa) that selectively targets calcitonin gene-related peptide (CGRP), is approved in the US for the preventive treatment of migraine in adults. Herein we evaluated the long-term efficacy of fremanezumab in adults with chronic migraine (CM) with concomitant preventive medication use.

Methods

In this 52-week, multicenter, randomized, double-blind, parallel-group study, patients with CM received either subcutaneous fremanezumab monthly (225 mg every month with a starting dose of 675 mg) or quarterly (675 mg every 3 months). The mean change from baseline was assessed for the monthly average number of headache days of at least moderate severity and migraine days, as was the percentage of patients with ≥50% or ≥75% reduction in the monthly average number of migraine days.

Results

A total of 268 patients with CM used concomitant preventive medications, the most common of which were topiramate (37%), amitriptyline (18%), and propranolol (11%). Headache days of at least moderate severity decreased from baseline of the blinded phase (mean quarterly 14.2 days, monthly 14.7 days) to Month 12 by 5.9 days in the quarterly group and 6.1 days in the monthly group. The mean change in the monthly average number of migraine days from baseline to Month 12 was – 6.9 days for quarterly and – 6.8 days for monthly dosing. The proportion of patients with ≥50% reduction in migraine days at Month 12 was 52.5% for quarterly and 47.7% for monthly dosing. The proportion of patients with ≥75% reduction in migraine days at Month 12 was 19.8% for quarterly and 24.3% for monthly dosing.

Conclusions

The efficacy of fremanezumab was maintained over 12 months of treatment in patients with CM with concomitant preventive medication use.

93 Long-term response rates in chronic and episodic migraine patients with concomitant preventive medication use: results from 1-year study

Peter J. Goadsby¹, David W. Dodick², Joshua M. Cohen³, Ronghua Yang³, Xiaoping Ning³, Steven D. Silberstein⁴

¹NIHR-Wellcome Trust King’s Clinical Research Facility, King’s College, London, United Kingdom, ²Mayo Clinic Arizona, Phoenix, AZ, USA, ³Teva Pharmaceuticals, Frazer, PA, USA, ⁴Jefferson Headache Center, Thomas Jefferson University, Philadelphia, PA, USA

Purpose

Some migraine patients may take more than one migraine preventive medication. Fremanezumab, a fully humanized monoclonal antibody (IgG2Δa) that selectively targets calcitonin gene- related peptide (CGRP), is approved in the US for the preventive treatment of migraine in adults. Herein we evaluated the response rate following treatment with fremanezumab in chronic (CM) and episodic migraine (EM) patients who used additional concomitant migraine preventive medications.

Methods

This was a multicenter, randomized, double-blind, parallel-group study consisting of a 12-month treatment period during which we evaluated two subcutaneous dose regimens of fremanezumab in adults with CM and EM. The study included patients rolled over from two placebo-controlled studies, as well as new patients. Patients could continue using a maximum of one (rollover patients) or two (new patients) concomitant oral migraine preventive medications, provided that dosing was stable for ≥2 consecutive months prior to study entry. Patients were assigned to either quarterly (675 mg every 3 months) or monthly (225 mg monthly; CM: starting dose of 675 mg) dosing. Post hoc analyses were performed to measure the proportion of CM and EM patients who used oral concomitant preventive medication and demonstrated a ≥ 50%, ≥75%, and 100% reduction in the monthly average number of migraine days and in the monthly average number of headache days of at least moderate severity at Month 12.

Results

This analysis included 268 CM patients (quarterly: n = 128; monthly: n = 140) and 181 EM patients (quarterly: n = 89; monthly: n = 92) who used oral concomitant preventive medications. At Month 12, the ≥50%, ≥75%, and 100% response rates for monthly average number of migraine days in CM patients receiving quarterly dosing were 53%, 20%, and 3%, respectively, and 48%, 24%, and 7%, respectively, with monthly dosing. CM patients also reported a ≥ 50%, ≥75%, and 100% reduction in the monthly number of headache days of at least moderate severity at Month 12 (quarterly: 51%, 23%, and 8%, respectively; monthly: 51%, 25%, and 10%, respectively). At Month 12, EM patients also reported a ≥ 50%, ≥75%, and 100% reduction in the monthly number of migraine days (quarterly: 58%, 27%, and 9%, respectively; monthly: 63%, 41%, and 18%, respectively). In EM patients, the ≥50%, ≥75%, and 100% response rates for monthly number of headache days of at least moderate severity at Month 12 were 63%, 30%, and 17%, respectively, with quarterly dosing and 61%, 42%, and 22%, respectively, with monthly dosing.

Conclusions

As measured by response rates throughout the 12-month treatment period, long-term treatment with fremanezumab led to a clinically meaningful reduction, which increased over time, in the monthly number of migraine days and headache days of at least moderate severity in CM and EM patients receiving concomitant oral migraine preventive medications.

94 Sustained response to erenumab over time in patients with episodic migraine

Peter McAllister¹, Ira Turner², Uwe Reuter³, Bert Vargas⁴, James Scanlon⁵, Jan Klatt⁶, Sharon Richards⁷, Denise Chou⁵, Gabriel Paiva da Silva Lima⁵

¹New England Institute for Neurology and Headache, Stamford, CT, USA, ²Island Neurological Associates, Plainview, NY, USA, ³Department of Neurology, Charité Universitätsmedizin Berlin, Berlin, Germany, ⁴UT Southwestern, Dallas, TX, USA, ⁵Amgen Inc., Thousand Oaks, CA, USA, ⁶Novartis, Basel, Switzerland, ⁷Amgen Ltd, Uxbridge, United Kingdom

Purpose

Erenumab is a fully human anti-calcitonin gene-related peptide (CGRP) receptor monoclonal antibody approved for migraine prevention. While many patients treated with erenumab experience onset of efficacy as early as one week, details about the maintenance of these clinical responses have not been reported. This analysis evaluated patterns of sustained response with continued erenumab treatment in patients with episodic migraine (EM).

Methods

This was a post hoc analysis of data from STRIVE (ClinicalTrials.gov NCT02456740), a 6-month, randomized, double-blind, placebo-controlled, phase 3 study of erenumab in patients with EM (N = 955). Patients were categorized as initial responders if they achieved a ≥ 50% reduction in monthly migraine days (MMD) at month 1. During the following months of treatment, patients with initial response were classified as having an ‘excellent’ (≥75% reduction in MMD) or ‘good’ (≥50% to 75% reduction in MMD) subsequent response. This analysis was limited to those randomized to erenumab treatment

Results

At month 1, 33% (102/312) of patients in the erenumab 70 mg group and 36% (113/318) of patients in the erenumab 140 mg group achieved an initial response of ≥ 50% reduction from baseline in MMD, and 11% and 14% achieved ≥75%.

Of the initial responders, a ≥ 50% MMD reduction from baseline was maintained by 72% (73/102) and 70% (79/113) of patients at month 2 and by 84% (86/102) and 84% (95/113) at month 2 or 3 in the 70 mg and 140 mg groups, respectively. An excellent response (≥ 75% reduction from baseline in MMD) was achieved at month 2 or month 3 by 54% (55/102) of the initial responders in the 70 mg group and 54% (61/113) in the 140 mg group. Of the patients who initially responded but did not maintain a ≥ 50% response through month 2, 45% (13/29) and 47% (16/34) regained a ≥ 50 response at month 3. A good or excellent response was maintained through month 6 based on mean MMD change over months 4 to 6 by 78% (80/102) of the initial responders in the 70-mg group and 74% (84/113) of the initial responders in the 140 mg group.

Conclusions

Most patients with EM who achieved a response after one month of erenumab treatment maintained or further improved their response following continued treatment.

This publication was supported by Novartis Pharmaceuticals Corporation, East Hanover, NJ, as part of a collaboration between Novartis and Amgen Inc.

95 Identifying Sociodemographics and Symptoms Associated with Emergency Department and Urgent Care Use in People with Migraine: Survey Results from Migraine in America Symptoms and Treatment Study

Todd Schwedt¹, Sagar Munjal², Michael Reed³, Kristina Fanning³, Leah Bensimon², Preeti Singh², Richard Lipton⁴

¹Mayo Clinic, Phoenix, AZ, USA, ²Dr. Reddy’s Laboratories, Princeton, NJ, USA, ³Vedanta Research, Chapel Hill, NC, USA, ⁴Albert Einstein College of Medicine, Bronx, NY, USA

Purpose

Unplanned medical treatment at a hospital emergency department or urgent care center (ED/UC) for a chronic condition such as migraine increases the economic burden and is considered by some clinicians as a treatment failure. The objective of this analysis was to identify sociodemographic and symptom characteristics associated with ED/UC utilization within the prior 6 months in a population sample of persons with migraine.

Methods

Respondents to the Migraine in America Symptoms and Treatment (MAST) Study were recruited from a nationwide online research panel. A stratified sample of US adults age 18 and older were invited to participate and migraine cases were identified using a validated symptom screener based on modified ICHD-3b criteria. Inclusion in the study required an average of at least one headache day per month over the last 3 months. In addition to headache symptoms, the assessment included sociodemographics (age, gender, race, income, smoking, BMI), monthly headache day (MHD) frequency, ictal cutaneous allodynia (ASC12), psychological symptoms (anxiety and depression; PHQ4). Logistic modeling was used to identify variables associated with ED/UC use after controlling for sociodemographics and MHD frequency.

Results

15,133 of 95,821 respondents met study inclusion criteria. There were 1284 (8.5%) with ³1 ED/UC visit (men 9.7%, women 8.0%; p < .001); mean number of visits was 2.4 (men 3.1, women 2.1; p < .001). ED/UC use occurred more often in younger respondents (39.3 vs 43.4 years; p < .001), non-Caucasians (25.4% vs 18.4%; p < .001), current smokers (24.8% vs 10.1%; p < .001) and those with below normal BMI (9.6% vs 2.6%, p < .001). Episodic migraine cases comprised 81.3% of ED/UC users and 18.7% met headache frequency criteria (³15 MHDs) for chronic migraine. Those with allodynia were 2.3 times more likely to be seen in ED/UC (95%CI:2.06–2.65), as were those with frequent vomiting OR 3.2 (95%CI:2.79–3.76), frequent nausea OR 2.0 (95%CI:1.77–2.26), PHQ anxiety OR 1.5 (95%CI:1.271.74) and PHQ depression OR 1.7 (95%CI: 1.45–2.00).

Conclusions

Men and younger respondents were more likely to report ED/UC use, as were current smokers, non-Caucasians and those with below normal BMI. After considering sociodemographics and MHD frequency, allodynia was associated with increased odds of ED/UC utilization, as were frequent nausea and vomiting, perhaps due to dehydration risk. The presence of clinical anxiety and depression were also risk factors.

96 Headache Treatment Pattern and Co-morbid Health Burden Associated with Emergency Department and Urgent Care Use in People with Migraine: Survey Results from Migraine in America Symptoms and Treatment Study

Todd Schwedt¹, Sagar Munjal², Michael Reed³, Kristina Fanning³, Leah Bensimon², Preeti Singh², Richard Lipton⁴

¹Mayo Clinic, Phoenix, AZ, USA, ²Dr. Reddy’s Laboratories, Princeton, NJ, USA, ³Vedanta Research, Chapel Hill, NC, USA, ⁴Albert Einstein College of Medicine, Bronx, NY, USA

Purpose

Unplanned medical treatment for migraine at a hospital emergency department or urgent care center (ED/UC) is expensive and taxing on healthcare resources. The objective of this analysis was to evaluate the role of different acute medication classes, treatment optimization and co-morbid health burden on ED/UC utilization in a population sample of persons with migraine.

Methods

Respondents to Migraine in America Symptoms and Treatment (MAST) Study were recruited from a nationwide online research panel. A stratified sample of US adults age ³18 were screened for migraine using modified ICHD-3b criteria. Inclusion required an average of at least one headache day/month in the last 3 months. The assessment included sociodemographics (age, gender, race, income, smoking, BMI), monthly headache day (MHD) frequency, acute medication use, migraine Treatment Optimization Questionnaire (mTOQ) and 20 co-morbid health problems previously diagnosed by a physician. Logistic modeling identified variables associated with ED/UC use after controlling for sociodemographics and MHDs.

Results

Of the 95,821 respondents, 15,133 met study inclusion criteria; 1284 (8.5%) reported one or more ED/UC visit in prior 6-months, with 2.4 mean visits. Prescription opioid users had significantly higher odds of utilizing ED/UC care (OR 3.6, 95%CI:3.1–4.1), as did ergotamine users (OR 11.4, 95%CI:7.80–16.78), oral triptan users (OR 2.09, 95%CI:1.81–2.44), subcutaneous triptan users (OR 6.2, 95%CI:4.48–8.55), and intranasal triptan users (OR 3.9, 95%CI:3.12–5.09). ED/UC users were also associated with reporting very poor/poor mTOQ treatment optimization compared to nonusers (52.8% vs 33.1%, Chi:250.52, p < .001). Increasing co-morbid health burden was associated with ED/UC use for migraine (ref migraine alone; 1–2 conditions OR 1.2, 95%CI:0.86–1.79; 3–4 OR 1.7, 95%CI:1.21–2.47; 5+ OR 3.0, 95%CI:2.13–4.34).

Conclusions

8.5% of MAST migraine cases reported ED/UC use in the past 6-months. After accounting for sociodemographics and MHD frequency, use of opioids, ergots and triptans were associated with higher odds of ER/UC visits, as were co-morbid health conditions when 3 or more were present. Very poor/poor acute treatment optimization occurred more often among those using ED/UC care, perhaps suggesting that improvements in acute management of migraine may reduce ED/UC utilization and decrease the direct economic burden of the disease

97 One-Year Incidence of Migraine in the US Population: Results from the Migraine in America Symptoms and Treatment (MAST) Study

Richard Lipton¹, Michael Reed², Sagar Munjal³, Preeti Singh³, Leah Bensimon³, Dawn Buse¹, Walter Stewart⁴, Todd Schwedt⁵, David Dodick⁵

¹Albert Einstein College of Medicine, Bronx, NY, USA, ²Vedanta Research, Chapel Hill, NC, USA, ³Dr. Reddy’s Laboratories, Princeton, NJ, USA, ⁴HINT Consultants, Orinda, CA, USA. ⁵Mayo Clinic, Phoenix, AZ, USA

Purpose

Surprisingly few longitudinal studies of migraine incidence have been reported. Prior studies have typically included modest samples or a limited range of ages. Larger studies have used self-reported age of migraine onset and current age to reconstruct cohorts and model incidence estimates. Herein, we present robust migraine incidence estimates from the longitudinal assessment among MAST Study respondents.

Methods

The baseline MAST Study surveyed and screened a representative sample of US adults for migraine applying modified ICHD-3 beta criteria. A total of 95,821 individuals completed the initial survey; 77,453 respondents free of migraine in the initial assessment were re-assessed 12 months later via the same Web-survey methodology. New onset (incident) migraine was defined if respondents met ICDH-3 beta criteria and reported headaches that began for the first time in the previous year. The MAST survey also assessed sociodemographics, monthly headache day (MHD) frequency, cutaneous allodynia (ASC-12), disability (MIDAS), treatment efficacy (mTOQ), hallmark symptoms of anxiety and depression (PHQ-4) and current medication use for migraine. Descriptive data are provided for the incident migraine cases.

Results

A total of 40,468 (52.2%) individuals free of migraine at baseline completed the 12-month follow-up assessment and provided usable data. Of these, 900 individuals (2.2%, 95%CI 2.08–2.37) met criteria for incident migraine (62.8% women, mean age 46.6 yrs). Incident migraine occurred in 1.5% (95%CI 1.36–1.69) of men and in 3.1% (95%CI 2.81–3.31) of women responding to the survey. Incidence declined with age (Table) in both women and in men. Only 21.3% of incident migraine cases reported a healthcare provider diagnosis of migraine or closely related conditions. Based on the MIDAS questionnaire, 11.8% had severe disability and 11.1% had moderate disability. Allodynia was present in 25.9% of cases (ASC-12) and 33.4% reported poor or very poor treatment efficacy (mTOQ). Finally, 2.2% of incident migraine cases had chronic migraine based on ³15 MHD criteria. Positive screen for anxiety occurred in 24.2% and for depression in 20.6% (PHQ-4). 18.1% used prescription medication to treat headache, 4.9% used a triptan and 63.7% used prescription or OTC NSAIDs.

Conclusions

The annual incidence of migraine in this sample is in-line with prior estimates. Incidence was twice as high in women than men and highest in the youngest age group. Rates of disability, allodynia and comorbidity were lower in incident cases versus comparable prevalent samples suggesting that migraine may worsen over time. In the total sample just under a quarter (22.9%) reported moderate to severe disability and just over a quarter (25.9%) were allodynic. Patients reported rates of diagnosis, use of acute headache/migraine medications and treatment optimization were also low supporting prior findings that obtaining a diagnosis and effective treatment is often delayed. The existence of a rapidly progressive subgroup is demonstrated by the 2.2% of incident cases meeting criteria for CM within 12 months of onset.

98 Identification of Pain, Activity Level, and Neuropsychiatric Symptoms in Chronic Pain Patients Receiving Joint and Soft Tissue Corticosteroid Injections

Rachel Ciota, Andrea Collins, Kevin Pan

Samford University, Birmingham, AL, USA

Purpose

Neuropsychiatric side effects resulting from corticosteroid use are a documented occurrence but available literature focuses on long-term oral and epidural injection steroid therapies rather than intermittent joint and soft tissue injections. No clear guideline exists that specifically addresses the dosage or duration between joint and soft tissue injections. The perceived and reported benefits of frequent (more often than every three months) administration of intra and peri-articular joint and soft tissue corticosteroid injections (CSI) by chronic pain patients in a private interventional pain management clinic make it difficult to limit this therapy without contention.

The purpose of this study is to identify the presence of neuropsychiatric symptoms in chronic pain patients receiving office-based CSIs more often than every three months (‘frequent’) compared to those receiving them less often (‘less frequent’), and to evaluate the benefit to pain and activity levels based on the frequency of injections.

Methods

The Iowa Model of Research-Based Practice to Promote Quality Care, which guides clinicians in evaluating for practice change and incorporating research findings into patient-centered care, is the chosen framework for this pilot study. A sample of 55 patients (29 frequent and 26 less frequent) accepted participation in the project. Generalized Anxiety Disorder (GAD-7) and Center for Epidemiologic Studies Depression Scale Revised (CEDS-R) screening test scores were obtained through an electronic behavioral health assessment tool and pain and activity level scores were obtained through the Indiana Polyclinic Combined Pain and Function Scales survey.

Results

Data provides no evidence that there is a difference in neuropsychiatric symptoms between frequent and less frequent CSI injections and no evidence that there is a correlation between total corticosteroid dose and neuropsychiatric symptoms. Data provides no evidence that there is a difference in pain or activity scores between frequent and less frequent CSI groups. The frequent CSI group had more pain relief with a p-value of 0.0266, however, this is not significant due to adjustment of the p-value threshold when completing multiple comparisons.

Conclusions

Future studies are needed to study the relationship between CSI frequency and neuropsychiatric symptoms. Given the potential for systemic side effects associated with corticosteroid use, and a lack of significant improvement in pain and activity, providers should consider limiting this therapy to meet the recommended interval of three months between intra and peri-articular injections.

99 The Effect of the Prescription Drug Monitoring Program on Emergency Department Opioid Prescribing Habits

Rahul Gupta¹, Sue Boehmer¹, David Giampetro², Christopher DeFlitch²

¹Pennsylvania State College of Medicine, Hershey, PA, USA, ²Pennsylvania State Hershey Medical Center, Hershey, PA, USA

Purpose

From 1999 to 2010, opioid prescriptions have quadrupled – many of which came from the emergency department (ED). Parallel to this trend is a four-fold increase in opioid overdose deaths. Therefore, the prescribing habits of ED providers have been brought under scrutiny. Currently, the primary method being utilized to monitor opioid prescriptions is a prescription drug monitoring program (PDMP), which documents patients’ prescribed controlled substances. Current literature examining opioid prescription rates after PDMP implementation fail to show consistent results, likely due to program variability. In addition, limited studies have examined the effect of a PDMP on opioid prescription rates within pain scale cohorts. Therefore, the objective of the current study is to determine if a PDMP implementation alters ED opioid prescription rates overall and in patients of different pain severities.

Methods

This study was approved by the institutional review board (IRB). A single-center retrospective review was conducted at an academic, suburban ED. The overall study examined patients discharged from the ED who received opioid prescriptions that were recorded in the electronic medical record (EMR), before and after the state implementing a PDMP system. Monthly rates of opioid prescriptions from December 2014 – August 2016 (pre-PDMP) were compared to the rates from September 2016 – May 2018 (post-PDMP). PDMP implementation occurred on August 25, 2016. The monthly rate was a ratio of the patients given ≥ 1 opioid prescription to the ED patients with a numerical pain score (NPS) > 0. An Interrupted Time Series Analysis was performed using SAS, Version 9.4. Pain scores were separated as follows: 1–4 (mild), 5–6 (moderate), and 7–10 (severe). The following data was extracted: 1) age, 2) gender 3) date of encounter 4) pain scale 5) name of drug.

Results

Pre-PDMP, 12,058 patient visits (7,399 male, 4,659 female), with a median age of 43 were reviewed. Of these patients, 3,049 reported mild pain, 2,621 reported moderate pain, and 6,388 reported severe pain. 51.3% of the patients in the pre-PDMP period received opioid prescriptions. Post-PDMP, 14,745 patient visits (8,986 male, 5,759 female) with median age of 42 were reviewed. Of these patients, 4,732 reported mild pain, 3,301 reported moderate pain, and 6,712 reported severe pain. 47.9% of the patients in the post-PDMP period received opioid prescriptions. Combining the cohorts, 26,803 patient visits with an NPS>0 were reviewed. 16,385 were male and 10,418 were female. 7,781 reported mild pain, 5,922 reported moderate pain, and 13,100 reported severe pain. The median age was 42 years old. Of all these ED pain patients, 13,239 patients were prescribed opioids.

The following changes were seen in ED opioid prescribing rates from the pre-PDMP period to the post-PDMP period. The overall ED opioid prescription rate significantly decreased from 51.3% (95% Cl, 50.4%-52.2%) to 47.9% (95% Cl, 47.0%-48.7%). The ED opioid prescription rate in male patients decreased significantly from 51.1% to 46.7% (p < 0.0001). The ED opioid prescription rate in female patients did not significantly change from 51.6% to 49.7% (p = 0.0529). The ED opioid prescription rate in patients with mild pain increased significantly from 27.5% to 34.3% (p < 0.0001). The ED opioid prescription rate in patients with moderate pain did not significantly change from 42.8% to 43.5% (p = 0.5924). The ED opioid prescription rate in patients with severe pain decreased significantly from 66.1% to 59.6% (p < 0.0001).

Conclusions

Some suggest the primary goal of the PDMP is to curb the opioid epidemic by allowing providers to detect patients who may be prescribed opioids too frequently. At the very least, it provides some transparency to the rate of opioid prescribing. In the current study, the implementation of the PDMP was associated with an overall significant decrease in opioid prescription rates in this ED. Therefore, findings demonstrate an overall success in reducing opioid prescription rates that may lead to subsequent opioid abuse and overdose deaths. In addition, the current study also found distinct changes in prescribing habits within different pain cohorts. With the PDMP implementation, mild pain patients were prescribed opioids more often while severe pain patients were prescribed opioids less often. These changes could be due to severe pain patients more often presenting with chronic pain and thereby more typically already prescribed opioids. Ultimately, this data evokes an interesting discussion and questions for further research, such as investigation of opioid prescription rates after direct point-of-care PDMP integration into the EMR.

100 Evaluation of the Efficacy of Intra-articular CNTX-4975 in Subjects With Knee Osteoarthritis: Results From an 8-Week Study

Randall M. Stevens¹, Kimberly Guedes¹, Eddie Armas², Valerie H. Smith³, Andrew Volosov³, James N. Campbell¹

¹Centrexion Therapeutics Corp, Boston, MA, USA, ²Well Pharma Medical Research Corp, Miami, FL, USA, ³Premier Research, Durham, NC, USA

Purpose

CNTX-4975 (highly purified formulation of capsaicin [>99.5% trans-capsaicin, <0.5% total impurities]) is being studied in phase 3 trials for the treatment of moderate to severe pain associated with knee osteoarthritis (OA). In a phase 2b, double-blind, randomized, placebo-controlled trial (TRIUMPH; NCT02558439), a single 1-mg intra-articular (IA) injection of CNTX-4975 into an index knee resulted in a statistically significant decrease in pain with walking on a flat surface versus placebo through 24 weeks post-dose. We conducted a phase 1 study (NCT03576508) to assess pharmacokinetics (primary endpoint; compared with 8% capsaicin patch), efficacy, safety, and local tolerability following a single IA injection of CNTX-4975 in subjects with moderate to severe knee OA pain. Herein we present efficacy results from this study.

Methods

This open-label, 2-way crossover study enrolled adults aged 50–75 years with moderate to severe knee OA pain with walking in 1 knee. The more painful knee was designated the index knee; the nonindex knee had no to mild pain (0–1 score on a 0–4 numeric rating scale [NRS]). Subjects were randomized 1:1 to 2 sequences: A (CNTX-4975 1 mg IA injection, index knee) followed by B (topical capsaicin 8% patch, posterior rib cage for 60 minutes) or BA sequence, with ≥7-day washout between study drug administration. The efficacy objective was to observe the improvement in symptoms in the index knee following IA CNTX-4975 injection. Efficacy was assessed by change from baseline (last measurement before CNTX-4975 injection) to day 56 (±5 days; week 8) in Knee Injury and Osteoarthritis Outcome Score (KOOS) for each subscale assessment in subjects receiving IA CNTX-4975 1 mg injection in the index knee (intent-to-treat [ITT] population). The KOOS questionnaire evaluated both short- and long-term consequences of knee injury. The five KOOS subscales, Pain, Symptoms, Function (Daily Living; Sports and Recreational Activities), and Knee-related Quality of Life, were calculated for the index knee. Each subscale was rated on a 5-point scale (0–4). Scores were normalized as 100 – ([average subscale score x 100]/4), with 100 = no symptoms and 0 = extreme symptoms. If a subject answered ≤50% of questions for a subscale, no normalized subscale score was calculated for that subject. The proportion of KOOS Pain with Walking and Pain Subscale responders with ≥30%, ≥50%, ≥70%, and ≥90% change from baseline was determined for the index knee. As KOOS was developed as an extension of the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), all three WOMAC dimension scores (A, Pain [5 KOOS questions; range 0–50], B, Stiffness [2 questions; 0–20], and C, Function [17 questions; 0–170]) were derived from the KOOS and converted to an 11-point NRS (0 = none, 10 = extreme); more negative scores indicated greater improvement (week 8 minus baseline). Efficacy data were reported using descriptive summaries and percent change and/or change from baseline; no formal inferential analyses were conducted.

Results

Sixteen subjects (mean age: AB 62 years, BA 61 years; female, 62.5% in each sequence group) were randomized. Two subjects in sequence BA withdrew from the study before receiving CNTX-4975; therefore, the ITT population comprised 14 subjects. All KOOS mean subscale scores improved from baseline to week 8. Mean (standard deviation [SD]) KOOS Symptoms score improved from 58.2 (19.53) to 71.4 (23.61), a 29% (47.8) mean change from baseline. Mean KOOS Pain score improved from 50.4 (14.45) to 72.6 (22.06); mean percent change from baseline was 48% (46.8). KOOS Function scores improved from 56.5 (15.86; Daily Living) and 34.6 (13.37; Sports and Recreational Activities) at baseline to 73.8 (20.65; 34% [35.3] mean change from baseline) and 62.1 (30.05; 88% [102.1] mean change from baseline), respectively. Mean Knee-related Quality of Life scores improved from 38.4 (14.47) to 63.0 (24.33); mean percent change from baseline was 84% (102.4). The cumulative responder analysis of KOOS Pain with Walking (Index Knee) found that 43%, 36%, 29%, and 29% of subjects had a ≥ 30%, ≥50%, ≥70%, and ≥90% improvement from baseline, respectively; for the Pain Subscale (Index Knee) analysis, corresponding responder rates were 50%, 43%, 29%, and 21%. Improvement was observed in all three WOMAC dimensions. Mean (SD) WOMAC A score improved from 22.7 (8.80) at baseline to 12.0 (10.25) at week 8, a decrease of 10.7 (9.63). Improvements in WOMAC B and C were also observed; WOMAC B score decreased from 9.1 (3.87) to 6.4 (5.07; −2.7 [4.21]), and WOMAC C decreased from 73.9 (26.96) to 44.5 (35.10; mean change −29.5 [29.16]).

Conclusions

A single IA CNTX-4975 injection produced symptom improvement from baseline to week 8 in subjects with moderate to severe knee OA pain. All KOOS subscale scores demonstrated improvement, with mean percent change from baseline across the 5 subscales ranging from 29% (Symptoms) to 88% (Function, Sports and Recreational Activities). Approximately 40% of subjects achieved ≥50% change from baseline in KOOS Pain in the cumulative responder analysis based on KOOS Pain with Walking and Subscale scores. Subjects experienced improvement in all three WOMAC dimensions. These findings are consistent with those reported in the TRIUMPH study.

101 Phase 1 Study of the Safety, Pharmacokinetics, and Pharmacodynamics of Multiple Ascending Doses of the Selective Oral CCR2 Antagonist CNTX-6970 in Healthy Subjects

Randall M. Stevens¹, Michael H. Silverman², Nilam Mistry¹, Lukasz Biernat³, Kimberly Guedes¹

¹Centrexion Therapeutics Corp, Boston, MA, USA, ²Accellient Partners, LLC, Harvard, MA, USA, ³Medpace Clinical Pharmacology, Cincinnati, OH, USA

Purpose

Chronic inflammatory pain, such as pain associated with osteoarthritis, is a major cause of disability. Inflammatory pain occurs in part due to monocyte chemoattractant protein-1 (MCP-1) activation of inflammatory signaling via CCR2 receptors in monocytes and in sensory neurons of the dorsal root ganglia (DRG), and through CCR2-mediated recruitment of macrophages to the DRG. CNTX-6970, a potent and selective CCR2 inhibitor, has demonstrated activity in animal models of inflammatory pain in preclinical studies.¹ A phase 1 single-ascending-dose (SAD) study showed that CNTX-6970 was well tolerated. Observed adverse events (AEs) were predominantly not related to CNTX-6970 and there were no serious AEs.^1,2 We report safety, pharmacokinetic (PK), and pharmacodynamic (PD) results from a phase 1 multiple-ascending-dose (MAD) study of CNTX-6970 (NCT03787004).

Methods

Healthy adults (age 18–64 years) were randomized 8:2 to receive oral CNTX-6970 (100, 300, or 600 mg QD) or placebo, based on findings from the previous SAD study, for 10 days. After assessment of safety, PK, and PD data from the first 3 dose cohorts, the Cohort Review Committee approved enrollment of a 300-mg BID cohort and a cohort of healthy elderly subjects (age 65–80 years) randomized 8:2 to receive 300 mg QD or placebo. Subjects were confined for 14 days for dosing and assessments. Safety assessments included treatment-emergent AEs (TEAEs), changes in vital signs, physical examinations, clinical laboratory tests, and electrocardiogram findings. PK parameters evaluated as secondary endpoints were maximum plasma concentration (C_max) after a single oral dose of CNTX-6970 and area under the concentration-time curve of CNTX-6970 in plasma over time (interval from baseline extrapolated to infinity [AUC_0-∞]). Other PK parameters assessed included interval from baseline to 24 hours (AUC_0-24), time from dosing to maximum measured concentration (t_max), and terminal half-life (t_1/2). PK variables calculated on day 1 were compared with those calculated on day 10. Biomarker endpoints evaluated were inhibition of MCP-1 ligand binding to CCR2 receptor and of RANTES ligand binding to CCR5 receptor. Absolute monocyte counts were monitored throughout the study. The safety population included all subjects who received any amount of study drug. The PK population included all subjects who received study drug, had no major deviations, and had at least 1 interpretable primary PK concentration value. The PD population included all subjects who received study drug, had no major deviations, and had at least 1 interpretable PD data value. Data were summarized using descriptive statistics. Dose-normalized PK parameters were calculated using standard noncompartmental methods. For C_max, AUC_0-∞, and AUC_0-24, dose proportionality was analyzed using a power model applied to natural log-transformed data.

Results

A total of 50 randomized subjects (younger cohorts: 100 mg QD, n = 8; 300 mg QD, n = 8; 600 mg QD, n = 8; 300 mg BID, n = 8; pooled placebo, n = 8; elderly cohort: 300 mg QD, n = 8; placebo, n = 2) were included in safety, PK, and PD analyses. There were 3 subjects who discontinued early from the study: 1 subject each in the younger group (600 mg QD) and elderly group (placebo) discontinued due to withdrawn consent; and 1 subject in the 300 mg BID cohort discontinued due to other reasons (≥50% decrease in monocyte count from baseline to <0.2 x 103/μL on 2 consecutive days as prespecified in protocol). TEAEs, all mild, occurred in 6 subjects across cohorts. In the younger cohorts, dizziness (300 mg QD), headache (300 mg BID), dermatitis contact (placebo), and orthostatic hypotension (placebo) were reported (n = 1 each). In the elderly cohort, 1 subject experienced worsening of benign prostatic hyperplasia and hematochezia (300 mg QD), and 1 subject reported constipation and nausea (placebo). Two TEAEs (headache [300 mg BID] and orthostatic hypotension [placebo]) were considered related to study drug. There were no serious AEs or AEs leading to discontinuation or death. No other clinically significant findings were observed with regard to vital signs, physical examinations, clinical laboratory tests, and electrocardiogram findings. CNTX-6970 was rapidly absorbed, with median t_max values between 0.5 and 1.5 hours on day 1 and between 0.5 and 1.0 hours on day 10 across dose groups. Mean t_1/2 on day 1 ranged from 3.6 to 8.8 hours. CNTX-6970 demonstrated dose-proportional PK on day 1 and day 10 for C_max, AUC_0-∞, and AUC_0-24 from 100 mg to 600 mg. PK parameters indicated exposure was higher in females versus males and in elderly versus younger subjects. Steady-state was reached on day 2 with repeated QD or BID dosing. In younger subjects, a trend toward decreased monocyte counts (generally within normal limits) was observed only at 4 hours postdose; this trend was transient and not clinically significant. CNTX-6970 resulted in dose-dependent inhibition of MCP-1 ligand binding to CCR2 receptors. Inhibition of CCR2 receptor binding was mostly similar between males and females, with a gender difference noted for the placebo and 100 mg QD cohorts, and greater in elderly subjects (300 mg QD) versus younger subjects receiving the same dose. Data for inhibition of RANTES ligand binding to CCR5 receptor were inconclusive.

Conclusions

In treatment with multiple doses of CNTX-6970, there were no serious AEs or AEs that led to discontinuation. CNTX-6970 showed an acceptable safety profile across the full dose range (100–600 mg) in healthy male and female subjects, and in elderly subjects (300 mg). CNTX-6970 exhibited a favorable PK profile and dose proportionality in C_max, AUC_0-∞, and AUC_0-24 values on days 1 and 10. CNTX-6970 inhibited CCR2 receptor binding to the MCP-1 ligand in a dose-dependent manner. These findings support the continued development of CNTX-6970.

References

• Stevens RM, et al. Presented at: 11th Annual Pain & Migraine Therapeutics Summit; 2017 Sep 27–28; San Diego, CA.
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• Stevens RM, et al. Presented at: Annual Meeting of the American Academy of Pain Medicine; 2018 Apr 26–29; Vancouver, BC, Canada.
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102 Phase 1 Study of the Safety, Tolerability, and Pharmacokinetics of Single Ascending Doses of the Novel Oral CCR2 Antagonist, CNTX-6970, in Healthy Volunteers

Randall M. Stevens¹, Gudrun Simons², Tobias Brand², Willem Hettema², Laura Corradini²

¹Centrexion Therapeutics, Boston, MA, USA, ²Boehringer-Ingelheim Pharma GmbH & Co. KG, Biberach an der Riss, Germany

Purpose

Chronic pain due to osteoarthritis (OA) is a major cause of disability, but few effective pharmacologic therapies are available. The inflammatory pain of OA occurs, in part, from monocyte chemoattractant protein (MCP-1)-mediated activation of inflammatory signaling via CCR2 receptors on monocytes and on sensory neurons of the dorsal root ganglia. CNTX-6970 is a CCR2 antagonist in development for the treatment of inflammatory pain, such as that associated with OA. We report results from a clinical study evaluating the safety, tolerability, and pharmacokinetics of CNTX-6970 (NCT02093819).

Methods

A phase 1 study evaluated the safety and pharmacokinetics of CNTX-6970 in healthy male subjects following oral administration of single ascending doses. Healthy adult males were partially randomized 6:2 to receive oral CNTX-6970 (10, 25, 50, 100, 200, 400, or 600 mg) or placebo. Randomization and treatment in higher-dose groups occurred if the preceding dose was deemed safe and well tolerated. The primary endpoint was the number of subjects with drug-related adverse events (AEs), reported using descriptive statistics. Other safety assessments included laboratory evaluations, electrocardiogram (ECG), vital signs, and physical examinations. Pharmacokinetic parameters, evaluated as secondary endpoints, were maximum plasma concentration (C_max) after a single oral dose of CNTX-6970 and area under the concentration-time curve of CNTX-6970 in plasma (interval from baseline extrapolated to infinity; AUC_0-∞). Other PK parameters assessed included: 1) the interval from baseline to the time of the last quantifiable endpoint (AUC_0-tz); 2) the time from dosing to maximum measured concentration (t_max); and 3) the terminal half-life (t_1/2). Dose-normalized parameters were calculated for C_max, AUC_0-∞, AUC_0-tz, and dose proportionality was analyzed using a linear regression model applied to log-transformed data. Other pharmacokinetic parameters were summarized using descriptive statistics. Biomarker assessments included CCR2 and CCR5 blocking of their respective receptors, MCP-1 and RANTES.

Results

Sixty subjects (mean age 34.5 years) were randomized, treated, and completed the observation period (placebo, n = 15; CNTX-6970 10 mg, n = 6; 25 mg, n = 10; 50 mg, n = 6; 100 mg, n = 6; 200 mg, n = 6; 400 mg, n = 5; 600 mg, n = 6). One subject (600 mg cohort) was excluded from the pharmacokinetic analyses due to vomiting. Three investigator-defined drug-related AEs occurred in 2 subjects: 1 (placebo), moderate paresthesia, and 1 (400 mg), moderate headache and mild diarrhea. Eleven (18.3%) subjects reported AEs on treatment, most (91%) of mild or moderate intensity; 1 subject (200 mg) experienced severe nausea. All AEs resolved by study end, and no AE caused discontinuation. No serious AEs or clinically relevant findings in physical examinations, vital signs, or ECG measurements were reported. CNTX-6970 was rapidly absorbed, with median time from dosing to t_max between 0.6 and 1.8 hours for all dose groups except the 25 mg group (3.0 hours). Mean t_1/2 ranged from 6.3–10.8 hours, without an apparent dose dependency. CNTX-6970 exhibited linear pharmacokinetics and dose proportionality in AUC and C_max values across the dose range from 50–600 mg, with a slight over-proportionality across the full dose range. CNTX-6970 caused dose-dependent inhibition of MCP-1 ligand binding to CCR2 receptors, and of RANTES ligand binding to CCR5 receptors. Plasma concentration of CNTX-6970 correlated with inhibition of MCP-1 binding to CCR2 to a greater extent than with the inhibition of RANTES binding to CCR5, consistent with preclinical findings that CNTX-6970 binds to CCR2 with greater affinity than to CCR5.

Conclusions

CNTX-6970 demonstrated acceptable safety and tolerability across the full dose range. In healthy adult male subjects, CNTX-6970 exhibited a favorable pharmacokinetic profile and dose proportionality after a single oral dose (50–600 mg). CNTX-6970 inhibited CCR2 and CCR5 receptor binding to their respective ligands. These results support further evaluation of CNTX-6970 in patients.

103 Evaluation of the Selective Oral CB2 Agonist CNTX-6016 for the Treatment of Neuropathic Pain: Pharmacokinetic, Efficacy, and Safety Findings from Preclinical Studies

Randall M. Stevens¹, Janet R. Nicholson², Achim Sauer², Thomas Nolte², Laura Corradini²

¹Centrexion Therapeutics Corp, Boston, MA, USA, ²Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riss, Germany

Purpose

CNTX-6016 is a potent and highly selective agonist (IC₅₀ CB1/CB2 ratio >15,000) of the cannabinoid receptor type 2 (CB2) in clinical development for the treatment of neuropathic pain. Preclinical data suggest a role for CB2 in regulating neuropathic pain signaling. CB2 is expressed in areas of the sensory nervous system that function in pain control, including peripheral and central immune cells, dorsal root ganglion (DRG) neurons, and the spinal cord. Expression of CB2 in the setting of pain signaling is upregulated under pathological conditions, such as avulsion-injured DRG, injured brachial plexus nerves, and painful distal upper limb neuromas. CB2 agonism has been shown to induce analgesia by modulating pain signaling in preclinical models of neuropathic pain. Activation of CB2 receptors on human sensory DRG neurons modulates transient receptor potential vanilloid 1–mediated nociceptive input, and was reported to inhibit the release of pro-inflammatory and neuron-sensitizing factors such as tumor necrosis factor alpha (TNF-α) and interleukin 1 beta (IL1-β). Current treatment options for neuropathic pain conditions include pregabalin (approved indications are inclusive of treatment of diabetic peripheral neuropathic pain [DPNP], postherpetic neuralgia, and spinal cord injury pain), duloxetine (indications include treatment of DPNP), and off-label treatments including tricyclic antidepressants, anticonvulsants, opioids, and topical analgesics (eg, lidocaine). However, these treatments may be associated with adverse events or limited efficacy; therefore, there is a need for novel therapies for neuropathic pain conditions. CNTX-6016 has shown efficacy in reversing pain-like behaviors in rodent models of DPNP and represents a promising therapeutic molecule for the treatment of neuropathic pain. Herein, we report preclinical data describing the efficacy, selectivity, pharmacokinetics (PK), and safety of CNTX-6016.

Methods

CNTX-6016 potency (EC₅₀) was evaluated in cyclic adenosine monophosphate (cAMP) assays of CNTX-6016 binding to human, rat, or dog CB2 expressed in Chinese hamster ovary cells. CNTX-6016 (10 mM) molecular selectivity was tested in a standard panel of 67 enzymes, channels, and receptors using radioligand binding assays. CNTX-6016 efficacy was assessed using a male Wistar rat model of neuropathic pain caused by partial nerve ligation (PNL) of the sciatic nerve. Mechanical hyperalgesia was investigated 2 weeks postsurgery by measuring the paw withdrawal threshold (PWT, g) response to increasing mechanical pressure. Mechanical PWTs were assessed 1 hour after a single oral dose of CNTX-6016 (0.1 and 0.3 mg/kg), while a time-dependent profile was measured at 1, 2, 4, 6, and 24 hours at doses of 1, 3, and 10 mg/kg. Groups treated with vehicle and lamotrigine (30 mg/kg) were used as negative and positive controls, respectively. As chronic analgesic dosing is reported to induce tachyphylaxis, the highest dose of CNTX-6016 (10 mg/kg) was given orally twice daily for 5 days in PNL rats to rule out this risk. PWT measurements were obtained 1, 2, 4, 6, and 24 hours after the last morning dose. The antinociceptive effect of CNTX-6016 was also evaluated in the streptozotocin (STZ) diabetic neuropathic pain rat model. Diabetes was induced by intraperitoneal injection of STZ (65 mg/kg), and pain-like behavior was assessed by Randall-Selitto test as PWT. Three weeks post-STZ injection, hyperalgesic rats received a single oral dose of CNTX-6016 (0.3, 1, and 3 mg/kg), vehicle, or duloxetine (30 mg/kg) and were tested 1 hour post-dosing. Central nervous system (CNS) side effects were evaluated using a rat locomotor activity assay. Male Crl:WI(Han) rats underwent the test 2 hours after oral administration of CNTX-6016 (1, 3, or 10 mg/kg), vehicle, or duloxetine (30 mg/kg). Preclinical studies evaluated general and safety pharmacology and PK parameters. Human PK parameters were estimated by allometric scaling and in vitro–in vivo correlation based on in vivo PK data from animals and in vitro data from human and animal hepatocytes. Phase 1–enabling repeat-dose toxicity, genotoxicity, and phototoxicity studies were performed.

Results

The cAMP assay showed potent CB2 agonism with CNTX-6016 (EC_50; human = 13 nM; rat = 9 nM; dog = 20 nM). In an analysis of overall molecular selectivity, no relevant activity was noted for CNTX-6016 among 67 targets. In the PNL rat model, CNTX-6016 demonstrated dose-dependent efficacy at doses of 0.1 and 0.3 mg/kg and of 1, 3, and 10 mg/kg at 1 hour post-dosing. Maximum efficacy comparable to lamotrigine was achieved starting with 1 mg/kg; the minimal effective dose (MED) was 0.3 mg/kg, corresponding to a minimal effective concentration (MEC) of 582 nM. A robust analgesic effect was observed after a single CNTX-6016 dose (1, 3, and 10 mg/kg) on day 1 that was maintained with repeated BID dosing (10 mg/kg) for 5 days; no evidence of tachyphylaxis was observed. In the STZ rat model, CNTX-6016 3 mg/kg demonstrated maximum efficacy comparable to duloxetine; MED was 1 mg/kg, corresponding to MEC of 660 nM. No dose-limiting CNS side effects were observed with CNTX-6016 in the rat locomotor activity test, whereas duloxetine significantly reduced rat locomotor activity. CNTX-6016 showed low binding to human and animal plasma proteins and high permeability in vitro. Low in vivo total plasma clearance, small mean volume of tissue distribution, and high oral bioavailability in animals suggest good absorption from the gastrointestinal tract. Identified elimination pathways were metabolism via CYP3A4 and 2C19, as well as renal and biliary excretion. The estimated effective human dose of 120 mg daily was associated with predicted C_max of 5.5 µM and AUC_0-24h of 49 µM•h. In safety analyses of repeat-dose toxicity studies in mice, no adverse findings were observed up to the highest dose tested (1500 mg/kg/day; safety margin, 41). Rat toxicity studies found stomach erosion at the highest dose tested (1000 mg/kg/day), with a no-observed-adverse-effect level (NOAEL) of 100 mg/kg/day in the 4-week good laboratory practice (GLP) study (safety margin, 18). In dog toxicity studies, adverse findings were clinical CNS signs starting at 45 mg/kg/day, prominent reduction in body temperature at 400 mg/kg/day, and pigmented Kupffer cells at 400 mg/kg/day, with a NOAEL of 40 mg/kg/day in the 4-week GLP study (safety margin, 17).

Conclusions

CNTX-6016 is a potent and highly selective CB2 agonist with demonstrated analgesic efficacy in preclinical models of neuropathic pain. No evidence of CNS side effects was observed in a rat locomotor activity study, and toxicology studies found favorable safety margins. For the treatment of neuropathic pain conditions, CNTX-6016 has the potential to provide therapeutic efficacy with a favorable safety profile compared with current standards of care.

104 Evaluation of the Selective Oral CCR2 Antagonist CNTX-6970 in the Treatment of Osteoarthritis Pain; Results from Preclinical Studies of Pharmacokinetics and Efficacy

Randall M. Stevens¹, Stefan Scheuerer², Niklas Schuelert², Laura Corradini²

¹Centrexion Therapeutics Corp, Boston, MA, USA, ²Boehringer-Ingelheim Pharma GmbH & Co. KG, Biberach an der Riss, Germany

Purpose

Chronic pain due to inflammation is a major cause of disability. Research has shown a link between chronic pain and the immune system. Inflammatory pain occurs in part due to monocyte chemoattractant protein-1 (MCP-1; also known as CCL2) activation of inflammatory signaling via chemokine C-C motif (CCR2) receptors in monocytes, activation of sensory neurons of the dorsal root ganglia (DRG), and recruitment of monocytes to the site of injury and DRG. CNTX-6970 is a CCR2 antagonist under investigation for the treatment of inflammatory pain. Here we report results from preclinical studies evaluating the efficacy and pharmacokinetics of CNTX-6970.

Methods

Analgesic activity of CNTX-6970 was investigated in the Complete Freund’s Adjuvant (CFA) rat model of inflammatory pain. Inflammatory pain was induced by CFA injection in the hind paw, followed in 24 hours by administration of oral CNTX-6970 (0.1, 1, and 10 mg/kg) or indomethacin (30 mg/kg; positive control). Efficacy was assessed against indomethacin by using the Randall-Selitto test for mechanical hypersensitivity. Pain reduction was described as a percentage of the maximal possible effect, defined by the response to indomethacin. Efficacy in osteoarthritis (OA) pain was tested in the monosodium iodoacetate (MIA) rat model with single oral doses of 10 and 30 mg/kg. OA pain was induced by intra-articular injection of MIA (1 mg/mL) in the right knee, with saline injected into the left knee as a sham control. Weight-bearing deficit (WBD) was measured and compared with morphine (positive control). Changes in pain were evaluated as the change in the WBD between the knee with induced OA pain and the control knee. The effect on spinal neuronal activity was also evaluated in the MIA pain model. Wide dynamic range (WDR) neurons with a defined receptive field on the MIA-treated knee joint were characterized (3–7 neurons per dose). A 1 MOhm Tungsten electrode was advanced into the dorsal horn of the spinal cord of anesthetized rats, and mechanical noxious stimulus (100 g von Frey) was applied for 10 seconds to the surface of the knee joint. WDR neuronal activity was recorded at baseline and after administration of vehicle, CNTX-6970 (1 mg/kg IV bolus followed by 2.4 mg/kg/30-minute IV infusion and 10 mg/kg bolus followed by 24 mg/kg/30-minute infusion), or morphine (positive control) administered as a bolus IV injection in accumulative doses after the highest CNTX-6970 dose. Spinal neuronal activity was assessed every 5 minutes until 45 minutes post-dosing. Peak inhibitory effect of both compounds was assessed by averaging 3 consecutive time points. Preclinical studies also evaluated pharmacokinetic parameters, including absorption, clearance, and plasma protein binding in rat (WI:Han), mouse (CD-1), and cynomolgus monkey models.

Results

A single oral dose of CNTX-6970 showed a dose-dependent antihyperalgesic effect in the CFA model. The highest dose, 10 mg/kg, achieved an effect comparable to indomethacin 30 mg/kg, with a minimum effective dose of 1 mg/kg. In the MIA OA pain model, a single oral dose of CNTX-6970 (10 or 30 mg/kg) significantly reduced pain-like behavior compared with vehicle, indicating a potential analgesic effect. In the MIA pain model assessing spinal neuronal activity, CNTX-6970 reduced neuronal activity of WDR neurons following mechanical stimulation, with peak effect 15–30 minutes post–IV bolus. In preclinical studies, intravenous CNTX-6970 demonstrated moderate clearance ranging from 17 mL/min•kg in cynomolgus monkeys to 34 mL/min•kg in rats. Tissue distribution after administration of a single dose of oral CNTX-6970 in male rats was rapid and widespread. Oral bioavailability was high in female rats (95%) and moderate in male rats (34%). CNTX-6970 displayed moderate to low (67%–89%) binding to proteins in mouse, rat, and cynomolgus monkey in the concentration range investigated (0.03 μM–30 μM). No saturation of binding was observed. No relevant sex differences in protein binding were observed in rats or cynomolgus monkeys. Minor species differences with respect to the fraction unbound were observed. The primary route of excretion in rats was via bile and feces. Results suggested a high degree of absorption of CNTX-6970 (60%–80%).

Conclusions

CNTX-6970 provided analgesia in animal models of inflammatory pain. In preclinical pharmacokinetic studies, CNTX-6970 demonstrated high absorption, moderate clearance, and moderate to low binding to plasma proteins.

105 Measuring Quality of Initial Opioid Prescribing: Pilot Testing Results for Pharmacy Quality Alliance in Medicaid, Medicare and Commercially Insured Patients

Ranna Ardebili¹, Olivia Letzkus¹, Holly Little¹, Barbara Tschirpke¹, Maithili Rao¹, Meridith Blevins Peratikos^1,2, Stacey Grant¹, Elizabeth Ann Stringer¹

¹axialHealthcare, Nashville, Tennessee, USA, ²Vanderbilt University Medical Center, Department of Biostatistics, Nashville, Tennessee, USA

Purpose

One of the most commonly prescribed analgesic drugs for alleviating or controlling pain is an opioid. Opiates have formally been approved for analgesia for close to 70 years, with the assumption that this class of medication is relatively safe. Meanwhile, the escalating rates of opioid abuse and overdose have raised concern about the safety of these drugs. The U.S. is in the midst of a major public health challenge: increased prescriptions of opioid medications have led to a widespread misuse, leading to an opioid crisis. In 2016, 11.1 million people reported misusing prescription opioids and more than 42,000 deaths were attributable to opioid overdoses, 40% of which were a result of an opioid prescription. To prevent the adverse risks associated with opioid consumption, providers should prescribe opioids only when necessary, in the lowest effective dose and for the shortest duration.

In response to the demand for judicious opioid prescribing, Pharmacy Quality Alliance (PQA) drafted three measures to retrospectively assess health plan performance for initial opioid prescriptions, including: 1) long duration, 2) high dosage, and 3) extended-release opioids. Each of the performance measures have been shown as significant predictors of continued opioid use, which increases the risk for complications, including opioid use disorder and opioid overdose. This analysis describes results for pilot testing of PQA initial opioid prescribing measures across Medicare, Medicaid, and Commercial member populations.

Methods

We reviewed medical and pharmacy claims for more than 2.5 million members across three Medicare (328,311 members), four Medicaid (735,307 members), and three Commercial (1,565,615 members) health plans. Adults ≥ 18 years with an initial opioid prescription fill between January 1 and December 31, 2017 who did not have a hospice or cancer indicator were eligible for inclusion in all three performance measures. Individuals included had continuous health plan enrollment during the measurement year and the 90 days prior to the index prescription start date (IPSD). The IPSD is the earliest date of service for an opioid medication during the measurement year. Initial opioid prescriptions were identified by the earliest date of service for an opioid prescription during the measurement year following a negative opioid history, where no opioid prescription was filled 90 days prior to the prescription fill date. Hospice or cancer exclusions were determined by the presence of at least one place of service or ICD-10-CM diagnosis code, respectively, during the measurement year and the 90 days prior to IPSD.

Among members meeting criteria for initial opioid prescribing and eligibility, mean average and range were calculated across health plans for three metrics, including: long duration, high dosage, and extended-release opioids. Long duration was defined as any initial opioid prescription with > 7 cumulative days’ supply. High dosage was defined as an average daily morphine milligram equivalent (MME) ≥ 50. Extended-release or long acting opioid formulations of interest were defined by PQA guidelines. Opioids included in the evaluation of each metric were also provided by PQA and included all opioids with an MME conversion; buprenorphine, injectable formulations, and opioid cough and cold products were excluded.

Results

Quality measures were assessed for each of three Medicare, four Medicaid, and three Commercial health plans, with 274,261 total members meeting inclusion criteria (49,531 Medicare; 77,129 Medicaid; 147,601 Commercial). Percentages of members filling initial opioid prescriptions with long duration were: 48.6% in Medicare (range: 44.7% to 53.8%), 20.5% in Medicaid (9.5% to 29.5%), and 25.1% in Commercial (23.7% to 26.8%). Percentages of members filling initial opioid prescriptions at high dosage were: 13.7% in Medicare (12.2% to 15.6%), 18.2% in Medicaid (16.7% to 20.5%), and 19.4% in Commercial (18.8% to 20.4%). Percentages of members filling initial opioid prescriptions for extended-release opioids were: 1.3% in Medicare (0.8% to 1.6%), 0.8% in Medicaid (0.1% to 1.2%), and 0.6% in Commercial (0.6% to 0.7%).

Conclusions

Patients enrolled in Medicare plans had nearly two times higher rates of initial opioid prescribing for long duration (>7 days supply) compared with Medicaid and Commercial plans. In contrast, Medicare plan patients had nearly 25% lower rates of initial opioid prescribing at high dosage (≥50 average daily MME) compared with patients enrolled in Medicaid and Commercial plans. Initial opioid prescribing for extended-release opioids was rare; however, patients enrolled in Medicare plans had nearly two times higher rates of initial opioid prescribing for extended-release opioids compared with Medicaid and Commercial plans. The Medicare population is more likely to have reduced renal function, decreased hepatic function and/or comorbid medical conditions, which could lead to the increased risk of falling or drug accumulation, and ultimately respiratory depression. comorbid medical conditions, U.S. federal, state, and health plan policies have been implemented for initial opioid prescriptions to assist in curbing the opioid epidemic. Such policies could have influenced these results, but were not considered as part of measure testing specifications.

106 Analgesic efficacy of combined Pectoral nerve blocks (PECS I & II) in surgeries for Breast carcinoma

Ravinder Kumar Pandey, Neethu M, Jyotsna Punj, Vanlalnghaka Darlong, Preet Mohinder Singh, Renu Sinha, Rakesh Garg

All India Institute of Medical Sciences, New Delhi, Delhi, India

Purpose

Breast surgeries commonly result in poorly controlled acute postoperative pain, which may be an important predictive factor in the development of chronic post-surgical pain. Various perioperative analgesic modalities including systemic and regional blocks are available for breast surgeries.

In this study we hypothesize that in patients scheduled for breast carcinoma surgeries, ultrasound guided pectoral nerve blocks (PECS I & II) with general anesthesia provide superior analgesia & less peri-operative opioid consumption compared to opioid mediated patient controlled analgesia (PCA) with GA technique.

The primary objective of this study was to evaluate the analgesic efficacy {amount of fentanyl requirement) of PEC I & PEC II blocks and secondary objectives were limitations of shoulder joint movement on the operated side and incidence of post-operative nausea and vomiting (PONV).

Methods

After Ethical Committee approval, 60 adult women, aged between 18–70 years, ASA status I or II, known case of carcinoma breast were included. All patients were randomly allocated into 2 groups of 30 patients each (Group P: Study group and Group C: Control group).

Group P, patients received both GA & Ultra sound guided combined pectoral nerve blocks (PEC I & PEC II) with 30 ml 0.25% Ropivacaine.

In Group C, patients received only GA. Post-operatively, all patients received PCA (Fentanyl 10 mcg / ml, lockout interval, 15 minutes).

We noted pain intensity at rest and shoulder joint movements (abduction of operated side upper limb), at 30 minutes, 1,2,3,4,5, 6 and 24 hours after surgery in both the groups. Total post-operative Fentanyl requirement in each patient was calculated and noted.

Time for first analgesic requirement by patients was also noted in both groups. Incidence of PONV & overall patient satisfaction for postoperative analgesia was also noted.

Limitation of shoulder joint movements on operative side at intervals mentioned above was also noted.

Results

Statistical methods used: Data for continuous variables were presented as the mean +- standard deviation (SD) and analysed by Student’s t- test. Data for categorical variables were presented as the counts (n).It was found that dependent variables at rest and movement, at different time period were not following normal distribution; therefore, non-parametric test had applied. The VAS score of P and C group were compared for the same subjects at different time periods by using Wilcoxon Signed Rank Test. All statistical analyses were performed using IBM SPSS 20.0 software (IBM, Armonk, NY, USA).All p values were two-sided. ‘P’ value of < 0.001 was considered as significant.

Group P showed significant reduction in total Fentanyl requirement in first 24 hours post-operatively as compared to Group C and the difference between two group was 171 microgram [138.40–203.59](95% CI : p value <0.001].

The mean time required for first analgesia requirement was significantly longer in Group P compared to Group C (44.33 ± 17.65 min vs 10.36 ± 4.97 minutes, p value <0.001).

Limitation of shoulder joint movements was significantly less in Group P as compared to Group C at 4th and 5th hour post operatively (p value <0.001). However, it was comparable at 6th and 24 hour post-operatively.

There was no difference in the incidence of PONV in both the groups but patients in Group P had better satisfaction for post-operative analgesia than Group C.

Conclusions

Combined PECS I and PECS II block in adult women undergoing modified radical mastectomy as compared to conventional group decreases total amount of fentanyl requirement in the intra-operative/post-operative period (24 h), increase duration for time to first analgesic requirement (VAS > 3) in post-operative period with less limitation of shoulder joint movement (pain free mobilization) on the operative site at 4 h and 5 h after surgery.

107 Is Administration of 5% Dextrose Reduces Post-Operative Nausea And Vomiting (PONV) In Laparoscopic Cholecystectomy ?

Ravinder Kumar Pandey, Ankita Mishra, Vanlalnghaka Darlong, Jyotsna Punj, Devalina Goswami, Renu Sinha, Vimi Rewari, Virinder Bansal

All India Institute of Medical Sciences, New Delhi, Delhi, India

Purpose

PONV is one of the most distressing concerns and is leading cause of unexpected hospital admissions following day care surgery. Even single episode of PONV increases hospital stay of 25 minutes. It needs to be dealt in a better tolerated and cost-effective way.

Preoperative oral carbohydrate load is associated with decreased incidence of PONV presumably by decreasing postoperative catabolism & insulin resistance. Its direct local action on wall of gastrointestinal tract reduces muscle contraction because of high osmotic pressure exerted by simple sugar. Optimal dose of Dextrose is needed to obtain this favourable outcome because larger volumes of intravenous dextrose do not prevent PONV in day care surgery & may increase PONV.

Thus, we plan to administer an optimal dose of 5% Dextrose (250ml) peri-operatively to see its effect on PONV incidence in patients undergoing laparoscopic cholecystectomy. In this study we examined the role of peri-operative administration of 5% dextrose v/s normal saline for reducing incidence of PONV in laparoscopic cholecystectomy and its effect on patient with high and low Afpel score.

Methods

Primary Objectives

Efficacy of peri-operative administration of 5% dextrose to reduce PONV and rescue antiemetics in patients with and without administration of 5% Dextrose

Secondary Objective

Efficacy of peri-operative administration of 5% dextrose to ↓ PONV in patients of high and low Apfel scores

Methods: 100 patients with ASA status I to II undergoing laparoscopic cholecystectomy were enrolled in the study. Patients were randomized into 2 groups [normal saline (NS) group and 5% dextrose (D) group]. Both the groups received balanced salt solution iv as maintenance fluid during intra-operative period. Besides this, patients of group NS received 250 ml of 0.9% normal saline and patients of group D received 5% dextrose @ 100ml/hour started at the time when gall bladder was out and continued in the postoperative period. For the purpose of blinding, the label of the study fluid (5% dextrose or normal saline) was removed by a senior anesthesiologist to prevent observer’s bias. The person who was administering the study fluid was kept unaware about the type of study fluid. In the recovery room or in the ward, an observer who was not aware of the type of study fluid, noted the numbers of PONV episodes. All patients received injection paracetamol (15mg/kg) intravenously at the end of surgery and were reversed with injection neostigmine and glycopyrrolate. All patients were assessed for PONV by using visual analogue scale (VAS) from 0 to 10, where 0 means no nausea and 10 means worst possible nausea or any episode of retching or vomiting.

Patients with VAS score of 3 or more received ondansetron 4 mg intravenously as a first line antiemetic treatment. However, if PONV persisted after 30 minutes after above treatment, then metoclopramide 10 mg was administered intravenously. The VAS score for PONV was recorded after 30 minutes, 60 minutes, 90 minutes, 6 hours, and 24 hours after patient arrival in PACU. The total amount of rescue antiemetic (intravenous ondansetron in an incremental dose of 4 mg) in 24 hours postoperatively was noted for every patient.

An independent observer observed incidence of PONV, Apfel score, use of rescue antiemetics, intra-operative opioids and fluids administered.

Results

Statistical analysis: Data analysis was carried out using Stata 12.0 (College station, Texas, USA). The data was presented as number (%) and mean ± standard deviation (SD) as appropriate. The baseline categorical and continuous characteristics were analyzed between the groups using Chi square test / Fisher’s exact test and student’s ‘t’ test for independent samples respectively. The primary outcome, incidence of PONV were compared between the two groups using ‘Z’ test and ANCOVA was carried out to adjust for the imbalance found in total intra-operative opioid consumption between the two groups. The results were presented as both unadjusted and adjusted difference in the incidence of PONV and 95% confidence interval. The change in hemodynamic parameters over a period of time between the two groups was assessed using repeated measures ANOVA. The p < 0.05 was considered statistically significant.

Demographic data was statistically similar. Out of total 100 patients, 47 patients (47%) had PONV. In group D, 14 patients (28%) had PONV while in group NS, 33 patients (66%) had PONV within 24 hours of surgery (p value 0.001). The incidence of PONV was reduced by 38% in group D which is significantly lower when compared with that of group NS (p value < 0.001). The consumption of single dose of rescue antiemetics in group D was also reduced by 26% when compared to that of group NS (p value 0.002).

Conclusions

PONV is one of the limiting factors in early discharge of day care surgery patients. Current approaches to prevent and treat PONV are limited and > 25% of patients experience PONV within 24 hours postoperatively. Universal pharmacologic PONV prophylaxis is associated with increased side effects (24.25). Non-pharmacological, peri-operative administration of 5% dextrose in laparoscopic surgeries reduces PONV significantly and is cost effective too.

The present study is unique in a way that it demonstrates a 38% reduction in PONV in patients receiving peri-operative dextrose when compared to patients receiving peri-operative normal saline which is the primary outcome of the study. This reduction is even more than that of previous studies.

Secondary outcome of the study is to find out the consumption of rescue antiemetics in both the groups has also shown better results in the group receiving dextrose. There is 26% reduction in use of single dose of ondansetron 4 mg in dextrose group.

In conclusion 5% dextrose when given perioperatively in laparoscopic surgery patients at the rate of 100 ml/hour can reduce PONV significantly and even then if PONV occurs, the quantity of rescue antiemetics used to combat PONV are reduced significantly.

108 Opioid Use for the Treatment of Osteoarthritis among Primary Care Physicians, Rheumatologists, and Orthopedic Surgeons

Thomas J. Schnitzer¹, Rebecca L. Robinson², Lars Viktrup², Joseph C. Cappelleri³, Andrew G. Bushmakin³, Leslie Tive⁴, Jennifer Mellor⁵, James Jackson⁵

¹Northwestern University, Evanston, IL, USA, ²Eli Lilly and Co, Indianapolis, IN, USA, ³Pfizer Inc, Groton, CT, USA, ⁴Pfizer Inc, New York, NY, USA, ⁵Adelphi Real World, Bollington, United Kingdom

Purpose

The Center for Disease Control and Prevention (CDC) federal guidelines for prescribing opioids were published in 2016, but opioid use in the United States (US) has been on a steady decline since 2012. The guidelines were intended for primary care physicians (PCPs) treating adults with nonmalignant chronic pain in an effort to improve patient outcomes and reduce potential harms associated with the use of opioids. Osteoarthritis (OA) is one of the most common and costly chronic pain conditions in the US that often gets treated with opioids especially in patients who fail to respond to lifestyle changes, non-pharmacological therapies, and other analgesics. Between 2007–2014, approximately 17% of insured patients with OA received opioids, and this rate remained stable during this period. Since the publication of the CDC guidelines, physicians’ treatment patterns and patients’ beliefs regarding the use of opioids in OA have not been widely reported but may provide insights into the care and treatment of patients with OA. The objective of this study was to describe physicians’ treatment patterns regarding the use of opioids for OA across three specialties (PCPs, rheumatologists [RHEUMs], and orthopedic surgeons [ORTHOs]) in the US one year after the publication of the CDC guidelines.

Methods

Data were analyzed using the US OA Adelphi Disease Specific Programme (DSP); a non-interventional, point-in-time, cross-sectional online survey of physicians conducted from February to May 2017. DSPs aim to provide a holistic assessment for illnesses by understanding how diseases are managed in clinical practices, based on physician and patient perspectives. Physicians (PCPs, RHEUMs and ORTHOs) first completed surveys regarding their management of patients diagnosed with OA, and then completed electronic patient record forms for nine consecutive adult patients diagnosed with OA. Data from patient records were assessed to obtain patient-level rates of current opioid use overall and for each disease severity (mild, moderate, and severe). All other measures were assessed at the practice-level using physician survey data. OA disease severity was reported by physicians to be primarily based on patients’ level of pain, functional impairment, and joint deterioration, including joint space narrowing based on X-ray. Practice-level trends in opioid use from the physician survey were assessed via 1) changes over the last year, 2) the influence of CDC guidelines on prescribing patterns, 3) barriers to prescribing, 4) concerns of dependence, and 5) use of opioid sparing approaches. Descriptive statistics, mainly percentages, were reported.

Results

This study included 81 (52.9%) PCPs, 35 (22.9%) RHEUMs, and 37 (24.2%) ORTHOs. Overall, 73% of physicians were male, within private practices (85%), and within office/outpatient settings (87%). Patients’ (n = 1357) OA severity (mild, moderate, and severe) was 39.3%, 39.6%, and 21.1% for PCPs, 24.7%, 47.3%, and 28.0% for RHEUMs, and 33.9%, 40.6%, and 25.5% for ORTHOs, respectively. A total of 20.6% of all patients with OA were currently prescribed opioids (PCPs: 22.0%, RHEUMs: 26.8%, and ORTHOs: 11.3%) with either weak or strong opioids from PCPs (12.9% and 5.1%), RHEUMs (18.9% and 3.8%), and ORTHOs (6.6% and 3.1%), respectively. At the practice-level over the last one year, opioid prescriptions decreased among 41.7%, 48.9%, and 43.2% of physicians, increased among 1.4%, 5.8%, and 14.4%, and remained the same for 56.8%, 45.3%, and 42.4% in the treatment of patients with mild, moderate, and severe OA, respectively. PCPs had the largest decrease (51.3%) in opioid prescriptions in patients with mild OA; a decrease that was less pronounced for RHEUMs (26.5%) and ORTHOs (33.3%). The largest increase in opioid prescriptions occurred in patients with severe OA (PCPs 15.4%, RHEUMs 17.6%, and ORTHOs 7.4%). When asked whether changes in opioid prescriptions were related to the publication of the CDC guidelines, 61.3% of physicians in the survey responded affirmatively, whereas the remaining physicians’ treatment patterns were not influenced by these guidelines, and 18.3% were unaware of the guideline. The most common barriers to opioid prescriptions across all specialties were fear of addiction (28.5%), fear of drug abuse (13.9%), and lack of efficacy as a chronic treatment for OA pain (12.5%). Fear of addiction was most pronounced among PCPs (33%), whereas lack of efficacy was a higher barrier among ORTHOs (20%). Fear of drug abuse was similar across physician specialties. RHEUMs in the survey considered guideline restrictions a greater barrier to prescribing opioids than PCPs or ORTHOs (13.1%, 5.2%, and 5.8%, respectively). Most of the physicians (92.2%) had concerns about drug dependence, but few (22.2%) adopted an opioid dose sparing approach and 56.9% had never heard of such an approach.

Conclusions

Approximately 1 year after the publication of the CDC guidelines for prescribing opioids, around one fifth of patients with OA had an opioid prescription, consistent with a recent report by DeMik and colleagues based on an administrative claims database from 2007 to 2014. In our study, weak opioids were prescribed 2–4 times more commonly than strong opioids. Overall, approximately equal numbers of physicians reported that their prescribing patterns for opioids largely remained the same or decreased over the last 12 months. PCPs had the largest decrease in opioid prescriptions, especially in patients with mild OA. Of those aware of guidelines, most felt their changes in prescribing patterns were related to the CDC guidelines. Moderate increases in opioid prescriptions were seen in patients with severe OA. Most physicians were concerned about drug dependence, although they were unaware of opioid sparing approaches. Overall, this small study suggests that the opioid prescription patterns among 3 physician specialties treating patients with OA in the US continues to change, especially among PCPs, but additional medical education may be warranted. Extrapolating the data from this study to the general opioid prescribing habits in US should be done with caution.

109 Measuring the Severity of Osteoarthritis: Do patients and physicians agree?

Rebecca L. Robinson¹, Valerie Bruemmer¹, Lars Viktrup¹, Joseph C. Cappelleri², Andrew G. Bushmakin², Leslie Tive³, Jennifer Mellor⁴, James Jackson⁴, Kurt Kroenke⁵

¹Eli Lilly and Co., Indianapolis, IN, USA, ²Pfizer Inc, Groton, CT, USA, ³Pfizer Inc, New York, NY, USA, ⁴Adelphi Real World, Bollington, United Kingdom, ⁵Regenstrief Institute, Indianapolis, IN, USA

Purpose

Osteoarthritis (OA) is a chronic degenerative disease characterized by a loss of joint cartilage and hypertrophic bone changes. Symptoms include pain, stiffness, and functional limitations resulting in increased disability and reduced quality of life. Changes in symptoms and structural disease progression are highly variable and not necessarily correlated. While some patients remain stable, others experience either worsening or improvement of symptoms. Patients’ perception of these symptoms and their therapeutic needs may not correlate with clinicopathologic assessments. The objectives of this study were to evaluate whether clinical measures associated with OA (pain intensity, functional impairment, and overall disease severity) were correlated from the patients’ and physicians’ perspectives, and to describe the demographic and medical history factors of patients whom clinical measures were concordant or discordant with physician-rated measures.

Methods

Data were collected from primary care physicians, rheumatologists, and orthopedic surgeons who participated in the OA Adelphi Disease Specific Programme in the United States from February–May 2017. Physicians completed electronic patient record forms for their next nine consecutive adult patients with OA. These patients were invited to participate in the study and consenting patients then completed questionnaires assessing their symptoms of OA. Descriptive data including patients’ demographic and clinical characteristics were collected. Medical history included the duration since OA diagnosis, location and number of affected joint(s) or anatomical areas, and body mass index (BMI). Clinical measures were assessed using pain intensity, level of functional impairment, and overall OA disease severity using comparable measures from both the patients’ and physicians’ perspectives. Pain intensity was measured using a numeric rating scale (NRS; 0 [no pain] to 10 [worst possible pain]). Patient-reported physical functioning was assessed using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC NRS 3.1) (0 [no difficulty] to 10 [extreme difficulty]) across a range of daily activities. Physicians rated their patients’ function (0 [fully functional] to 10 [completely impaired]). Pain and functional impairment scores were classified into levels as mild [0–3], moderate [4–6], and severe [7–10]. Patients and physicians were also asked to provide an overall rating of OA disease as mild, moderate, or severe. To provide context, physicians were asked to specify the top factors influencing their overall disease severity; however, this was not collected from patients. Pearson’s correlation coefficients were used across the 3 patient and 3 physician clinical measures using continuous scores where available. The strength and direction of the correlation was considered using standard metrics including strong (>+0.70), moderate (>+0.50), or weak (>+.30). Categorical clinical measures (mild, moderate, severe) were used to derive rates of concordance between patient-reported and physician-rated measures. T-tests, chi-squared and Fisher’s exact tests were used to compare patients’ demographics and medical history of the concordant and discordant groups.

Results

Patients (n = 866) had a mean (standard deviation [SD]) age of 64.7 (11.7) years, 61.2% were female, 77.7% were Caucasian, and 34.1% were in full time employment. The mean (SD) duration since OA diagnosis was 2.3 (3.8) years, with 3.1 (2.5) affected joints. The most ‘troublesome joint’ was the knee for 42.6% of patients, followed by the back (22.1%) and hip (17.7%). The mean (SD) BMI was 28.7 (5.9) and 35.1% were obese (BMI >30). Pain intensity was reported as moderate on average based on NRS of 4.2 (2.5) by patients and 4.1 (2.3) by physicians, and functional impairment was reported on average as 3.3 (2.4) by patients and 3.9 (2.6) by physicians. Patient-reported and physician-rated disease severity was categorized as mild (43.2% and 38.0%), moderate (44.9% and 48.1%), or severe (11.9% and 13.8%), respectively. The top factors physicians reported as important in rating overall disease severity included functional impairment, pain intensity, joint space narrowing, as captured via x-rays, and joint deterioration. All assessments were positively correlated. Pain intensity was most strongly correlated (0.73), followed by OA disease severity (0.68), and functional impairment (0.54) when comparing patient-reported and physician-rated measures. Patients and physicians were concordant in their assessment of pain (68%), overall disease severity (74%), and functional impairment (61%). Physicians tended to both underestimate (10%–17%) and overestimate (15%–22%) clinical measures compared with patients. Factors that were significantly associated with physician-patient discordance on pain severity included; white race, higher BMI, longer time since diagnosis, having neck or shoulder as the most troublesome joint, and having a higher number of joints affected by OA (all p < 0.05). Factors that significantly contributed to physician-patient discordance on overall disease severity included; older age, higher BMI, and having hip as the most troublesome joint, whereas for functional impairment included; older age, white race, higher BMI, having back as the most troublesome joint, and having a higher number of joints affected by OA (all p < 0.05).

Conclusions

Clinical measures associated with OA from the patients’ and physicians’ perspectives were positively correlated, with pain intensity resulting in the strongest correlation and functional impairment resulting in the weakest correlation. Higher BMI was the only characteristic that was significantly associated with discordant rating for pain, function and disease severity. Other patient characteristics were associated with the discordance between physician and patient in varying degree across the different clinical measures. The study is limited in that physician-patient assessments were not identical and results are exploratory. Assessments of functional impairment were most disparate with physicians providing a single global assessment and patients completing a 17-item survey that assessed functional level with various everyday activities. These results may suggest that better measurement, monitoring and understanding of the function may improve the management of patients with symptomatic OA.

110 Analysis of testosterone use in male veterans in the setting of opioid cessation or down titration

Rebekka Burch, Carla Figura, Michelle Colvard, Ashley Yost

VA Tennessee Valley Healthcare System, Nashville, TN, USA

Purpose

Testosterone replacement therapy is associated with risks including myocardial infarction, stroke, depression, and aggression. There are several known reversible causes of hypogonadism, one of which is chronic opioid therapy. Following a rise in prescription opioid abuse, the Center for Disease Control (CDC) released guidelines for prescribing opioids for chronic pain in March 2016; the VA/Department of Defense (DoD) followed with their own chronic opioid therapy guidelines in February 2017. The goal of both guidelines was to reduce the use of high dose opioids. The primary objective of this study was to assess for reevaluation safety and appropriateness of testosterone replacement therapy in the 12 months following opioid discontinuation or dose decrease. The secondary objective was to characterize opioid changes in patients with possible opioid-induced hypogonadism, including change in MEDD.

Methods

This was a multisite, retrospective, cohort study, that took place from March 1, 2016 to February 28, 2018. Patients included for analysis were males veterans with active prescriptions for testosterone replacement therapy and chronic opioids on March 1, 2016; chronic opioid therapy was defined as a minimum of 90 consecutive days of opioids. Patients were excluded if they received testosterone or opioids from a non-VA provider or pharmacy, had a diagnosis of HIV or gender identity disorder, were prescribed opioids for cancer-related pain, were prescribed testosterone therapy prior to opioid initiation, or were receiving buprenorphine or tramadol therapy in the absence of other full-opioid agonists. Patient records were assessed through February 28, 2018 for opioid discontinuation or a significant dose reduction; a significant dose reduction was defined as a change from ≥ 90 morphine equivalent daily dose (MEDD) to < 90 MEDD. Opioid prescribed, dose, quantity, date of fill, and MEDD as well as testosterone formulation, dose, directions, and date of fill were collected via manual chart review for the initial and final day of the study period. Also collected through data warehouse extraction and manual chart review were potential confounding causes of hypogonadism, including diabetes, obesity sleep apnea, alcohol/marijuana use, end stage renal disease, and hyperprolactinemia. Safety was assessed by evaluating patient charts for diagnoses of breast cancer, prostate cancer, myocardial infarction, or stroke. This population was then evaluated through chart review to determine if follow-up assessment of hypogonadism was conducted within 12 months of opioid change as indicated by the 2018 Endocrine Society Testosterone Guidelines. An adequate assessment of testosterone replacement therapy was defined according to national VA criteria for use and included laboratory monitoring of free or total testosterone level, hematocrit, lipid panel, and liver function tests. Compliance with the VA criteria for use is required for continuation of testosterone therapy and must be submitted for prior authorization drug review annually. Secondarily, written chart notes were reviewed to see if there was a written assessment and plan, however this was not required for adequate assessment.

Results

A total 363 patients were identified as having possible opioid-induced hypogonadism. Of that population, 136 patients were included for analysis according to inclusion and exclusion criteria and 39% (n = 53; 95% CI: 0.3118–0.4737) of those patients analyzed experienced an opioid discontinuation or significant dose reduction and were analyzed for the primary endpoint. Testosterone therapy was adequately assessed in 64.3% (n = 18) of those patients with opioids discontinued and in 88.9% (n = 8) of those patients experiencing a significant opioid dose reduction. The number of patients with an MEDD ≥ 90 decreased from 39 at study start to 15 at study conclusion (p = 0.0004).

Conclusions

Testosterone was adequately reassessed in large portion of patients in the cohort assessed. This finding most likely highlights the benefit of a pharmacy-run prior authorization process on safe medication use. Provider education regarding the importance of continual evaluation of testosterone therapy after significant changes in opioid therapy may further improve the safe and appropriate use of testosterone. This study also confirmed that there was a significant change in opioid prescribing in line with the CDC and VA/DoD guideline recommendations, which further emphasizes the need for reassessment of testosterone in patients with potential opioid-induced hypogonadism.

111 Demographics, Headache Characteristics, and Other Factors Associated With Opioid Use in People With Migraine: Results From the CaMEO Study

Richard B. Lipton¹, Todd J. Schwedt², Benjamin W. Friedman¹, Kristina M. Fanning³, Michael L. Reed³, Aubrey Manack Adams⁴, Dawn C. Buse¹

¹Albert Einstein College of Medicine, Bronx, NY, USA, ²Mayo Clinic, Phoenix, AZ, USA, ³Vedanta Research, Chapel Hill, NC, USA, ⁴Allergan plc, Irvine, CA, USA

Purpose

To identify variables associated with opioid use among those using acute prescription medications for migraine.

Methods

The Chronic Migraine Epidemiology and Outcomes (CaMEO) Study identified persons with ICHD-3 migraine from a Web panel demographically matched to the US population. We compared the features of self-reported opioid users (currently using opioids or having them on hand for migraine) with those of nonusers. Nested, multivariable binary logistic regression models evaluated opioid use/nonuse as the outcome. Covariates were entered in blocks (sociodemographics, headache and respondent characteristics, psychiatric comorbidities, emergency facility use for headache in the preceding 6 months, and ≥1 cardiovasular [CV] comorbidity). Nonsignificant sociodemographic variables were trimmed from the model.

Results

Of 2,388 people with migraine currently using acute prescription medications, 867 (36.3%) were opioid users. Factors significantly associated (odds ratio [95% CI]) with opioid use included male sex (1.74 [1.38, 2.19), increasing BMI (1.02 [1.00, 1.03]), allodynia (1.39 [1.14, 1.70]), increasing monthly headache day frequency (0–4 days [reference] vs 10–14 days: 1.37 [1.02, 1.82]; ≥15 days: 1.62 [1.24, 2.13]), increasing Total Pain Index (TPI) (excluding head, face, neck; 1.32 [1.15, 1.52]), anxiety (1.37 [1.08, 1.73]), depression (1.49 [1.18, 1.89]), ≥1 CV comorbidity (1.56 [1.28, 1.90]), and emergency facility use for headache (1.73 [1.30, 2.31]). Physician-diagnosed migraine or CM (0.38 [0.30, 0.48]) and a lower migraine symptom severity score (0.94 [0.91, 0.97) were associated with a significantly decreased likelihood of opioid use.

Conclusions

Opioid use is common among migraine patients using prescription medication and is generally associated with markers of worse health, including elevated BMI, CV, and psychiatric comorbidities, elevated TPI, and emergency facility use. Modifiable variables associated with opioid use include presence/absence of physician diagnosis and monthly headache days.

112 Long-term impact of fremanezumab on response rate, acute headache medication use, and disability in episodic migraine patients with acute medication overuse at baseline: results of a 1-year study

Richard B. Lipton¹, Joshua M. Cohen², Sanjay K. Gandhi², Ronghua Yang², Xiaoping Ning², Ira M. Turner³

¹Department of Neurology, Albert Einstein College of Medicine, New York, NY, USA, ²Teva Pharmaceuticals Industries, Frazer, PA, USA, ³Island Neurological, Plainview, NY, USA

Purpose

Overuse of acute headache medications, including triptans, ergot derivatives, opioids, and combination analgesics, in patients with episodic migraine (EM) has been shown to increase risk of developing chronic migraine (CM). Fremanezumab, a fully humanized monoclonal antibody (IgG2Δa) that selectively targets calcitonin gene-related peptide (CGRP), is approved in the US for migraine preventive treatment in adults. Herein we evaluate the long- term impact of fremanezumab on response rate, the use of acute headache medication, and disability in EM patients with acute medication overuse at baseline.

Methods

In this 12- month, multicenter, randomized, double-blind, parallel- group study, adults with EM received subcutaneous fremanezumab either quarterly (675 mg every 3 months) or monthly (225 mg monthly). This post hoc analysis was limited to the subset of EM patients with acute medication overuse at study baseline. Acute medication overuse was defined as acute headache medication use on ≥15 days, migraine-specific acute medication use on ≥10 days, or use of combination medications for headache on ≥10 days. The proportions of patients achieving ≥50% reduction in the monthly average number of migraine days and with ≥50% reduction in the monthly number headache days of at least moderate severity, respectively, as well as the mean change from baseline in the monthly number of days with use of any acute headache medication were measured at Month 6 and Month 12. The effect of fremanezumab on headache-related disability was also assessed using the Migraine Disability Assessment (MIDAS) questionnaire.

Results

Of the 100 EM patients with medication overuse at baseline, 58 received quarterly dosing and 42 received monthly dosing of fremanezumab. For EM patients with acute medication overuse, the mean monthly number of migraine days at baseline was 12.2 days in the quarterly fremanezumab group and 12.3 days in the monthly fremanezumab group; the mean monthly number of headache days of at least moderate severity at baseline was 11.8 and 11.5 days, respectively; the mean monthly number of days with any acute headache medication use at baseline was 12.1 and 12.2 days, respectively; and the mean MIDAS score at baseline was 36.1 and 46.0, respectively. The proportion of EM patients with a ≥ 50% reduction in monthly migraine days was maintained at Month 6 (quarterly: 47%; monthly: 34%) and Month 12 (quarterly: 55%; monthly: 43%). A ≥ 50% reduction in the monthly number of headache days of at least moderate severity was reported by 49% and 29% of patients with quarterly and monthly dosing, respectively, at Month 6, and this reduction was maintained at Month 12 in both dosing groups (quarterly: 59%; monthly: 43%). The mean change from baseline to Month 6 in the monthly number of days EM patients used any acute headache medication was – 5.5 days for quarterly and – 3.7 days for monthly dosing; from baseline to Month 12 it was – 6.1 days for quarterly and – 5.3 days for monthly dosing. The mean change from baseline to Month 6 in the MIDAS score was – 21.3 for quarterly and – 19.1 for monthly dosing; from baseline to Month 12 it was – 20.8 for quarterly and – 28.2 for monthly dosing.

Conclusions

These data demonstrate that long- term treatment with fremanezumab maintained efficacy while reducing the use of acute headache medications and improving headache-related disability in EM patients with acute medication overuse at baseline.

113 Abuse of XTAMPZA ER is rare relative to other opioid analgesics

Stevan Geoffrey Severtson¹, Kevin Wogenstahl¹, Theodore Cicero², Janetta Iwanicki¹, Richard C. Dart¹

¹Rocky Mountain Poison & Drug Safety – Denver Health and Hospital Authority, Denver, CO, USA, ²Washington University in St. Louis School of Medicine, St. Louis, MO, USA

Purpose

Extended-release (ER) oxycodone products are schedule II opioid analgesics designed to provide steady pain relief over several hours. However, these products can become preferred drugs for abuse because they contain a large amount of active pharmaceutical ingredient. Some individuals who abuse ER oxycodone tamper with the medication in order to bypass the controlled-release mechanism to release the entire amount of drug in a short period of time. Products that are more difficult to manipulate may be effective at reducing abuse via tampering and/or unintended routes of administration. XTAMPZA® ER is an abuse deterrent ER oxycodone product that uses DETERx® technology designed to discourage tampering. Studies suggest that XTAMPZA ER maintains ER properties after physical manipulation and administration via the oral or nasal routes. The FDA has granted XTAMPZA ER abuse-deterrent labeling with respect to oral, nasal and IV routes of administration. This study examines the frequency and routes of abuse of XTAMPZA ER and other opioid analgesics using two surveillance systems.

Methods

Descriptive data collected from 2016Q3 through 2018Q4 are presented from two Researched Abuse, Diversion, and Addiction-Related Surveillance (RADARS®) System data sources: the Poison Center Program and the Treatment Center Programs Combined. The Poison Center Program obtains information on exposures from participating poison centers within the United States. Information obtained includes the reason for exposure, the route of administration, and the product involved in the exposure. In the Treatment Center Programs Combined, respondents entering treatment for opioid use disorders complete a questionnaire where they select from a list of prescription medications those they abused in the past month. Respondents are also asked to select the routes by which they administered the product (e.g. snorted, injected). Prescriptions dispensed information was obtained from the IQVIA® (Danbury, CT) US-Based Longitudinal Patient Data. Cases involving XTAMPZA ER were compared to three groups: other abuse deterrent formulation (ADF) ER opioids, non-ADF ER opioids, and immediate-release (IR) oxycodone. Abuse deterrent ER opioids included OXYCONTIN®, EMBEDA®, HYSINGLA® ER, ARYMO® ER, and MORPHABOND^TM ER. Non-abuse deterrent ER opioids included ZOHYDRO ER, MSCONTIN®, and other extended-release morphine products.

Results

From 2016Q3 through 2018Q4, there were 394,000 prescriptions dispensed for XTAMPZA ER, 7.6 million for other ADF ER opioids, 14.4 million for non-ADF ER opioids, and 113 million for IR oxycodone. In the Poison Center Program there were 5,531 intentional abuse exposure cases involving hydrocodone, morphine, or oxycodone; 3 involved XTAMPZA ER, 380 involved other ADF ER opioids, 91 involved non-ADF ER opioids, and 1,743 involved IR oxycodone. The percentage of intentional abuse exposures that involved the injection route of administration was 0% for XTAMPZA ER, 7.4% for other ADF ER opioids, 5.5% for non-ADF ER opioid exposures, and 2.8% for IR oxycodone exposures. The percentage of intentional abuse exposures that involved the inhalation route of administration was 0% for XTAMPZA ER, 15.3% for other ADF ER opioids, 5.5% for non-ADF ER opioid exposures, and 12.3% for IR oxycodone. There were 22,119 valid surveys returned in the Treatment Center Programs Combined; 17 respondents reported abuse of XTAMPZA ER, 1,826 reported abuse of other ADF ER opioids, 569 reported abuse of non-ADF ER opioids, and 3,825 reported abuse of IR oxycodone. The percentage of respondents who indicated injection use among those who reported abuse was 11.8% for XTAMPZA ER, 16.5% for other ADF ER opioids, 29.3% for non-ADF ER opioids, and 12.7% for IR oxycodone. The percentage of respondents who indicated inhalation use among those who reported abuse was 23.5% for XTAMPZA ER, 30.4% for other ADF ER opioids, 17.9% for non-ADF ER opioids, and 38.2% for IR oxycodone.

Conclusions

Abuse of XTAMPZA ER is infrequent. No abuse of XTAMPZA ER via unintended routes of administration was reported in the Poison Center Program. The proportion of cases involving use via unintended routes of administration tended to be lower for XTAMPZA than for comparator drug groups among individuals entering treatment for opioid use disorders. A notable limitation of these analyses is that abuse of specific products is self-reported. In the Treatment Center Programs Combined, even if false positives endorsements on the survey are rare they are more likely to disproportionately inflate estimates of less common products such as XTAMPZA ER than more commonly prescribed comparators. Noting these limitations, continued monitoring in these surveillance systems can aid in identifying changes in abuse of XTAMPXA ER and other opioid analgesics.

114 The diversion and street price of XTAMPZA® ER relative to other prescription opioids

Richard C. Dart¹, Stevan Geoffrey Severtson¹, Kevin Wogenstahl¹, Mance E. Buttram², Steve Kurtz², Janetta Iwanicki¹

¹Rocky Mountain Poison & Drug Safety – Denver Health and Hospital Authority, Denver, CO, USA, ²Center for Applied Research on Substance Use and Health Disparities, Department of Human Services, Abraham S. Fischler College of Education and School of Criminal Justice, Nova Southeastern University, Miami, FL, USA

Purpose

Prescription opioids are a common treatment for chronic and severe pain; however, these medications have a well-documented risk of abuse. Many individuals who abuse prescription opioids obtain these medications after they are diverted from legal distribution channels. The frequency with which a particular product is diverted and the price paid in illegal markets may be indicators of the demand among individuals who abuse opioids. Both measures have been shown to be sensitive to targeted interventions intended to reduce non-medical prescription opioid abuse. XTAMPZA® ER is an abuse deterrent extended-release (ER) oxycodone product that uses DETERx® technology designed to discourage product manipulation for misuse and abuse by oral and non-oral routes. This study assesses the extent of diversion and average street price paid for XTAMPZA ER relative to other prescription opioid analgesics.

Methods

Data from the Researched Abuse, Diversion and Addiction-Related Surveillance (RADARS®) System Drug Diversion Program and StreetRx Program were used. The Drug Diversion Program obtains information on new cases of diversion reported by law enforcement and regulatory agencies in 49 states. The StreetRx Program collects black market drug price information via anonymous submissions to the StreetRx.com website. The distribution of diversion and price reports were compared to the distribution of prescriptions dispensed obtained from the IQVIA® (Danbury, CT) US-Based Longitudinal Patient Data. Cases involving XTAMPZA ER were compared to three groups in the Drug Diversion Program: other abuse deterrent formulation (ADF) ER opioids, non-ADF ER opioids, and immediate-release (IR) oxycodone. In the StreetRx Program, XTAMPZA ER was compared to other ADF ER opioids, non-ADF ER opioids, and IR oxycodone. ADF ER opioids included OXYCONTIN®, EMBEDA®, HYSINGLA® ER, ARYMO® ER, and MORPHABOND™ ER. Non-ADF ER opioids included ZOHYDRO ER, MSCONTIN®, and other extended-release morphine products. Geometric mean price per milligram strength was compared between drug groups. Price comparisons with IR oxycodone did not include combination ingredient tablets due to differences in dosage strengths between products.

Results

From 2016Q3 through 2018Q4, there were 135 million prescriptions dispensed of the drug groups of interest; 394,000 (0.3%) for XTAMPZA ER, 7.6 million (5.7%) for other ADF ER opioids, 14.4 million (10.6%) for non-ADF ER opioids, and 113 million (83.5%) for IR oxycodone. During this time, there were 4,430 cases of diversion involving drug groups of interest captured in the Drug Diversion Program; 4 (0.1%) involved XTAMPZA ER, 295 (6.7%) involved other ADF ER opioids, 337 (7.6%) involved non-ADF ER opioids, and 3,794 (85.6%) involved IR oxycodone. There were 14,284 purchase prices reported on StreetRx.com for the drug groups of interest: 155 (1.1%) for XTAMPZA ER, 2,284 (16.0%) for other ADF ER opioids, 912 (6.4%) for non-ADF ER opioids, and 10,933 (76.5%) involved IR oxycodone. Of the 10,933 IR oxycodone price reports, 9,521 were for combination-ingredient IR oxycodone and 1,412 were for single-ingredient IR oxycodone. The reported price paid for an XTAMPZA ER capsule ranged from $0.75 to $80. The geometric mean price paid per mg was $0.56 (95% CI: $0.48 -$0.65) for XTAMPZA ER, $0.48 ($0.46-$0.50) for other ADF ER opioids, $0.33 (95% CI: $0.31-$0.36) for non-ADF ER opioids, and $0.76 (95% CI: $0.73-$0.80) for single-ingredient IR oxycodone.

Conclusions

Diversion of XTAMPZA ER was observed though it comprises a smaller proportion of cases than would be expected based on prescription volume. XTAMPZA ER makes up a larger proportion of StreetRx Program price quotes than would be expected on based on prescription volume. Findings indicate that the street price of XTAMPZA ER is lower than single-ingredient IR oxycodone products among individuals who abuse opioids. XTAMPZA ER and other ADF ER opioids had a greater price per mg in illegal purchases than non-ADF ER opioids. Further investigation is needed to understand the effect of dosage strength, active pharmaceutical ingredient, and other potential confounders on street price. Limitations of the StreetRx Program should be considered when interpreting these results. Differences in the distribution of StreetRx Program price quotes with both diversion reports and prescriptions dispensed may reflect misidentification of products in the StreetRx Program.

115 Perception XTAMPZA® ER and other abuse-deterrent opioid formulations on the internet

Richard Dart, Joshua Black, Zachary Margolin, Janetta Iwanicki

Rocky Mountain Poison & Drug Safety, Dener, CO, USA

Purpose

Opioid abuse-deterrent formulations (ADF) were developed to reduce the improper use of opioids. Patient experiences and impressions of the opioid ADFs can inform how effective and safe the medications are as used by the community. The internet is used to communicate about use of these medications, and internet anonymity allows posters to reveal experiences that might not otherwise be captured in traditional epidemiological studies. XTAMPZA ER is an extended-release (ER), abuse-deterrent oxycodone product that uses DETERx® technology designed to reduce tampering. The Web Monitoring Program from the Researched Abuse, Diversion and Addiction-Related Surveillance (RADARS®) System was used to examine the sentiment of safety-related posts of XTAMPZA ER and other opioids. The goal was to determine if this new product had a better sentiment profile than other ER opioid products.

Methods

The universe of public websites on the internet (over 150,000,000 websites) were scraped to find online posts made from 2017–2018 regarding XTAMPZA ER, other extended-release (ER) ADF opioid tablet products, ER non-ADF opioid tablet products without abuse-deterrent forms, and single-ingredient immediate release (IR) oxycodone. The other ER ADF opioid product group includes posts mentioning: OXYCONTIN®, EMBEDA®, HYSINGLA® ER, MORPHABOND® ER, and ARYMO® ER. Only posts involving substantive, personal discussion were included; posts without substantive discussion (e.g., spam, news articles, and advertisements) were removed. Additionally, posts must mention 1) an explicit product name, or 2) tablet/capsule formulations along with release type to be included; this likely resulted in an undercount for ER non-ADF opioid product group and the single-ingredient IR oxycodone group. Sentiment is defined as the dominating view or opinion of a drug within the post. Qualitative research methods were used to categorize posts as negative, positive, or neutral sentiment; posts where sentiment was unable to be determined were removed from the analysis. Positive sentiments promote the therapeutic benefits or safe use of a drug. Negative sentiments encourage unsafe or inappropriate use of a drug, or report ineffectiveness or side effects. Neutral sentiments are when the post has no predominant opinion or the sentiment cannot be determined. The sentiment of online posts was examined for three specific topics of discussion regarding opioid products: discussion of abuse, discussion of addiction, or non-professional persons offering guidance on medical or non-medical use. Additionally, posts were examined to determine if the drug product was directly implicated as being involved in addiction, overdose, or death of an individual. All posts from XTAMPZA ER were coded. Due to the large volume, posts for comparators were sampled prior to coding, and estimates of total numbers of posts were calculated. The total number of prescriptions for tablet/capsule forms for each group was calculated to evaluate the relative market availability of each group.

Results

A total of 362 posts were observed for XTAMPZA ER, an estimated 244,941 posts for other ER ADF opioid products, and an estimated 530 posts for ER non-ADF opioid products. There were 386,948 total number of prescriptions filled for XTAMPZA ER, 7,184,491 for other ER ADF opioid products, and 10,919,155 for ER non-ADF opioid products. The percentages of posts that conveyed negative sentiment (encouraging inappropriate use, ineffectiveness, or side effects) were 18.8% for XTAMPZA ER, 52.3% for ER ADF products, and 29.6% for ER non-ADF products. The percentages of posts that conveyed positive sentiment (encouraging safe use) were 11.6% for XTAMPZA ER, 2.7% for ER ADF products, and 19.7% for ER non-ADF products. There were few posts involving the single-entity IR oxycodone group (n = 33), and therefore data were too sparse to calculate estimated number of posts or percentages.

The percentages of abuse posts that conveyed negative sentiment (encouraging inappropriate use, ineffectiveness, or side effects) were 6.2% for XTAMPZA ER and 61.0% for ER ADF opioid products. The percentages of addiction posts that conveyed negative sentiment (encouraging inappropriate use, ineffectiveness, or side effects) were 35.7% for XTAMPZA ER and 74.9% for ER ADF opioid products. The percentages of non-professional advice posts that conveyed negative sentiment (encouraging inappropriate use, ineffectiveness, or side effects) were 3.0% for XTAMPZA ER and 41.5% for ER ADF opioid products. The percentages of abuse posts that conveyed positive sentiment (encouraging safe use) were 43.8% for XTAMPZA ER and 8.4% for ER ADF opioid products. The percentages of addiction posts that conveyed positive sentiment (encouraging safe use) were 42.9% for XTAMPZA ER and 3.9% for ER ADF opioid products. The percentages of non-professional advice posts that conveyed positive sentiment (encouraging safe use) were 24.2% for XTAMPZA ER and 18.6% for ER ADF opioid products. Due to the low number of topic-specific posts observed for the ER non-ADF opioid product group, sentiment could not be calculated.

The percentages of posts that directly implicated each drug in overdose were 0.0% for XTAMPZA ER (zero posts found) and 0.3% for other ER ADF opioid products. The percentages of posts that directly implicated each drug in death were 0.0% for XTAMPZA ER (zero posts found) and 0.5% for other ER ADF opioid products. The percentages of posts that directly implicated each drug in addiction were 1.1% for XTAMPZA ER and 1.2% for other ER ADF opioid products.

Conclusions

Online sentiment of XTAMPZA ER was primarily neutral, though a higher proportion was negative (encouraging inappropriate use, ineffectiveness, or side effects) than positive (encouraging safe use). Negative sentiment (encouraging inappropriate use, ineffectiveness, or side effects) of XTAMPZA ER was much less prevalent than for other ER ADF opioid products. When three key topics are discussed, XTAMPZA ER was generally discussed with less negative (encouraging inappropriate use, ineffectiveness, or side effects) and more positive (encouraging safe use) sentiments than other ER ADF opioid products. XTAMPZA ER was not implicated in critical medical outcomes of overdose and death where other ER ADF opioid products were. The comprehensiveness of the public web search was a key strength of this analysis. However, some websites (e.g., Facebook, Bluelight) prohibit public web scraping, and these sites could include important information not captured here. Further, categorization of posts is limited to what individuals divulge, and therefore some posts might not be included in the groupings because key information (e.g., formulation) is missing.

116 Dramatic Relief of Non-Combat PTSD after Stellate Ganglion Block: A Case Report

Rikin Shah¹, Rajnikant Shah², Niteesh Bharara³

¹Trinity School of Medicine, Alpharetta, Georgia, USA, ²West Virginia Univeristy, Morgantown, WV, USA, ³Viriginia Spine Institute, Reston, VA, USA

Purpose

The DSM-V defines Post-Traumatic Stress Disorder (PTSD) as a pathologic trauma and stressor disorder occurring in some individuals after severe trauma exposure. This case study describes the great efficacy of Stellate Ganglion Block (SGB) for PTSD symptoms in a non-combat veteran.

It is estimated that nearly 8% (24.4million) Americans suffer from PTSD. Women are twice as likely as men to develop PTSD; in the US military, 71% of females develop PTSD due to sexual assault while enlisted. WHO recommends psychotherapeutic modalities and pharmacologic interventions. Current first line pharmacologic interventions are effective in only about 50% of patients. Multiple case reports and a case series have shown efficacy using SGB in combat-related PTSD patients; however, limited case reports have documented the efficacy in non-combat PTSD patients.

Here we present a 46-year old female, non-combat veteran had been suffering from PTSD for the last 10 years. Unfortunately, conservative management failed; her depression, anxiety, and memory dysfunction worsened. Three treatments of SGB were performed 2 months apart and the severity of the patient’s PTSD symptoms decreased by 26% after the 1st SGB. At each 2 month follow-up, the patient reported immediate benefit in the days following the procedure as well as sustained relief from PTSD symptoms.

Methods

The SGB was performed using a standard fluoroscopic technique using 3cc of Lidocaine and injecting with a 22 Gauge spinal needle at the C6 level on the right side of the patient’s neck. Iodinated contrast was used to confirm appropriate flow without vascular uptake. Horner’s Syndrome was observed immediately after the procedure; this provided additional confirmation of the proper placement of the block.

Prior to the procedure the patient completed a PCL-M, which is a 17 item self-report questionnaire that has been validated by the National Center for PTSD as a diagnostic tool for PTSD. Each question is graded from 1 to 5 and a total score is calculated ranging from 17 (no symptoms at all) to 85 (severe symptoms). This patient completed a PCL-M questionnaire prior to (pre) and after (post) each of the 3 SGB procedures. The procedures occurred in approximately 2 month intervals.

Results

The patient had an average of 25% improvement in PCL-M score after each SGB. The patient reported feeling an overall 80% improvement after each SGB. The patient was able to attend work each day and able to have a successful relationship for the first time in several years. The pre-procedure PCL-M score dropped approximately 25% between the 1st and 3rd procedure. This indicates a sustained improvement of PTSD symptoms over 6 months.

Conclusions

Several studies have identified the benefit of SGB in combat-related PTSD; however, few studies have examined the role and efficacy of SGB in non-combat related PTSD.

The Stellate Ganglion Block (SGB) is a minimally-invasive procedure that has been widely used to treat complex regional pain syndrome; however, SGB now has a likely role in the treatment of PTSD – particularly in patients that have not responded to conservative management or other more traditional forms of PTSD treatment.

More studies need to be performed to adequately determine the optimal volume of anesthetic needed for blockade as well as to determine the most effective duration for intervals between procedures.

117 Autologous, Micro Fragmented Adipose Tissue as a Treatment for Bilateral Chronic Shoulder Pain in a Paraplegic Individual

Rikin Shah¹, Niteesh Bharara²

¹Trinity School of Medicine, Alpharetta, Georgia, USA, ²Virginia Spine Institute, Reston, Virginia, USA

Purpose

Shoulder pain is the 3^rd most common injury in able-bodied individuals and a frequent complaint for individuals who are wheelchair bound. Shoulder pain in manual wheelchair users can lead to an inability to perform daily activities and further debilitation. Current treatment largely involves regular physical therapy and repetitive corticosteroid injections. Surgical intervention is often the only option once those treatments have been exhausted. However, surgical repair is often not a practical option for manual wheelchair users due to the length of post op recovery; which requires patients to be completely dependent on a caretaker and can lead to further deconditioning.

Methods

A 60-year-old male, manual wheelchair user complains of severe bilateral shoulder pain secondary to a spinal cord injury 20 years prior. The patient reports shoulder pain for 2 decades, with the past 5 years being severe. Physical Therapy and corticosteroid injections which were once useful to the patient now have less efficacy and decreasing benefit in the patient’s pain and range of motion. Magnetic Resonance Imaging (MRI) shows severe degenerative joint disease in both the left and right shoulder joint.

Due to the failure of traditional nonoperative care, surgical consultation was obtained and bilateral total shoulder replacement was recommended. Unfortunately, the patient would not be able to tolerate the post-operative recovery required. At this point, autologous micro fragmented adipose tissue was recommended as an alternative.

This procedure was performed by obtaining 100ccs of lipoaspirate from the abdominal region using the traditional tumescent technique. Then, this was processed using the Lipogems system and a total of 24ccs of micro fragmented adipose was obtained. Using strict ultrasound guidance with a posterior approach, a total of 12ccs of micro fragmented adipose was injected into each Glenohumeral Joint. The patient tolerated the procedure without complication.

Results

The patient had no improvement at 2 weeks post procedure; however, at 6 weeks post procedure, the patient’s pain had completely resolved without improvement in his range of motion. His pain, as assessed by the Visual Analog Score (VAS), improved from 8/10 to 0/10. The patient then started a physical therapy regimen – during which abduction of the joint improved from 50 degrees to 100 degrees and flexion improved from 40 to 60 degrees. Subjectively, the patient reported improved shoulder stability.

Conclusions

This case demonstrates that autologous micro fragmented adipose tissue has the potential to effectively treat chronic and debilitating shoulder pain without the drawbacks of surgical repair. The current approach to chronic shoulder pain that has failed traditional non-operative treatment is to move forward with surgical interventions. The use of micro fragmented adipose is a novel alternative that benefits those who are not ideal surgical candidates. Further research is needed to explore which intervention would allow for a better outcome with minimal complication and an easier post-operative course.

118 ‘Deuterated’ Drugs: Application to Analgesics?

Robert Raffa^1,2,3, Joseph V. Pergolizzi, Jr^3,4, Robert Taylor, Jr⁴

¹Adjunct Professor, University of Arizona College of Pharmacy, Tucson, AZ, USA, ²Professor Emeritus, Temple University, Philadelphia, PA, USA, ³Neumentum, Inc, Palo Alto, CA, USA, ⁴NEMA Research, Inc, Naples, FL, USA

Purpose

The first ‘deuterated’ drug has recently been approved by FDA. A ‘deuterated’ drug is one in which the H atom in one or more C-H bonds is replaced by deuterium (D), an isotope of H that has one instead of the usual no neutrons. Since a C–D bond is more stable in the body than is a C–H bond, if D is strategically located in a drug’s structure, the extra stability of the bond will be more resistant to metabolic breakdown, and the duration of drug action will be prolonged. We review the general concept of deuterated drugs.

Methods

A search was conducted of the published literature (in English) using sources such as PubMed and MedLine. The identified material was reviewed and synthesized.

Results

The first FDA-approved deuterated drug is deutetrabenazine (AUSTEDO®; Teva Pharmaceuticals). Tetrabenazine has been used clinically for many years as treatment for movement disorders. Deutetrabenazine is metabolized at a slower rate than is non-deuterated tetrabenazine, which imparts less patient-to-patient variability and a dosing advantage to the deuterated drug.

Conclusions

One or more well-placed D in place of H in a drug molecule can delay its metabolism and extend its half-life. The hoped-for result is less-frequent administration, enhancing patient compliance. Since the strategy is so attractive for new drugs and for revamping older ones, at least a dozen companies are pursuing the approach. However, the strategy does not always work, and the path to regulatory approval is not always shortened. In addition, there is question about patentability and other intellectual property issues. Nevertheless, the approach could provide promise as a new tool for the development of analgesic drugs.

119 Is Some e-Cigarette Use, Like Some Cigarette Use, Chronic-Pain Coping?

Jan M. Kitzen^1,2, Joseph V. Pergolizzi, Jr^3,4, Jamie L. McConaha⁵, Megan L. Bookser⁶, Robert Taylor, Jr⁴, Robert Raffa^3,7,8

¹Kitzen Pharmaceutical Consulting, Collegeville, PA, USA, ²Adjunct Associate Professor Emeritus, Temple University School of Medicine, Philadelphia, PA, USA, ³Neumentum, Inc, Palo Alto, CA, USA, ⁴NEMA Research, Inc, Naples, FL, USA, ⁵Duquesne University School of Pharmacy, Pittsburgh, PA, USA, ⁶Preferred Primary Care Physicians, Pittsburgh, PA, USA, ⁷Adjunct Professor, University of Arizona College of Pharmacy, Tucson, AZ, USA, ⁸Professor Emeritus, Temple University, Philadelphia, PA, USA

Purpose

Individuals with chronic pain often report smoking cigarettes partly as a means of coping with their condition. This tends to promote greater use, and presents a barrier to cessation of use. Electronic nicotine-delivery systems (ENDS) are battery-powered devices that facilitate the inhalation of nicotine and/or other substances in aerosolized form. e-Cigarettes (electronic-cigarettes), the most commonly-used ENDS, have been proposed to be smoking-cessation aids. However, despite a rapid surge in popularity, little is known about the long-term health consequences of e-cigarette use. We review published data to see if they deliver what they promise.

Methods

A search was conducted of the published literature (in English) using sources such as PubMed and MedLine. The identified material was reviewed and synthesized.

Results

There are significant inconsistencies in the evidence available for assessing the efficacy and safety of e-cigarettes as a viable tool for smoking cessation. Additional data and examination is necessary into the long-term implications of exposure to e-cigarette products, and improved quality-control measures need to be adopted and implemented before their utility in contributing to successful smoking cessation is accepted. Emerging evidence suggests that e-cigarettes might not be as effective as hoped.

Conclusions

Although e-cigarettes have been proposed to be a safe approach useful for encouraging smoking cessation, there are inconsistencies in the available data regarding efficacy and safety. Whether or not the absence of nicotine in some of these products would have an impact (either positive or negative) on the use of cigarettes by chronic pain patients as a coping mechanism has not been studied.

120 Buprenorphine: Unique Supraspinal Mechanism of Analgesic Action?

Robert Raffa^1,2,3, Joseph V. Pergolizzi, Jr^3,4, Robert Taylor, Jr⁴

¹Adjunct Professor, University of Arizona College of Pharmacy, Tucson, AZ, USA, ²Professor Emeritus, Temple University, Philadelphia, PA, USA, ³Neumentum, Inc, Palo Alto, CA, USA, ⁴NEMA Research, Inc, Naples, FL, USA

Purpose

Buprenorphine displays attributes of an opioid, but also some clinical features distinct from standard opioids. We review studies undertaken to determine if there is a difference in the supraspinal or spinal signal-transduction of buprenorphine compared to morphine and fentanyl. Significant differences are noted.

Methods

A search was conducted of the published literature (in English) using sources such as PubMed and MedLine. The identified material was reviewed and synthesized.

Results

Spinal (intrathecal, IT) administration of naloxone (NLX) or pertussis toxin (PTX) significantly reduces antinociception (analgesia) induced in mice by subcutaneous (SC) administration of morphine, fentanyl, or buprenorphine. In contrast to the spinal route, supraspinal (intracerebroventricular; ICV) administration of either NLX or PTX antagonizes morphine- and fentanyl-, but not buprenorphine-induced antinociception. The same results were obtained in a second nociceptive model. Spinal pretreatment with G_z antisense does not alter buprenorphine-, morphine-, or fentanyl-induced antinociception and ICV pretreatment with G_z antisense does not alter morphine- or fentanyl-induced antinociception. However, pretreatment with ICV G_z antisense (but not random-sense) significantly reduces buprenorphine-induced antinociception. Peripheral administration of JTC-801 (nociceptin receptor antagonist) significantly enhances buprenorphine’s dose-response curve, but only IT, not ICV, nociception (NOP) enhances buprenorphine-induced antinociception

Conclusions

These results seem to reveal a possible novel supraspinal non-opioid (i.e., naloxone-, PTX-, NOP-insensitive), G_z protein-sensitive component to buprenorphine’s supraspinal mechanism of analgesic action.

121 Partial Agonism: Basic Principles and Clinical Implications

Robert Raffa^1,2,3, Joseph V. Pergolizzi, Jr^3,4, Robert Taylor, Jr⁴

¹Adjunct Professor, University of Arizona College of Pharmacy, Tucson, AZ, USA, ²Professor Emeritus, Temple University, Philadelphia, PA, USA, ³Neumentum, Inc, Palo Alto, CA, USA, ⁴NEMA Research, Inc, Naples, FL, USA

Purpose

There have been recent attempts to give a qualitative ‘definition’ of the term ‘partial agonist’. Yet, there is only one definition. We review it here, and show that the term ‘partial agonist’ is situation-dependent, and is consistent with a different level of effect at one endpoint (e.g., analgesia) and a simultaneous different level of effect at another endpoint (e.g., an adverse effect).

Methods

A search was conducted of the published literature (in English) using sources such as PubMed and MedLine. The identified material was reviewed and synthesized.

Results

The definition of ‘partial agonist’ provides a link between action at the receptor level (different from the concept of ‘affinity’) with an observed effect (different from the concept of ‘potency’). It successfully explains how the same analgesic drug molecule can produce different levels of effect against different levels of pain and it also explains why the term ‘partial agonist’ can be differentially applied to different effects produced by the same analgesic (e.g., therapeutic vs adverse).

Conclusions

The definition of ‘partial agonist’ means that it is situation-dependent (i.e., it is not a physical constant), that a drug cannot be defined as a ‘partial agonist’ without the particulars of the context, and is consistent with a different level of a drug’s effect at one endpoint (e.g., analgesia) and a simultaneous different level of effect at some other endpoint (e.g., ‘ceiling effect’ on an adverse effect).

Acknowledgment: The authors wish to gratefully acknowledge the many significant contributions made by Ronald J. Tallarida, PhD to this topic and to his dedication to instilling the importance of precise definitions and quantitative rigor in basic and applied pharmacology.

122 The Concept of a ‘µ-Load’

Robert Raffa^1,2,3, Joseph V. Pergolizzi, Jr^3,4, Christian Elling⁵, Thomas M. Tzschentke⁵

¹Adjunct Professor, University of Arizona College of Pharmacy, Tucson, AZ, USA, ²Professor Emeritus, Temple University, Philadelphia, PA, USA, ³Neumentum, Inc, Palo Alto, CA, USA, ⁴NEMA Research, Inc, Naples, FL, USA, ⁵Grünenthal GmbH, Aachen, Germany

Purpose

To make an effort using basic receptor theory to estimate for a representative multi-mechanism analgesic the relative contribution of each component to its analgesic effect and to adverse effects relative to a pure opioid.

Methods

A search was conducted of the published literature (in English) using sources such as PubMed and MedLine. The identified material was reviewed and synthesized.

Results

In terms of analgesic response, the main relevant receptor for most commonly-used opioids is the m-opioid receptor (MOR). Therefore, when considering the balance between analgesia and opioid-typical adverse effects, the opioids are somewhat mono-mechanistic. But for some of the ‘atypical’ opioids, such as buprenorphine, tapentadol, and tramadol, the analgesic effect results from the combined contributions of an opioid component and a non-opioid component. We used three approaches that we loosely call ‘in vitro and PK’, ‘in vivo’, and ‘clinical’. The ‘in vitro’ approach emanates from receptor affinity, intrinsic activity, and pharmacokinetic data. The ‘in vivo’ approach involves novel analysis, but is essentially a type of component factor analysis. And the ‘clinical’ approach utilizes available clinical data.

Conclusions

We develop the concept of ‘µ-load’, the percent contribution of an opioid component to the adverse effect magnitude relative to a pure/classical µ-opioid at equi-analgesia.

123 Treating Opioid-Induced Constipation (OIC): Is CYP450 Drug Interaction a Concern?

Joseph V. Pergolizzi, Jr^1,2, Robert Taylor¹, Mate Kalapos¹, Robert Raffa^2,3,4

¹NEMA Research, Inc, Naples, FL, USA, ²Neumentum, Inc, Palo Alto, CA, USA, ³Adjunct Professor, University of Arizona College of Pharmacy, Tucson, AZ, USA, ⁴Professor Emeritus, Temple University, Philadelphia, PA, USA

Purpose

Constipation is an adverse effect that is experienced by many patients who are administered opioids. Opioid-induced constipation (OIC) can be treated with one of the new peripherally-acting µ-opioid receptor antagonist (PAMORA) drugs. We summarize these drugs, with an emphasis on comparison of their metabolic routes of elimination.

Methods

A search was conducted of the published literature (in English) using sources such as PubMed and MedLine. Emphasis was placed on the mechanism of action of the PAMORAs, their metabolic pathways, drugs co-administered with opioids, and potential drug-drug interactions (particularly at the level of CYP450 isozyme drug metabolism). Each source was evaluated and synthesized into the review.

Results

PAMORAs dose-dependently antagonize the access of opioid agonist molecules to opioid receptors, thereby directly eliminating or reducing OIC. But they differ from other opioid antagonists in that they are restricted to the periphery. Hence, they block constipation, but leave central opioid receptor-mediated pain relief undiminished. The PAMORAs have similarly good efficacy and safety profiles, but many pain patients have comorbidities and thus are taking other medications, which increases the potential for metabolic drug interactions.

Conclusions

Managing OIC in patients who have failed OTC or other therapies can be accomplished using a PAMORA, but healthcare providers must make prudent decisions that avoid or at least mitigate the potential for metabolic drug interactions in those patients with other comorbidities being managed medically by rational polypharmacy.

124 Benzodiazepines and Opioids

Robert Raffa^1,2,3, Joseph V. Pergolizzi, Jr^3,4, Robert Taylor⁴

¹Adjunct Professor, University of Arizona College of Pharmacy, Tucson, AZ, USA, ²Professor Emeritus, Temple University, Philadelphia, PA, USA, ³Neumentum, Inc, Palo Alto, CA, USA, ⁴NEMA Research, Inc, Naples, FL, USA

Purpose

To review new information and proposals related to the basic pharmacology of benzodiazepines (BZDs) and other BZD receptor agonists (BzRAs) that heightens concern about excess prescribing of benzodiazepines (BZDs) and concomitant use with opioids.

Methods

A search was conducted of the published literature (in English) using sources such as PubMed and MedLine. The identified material was reviewed and synthesized.

Results

It is now known that:

• Down-regulation of BZD receptors and GABA_A receptor subunits and receptor mRNA occur – with a concomitant decrease in receptor responsiveness

• There is a surprising lack of information available about the receptor binding profile of most BzRAs

• Non-GABAA receptor action – e.g., BZDs potentiate adenosine A_2A receptor-mediated effects, allosterically modulate α1-adrenoceptor signaling by inhibiting PDE-4, and possibly have agonist action at oxytocin receptors

• Little-known, and even less-understood, BZD binding sites are located peripherally in abundance – critically, on mitochondria and immune cells

• Control-system compensatory mechanisms, such as hysteresis – might accelerate or magnifying the development of tolerance or physical dependence

• An enigmatic protracted withdrawal is experienced by some patients – a phenomena possibly related to peripheral BZD receptors or translational or epigenetic changes

Conclusions

Until the peripheral receptors and prolonged withdrawal phenomena are better understood, the evidence questions the use of BzRAs beyond about 4 weeks.

125 Prevalence of Gastric Ulcer Disease (UD) and Association with NSAID Use among Persons with Migraine: Results from the Migraine in America Symptoms and Treatment (MAST) Study

Richard Lipton¹, Sagar Munjal², Dawn Buse¹, Michael Reed³, Kristina Fanning³, Preeti Singh², Leah Bensimon², Todd Schwedt⁴, David Dodick⁴

¹Albert Einstein College of Medicine, Bronx, NY, USA, ²Dr. Reddy’s Laboratories, Princeton, NJ, USA, ³Vedanta Research, Chapel Hill, NC, USA, ⁴Mayo Clinic, Phoenix, AZ, USA

Purpose

Determine lifetime prevalence for UD in people with migraine vs those without migraine and investigate associations of gastric ulcers with NSAID use.

Methods

The 2017 MAST Study is a US Web-based survey of people with migraine and a control sample free of migraine. Sociodemographics and co-morbid health problems (via self-reported physician diagnoses) were obtained for n = 15,133 who met migraine ICHD-3beta criteria and for 77,453 controls. Logistic regression modeling (controlling for sociodemographics) compared the two samples on UD prevalence and assessed influence of monthly headache day (MHD) frequency. Odds ratios (OR) and 95% confidence intervals (CI) were calculated. NSAID usage was also assessed among migraineurs with UD.

Results

UD was 3 times more common in migraine vs non-migraine (unadjusted 4.5% vs 1.9%, OR 3.11, CI 2.81, 3.45) and increased incrementally with MHD frequency [range: from OR 2.6 (CI 2.30, 2.96) for 1–4 MHDs to OR 5.91 (CI 4.43, 7.88) for ³21 MHDs]. Mean days of NSAID use was also higher in those with UD (10.5 vs 6.1, P < .01) and increased incrementally from 5.0 days/month for those with 1–4 MHDs to 19.1 days/month for those with ³21 MHDs.

Conclusions

Gastric ulcer disease was more common among people with migraine. Links between UD, MHD frequency and migraine require further study. Research findings may be attributable to direct causality, reverse causality, shared underlying predisposition or risk factors, and/or exacerbated by NSAID use in those pre-disposed to UD.

126 Most Bothersome Associated Migraine Symptom: Results from 2017 Migraine in America Symptoms and Treatment (MAST) Study

Michael Reed¹, Sagar Munjal², Aftab Alam², Kristina Fanning¹, David Dodick³, Todd Schwedt³, Dawn Buse⁴, Richard Lipton⁴

¹Vedanta research, Chapel Hill, NC, USA, ²Dr. Reddy’s Laboratories, Princeton, NJ, USA, ³Mayo Clinic, Phoenix, AZ, USA, ⁴Albert Einstein College of Medicine, Bronx, NY, USA

Purpose

Freedom from MBS is a co-primary endpoint in clinical trials of acute migraine therapies. Patterns of MBS based on symptom profiles, have not been assessed in representative non-trial cohorts of persons with migraine. The objective of this analysis was to assess the most bothersome migraine associated symptom (MBS) in a representative sample of persons with migraine stratified by the pattern of associated symptoms.

Methods

The Migraine in America Symptoms and Treatment (MAST) Study, a Web-based survey, identified a representative cohort of US adults with migraine according to ICHD-3 beta criteria with ≥1 headache day/month in the preceding three months. Respondents were asked to choose their MBS prior to taking medication and were stratified into five groups: Nausea, Nausea+Photophobia, Nausea+Phonophobia, Photophobia+Phonophobia and Nausea+Photophobia+Phonophobia.

Results

Among 6,045 eligible respondents who completed the MBS questions, the mean age was 46.4 years, 76% were women, and 84.8% were Caucasian. In the entire sample, the MBS in order of frequency were: photophobia (49.1%), nausea (28.1%), and phonophobia (22.8%). Most respondents endorsed experiencing Nausea+Photophobia+Phonophobia (64.9% of respondents), followed by Photophobia+Phonophobia (24.3%), and Nausea alone (4.3%). For those with Nausea+Photophobia+Phonophobia or Photophobia+Phonophobia, photophobia was most often rated the MBS. When nausea was present with either photophobia or phonophobia alone, nausea was rated as the MBS.

Conclusions

This study examined MBS among respondents with different combinations of associated symptoms. Though photophobia was the most common MBS overall and in persons with all 3 symptoms, nausea was most often the concurrent MBS when associated with either photophobia or phonophobia.

127 Poor Acute Treatment Optimization and Frequent Nausea in Episodic Migraine (EM) are Associated with New Onset Chronic Migraine (CM): Results from 2017 Migraine in America Symptoms and Treatment (MAST) Study

Aftab Alam¹, Michael Reed², Kristina Fanning², Dawn Buse³, Todd Schwedt⁴, Sagar Munjal¹, David Dodick⁴, Richard Lipton³

¹Dr. Reddy’s Laboratories, Princeton, NJ, USA, ²Vedanta Research, Chapel Hill, NJ, USA, ³Albert Einstein College Of Medicine, Bronx, NY, USA, ⁴Mayo Clinic, Phoenix, AZ, USA

Purpose

Poor acute treatment optimization and frequent nausea are independent risk factors for the onset of CM in persons with EM, but their joint influence has not been evaluated. The objective of this analysis was to examine the separate and joint association of poor acute treatment optimization and frequent nausea during migraine attacks on the rate of CM onset in adults with EM.

Methods

The MAST Study is a prospective, longitudinal, Web-based survey of people with ICHD-3 beta migraine (n = 15,133). Inclusion required and average of at least 1 monthly headache day (MHD) during the preceding 3 months. Baseline sociodemographics, MHDs, migraine symptom frequency, and acute treatment optimization (from Migraine Treatment Optimization Scale) were obtained. A 6-month follow-up assessment evaluated progression from EM (<15 MHDs) to CM (≥ 15 MHDs).

Acute treatment optimization was dichotomized as Poor Optimization (poor or very poor response to acute medication) vs Good Optimization (moderate or maximum response). Nausea was dichotomized as Frequent Nausea (occurring half the time or more with headache) vs Rare Nausea (never, rarely, less than half the time). Progression rates for separate and combined effects were evaluated; combined effects at six months are reported here. Chi-square for linear trend tested statistical significance for the pattern of findings.

Results

The eligible sample included 4857 participants with EM who used acute prescription medication at baseline and completed the 6-month follow-up. The mean age was 45.5, 73.4% were women, 84.2% were Caucasian. CM emerged in 3.3% with Good Optimization and Rare Nausea, in 3.8% with Good Optimization and Frequent Nausea, in 5.9% with Poor Optimization and Rare Nausea, and in 6.5% with Poor Optimization and Frequent Nausea (Chi for trend 18.317, P < .001).

Conclusions

Poor acute treatment optimization and frequent nausea are associated with an increased risk of CM onset in persons with EM.

128 Women with migraine vary in time to peak headache pain intensity, functional impairment and pain interference based on menstrual migraine status: Results from the 2017 Migraine in America Symptoms and Treatment (MAST) Study

Jelena Pavlovic¹, Dawn Buse¹, Michael Reed², Kristina Fanning², Sagar Munjal³, Aftab Alam³, Todd Schwedt⁴, David Dodick⁴, Richard Lipton¹

¹Albert Einstein College of Medicine, Bronx, NY, USA, ²Vedanta Research, Chapel Hill, NC, USA, ³Dr. Reddy’s Laboratories, Princeton, NJ, USA, ⁴Mayo Clinic, Phoenix, AZ, USA

Purpose

Women with migraine are divided into 3 subgroups based on headache relation to menses: Non-Menstrual Related Migraine (NMRM), Pure Menstrual Migraine (PMM) and Menstrual Related Migraine (MRM). PMM and MRM experience peri-menstrual attacks which are typically more severe and refractory to treatment. Time to peak pain intensity and/or impairment has not been previously examined among the subgroups. The objective of this analysis was to examine time to peak headache pain intensity, functional impairment and pain interference by menstrual migraine status in subgroups of women in a large US sample.

Methods

MAST study participation included US respondents who met ICHD criteria for migraine with ≥1 monthly headache day over 3 months. This analysis included women with episodic migraine aged 18–55, with ≥1 menstrual period <12 months. We assessed time to peak headache pain intensity, time to initial functional impairment, and time to peak functional impairment dichotomizing onset times into rapid (≤60 minutes) and slow (>60 minutes) for all attacks. The PROMIS Pain Interference Short Form 6b assessed work and social consequences of pain.

Results

Among 2,833 women, 73(2.6%) met study PMM criteria, 817(28.8%) met MRM criteria and 1,943(68.6%) met NMRM criteria. Overall, 62.9% experienced peak pain intensity, 61.5% experienced initial functional impairment and 48.2% experienced peak functional impact within an hour of the start of an attack. 64.4% NMRM women reached peak pain intensity within 60 minutes compared with MRM (60.3%;p = .044) and PMM (52.1%;p = 0.031). Pain interference was highest among MRM (standardized score 57.1) vs NMRM (56.0) and PMM (52.9) (F = 12.4, p < .001).

Conclusions

Women with MRM reported the highest overall pain interference, consistent with prior knowledge that women with MRM have higher burden of migraine than those with NMRM. Interestingly, NMRM group reported more rapid pain onset and impairment compared to PMM and MRM. This novel information may assist healthcare professionals in tailoring treatment choices for women with migraine.

129 Association and Impact of Monthly Migraine Headache Frequency and Pain Intensity on Comorbidities and Concomitant Health Conditions: Results from the Migraine in America Symptoms and Treatment (MAST) Study

Dawn Buse¹, Michael Reed², Ryan Bostic², Sagar Munjal³, Leah Bensimon³, Preeti Singh³, Richard Lipton¹

¹Albert Einstein College of Medicine, Bronx, NY, USA. ²Vedanta Research, Chapel Hill, NC, USA. ³Dr. Reddy’s Laboratories, Princeton, NJ, USA

Purpose

Prior work evaluated the rates of associated comorbid health conditions among migraine vs non-migraine persons. This analysis explores the individual impact of monthly headache days (MHD) and headache pain intensity (HPI) on rates of comorbid and concomitant health conditions among persons with migraine.

Methods

Using a Web-based panel, respondents to the Migraine in America Symptom and Treatment (MAST) Study were screened for migraine using a validated questionnaire. Individuals who met modified ICHD-3 beta symptom criteria for migraine and reported an average of ³1 MHDs were invited to complete the survey which captured sociodemographics (sex, age, race, ethnicity, marital and employment status, income), MHD frequency (categorized as 1–4, 5–9, 10–14, 15–20 and ³21), HPI level (low, moderate, high), and a range of comorbid conditions derived from respondent self-report of healthcare professional diagnosis. Conditions included vascular disease, pain, respiratory, cardiovascular risk factors, general medical, dermatological, and psychological conditions (see Table for complete list). Separate logistic regression models were used to assess the influence of MHDs and HPI on the relative odds of each condition (adjusting for sociodemographics). Combined models are presented using 1–4 MHD as the reference for MHD and low HPI as the reference for HPI effects.

Results

15,133 subjects met migraine symptom and headache frequency inclusion criteria (73% women, mean age 43 years). In combined models (with sociodemographics, MHD and HPI), respondent age was frequently associated with increased odds of comorbid conditions (i.e., diabetes age 25–34 OR = 1.53, 35–44 OR = 2.35, 45–54 OR = 3.47, 55–64 OR = 3.74, ³65 OR = 4.29) while being non-Hispanic (OR = 0.79) and/or employed (OR = 0.66) were protective. As MHD frequency increased, the odds of many health problems also increased (Table). This was particularly true for insomnia (5–9 MHDs OR = 1.47, 10–14 OR = 2.0, 15–20 OR = 2.08, ³21 OR = 2.46), anxiety and depression (similar pattern, all p < .01). Severe HPI was associated with increased odds (p < .01) of rheumatoid arthritis (OR = 1.95), gastric ulcer disease (OR = 2.31), hypertension (OR = 1.33), psoriasis (OR = 2.78), allergy/hay fever (OR = 1.58), insomnia (OR = 2.20), anxiety (OR = 2.05), and depression (OR = 2.13) (Table). Reports for kidney disease were related to age but not affected by MHD or HPI.

Conclusions

In demographically adjusted models age, increasing MHD frequency and HPI ratings are associated with increased risk of many conditions in persons with migraine. These findings may be due to direct causality or reverse causality, shared risk factors or potential detection or reporting bias among MAST respondents. Further research is needed to understand the underlying pathophysiology associated with these comorbidities and their association with migraine.

130 Impact of Monthly Headache Day Frequency on Work Productivity and Impairment in Non-Work Activities among Persons with Migraine: Results from the Migraine in America Symptoms and Treatment Study

Sagar Munjal¹, Preeti Singh¹, Leah Bensimon¹, Michael Reed², Ryan Bostic², Dawn Buse³, Richard Lipton³

¹Dr. Reddy’s Laboratories, Princeton, NJ, USA, ²Vedanta Research, Chapel Hill, NC, USA, ³Albert Einstein College of Medicine, Bronx, NY, USA

Purpose

Migraine causes impairment in daily life activities. This analysis examines the relationship of monthly headache day (MHD) frequency to impairment in daily activity in four areas: missed work (absenteeism), reduced efficiency at work (presenteeism), total work loss and impairment in non-work activities.

Methods

The Migraine in America Symptom and Treatment (MAST) Study is a web-based assessment of persons with migraine who were identified using modified ICHD-3 beta criteria. Respondents meeting ³1 average MHD frequency inclusion criteria were invited to complete the survey which captured sociodemographics, MHD frequency (categorized as 1–4, 5–9, 10–14, 15–20 and ³21) and included Work Productivity and Activity Impairment (WPAI) scale. This validated scale assesses the percent of scheduled work time missed in the past week (absenteeism), the percent of time at work with impairment (presenteeism), and overall percent of work time lost to headache (absenteeism plus presenteeism) among employed respondents. It also assesses the percent of non-work-related activity impairment due to headache over the past week for all respondents. Estimated marginal means (and 95% CIs) were calculated from separate generalized linear models for each of the four WPAI measures, adjusting for sociodemographics (gender, age, race, BMI, and household income).

Results

15,133 subjects met study inclusion criteria (73% women, mean age 43 years) including 10,903 (72%) who were currently employed. Among employed respondents, absenteeism impacted 4.9% of work time while presenteeism impacted 31.5% of work time. Both measures increased with MHD frequency (Table). The percent of total overall impairment at work also increased with MHD frequency: 29.4% of work time for 1–4 MHDs, 43.4% for 5–9 MHDs, 50.7% for 10–14 MHDs, 53.7% for 15–20 MHDs, and 57.3% for those with ³21 MHDs. Non-work-related activity impairment followed a similar pattern among all respondents: 30.7% of non-work activity time for 1–4 MHDs, 43.8% for 5–9 MHDs, 51.1% for 10–14 MHDs, 55.2% for 15–20 MHDs, and 58.9% for those with ³21 MHDs.

Conclusions

Work productivity and non-work-related activity impairment are common in persons with migraine and increases with MHD frequency. Presenteeism accounts for the majority of work-related productivity loss. With MHD frequency ³10, work productivity loss exceeds 50% of work time among employed respondents; and non-work activity impairment exceeds 50% for persons with a MHD frequency ≥10. Lost work and non-work time is substantial. Modeling is underway to assess the productivity related burden of migraine and to estimate the potential economic benefits of reduced MHD frequency.

131 Comorbidity, Treatment Patterns, and Economic Burden of Primary Headache Disorders: an Administrative Claims Data Analysis

David Kudrow¹, Sagar Munjal², Leah Bensimon², Tasneem Lokhandwala³, Binglin Yue³, Stephen Silberstein⁴

¹California Medical Clinic for Headache Neurological Research Institute, Santa Monica, CA, USA, ²Dr. Reddy’s Laboratories, Princeton, NJ, USA, ³Xcenda, Palm Harbor, FL, USA, ⁴Thomas Jefferson Headache Center, Philadelphia, PA, USA

Purpose

Tension-type headache (TTH), migraine, and cluster headache (CH) account for majority of headache disorders; understanding the treatment patterns and burden of which may assist in evidence-based treatment decisions. The purpose of this analysis was to describe comorbidity burden, real-world healthcare resource utilization (HCRU) and costs, and treatments among adults diagnosed with primary headache disorders, using integrated health insurance claims data.

Methods

The study employed a retrospective cohort design using data from Jan 2012 through Dec 2017. Adults diagnosed with TTH, migraine, or CH, identified by ICD-9/10-CM codes, were included. The index date was the earliest primary headache disorder date between Jan 2013 and Dec 2016. Patients not continuously enrolled during the 12-month pre- and post-index periods were excluded. Comorbidities were assessed during the pre-index period. Treatments, annual all-cause and headache-related HCRU and costs (USD 2017) were assessed post-index per patient.

Results

The following patient cohorts were identified: TTH (n = 34,147), migraine (n = 363,976), CH (n = 4,326), and >1 primary headache type (n = 16,330). The mean age across the 4 cohorts ranged from 44–48 years. Majority of the CH patients were male (63%), whereas the TTH, migraine, and >1 headache type patients were predominantly female (76–84%). Most prevalent comorbidities across all 4 cohorts were sinusitis (20–31%), hypertension (21–28%), and anxiety disorders (16–23%). Majority of the patients had evidence of analgesic (54–73%), and psychotropic (57–81%) drug use: primarily opioids (36–53%), NSAIDs (31–41%), and antidepressants (33–59%). Adherence to prophylactic treatments was low (mean proportion of days covered range: 0.2–0.4). Triptans (10–50%) were the predominant acute headache treatment after opioids (36–53%) for all cohorts, except TTH patients. One-tenth (8–10%) of the patients were hospitalized over the year, one-third had emergency department visits (26–36%), and 21–54% had neurologist visits. Patients diagnosed with >1 headache type incurred the highest mean (SD) annual all-cause costs ($17,853 [$32,073]), followed by migraine ($15,320 [$31,802]), CH ($15,037 [$40,018]), and TTH ($12,825 [$27,829]). Headache-related costs accounted for approximately one-fifth of all-cause costs.

Conclusions

Patients diagnosed with primary headache disorders have significant comorbidity and economic burden; especially patients diagnosed with >1 headache type. Opioids are predominantly used for acute treatment.

132 Recurrent Pain Abdomen in young Children

Sanjiv Nanda, Kapil Bhalla

Postgraduate Institute of Medical Sciences, Rohtak, Haryana, India

Purpose

Recurrent abdominal pain (RAP) in children is defined as presence of at least three episodes of abdominal pain severe enough to disrupt normal lifestyle and affect their activities over a period longer than three months.

The incidence of organic and non-organic causes of RAP are variable in different studies (10% −20%) of which organic lesion is present in 5 to 10% of the children, common causes being H. Pylori infection, parasitic infestations and cholelithiasis. Non-organic RAP has been found to be common in the setting of school phobia, sibling rivalry and a family history of multiple abdominal complaints, psychological stressful problems and disturbed interpersonal relationships. The aim of study was to determine the organic and non-organic causes of RAP in young children (2–6 years). Most of the earlier studies were conducted on older children (5–12 years).

Methods

One hundred and fifty children between the ages of 2 to 6 years attending pediatric clinic for recurrent pain of abdomen from March 2015 to March 2016 were enrolled for the study. A detailed history and examination, complete hemogram, urinalysis and stool examination (three consecutive days) were done in all cases. Special investigations like skiagram chest and abdomen, ultrasonography of abdomen, serological tests for tuberculosis and upper gastrointestinal endoscopy were performed whenever indicated. The children who were having organic cause were treated as per the cause and followed for at least 3 months. RAP was labelled when:-

1. An organic cause was demonstrated;

2. There was clinical and laboratory response to treatment; and

3. There was remission from abdominal pain for at least three months after treatment.

The children in whom cause was non-organic RAP (NORAP) a detailed family history was taken and counselling done.

Results

Out of 150 children complaining of RAP, there was significant male predominance 102 (68%). Ninety three (62%) were in the age 4 to 6 years while rest belonged to 2 to 4 years group The mean duration of illness at the time of presentation was longer in the NORAP group possibly because patients with ORAP have their causes identified at some stage. The organic cause was found in 90 (60%) children and non-organic in 60 (40%). The parasite infestation was commonest cause which included giardiasis (38 cases) either alone or with other parasites like entamoeba histolytica, enterobius vermicularis etc. Ascariasis (19 cases) was also a common cause. In addition to RAP, there were other features in form of failure to thrive, anorexia and diarrhoea off and on and pica. Recurrent urinary tract infection was the cause of RAP in 9 children which were diagnosed by urinalysis and culture. Abdominal tuberculosis was detected in 9 children. There was family history of pulmonary tuberculosis in all these 9 cases. ELISA tests and examination of ascitic fluid confirmed the diagnosis. Gallstones were detected in 3 children on ultrasonography who were 6 years old. None of these children had clinical features of chronic haemolytic anaemia, liver disease or hyperlipidemia.

Non-organic recurrent pain abdomen was seen in 60 (40%) children. School phobia, sibling rivalry, unpleasant parent relations among parents and nocturnal enuresis were associated factors. Children with NORAP were living in different psychosocial environment at school and home.

Most of the cases were above 4 years of age. Family history, sibling rivalry, school phobia and punishment were associated with NORAP. Patients with NORAP belonged to families with higher prevalence of marital discord, irritable bowel syndrome (IBS), chronic painful disorders, migraine, maternal dysmenorrhoea and RAP The children were treated symptomatically and followed up to 3 months.

Conclusions

Giardiasis an intestinal protozoal infection was the most common cause of organic abdominal pain accounting alone for 60% and it was adequately treated.

Many of these children were having anorexia, diarrhoea off and on and were also having history of pica. Worm infestation has never been taken seriously as cause of abdominal pain due to high prevalence even in asymptomatic patients.

Gall stones have been reported to be a cause of RAP in young children. Three of the cases had gall stones as cause of RAP. Jaundice, localized abdominal pain or intolerance to fatty food were not seen in these cases.

Patients with NORAP belonged to families with higher prevalence of marital discord, irritable bowel syndrome (IBS), chronic painful disorders, maternal dysmenorrhoea and RAP.

Thorough investigations are must before labelling recurrent abdominal pain (RAP) to be of organic or psychogenic origin.

Both the child and the parents need to be counselled on stress coping strategies and provided with ample reassurance that there is no serious organic disease. Psychological interventions, such as cognitive behavioural and family therapy are effective in reducing symptoms and improving school attendance.

133 Impact of a Health System Wide Opioid Stewardship Program on Prescribing Practices Following Orthopedic Surgery

Sara Meyer, Bridget Bridgman, Bryan Edwards, Kaitlyn Uhl

Novant Health, Winston Salem, NC, USA

Purpose

Novant Health’s Opioid Stewardship Program aims to alleviate the opioid crisis in the communities it serves by safely and appropriately using opioids for pain management while optimizing alternative therapies. Four key areas of focus for the program include improved post-operative prescribing, risk assessment and mitigation via the Opioid Risk Tool^© and use of a treatment agreement, and screening patients with Opioid Use Disorder for Hepatitis C and HIV. The greatest opportunity for improved prescribing after surgery was identified within orthopedic surgery.

Novant Health is a 14 hospital not-for-profit health system with acute care facilities located in North Carolina and Virginia. All hospitals within the system perform orthopedic surgery, with an estimated 25,000 orthopedic procedures performed annually. Orthopedic services are provided by both Novant Health and non-affiliated providers.

An Opioid Steering Committee oversees four workgroups dedicated to improving opioid management across the continuum of care and reducing stigma associated with opioid use disorder and other types of addiction. Focused work on improved post-operative prescribing is generated via a multidisciplinary acute care workgroup led by a Clinical Pharmacist and the Orthopedic Institute Clinician Executive.

Numerous studies link prescriptions for acute post-operative pain to long term use of opioids^1,2. At the time of program creation, little guidance was available to surgeons on the optimal treatment of pain or duration of opioid therapy following orthopedic surgery. In an effort to improve prescribing, a goal was set for 90% of initial post-operative prescriptions to be less than 350 Morphine Milligram Equivalents (MME). This goal was based on North Carolina legislation limiting post-operative prescriptions to a 7 day supply in combination with data showing increased risk of overdose when exceeding 50 MME per day³. Providers have an option of prescribing additional opioids after the initial seven day prescription at their discretion. Baseline data in orthopedics obtained in January 2018 revealed 60% of prescriptions were <350 MME. Facility specific rates ranged from 38% to 100%.

Methods

The acute care workgroup began receiving discharge prescription data in July 2018 from an internal data and analytics team. All prescriptions generated from the Electronic Health Record (EHR) tied to a discharge surgical encounter are included. Non-electronic prescriptions or those prescribed in an ambulatory encounter are lost to capture, however legislation will soon prohibit written prescriptions for all narcotics effective 2020. Patients undergoing spine surgery or with an active oncologic diagnosis are excluded due to a greater prevalence of opioid tolerance and chronic pain in these populations. Data reports are provided on a monthly basis with a two month lag time and include a facility level breakdown and categorization into inpatient and outpatient procedures. Provider specific breakdowns are available upon request.

Efforts to improve prescribing practices centered on education, electronic medical record (EMR) support, and data sharing. Order sets for orthopedic surgery contain options for pre-emptive analgesia and multi-modal therapy after surgery. Anesthesia is available for placement of spinal blocks, peripheral nerve blocks and infusion catheters. The Novant Health affiliated orthopedic surgeons employ a co-management agreement with the non-affiliated surgeons. In August 2018, Opioid Stewardship was adopted as a focus area for the co-management group. Posters detailing examples of prescriptions <350 MME were posted in physician alcoves located in surgical areas in September 2018. During the same time frame, workgroup members provided education at the Orthopedic Best Practice Exchange Team and OR Committee. In January 2019, the EMR library of opioid prescriptions was updated from a ten day supply default to include five and seven day supply options. In April 2019, a Best Practice Advisory EMR pop-up was activated to flag discharge prescriptions greater than 50 MME/day. Providers have an option to continue with their original order or modify the orders through the Best Practice Advisory. Additionally, the Orthopedics Clinician Executive is provided individual clinician data as requested based on facility compliance rates. This data is shared with prescribers by the Executive with recommendations for improvement.

Results

Orthopedic discharge prescriptions ≤350 MME have increased from a baseline of 60% in January 2018 to 88% in April 2019. In February and March of 2019, 92% and 90% of all prescriptions were ≤350 MME, respectively. A three month average for February through April 2019 represents a 43% increase in goal from the same time period of 2018. Facility specific data during this time frame ranges from 67% to 99% compliance with goal.

Conclusions

Significant improvement is seen in orthopedic surgery opioid prescribing practices. This improvement was driven primarily through physician education, expectation setting, data sharing, and a strong partnership with Orthopedics leadership. Any additional improvement by the Best Practice Advisory is not yet reflected in the data set.

Future efforts to improve prescribing and pain control include utilization of a multi-modal dashboard, an orthopedics Enhanced Recovery after Surgery (ERAS) program, and enhanced discharge education including guidance on tapering opioids and continuation of non-opioid agents.

Data will be collected through the end of 2020 to monitor maintenance of improved prescribing habits.

134 Characteristics of Patients with Migraine Initiating Galcanezumab for the Preventive Treatment of Migraine

Shonda A. Foster, Margaret Hoyt, Karen Hamrick Samaan, Wendy Wenyu Ye, Christopher Marrone, Janet H. Ford

Eli Lilly and Company, Indianapolis, IN, USA

Purpose

Galcanezumab (Emgality ®; Lilly, Indianapolis, IN) is approved for the preventive treatment of migraine. It is a monoclonal antibody specifically designed to bind to and inhibit the activity of calcitonin gene-related peptide (CGRP). The purpose of this study is to describe the demographic and clinical characteristics of patients with migraine who initiated galcanezumab following (FDA) approval.

Methods

Adult patients with at least 1 claim for migraine (ICD-10 code G43.XX) and ≥1 pharmacy claim for galcanezumab were identified within the HealthCore Integrated Research Database (HIRD) from 10/01/2018–04/30/2019 (index period). HIRD includes longitudinal administrative claims data for more than 38 million enrollees in commercial and Medicare Advantage insurance plans. Patients were required to be continuously enrolled for 12-months prior to the index date (date of first fill of galcanezumab during the index period). Descriptive analyses of pre-index demographic and clinical patient characteristics including age (at index), prescriber specialty (at index or within 60 days prior), prior preventive and acute medication use, all-cause health care resource utilization and costs were conducted.

Results

A total of 1,886 patients with migraine who initiated galcanezumab were identified (mean age: 46 years; female: 86.6%). Neurologists (53.5%), non-physician clinicians (e.g., nurse practitioners, physician assistants) (25.6%), and primary care physicians (14.0%) were the most common prescriber specialties. Approximately 75% of patients who initiated galcanezumab were on a prior preventive therapy during the previous 12 months (anti-epileptics (40.9%), neurotoxin (24.5%), antidepressants (22.6%), beta-blockers (17.2%), and CGRP antagonists (14.5%)). In addition, 64.3% were on triptans. 32.3% had an all-cause emergency room (ER) visit within the previous 12 months and 7.8% had an all-cause inpatient visit. The mean (SD) all-cause total healthcare cost was $54,765.90 ($83,052.11).

Conclusions

The majority of patients who initiated galcanezumab were on prior preventive therapy and were seen by neurologists and non-physician clinicians. Additionally, within the 12 months prior to starting galcanezumab, nearly one out of three patients had an all-cause ER visit and average all-cause healthcare costs exceeded $50,000 per patient. Understanding the characteristics of patients initiating galcanezumab and other CGRP inhibitors will provide valuable insights for healthcare providers and value-based decision makers.

135 Pain relief after Lower Segment Cesarean Section : Comparison between Tramadol and Paracetamol.

Smiti Nanda, Meenakshi Chauhan

Postgraduate Institute of Medical Sciences, Rohtak, Haryana, India

Purpose

Pain control is an important part of postoperative patient care. Opioids and NSAIDS are effective agents commonly used in postoperative pain management, both of which have potentially harmful side effects. Tramadol, being centrally acting analgesic, and unlike other opioids does not depress respiration and provoke sedation, is found to be effective analgesic in post-operative patients. Paracetamol is said to have least side effect potential as compared to NSAIDS.

The aim of the present study was to compare the efficacy of intravenous Paracetamol and Tramadol for postoperative analgesia in patients undergoing elective cesarean section while observing its effect on hemodynamic stability and the presence of adverse drug reactions, if any.

Methods

The present prospective study was carried on 200 patients undergoing elective cesarean section. Patients were allocated to two groups of 100 each. Group A received IV infusion of paracetamol 1gm in 100 ml solution, while Group B received IV infusion of Tramadol 100 mg in 100 ml NS at 0 (first complain of pain postoperatively), 8 and 16 hours respectively. Pain intensity was measured by a 10 point Visual Analogue Scale [VAS] (0→no pain and 10→worst imaginable pain). VAS at T(0)→just before analgesic administration, 15, 30 minutes, 1, 2, 4, 6 and 8 hours was monitored in addition to routine post-operative care. The efficacy and side effects of both drugs were compared. Chi-square test and Student t-test were applied and p-value <0.05 was considered significant.

Results

The demographic profiles were comparable among the two groups. The p-values for the VAS Score at 15, 30 min,1, 2, 4, 6 hours were insignificant in both subgroups. But, at 8 hours it was found that subgroup B (Tramadol, mean VAS = 4.025 + 1.646) had lower mean VAS as compared to subgroup A (Paracetamol, mean VAS = 5.10 + 1.236) and the difference was statistically significant (P value-0.002). Requirement of additional analgesia was more with paracetamol infusion (28% vs 22%). There was no difference in the values of liver and renal function tests before and after the administration of two drugs. Side effects observed were nausea and vomiting (4%) in Group A and drowsiness (20%), nausea and vomiting (8%), headache (4%) and respiratory difficulty (4%) in Group B.

Conclusions

The analgesic effects of both drugs are comparable in post Lower segment cesarean section patients. However, paracetamol is better tolerated drug, having lesser side effects as compared to tramadol. Intravenous paracetamol is a safer and effective non-opioid analgesic for the treatment of postoperative pain.

136 What Matters Most in the Diagnosis and Monitoring of Osteoarthritis by Physician Specialty?

Srinivas Nalamachu¹, Rebecca L. Robinson², Lars Viktrup², Joseph C. Cappelleri³, Andrew G. Bushmakin³, Leslie Tive⁴, Jennifer Mellor⁵, James Jackson⁵

¹Mid America PolyClinic, Overland Park, KS, USA, ²Eli Lilly and Co., Indianapolis, IN, USA, ³Pfizer Inc, Groton, CT, USA, ⁴Pfizer Inc, New York, NY, USA, ⁵Adelphi Real World, Bollington, United Kingdom

Purpose

Osteoarthritis (OA) is associated with bone remodeling, cartilage degradation, formation of osteophytes, as well as joint inflammation and diminished joint function. The tests and procedures used to diagnose and monitor OA can vary across medical specialties in clinical practice. The objective of this study was to evaluate the relative importance of diagnostic and monitoring procedures for patients with OA by physicians with different specialties. This study also aimed to identify 1) the most common factors used by physicians to classify patients in terms of their OA disease severity, and 2) the clinical factors considered in the assessment of OA progression by physician specialty.

Methods

This was a cross-sectional, observational study utilizing data from the Adelphi Disease Specific Programme (DSP) for OA. The Adelphi DSP is based on a standardized methodology collecting data on disease management in real-world clinical practices with a focus on physician and patient perspectives. The study included primary care physicians (PCPs), rheumatologists (RHEUMs) and orthopedic surgeons (ORTHOs) in the United States. Data were collected from February 2017–May 2017 from participating clinics. Patient demographic data were collected for each physicians’ nine consecutive patients, who were seeking treatment for their OA. Physicians provided information on the tests and procedures used to confirm an OA diagnosis and to monitor the OA progress. These included imaging (X-rays, magnetic resonance imaging [MRIs], computerized tomography scans), laboratory based tests, joint-related assessments (joint aspiration, tender joint count, swollen joint count, arthroscopy), 6-minute walk test, and patient-reported assessments of pain and function (Western Ontario and McMaster Universities Osteoarthritis Index [WOMAC] questionnaire, and the Lequesne Index). Physicians were asked to estimate the proportion of patients with mild, moderate or severe OA in their practices. Physicians were also asked to select the top three most important factors they use when determining a patient’s severity classification, including structural changes, pain, and functional impairment. In addition, physicians were asked to identify the factors used in their assessment of OA progression. Comparisons were made across specialties using chi-square and analysis of variance tests. Results are exploratory and therefore no adjustments were made for multiple testing.

Results

Participants included 81 (52.9%) PCPs, 35 (22.9%) RHEUMs, and 37 (24.2%) ORTHOs. Overall, the majority (72.5%) of physicians were male, within private practices (84.7%), and within office/outpatient (87.2%) settings. Patients’ (n = 1357) OA severity (mild, moderate, and severe) was 39.3%, 39.6%, and 21.1% for PCPs, 24.7%, 47.3%, and 28.0% for RHEUMs, and 33.9%, 40.6%, and 25.5% for ORTHOs, respectively. The mean (standard deviation [SD]) number of tests/procedures typically used to confirm an OA diagnosis were 4.4 (2.9) for PCPs, and 5.2 (3.1) for RHEUMs, and 3.2 (2.0) for ORTHOs (p < 0.01). X-ray was the most frequently reported procedure used by all physicians to confirm diagnosis (91%; 100%, 100%; p ≤ 0.05) and to monitor OA (59%, 71%, 81%; p ≤ 0.05). The mean (SD) number of OA monitoring procedures typically performed were 4.1 (3.0) for PCPs, 4.1 (2.7) for RHEUMs, and 2.5 (2.0) for ORTHOs (p < 0.01). ORTHOs were most likely and PCPs were least likely to request X-rays for their patients at the time of diagnosis of mild (75.0% and34.5%), moderate (85.3% and 57.2%) and severe OA (88.9% and 67.3%), respectively. Other procedures commonly used to confirm diagnosis and monitor OA included MRIs (61% and 31%), tender joint count (43% and 36%), and swollen joint count (43% and 37%), respectively. Notably, the WOMAC questionnaire was used for assessing severity and monitoring symptoms of OA, and infrequently used to diagnose (13%) or monitor OA (15%) with no significant differences by specialty. The most important factors in determining disease severity varied by specialty: functional impairment was the most important to PCPs (62%), pain severity to RHEUMs (73%), and joint space narrowing (JSN) to ORTHOs (83%). Other factors considered important when determining OA severity across all specialties included severity of joint deterioration (30%), frequency of pain symptoms (26%), MRI results (19%), ability to work (17%), number of joints affected by OA (15%), increase in treatment dose or frequency of drugs to control OA pain (10%), ability to sleep (4%), and WOMAC (1%). In contrast, OA progression was most likely determined by pain severity (PCPs), increased impairment, higher severity of pain, less mobility, and structural degeneration (RHEUMs), and JSN and structural degeneration (ORTHOs).

Conclusions

Reliance on X-rays is a key driver in the diagnosis of OA especially as disease severity increases, particularly among ORTHOs. This study shows that, while X-rays are key in the diagnosis of OA, the tests and procedures used for monitoring OA vary by physician specialty. Moreover, patient-reported assessments measuring pain and function that are commonly used in research were infrequently used by physicians for diagnostic or monitoring purposes. In contrast, when monitoring OA progression, the most important determinants vary among physician specialties. OA progression is most likely to be determined by pain severity for PCPs, JSN for ORTHOs, and equally determined by pain, function, and structural degeneration for RHEUMs.

137 Long-term impact of fremanezumab on response rate, acute headache medication use, and disability in chronic migraine patients with acute medication overuse at baseline: results of a 1-year study

Stephen D. Silberstein¹, Joshua M. Cohen², Sanjay K. Gandhi², Ronghua Yang², Xiaoping Ning², David Kudrow³

¹Jefferson Headache Center, Thomas Jefferson University, Philadelphia, PA, USA, ²Teva Pharmaceuticals Industries, Frazer, PA, USA, ³California Medical Clinic for Headache, Santa Monica, CA, USA

Purpose

Overuse of acute headache medications, including triptans, ergot derivatives, opioids, and combination analgesics, is common among patients with chronic migraine (CM). Fremanezumab, a fully humanized monoclonal antibody (IgG2Δa) that selectively targets calcitonin gene- related peptide (CGRP), is approved in the US for the preventive treatment of migraine in adults. Herein we evaluated the long- term impact of fremanezumab on response rate, the use of acute headache medication, and disability in CM patients with acute medication overuse at baseline.

Methods

In this 12-month, multicenter, randomized, double-blind, parallel-group study, adults with CM received subcutaneous fremanezumab either quarterly (675 mg every 3 months) or monthly (225 mg monthly with a starting dose of 675 mg). This post hoc analysis was limited to CM patients with acute medication overuse at baseline. Acute medication overuse was defined as acute headache medication use on ≥15 days, migraine-specific acute medication use on ≥10 days, or use of combination medications for headache on ≥10 days. The proportions of patients with ≥50% reduction in the monthly number of migraine days and with ≥50% reduction in the monthly number headache days of at least moderate severity, respectively, as well as the mean change from baseline in the monthly number of days with use of any acute headache medications were measured at Month 6 and Month 12 in both fremanezumab dosing groups. The effect of fremanezumab on headache- related disability was also assessed using the 6-item Headache Impact Test (HIT-6).

Results

Of the 599 CM patients with acute medication overuse at baseline, 292 were randomized to quarterly dosing and 307 to monthly dosing. For CM patients with acute medication overuse, the mean monthly number of migraine days at baseline was 17.5 days in the quarterly fremanezumab group and 17.7 days in the monthly fremanezumab group; the mean monthly number of headache days of at least moderate severity at baseline was 15.7 days and 15.3 days, respectively; the mean monthly number of days with any acute headache medication use at baseline was 18.1 and 18.5 days, respectively; and the mean HIT-6 score at baseline was 64.3 and 64.7, respectively. The proportion of patients with a ≥ 50% reduction in monthly migraine days was maintained at Month 6 (quarterly: 37%; monthly: 48%) and Month 12 (quarterly: 51%; monthly: 52%). A ≥ 50% reduction in the monthly number of headache days of at least moderate severity was reported by 42% and 53% of patients with quarterly and monthly dosing, respectively, at Month 6, and this reduction was maintained at Month 12 in both dosing groups (quarterly: 50%; monthly: 54%). The mean change from baseline to Month 6 in the monthly number of days CM patients used any acute headache medication was – 6.9 days with quarterly and – 7.8 days with monthly dosing; from baseline to Month 12 it was – 8.1 days for quarterly and – 8.2 days for monthly dosing. The mean change from baseline to Month 6 in the HIT-6 disability score was – 6.2 with quarterly and – 7.5 with monthly dosing; from baseline to Month 12 it was – 6.9 with quarterly and – 8.1 with monthly dosing.

Conclusions

These data demonstrate that long- term treatment with fremanezumab maintains efficacy while reducing the use of acute headache medications and improving headache-related disability for up to 1 year in CM patients with acute medication overuse.

138 Long-term efficacy of fremanezumab in chronic and episodic migraine patients with acute medication overuse at baseline: results of a 1-year study

Stephen D. Silberstein¹, Joshua M. Cohen², Michael J. Seminerio², Ronghua Yang², Xiaoping Ning², Messoud Ashina³

¹Jefferson Headache Center, Thomas Jefferson University, Philadelphia, PA, USA, ²Teva Pharmaceuticals Industries, Frazer, PA, USA, ³Danish Headache Center, Department of Neurology, Glostrup, Denmark

Purpose

Overuse of acute headache medications, such as triptans, ergot derivatives, opioids, and combination analgesics, can cause medication overuse headache (MOH). MOH is common in patients with chronic migraine (CM) and may lead to progression from episodic migraine (EM) to CM. Fremanezumab, a fully humanized monoclonal antibody (IgG2Δa) that selectively targets calcitonin gene- related peptide (CGRP), is approved for the preventive treatment of migraine in adults. We assessed the long- term efficacy of fremanezumab in migraine patients and baseline acute medication overuse.

Methods

This 12-month, multicenter, randomized, double-blind, parallel-group study evaluated two subcutaneous dose regimens of fremanezumab in adults with CM and EM. The study included patients rolled over from two placebo-controlled studies, as well as 312 new patients. Patients were assigned to either quarterly (675 mg every 3 months) or monthly (225 mg monthly; CM: starting dose of 675 mg) dosing. The mean change from baseline (assessed prior to the placebo-controlled phase) in migraine days and headache days of at least moderate severity was measured in patients with and without baseline acute medication overuse. Acute medication overuse was defined as either acute headache medication use on ≥15 days, migraine- specific acute medication use on ≥10 days, or use of combination medications for headache on ≥10 days.

Results

A total of 599/1103 (54%) CM patients and 100/775 (13%) EM patients reported acute medication overuse at baseline. The mean monthly number of migraine days at baseline for CM patients with acute medication overuse was 17.5 days in the quarterly group and 17.7 days in the monthly group; for CM patients without acute medication overuse, 15 days in both dosing groups; for EM patients with acute medication overuse, 12.2 and 12.3 days, respectively; and for EM patients without acute medication overuse, 8.7 days in both dosing groups. At baseline, the mean number of headache days of at least moderate severity for CM patients with acute medication overuse was 15.7 days in the quarterly group and 15.3 days in the monthly group; for CM patients without acute medication overuse, 11.2 and 11.5 days, respectively; for EM patients with acute medication overuse, 11.8 and 11.5 days, respectively; and for EM patients without acute medication overuse, 6.7 and 6.8 days, respectively. At Month 12, there was a sustained reduction in the monthly number of migraine days in patients with CM with acute medication overuse at baseline (quarterly [mean change]: – 7.5 days; monthly: – 8.2 days) and EM (quarterly: – 5.9 days; monthly: – 5.1 days). Reductions in migraine days were also seen in patients without acute medication overuse at baseline (CM: quarterly: – 6.9 days; monthly: – 7.9 days; EM: quarterly: – 5.1 days; monthly: – 5.1 days). At Month 12, there was also a sustained reduction in the monthly number of headache days of at least moderate severity in CM (quarterly: – 7.0 days; monthly: – 7.4 days) and EM (quarterly: – 6.1 days; monthly: – 4.6 days) patients with acute medication overuse at baseline. Reductions in headache days of at least moderate severity were also seen in patients without acute medication overuse at baseline (CM: quarterly: – 5.5 days; monthly: – 6.2 days; EM: quarterly: – 4.1 days; monthly: – 4.2 days).

Conclusions

Fremanezumab demonstrated efficacy over 12 months of treatment in migraine patients regardless of acute medication overuse at baseline. Patients with acute medication overuse at baseline achieved larger reductions in both migraine days and headache days of at least moderate severity than those without medication overuse at baseline.

139 Tapentadol is the least common finding in admission urine drug-test results at a substance-use treatment facility in Ohio

Adam Rzetelny¹, Diana Meske¹, Shawn Ryan², Steve Passik¹

¹Collegium Pharma, Stoughton, MA, USA. ²Brightview Health, Akron, OH, USA

Purpose

A better understanding of the potential abuse profile of opioid medications remains critically important for optimizing the balance of risks and benefits for patients in pain and for the community. Data from several recent post-marketing, or real-world, studies suggest that opioid medications have different abuse profiles, with tapentadol among the lowest for diversion,¹ street value,² and self-reported abuse from poison-control centers and substance-use treatment admissions.³ Urine drug testing (UDT) data could contribute to a better understanding of abuse because it is not prone to the limitations of self-report methods. Thus, the focus of the present retrospective observational study was to utilize the results of UDT to investigate differential patterns of substance abuse among various opioid medications. A better understanding of the potential abuse profile of opioid medications remains critically important for optimizing the balance of risks and benefits for patients in pain and for the community. Data from several recent post-marketing, or real-world, studies suggest that opioid medications have different abuse profiles, with tapentadol among the lowest for diversion,¹ street value,² and self-reported abuse from poison-control centers and substance-use treatment admissions.³ Urine drug testing (UDT) data could contribute to a better understanding of abuse because it is not prone to the limitations of self-report methods. Thus, the focus of the present retrospective observational study was to utilize the results of UDT to investigate differential patterns of substance abuse among various opioid medications.

Methods

In this retrospective observational study, we examined the UDT records of patients admitted at a large midwestern intensive outpatient addiction-treatment facility during the period from December 2016 to March 2019. We chose to focus on nine opioids (oxycodone, oxymorphone, hydrocodone, hydromorphone, tramadol, tapentadol, codeine, fentanyl, and morphine) that are currently available by prescription. Testing was performed with liquid chromatography/tandem mass spectrometry. A positive result was removed from analysis if the patient had a prescription for that drug.

In order to examine rates of UDT positives adjusted by drug availability in the community, we calculated the ratio of UDT positives per million morphine milligram equivalents dispensed (UDT:MMED) for each opioid utilizing a prescription database from approximately the same timeframe. UDT:MME was calculated for each opioid as follows: # of UDT Positives/(# of pills x dosages x MME conversion ratios / 1 million)

Results

At admission, one urine specimen was collected from each of 4162 patients. This patient population was positive 92.81% of the time for at least one of the nine opioids, with positivity rates from lowest to highest as follows: tapentadol (0.12%), hydrocodone (2.64%), tramadol (4.95%), hydromorphone (5.89%), oxymorphone (6.37%), codeine (6.54%), oxycodone (7.04%), fentanyl (28.86%), and morphine (29.34%). The UDT:MME values from lowest to highest were as follows: tapentadol (0.43), hydrocodone (0.66), oxycodone (0.68), tramadol (3.48), codeine (14.84), morphine (16.33), hydromorphone (23.38), fentanyl (24.02), and oxymorphone (32.24). Because there is some controversy around the CDC’s MME conversion ratio for tapentadol of 0.4, we additionally calculated the adjusted value for tapentadol utilizing a conversion ratio of 0.3, which yielded a tapentadol UDT:MMED of 0.57. This value was higher than that obtained with the CDC MME conversion ratio but remained lower than the other opioids being studied.

Conclusions

The 9 opioids we investigated demonstrated a wide range of positivity rates and UDT:MME values, with tapentadol the lowest on both measures. This data is consistent with the results of previous real-world abuse studies of tapentadol in suggesting a potentially lower preference for tapentadol as a target of abuse, but caution is warranted in interpreting these results. It is noteworthy that these results suggest that tramadol and codeine abuse is not uncommon, which is perhaps not surprising given their less restrictive scheduling than the other opioids. The limitations notwithstanding, it is hoped that the results of the present study, when viewed in the context of real-world opioid abuse data, will be helpful to prescribers and policy makers when considering the relative abuse potential of various opioid analgesics. The frequency of positive UDT results in this addiction treatment sample was lowest for tapentadol and remained lowest when adjusting for the relative availability of these opioids according to prescription data from the community.

140 Triptan Discontinuation and Treatment Patterns Among Migraine Patients Initiating Triptan Treatment in a US Commercially Insured Population

Steven C. Marcus¹, Anand R. Shewale², Stephen D. Silberstein³, Richard B. Lipton⁴, William B. Young³, Hema N. Viswanathan², Jalpa A. Doshi¹

¹University of Pennsylvania, Philadelphia, PA, USA, ²Allergan plc, Irvine, CA, USA, ³Jefferson Headache Center, Thomas Jefferson University, Philadelphia, PA, USA, ⁴Albert Einstein College of Medicine, Bronx, NY, USA

Purpose

To examine real-world patterns of acute treatment of migraine among new triptan users in a commercially insured US population.

Methods

Adult patients were selected if they had ≥1 triptan claim between January 1, 2013 and December 31, 2013 (first claim assigned as index date) and at least 12 months of pre- and 24 months of post-index continuous enrollment in the Optum Clinformatics™ claims database. Patients were required to have ≥1 migraine diagnosis but no prior triptan claims in the pre-index period. Treatment patterns among these patients initiating a new triptan were examined over a 12- and 24-month period.

Results

In our sample of 10,509 new triptan users, 50.8% did not refill their index triptan over the 12-month post-index period and 43.6% did not refill it over the 24-month period. The majority of the new triptan users (56.4%) had a quantity of ≤4 pills on their first fill; refill rates were similarly low in these patients. Only 8.4% of the new triptan users received 2 different triptan agents and 1% received 3 different triptan agents over 24 months. Approximately 35% of patients filled ≥1, whereas another 10% filled ≥2, guideline-listed agents from a non-triptan acute medication class over 24 months, most commonly for an NSAID followed by butalbital combination. However, over half of all new triptan users (54.3%) and the subgroup with no refills for their initial triptan (52.6%) had filled a guideline- or non–guideline-listed opioid medication over the 24-month follow-up.

Conclusions

These results demonstrate poor refill patterns and minimal use of >2 different triptan agents over a 2-year period in a large, commercially insured population of new triptan users in the US.

141 Sustained response to erenumab over time in patients with chronic migraine

Stewart Tepper¹, Sylvia Lucas², Messoud Ashina³, Todd Schwedt⁴, Jessica Ailani⁵, James Scanlon⁶, Jan Klatt⁷, Denise Chou⁶, Sharon Richards⁸, Gabriel Paiva da Silva Lima⁶

¹Geisel School of Medicine at Dartmouth, Hanover, NH, USA, ²University of Washington Medical Center, Seattle, WA, USA, ³Department of Neurology, Danish Headache Center; University of Copenhagen, Copenhagen, Denmark, ⁴Mayo Clinic, Phoenix, AZ, USA, ⁵Georgetown University, Washington, DC, USA, ⁶Amgen Inc., Thousand Oaks, CA, USA, ⁷Novartis, Basel, Switzerland, ⁸Amgen Ltd, Uxbridge, United Kingdom

Purpose

Erenumab is a fully human, anti-calcitonin gene-related peptide receptor antibody approved for migraine prevention. We evaluated whether initial responses to erenumab in patients with chronic migraine (CM) are maintained and improved with continued erenumab treatment.

Methods

This was a post hoc analysis of data from a pivotal, randomized, double-blind, placebo-controlled study of erenumab 70 mg or 140 mg administered once per month to patients with CM (≥ 8 migraine days per month and ≥15 headache days per month; ClinicalTrials.gov, NCT02066415). We conducted an analysis of response with continued erenumab treatment in the subset of patients who achieved a 50% or greater reduction in monthly migraine days (MMD) from baseline (≥50% reduction in MMD) during the first month of treatment (initial responders). Sustained responses among initial responders were assessed at months 2 and 3. During continued treatment, initial responders were classified as having an ‘excellent’ (≥75% reduction in MMD) or ‘good’ (50% to <75% reduction in MMD) response. Patients with CM were also assessed for ‘modest’ (≥30 to <50%) reductions in MMD.

Results

Of 188 and 187 patients randomized to erenumab 70 mg and 140 mg, 24% (45/188) and 28% (53/187), were initial responders (≥ 50% reduction in MMD at month 1), and 57% (108/188) and 54% (101/187), respectively, responded at least once through month 3. Among the subset of initial responders who received erenumab 70 mg or 140 mg, 49% (22/45) and 70% (37/53), respectively, maintained a good or excellent response at months 2 and 3; 84% (38/45) and 91% (48/53) achieved a good or excellent response at months 2 or 3. Furthermore, 18% (8/45) and 32% (17/53) achieved an excellent response throughout all 3 months, and 56% (25/45) and 59% (31/53) achieved an excellent response at months 2 or 3. Of the patients who were not initial responders and who had ‘modest’ reduction in MMD at month 1, 64% (29/45) and 79% (27/34) of patients in 70 mg and 140 mg group, resepectively, achieved a good or excellent response at months 2 or 3 with continued treatment.

Conclusions

The majority of erenumab-treated patients with CM who achieved initial modest, good, or excellent reductions in MMD at month 1 experienced sustained or improved clinical benefit with continued erenumab treatment.

This publication was supported by Novartis Pharmaceuticals Corporation, East Hanover, NJ, as part of a collaboration between Novartis and Amgen Inc.

142 The Slipped Rib Syndrome in an Active Duty Military Member – Long Term Disability followed by Successful Return to Work After Pulsed Radiofrequency at the T12 Dorsal Root Ganglion Combined with Physical and Psychological Therapy

Tara Sheridan, David Goff, Ian Fowler, Thomas Fitzgerald, Jennifer Muir

Naval Medical Center San Diego, San Diego, CA, USA

Purpose

Purpose: To present a case report of a young active duty female who suffered from severe chronic chest wall pain for two years while serving on active duty in the U.S. Navy, due to slipped rib syndrome.

Pain began acutely in December 2017, without known injury or traumatic event, although possibly related to the physical nature of her work in the military, located along the left back, flank and anterior abdomen, described as sharp and knife like, associated with nausea and anorexia when most intense. Pain was improved with lying flat and aggravated by all movement and activity, making her very fearful of all movement, to the point of not wanting to engage in physical therapy or to comply with ongoing attempts at acupuncture, dry needling or home exercise program.

She underwent multiple reassuring studies, including chest X-ray, t-spine imaging, pelvic ultrasound, and CT Abdomen and pelvis, MRI of L-spine. She underwent a transthoracic echocardiogram, and an upper endoscopy. She was evaluated by Differential diagnosis included peptic ulcerative disease, nephrolithiasis, splenic infarction, hernia, SV thrombosis, yet all imaging studies were reassuring and non-revealing.

The patient was trialed on Naproxen, Ibuprofen, Pantoprazole, Acetaminophen, Docusate, Trazodone, Amitriptyline, Pregabalin, Duloxetine, Lidoderm, Magnesium Oxide and Tylenol without sustained benefit.

After two years she was place on a Limited Duty status and transferred from her overseas duty station in Japan back to the United States, to seek further care. She was seen at the pain clinic at Naval Medical Center San Diego (NMCSD) and the syndrome was diagnosed by clinical test (the hooking maneuver) on physical examination.

Methods

Methods: Patient underwent a diagnostic selective nerve block at T12 with fluoroscopic guidance, in which a 22-gauge needle was carefully advanced until it was adjacent to the left T12 nerve root with noted mild paresthesia. After confirmation of the needle tip on AP and lateral projection injected with contrast to verify location, 2 cc of 0.25% Marcaine with 40 mg triamcinolone was injected slowly. After the procedure, the patient’s pain score decreased from 5 to 1/10, and she was scheduled for pulsed radiofrequency. For that procedure, a 20 gauge radiofrequency needle was placed at the dorsal root ganglion of the same level, and pulsed radiofrequency treatment was performed for 240 seconds at 42 degrees centigrade.

As well, she was referred to NMCSD pain psychiatry to address her comorbid major depressive disorder and pain associated kinesiophobia, and to physical therapy to optimize her chance for recovery during the 6 month Limited Duty period.

Results

Results: As of publication, patient report 0/10 pain. She has been able to come off of Limited Duty, and has returned to all the duties of her rate and rank. She will be able to transition off of her selective norepinephrine serotonin reuptake inhibitor at the end of next month, per psychiatry’s recommendation, and has been able to pass her mandatory physical fitness tests.

Conclusions

Conclusions: This case demonstrates the importance of physical examination, which was the key to diagnosis in this case. Slipping Rib Syndrome (SRS) is an infrequent condition that can affect children, adolescents and adults alike, with a slight bias towards females. It is often an overlooked cause of upper abdominal and thoracic chest wall pain and can consequently remain undiagnosed for months to years. It is caused by hypermobility and ultimate subluxation of the anterior false ribs 8, 9, or 10 due to weakness of the sternocostal (rib-sternum), costochondral (rib-cartilage), costovertebral/costotransverse (rib-vertebral) ligaments.

The condition may be congenital, or a development deformity, or may be acquired through a mild to moderate traumatic event (patients even may be unaware of the event).

Classically, SRS is diagnosed on physical examination utilizing the hooking maneuver, a relatively simple clinical test, first described in 1977. The clinician places his or her fingers under the lower costal margin and pulls the hand in an anterior direction. Pain or clicking indicates a positive test.

In this case, the procedures was essential to successfully treating her condition, including the multidisciplinary approach of incorporating physical therapy and pain psychiatry, facilitating her return to full duty active duty service.

143 A Functional Restoration Program for Active Duty Military Personnel with Chronic Pain: Comparing Patient Reported Effectiveness Relative to Standard Medical Treatment at the Pain Clinic

Emmanuel Espejo, Tara Sheridan, Kathleen McChesney, Wade Dowling, Jennfer Muir

Naval Medical Center San Diego, San Diego, CA, USA

Purpose

Chronic pain is a debilitating issue for tens of thousands of active duty military members, costing billions of dollars annually to the Department of Defense in healthcare expenses and lost productivity. As well, inability of service members to perform their duties affects the military readiness of United Stated Armed Forces. Recent findings by the Walter Reed Army Institute of Research noted that service members returning from Middle East deployment operations experience a higher prevalence of pain and a greater severity of pain than faced by civilian counterparts in the primary care setting.¹ Further, the prevalence of chronic pain (44.0%) and opioid use (15.1%) in this setting are higher than estimates in the general civilian population of 26.0% and 4.0%, respectively.²

An evidence based pain management strategy has been endorsed as a national priority by The National Center for Complementary and Integrative Health (NCCIH), The Veterans Health Administration (VHA) 1998 under their National Pain Management Strategy, and the Department of Defense (DOD). Under the DOD, the Navy established the Functional Restoration Pain Program (FRPP) at Naval Medical Center San Diego in 2014.

The FRPP is a multidisciplinary stepped-care approach to the treatment of chronic pain that addresses not only adequate pain control but improved quality of life and function. It is an eight week intensive out-patient program of medical care, progressive mental health and physical reconditioning.

Methods

Methods: The current study includes 81 ADSM with chronic pain who participated in the FRPP and a matched sample of ADSM receiving SMT at the Pain Management Clinic at NMCSD. All patients completed a battery of questionnaires.

These included measures of self-reported pain, pain interference, and physical and social functioning, as well as measures of anxiety, depression, anger, fatigue and sleep impairment at the initiation of treatment and following eight weeks of care.

Questionnaires relied on validated research tools such as the Pain Assessment Screening Tool and Outcomes Registry (PASTOR), developed by the National Institutes of Health (NIH). The PASTOR was created to facilitate pain research and provide clinical outcomes data to inform evidence-based decision-making by providers.16 PASTOR uses instruments developed by the National Institutes of Health, collectively known as the Patient Reported Outcomes Measurement Information System (PROMIS), to administer select questions as part of a survey covering a wide range of pain-related areas, including sleep disturbance or physical function. PASTOR also incorporated the DVPRS and other pain-related questions specific to the military population.

Results

Data included in the analysis are from patients that completed the entire program.

Among the 81 participants who completed the 8-week program, 82.5% (N = 67) were classified as ‘fit for full’ duty upon program completion by consensus of the treating pain physicians, psychologists, and physical therapists. Analyses of baseline to post-treatment changes in PASTOR measures revealed significantly improved scores among FRPP participants for average pain, pain interference, physical function, social satisfaction, depression, fatigue, sleep, and anger (all ts > 3.13, all ps <0.005) with marginally significant improvement in anxiety also observed (t(80) = 1.76, p = .082). In comparison, participants receiving standard pain treatment over a similar 8-week period report a significant reduction only in Pain Interference (t(80) = 2.29, p = .025) and marginally significant improvement in anxiety, t(80) = 1.94, p = .056, and anger, t(80) = 1.94, p = .056. Results from MANOVA indicate that changes observed among FRPP participants were significantly greater than those changes observed in the matched standard treatment sample in average pain, pain interference, physical functioning, social satisfaction, fatigue, and sleep impairment (all Fs > 7.59, all ps <0.008). Analyses of baseline to 3-month follow-up PASTOR measures revealed that improvements were maintained across all domains for FRPP participants, including significantly improved scores in anxiety (all ts >2.23, all ps <0.04). In comparison, participants receiving standard pain treatment over a similar 5-month period report a significant reduction only in Pain Interference (t(43) = 2.20, p = .034) and marginally significant improvement in average pain, t(43) = 1.93, p = .060.

Conclusions

This report is a preliminary examination of a comprehensive, integrated, and progressive program of physical reconditioning and psychosocial interventions implemented at NMCSD aimed at successfully returning ADSM with chronic pain to full military fitness for duty. Patients completing the FRPP demonstrated significant improvement on multiple measures of functioning and emotional well-being assessed by PASTOR which were maintained at 3 month follow-up. Importantly, improvements among FRPP participants were significantly greater than those reported by ADSM with chronic pain receiving standard medical treatment over a comparable time frame across multiple PASTOR domains.

These improvements in multiple biopsychosocial parameters led to 82.5% of patients completing the FRPP being found ‘fit-for-full’ duty and world-wide deployable at the completion of the 8-week program.

144 An Assessment of the Long-Term Safety, Tolerability, and Durability of Treatment Effect of Cannabinoids in Adult Outpatients with Chronic Pain

Terrance Bellnier^1,2, Geoff Brown^1,2, Tulio Ortega¹, Tulio Ortega, Jr^1,3, Robert Insull¹

¹Geriatric Pharmacotherapy Institute, Rochester, NY, USA, ²SUNY University at Buffalo, Buffalo, NY, USA, ³University of Pittsburgh, Pittsburgh, PA, USA

Purpose

Medical cannabis is frequently claimed to be an effective treatment for chronic or refractory pain. Studies in humans and animals suggest that cannabinoids produce analgesia through a G-protein coupled mechanism blocking the release of pain-propagating neurotransmitters in the central nervous system.^1,2Delta-9 tetrahydrocannabinol (THC), the cannabinoid responsible for cannabis’ euphoric effects, enhances the potency of opioids suggesting a close connection between opioid and cannabinoid signaling.

Apart from GW Pharma, there’s been little progress developing cannabinoid drugs via the Investigational New Drug program (IND). The IND pathway is costly and time-consuming but has proven to be the safest way to make new drugs available for patients. The authors and our University at Buffalo colleagues are in favor of a more ‘blended approach’ to cannabinoid drug development.³This approach uses implementation and traditional translational research to evaluate cannabis products available for therapeutic use from community dispensary systems. Our ultimate goal is to assist in the development of evidence-based treatment guidelines.

While this approach reduces costs and is less time-consuming, it also has shortcomings. Thirty-four states and three U.S. districts currently have medical cannabis programs that provide patients with quasi-regulated cannabis products.⁴Products available through these programs vary by state, and range from whole cannabis flower to derivatives such as edibles, oils, and topicals. The cannabinoid content of products available in many states doesn’t reflect their labeled dosages.^5,6

Medical cannabis products available through the New York State Medical Marijuana Program require pharmaceutical grade excipients, stringent packaging and labeling, and each lot of products must be tested by an independent laboratory for cannabinoid content and contaminants.^7,8We prefer this type of product be termed ‘Cannabinoid Drug Product’ (CDP), which better contextualizes this form of medical cannabis within the predominant trends in the United States. CDPs in NY are not smokable or edible, require pharmacist dispensing and counseling, and are held to the same reporting standards as Schedule II-IV controlled substances.

The purpose of this study is to evaluate the effectiveness, safety, costs, and dose-response of CDPs for the treatment of chronic pain under the highly regulated conditions in NY.

Methods

Institution Review Board approval was given to conduct this retrospective chart review. All patients meeting inclusion criteria and no exclusion criteria were included. A repeated measures, mirror-image design was utilized with missing data addressed by a last observation carried forward model. Efficacy and durability of response was measured by the Pain Quality Assessment Scale (PQAS),⁹EQ-5D quality of life health questionnaire,¹⁰General Anxiety Disorder-7 item (GAD-7),¹¹and Patient Health Questionaire-9 (PHQ-9) for Depression.¹²Safety and tolerability were assessed by opioid consumption measured as morphine (MSO4) equivalents, incidence of adverse effects (AE), and the Drug Effect Questionnaire 5-item (DEQ-5).¹³The DEQ-5 was administered one month post cannabinoid exposure (1mo) and periodically for up to 24 months (24mo) of treatment. The version utilized was a 100mm visual analog scale with anchors of ‘not at all’ to ‘extremely’ for the following questions: do you feel a drug effect (FEEL), do you feel high (HIGH), and would you like more of the drug (MORE). Service utilization was comprised of treatment cost and average daily dose (ADD). Records were reviewed for up to 24 months prior to CDP initiation and 24 months post-exposure. Kruskal-Wallis was utilized to measure variance and Wilcoxon-signed rank test for significance evaluated service utilization with a repeated measures analysis for efficacy, durability of response, and safety and tolerability.

Results

92 patients, with a variety of diagnoses, suffering chronic pain were included in this evaluation. Patient’s demographics: Age: 57 (+- 14) years, Ethnicity: 96% Caucasian, 2% African American, 2% Asian, Gender: 42 males, 50 females, Duration of illness: 12.4 (+-6.6) years.

Efficacy and durability of treatment: PQAS by item prior to cannabinoids (PRE) and after 24 months exposure (POST). Intense (PRE 7.52+-1.19 – POST 3.27+-0.96, P < .0001), Sharp (PRE 6.57+-2.67, POST 2.91+-1.63, P < .0001), Hot (PRE 5.06+-3.16- POST 2.11+-1.63, P < .0001), Dull (PRE 3.57 +- 2.53 – POST 1.81+-1.44, P < .0001), Cold (PRE 2.18+-2.86 – POST 0.80 +- 1.26, P < .0001), Sensitive (PRE 4.01 +- 2.81 – POST 1.62+- 1.41, P < .0001), Tender (PRE 5.13+-3.02 – POST 1.93 +- 1.63, P < .0001), Itchy (PRE 2.12+-2.55 – POST 0.66+-1.06, P < .0001), Shooting (PRE 6.25+-2.72 – POST 2.73+-1.79, P < .0001), Numb (PRE 5.01+-3.29 – POST 1.97+-1.49, P < .0001), Electrical (PRE 5.17+-3.29 – POST 1.97+-1.49, P < .0001), Tingling (4.79+-3.17 – POST 2.33+-1.86, P < .0001), Cramping (PRE 5.87+-2.83 – POST 2.80+-1.61, P < .0001), Radiating (PRE 6.21+-3.13 – POST 2.80+-1.87, P < .0001)), Throbbing (PRE 5.82+-3.03 – POST 2.24+-1.79, P < .0001), Aching (PRE 6.73+-2.49 – POST 2.35+-1.49, P < .0001), Heavy(4.43+-3.38 – POST 1.76+-1.85, P < .0001), Unpleasant (PRE 6.92+- 1.84 – POST 3.05+-1.13, P < .0001), Intense deep (PRE 7.18+-2.19 – POST 3.04+-1.72, P < .0001), Intense surface (PRE 6.39+-2.69 – POST 2.82+-1.49, P < .0001), Time qualities: Intermittent (PRE 4 – POST 26), Variable (PRE 80 – POST 66), Stable (PRE 6 – POST 0). PQAS Factor Analysis: Paroxysmal (PRE 5.85+-1.70 – POST 2.50+-0.91, P < .0001), Surface (PRE 3.69+-1.65 – POST 1.48+- 0.67, P < .0001), Deep (PRE 5.26+-1.68 – POST 2.15+-0.79, P < .0001). EQ-5D quality of life health questionnaire (PRE 27.41+-17.41 – POST 48.36+-25.07, P < .0001): GAD-7 (PRE 7.26+-2.42 – POST 1.51+-1.53, P < .0001), PHQ-9 (PRE 6.79+-2.67 – POST 6.59+-2.76, P = 0.12).

Safety and tolerability AEs were reported in 18% of subjects after one month of treatment and two percent of subjects after 24 months of treatment. No subjects discontinued treatment due to AEs. Results of DEQ-5 were FEEL (1mo 6.17+- 5.85, 73% of subjects reporting (SR) – 24mo 1.03+-1.86, SR 34%), HIGH (1mo 1.22+-1.92 SR 40% – 24mo 0.43+-1.11, SR 16%), MORE (1mo 1.22+-1.92, SR 8% – 24mo 0.90+-1.58, SR 2%).

Service utilization found average monthly pain medication costs prior to treatment (PRE) and total pain medication costs plus average monthly CDP costs after 24 months of treatment (POST) were (PRE $336.66 +- 74.98, – POST $204.50+-121.39, P < .05). Percent of subjects taking opiates and average MSO4 equivalents per day were (PRE 90%, 68.99+-91.39 – POST 35%, 32.20+-75.13, P < .05). ADD of THC and Cannabidiol (CBD) one month after initiation (PRE) and up to 24 months of treatment (POST) were (PRE 12.92+-7.89 THC, 5.40+-6.55 CBD – POST 11.05+-7.89 THC, 4.832+-5.53 CBD).

Conclusions

Due to study limitations, these results may not be applicable to the general population. The current study provides evidence that CDPs are efficacious for the treatment of chronic pain. The treatment effect associated with cannabinoids is sustained over a long period of time with minimal changes in ADD along with a significant decrease in opiate analgesic use. The daily dose of THC and CBD changed minimally over 24 months of treatment. Additionally, a marked reduction in opiate needs was seen. Efficacy of pain management seems to be independent of THC’s euphoric effects at the daily dose we observed over time. Service utilization suggests this is a cost-effective treatment option for chronic pain. What is needed in the current regulatory environment, is a large, simple trial to further evaluate the role of cannabinoids in the treatment of chronic pain. References upon request.

145 Patient and Healthcare Provider Perspectives on the Unmet Needs and Stigma of Migraine

Theresa Mallick-Searle¹, Daniel Kantor², Kayleen Hilyer³, Merle L Diamond⁴, Marissa Boruchow⁵, Srinivas Nalamachu⁶

¹Stanford Outpatient Medical Center, Division Pain Medicine, Redwood City, CA, USA, ²Schmidt College of Medicine, Florida Atlantic University, Boca Raton, FL, USA, ³XXXXXXXXXX, Erie, PA, USA, ⁴Diamond Headache Clinic, Chicago, IL, USA, ⁵XXXXXXXXXX, New York, NY, USA, ⁶Mid America PolyClinic, Overland Park, KS, USA

Purpose

Episodic migraine (EM) and chronic migraine (CM) impart a high burden to patients and often come with significant stigma affecting patients’ quality of life. In addition to the pain associated with migraine attacks, patients can experience symptoms and comorbidities that increase the burden of migraine. Effective communication between patients and healthcare professionals (HCPs) is key to meeting the needs of patients. We sought insights from patients and HCPs to examine unmet needs and stigma associated with migraine.

Methods

Telephone interviews conducted with patient authors, KH and MB, regarding their experiences with CM and EM, respectively, were followed-up with written questions including those on non-pain symptoms associated with their migraines. HCPs’ perspectives were provided by a nurse practitioner (NP; TM-S), a neurologist (DK), a headache specialist (MD), and a pain specialist (SN).

Results

CM Patient: KH said the public use of the term ‘migraine’ interchangeably with ‘headache’, underestimates the impact of migraine on patients’ lives. KH felt that it was difficult to convey CM symptom severity and disability, and spoke of the stigma and shame associated with it, because of inability to work. KH’s current HCPs are involved in all aspects of her care and listen to her needs. She visits the emergency room (ER) when her medication does not control her migraines, but does not use opioids and is concerned about medication overuse. KH has visited the ER only once since initiating anti-calcitonin gene-related peptide therapy a year ago, compared with visits every 2 weeks while on previous therapies. KH is now free of headaches and, for the first time in 11 years, she is preparing to return to work.

EM Patient: MB has experienced misunderstanding by the public and HCPs regarding severity and impact of her migraines, and expressed frustration at disruption of daily life with the unpredictable nature of migraines. She currently receives effective treatment in the care of a headache specialist neurologist, who is communicative and responsive to her needs.

While KH (CM patient) reported various symptoms including nausea/vomiting, tiredness, and light/sound sensitivity that increased the burden of her migraine, MB (EM patient) reported increased exhaustion lasting up to 2 days post migraine.

The HCPs expressed concerns about the impact of headaches on patients’ ability to work, their sleep quality and anxiety, and the effect on family life. Stigma associated with ‘invisible’ diseases like migraine affects family members, public perception, and HCPs.

Conclusions

Patients with EM and CM face misunderstanding of the level of disability associated with migraines and the impact of migraines on ability to work and social interactions. The incapacity and needs of patients with migraine are often underestimated by HCPs, family members, coworkers, and members of the public encountered in daily life. This can lead to stigma for both patients with EM and those with CM. Each patient has unique and valuable insights into impact of migraine on quality of life. Opportunities to improve communication between patients and HCPs and increase listening to patients’ perspectives and encouraging their participation in diagnosis and treatment of disease should ultimately improve outcomes

This publication was supported by Novartis Pharmaceuticals Corporation, East Hanover, NJ, as part of a collaboration between Novartis and Amgen Inc.

146 A cross-sectional survey evaluating questions on patient motivation for use of prescribed opioids to assist in identifying Opioid Use Disorder

Joseph A Boscarino¹, Carrie A Withey¹, Ryan J Dugan¹, Jessica Auciello², Thomas Alfieri²

¹Department of Epidemiology and Health Services Research, Geisinger Clinic, Danville, PA, USA, ²Purdue Pharma L.P., Stamford, CT, USA

Purpose

Appropriately managing chronic pain while also effectively identifying patients at risk for opioid use disorder (OUD), and taking appropriate actions with those individuals, is of critical importance. However, identifying OUD in patients prescribed long-term opioid therapy for chronic pain is challenging. Behaviors and attitudes associated with OUD may also be associated with reasons other than abuse, such as the need for pain relief. For example, the DSM-5 criterion ‘opioids are often taken in a larger amount or over a longer period of time than intended’ may be associated with disease progression with escalating or unabating pain. Items on the Severity of Dependence Scale (SDS) such as ‘How difficult did you find it to stop or go without opioids?’ may be confusing to patients taking opioids for pain relief.

This research explores the idea that separately assessing a patient’s motivation to take opioids for pain relief from their motivation to take opioids for reasons other than pain relief (e.g., euphoric effects) may assist health care providers to identify patients most at risk for OUD.

The Drug Effects Questionnaire (DEQ) is a patient-reported outcome assessment that measures the abuse potential of substances by evaluating concepts such as the subject’s ‘drug-liking,’ ‘desire to take drug again,’ and ‘feeling good drug effects.’ In previous research, items from the DEQ were modified to assess the different motivations to take opioids. The modified items link these concepts to the desire for pain relief or to reasons excluding pain relief, with an understanding that patients’ desire for medicine may be driven by either of these motivations or a combination. Prior cognitive debriefing interviews demonstrated that comprehension for these items was improved when specified in this manner.

In this study, the modified DEQ items were administered to a group of patients currently being prescribed opioid medication. We hypothesized that patients would more strongly endorse items that specified pain relief compared to those that excluded pain relief. We also hypothesized that patients who more strongly endorsed items that excluded pain relief would be at higher risk for OUD, as determined by survey questions based on DSM-5 criteria.

Methods

A cross-sectional survey was administered via telephone to adult (age 18–75) outpatients within the Geisinger Clinic who were prescribed at least 4 prescription orders of Schedule II full opioid agonists in oral tablet or capsule formulation within the past 12 months. Patients with a malignant cancer diagnosis in the past 12 months were excluded, as were patients who indicated that they took none of their prescription medication. Patients with previous substance use disorder (SUD) diagnoses were not excluded.

Participants were randomly selected from all qualified patients identified from searching the Geisinger EHR based on study inclusion and exclusion criteria. Patients were enrolled to participate in the 30-minute telephone interview after informed consent was reviewed and participants indicated their understanding of the study procedures, risks and potential benefits, and permitted access to a 2-year retrospective review of their EHR. The Geisinger Institutional Review Board approved the study protocol. Surveys were conducted from March 11 to May 15, 2019.

The Drug Effects Questionnaire (DEQ) items that assessed the concepts of drug-liking, desire to take the drug again, and feeling good effects of the drug were modified to specify for reasons of pain relief (e.g., ‘I would take this drug again for pain relief,’ ‘my liking for this drug for pain relief is…’) or for reasons excluding pain relief (e.g., ‘Excluding pain relief, my liking for this drug is…’ ‘Excluding pain relief, I would take this drug again’). Items were further altered from the original visual analog scale presentation to be appropriate for administration via the telephone. Both the original and modified DEQ were administered in this study regarding patients’ opioid medications taken over the past 12 months. Scale responses ranged from 0 (‘strong disliking’ or ‘definitely not take again’) to 100 (‘strong liking’ or ‘definitely take again’).

A series of items based on the DSM-5 criteria for OUD were also administered. Also included in the survey were the Severity of Dependence Scale (SDS), self-reported measures of non-medical prescription opioid use, illicit drug use, and marijuana use. A 2-year retrospective search of the patients’ EHR was used to identify any SUD diagnoses.

Results

Of the 200 patients who completed the survey, 127 (63.5%) were women, 190 (95%) identified as Caucasian, 102 (51%) were currently married, 53 (26.5%) were currently employed, and 49 (24.5%) were college graduates. The average age (SD) was 53 (13.2) years. Most patients were prescribed only IR opioids within the past 12 months (71.5%), and the remaining were prescribed both IR and ER opioids (28.5%). None were prescribed only ER opioids.

Based on DMS-5 criteria for OUD, 32 (16%) had moderate or severe OUD. When tolerance and withdrawal items were removed, consistent with DSM-5 criteria for patients taking opioids solely under medical supervision, 15 (7.5%) still met the qualification for moderate or severe OUD. Nine percent of patients reported non-medical use of prescription opioids, and 6.5% specifically reported using opioids to get high. Eight patients (4%) reported ever using heroin, and 59% reported ever using marijuana. 12.5% had a diagnosis of substance abuse in their EHR.

Modified Drug Effects Questionnaire

Mean scores of the modified DEQ items supported the hypothesis. The mean (SD) score for the unspecified ‘drug liking’ item was 54 (33.4). When the item specified pain relief, the mean [SD] score significantly increased (70 [27.8], p < .01) and when specified for excluding pain relief, a significant reduction was observed (24 [31.2], p < .01). Similarly, the mean (SD) score for the unspecified ‘desire to take the drug again’ was 70 (35.9) When specified for pain relief the mean score [SD] increased (83 [27.1], p < .01) and decreased when excluding pain relief (12 [25.1], p < .01). Finally, the mean [SD] scores for ‘feel good drug effects for pain relief’ (66 [31.4]) were significantly higher than for ‘feel good drug effect excluding pain relief’ (32 [32.9], p < .01).

To test the second hypothesis, scores from the three items that exclude pain relief were summed to create an ‘Excluding Pain Relief Index’ (mean = 68, SD = 72.9, range 0 to 300 with skew toward 0). A regression analysis revealed that higher scores on this index were significantly associated with DSM-5 OUD criteria, SUD diagnoses, previous use of opioids ‘to get high,’ as well as with being male, unemployed, single, and without a college education. The similarly constructed ‘Pain Relief Index’ (mean = 218, SD = 70.6, range 0 to 300 with skew toward 300) was not significantly associated with these variables.

Conclusions

When assessing concepts of ‘drug liking,’ ‘desire to take drug again,’ and ‘feel good effects of a drug,’ patients were significantly more likely to agree with items that specified pain relief compared to items that excluded pain relief or made no specifications.

Patients who scored relatively high on items that excluded pain relief (i.e., ‘Excluding pain relief, I would take this drug again’) were more likely to indicate previous misuse of prescription opioids, to have a SUD diagnosis, and to have risk factors and some demographic characteristics more commonly associated with misuse.

Study findings are limited by the self-reported data and the fact that EHR data were collected for treatment, not research purposes. Generalizability of the finding may be limited given the sample was drawn entirely from the Geisinger patient population (in central Pennsylvania). Results of this study suggest that a closer examination of patients’ motivation for opioid medication use may help HCPs to identify those at risk for OUD. Additional research would be needed to fully validate these modified items in the population of patients being prescribed opioid medications.

147 Online Continuing Medical Education Program Improves Knowledge Among Neurologists and Primary Care Physicians Regarding the Management of Opioid Withdrawal Syndrome

Thomas Finnegan¹, Catherine Murray¹, Jovana Lubarda¹, Thomas Kosten²

¹Medscape Education, New York, NY, USA, ²Baylor College of Medicine, Houston, TX, USA

Purpose

One of the consequences of the current opioid epidemic is the cessation or dose reduction of prescription and illicit opioids. When patients with a history of opioid use either immediately stop using completely or rapidly reduce the dose of opioid too quickly, opioid withdrawal syndrome (OWS) is an expected consequence. Given the general lack of knowledge among clinicians regarding opioid use, an online educational activity was developed with the goal of improving neurologists’ and primary care physicians’ knowledge of the management of OWS.

Methods

An online educational intervention was developed in the form of a 30-minute video lecture with synchronized slides. Educational effectiveness was assessed with a repeated pairs pre-/post- assessment study design in which each individual served as his/her own control. Responses to 3 knowledge-based and 1 self-efficacy questions were analyzed. A chi-square test assessed changes from pre- to post-assessment. Cramer’s V was used to calculate the effect size of online education. Data from the assessment were collected between December 7, 2018 and January 11, 2019.

Results

The education resulted in a considerable educational effect for both primary care physicians (n = 338; V = .171; P < .05) and neurologists (n = 111; V = .189; P < .05). Participation in this educational intervention showed improvements in the following areas (P < .05): neurotransmitter involved in symptoms of OWS; clinical trial outcomes of medication studied for the management of OWS; and selection of an appropriate pharmacotherapy for the management of OWS. Activity participation resulted in approximately 20% of participants noting an increase in confidence in managing OWS.

Conclusions

This study demonstrated the success of a targeted online, video lecture on improving neurologists’ knowledge of factors important for the management of OWS. Additional education should continue to focus on how clinicians can best manage OWS.

148 DHEA Deficiency in Fibromyalgia

Thomas Omano

East Ohio Regional Hospital, Martins Ferry, Ohio, USA

Purpose

Patients with Fibromyalgia (FM) have been found to have numerous co-morbidities. Many patients with FM are very challenging and difficult to treat. This is especially so if co-morbidities are not identified and eliminated or ameliorated. FM patients frequently complain of fatigue, decreased stamina, and weakness in addition to pain. Such problems are also associated with endocrine abnormalities. One such problem, a deficiency of the adrenal hormone, dehydroepiandrosterone (DHEA) can cause all of those nonpainful symptoms. This study was undertaken to determine if DHEA deficiency exists in some FM patients and, if so, how frequent is the association. Failure to correct DHEA deficiency in FM patients would likely result in suboptimal responses to therapeutic interventions in patients notoriously difficult to treat optimally.

Methods

108 consecutive female FM patients, mean age 48.87 years (range 25–68 years) were evaluated in a solo private community-based rheumatology/pain management practice between 2012 and 2016. All fulfilled American College of Rheumatology 1990 and 2010 FM criteria. Blood samples to test for serum levels of DHEA-sulfate were obtained on the initial visit and sent to Quest Diagnostics (Pittsburgh, PA) for analysis. Since DHEA-sulfate levels are age-dependent, comparisons were made between the observed levels and published norms.

Results

Of the 108 female FM patients tested, 83 (77%) had low-for-age DHEA-sulfate levels. Six FM patients had no detectable DHEA-sulfate levels at all. The FM patients’ DHEA-sulfate levels ranged from 0 to 679 mcg/dl, with 75 FM patients having levels under 100 mcg/dl. The mean DHEA-sulfate level for the 108 FM patients was 96.8 mcg/dl, much lower than the expected level of approximately 150 mcg/dl.

Conclusions

Based on this study, one can conclude that a very high percentage of female FM patients are deficient in DHEA, suggesting that many of their constitutional symptoms can be attributed in part or wholly to DHEA deficiency. If a female FM patient complains of fatigue, decreased stamina and weakness, as well as having physical findings of deconditioning and/or poor muscle tone/strength, she should be evaluated for DHEA deficiency.

149 How do you feel about Cannabidiol? Lessons from a survey in a pain clinic environment

Tobias Moeller-Bertram¹, Jan Schilling¹, Chloe Hughes¹, Mark Wallace², Michelle Sexton², Miroslav Backonja³

¹VitaMed Research, Rancho Mirage, CA, USA, ²UCSD, San Diego, CA, USA, ³University of Washington, Seattle, WA, USA

Purpose

To investigate knowledge, experience and attitude of patients about cannabidiol in general and in consideration for pain treatment and management.

Methods

After IRB review (exempt status) we utilized the internet survey platform SurveyMonkey to administer the survey online.

Our participants were 45.26 ± 14.02 (Mean/SD) years old, the majority identified as white, had an annual household income of less than $20,000, and were insured by Medicare or Medicaid.

Results

Among our participants, 63% report to have tried at least a CBD product (including products containing THC). The majority responded that CBD products have helped their pain and have reduced their pain medication, including opioids. They believe it is a good treatment option, not harmful, and not addictive. About half of our participants would be more comfortable if their physician could prescribe CBD. The overall attitude and experience of participants regarding CBD is reported as positive and 92% of people expressed a desire to learn more about it.

Conclusions

This survey points to relatively wide experience and even larger interest in learning more about CBD as one of the options for pain treatment and management.

150 Can CBD Reduce the Use of Pain Medication? Insights from a Survey in a Pain Clinic Environment

Tobias Moeller-Bertram¹, Jan Schilling¹, Chloe Hughes¹, Mark Wallace², Michelle Sexton², Miroslav Backonja³

¹VitaMed Research, Rancho Mirage, CA, USA, ²UCSD, San Diego, CA, USA, ³University of Washington, Seattle, WA, USA

Purpose

To take a look at whether CBD could reduce use of pain medications in the pain clinic environment.

Methods

Survey had an IRB review and was given exempt status. Internet survey platform SurveyMonkey was utilized to administer the survey online.

253 patients participated in the survey and participants were 45.26 ± 14.02 (Mean±SD) years old. The majority identified themselves as white, had an annual household income of less than $20,000, and were insured by Medicare or Medicaid.

Results

From among our participants, 63% report to have tried at least a CBD product (this also included products containing THC) and 37.30% of these answered that they used CBD product that did not contain THC. Of these, the majority responded that CBD products have helped their condition (57.45%) and reduced their pain medication (61.7%), including opioids (44.68%).

Among the pain conditions patients reported relieve were back pain (63.83%), nerve pain (38.30%), neck pain (38.30%), migraines (29.79%), limb pain (19.15%), fibromyalgia (19.15%), and other (19.15%).

Overall, participants familiarity with the dosing of their CBD product varied. Generally, participants believe CBD was a good treatment option, and not harmful. The overall attitude and experience of participants regarding CBD products was positive and CBD only was reported to reduce pain medication, including opioids.

Conclusions

In summary, majority patients surveyed reported positive experience in terms of being able to decrease the doses of their pain medications and in terms of good tolerability.

151 Chronic pain treatment satisfaction in musculoskeletal disease: differences between osteoarthritis and chronic low back pain in medication switching, opioid use, and utilization of non-drug treatments

Jimmy Mali¹, Joaquim Nascimento², Joanna Atkinson³, Rebecca Robinson⁴, Martha Port⁴, Valerie Bruemmer⁴

¹Emerge Ortho, Durham, NC, USA, ²Vanguard Strategy, London, United Kingdom, ³Pfizer Ltd, Tadworth, Surrey, United Kingdom, ⁴Eli Lilly and Company, Indianapolis, IN, USA

Purpose

Chronic pain affects the lives of one in five people worldwide, and two of the most common chronic pain conditions are osteoarthritis (OA) and chronic low back pain (CLBP). Patients continually strive to find better therapies and treatments to manage chronic pain due to OA and CLBP. In this study we examined the differences between people with OA and CLBP in self-reported satisfaction of their chronic pain management and how these measures of satisfaction correlated with switching to different prescription medications, the use of opioid medication, and the use of non-pharmacologic therapies to treat their OA- and CLBP-related pain.

Methods

A total of 2,004 people with chronic pain due to OA or CLBP responded to an online survey regarding pain management and satisfaction with treatment in March 2018. Respondents were all 18 years or older and had been diagnosed with OA (hip or knee only) or CLBP for more than 12 months. They were also covered by medical insurance and had used at least one prescription or over-the-counter medication to treat their OA or CLBP pain in the past 12 months. Only subjects who experienced pain related to OA or CLBP at least one day per week and rated their pain as being 5 or higher on a pain scale of 0–10, were included in the study. Participants were offered a small, one time compensation (less than $5) to complete the survey.

Of the total respondents, 47% identified themselves as experiencing chronic pain predominantly from OA while 53% stated that their chronic pain was due mostly to CLBP. People with OA and CLBP were further divided into those who had or had not, in the past 12 months, switched prescription pain medications, used opioid pain medications, and used non-pharmacologic therapies to treat their pain. Three measures were used to assess satisfaction with pain treatment; 1) pain relief, 2) pain impact on life, and 3) side effects. Study subjects were asked to use a categorical 7-point scale to rate their satisfaction with the three measures and higher scores indicated greater satisfaction for all measures.

Results

The 939 respondents with OA had a mean age of 65.1 years, time since first diagnosis of 9.9 years, and body mass index of 29.7; 75% were female and 55% had daily pain. The 1,065 respondents with CLBP had a mean age of 61.8 years, time since first diagnosis of 11.5 years and body mass index of 28.2; 58% were female and 48% had daily pain. Pain level (1–10) was 6.23 for OA and 6.37 for CLBP. In two of three measures of treatment satisfaction, participants with OA and CLBP reported similar levels of satisfaction with their pain management. However, people with CLBP reported lower levels of satisfaction with side effects compared to the OA group.

A total of 952 respondents (48%) had used one or more prescription medicines in the past 12 months, and 43% of these prescription users had switched their medication during this time. Respondents in the OA group who had switched medication within the past 12 months reported a lower score for their satisfaction with pain relief (p = 0.02) compared to those who had not switched, while people with CLBP showed no differences related to switching in all three measures of satisfaction.

A total of 428 people (21%) reported having used opioids to treat their OA- or CLBP-related pain in the past 12 months and opioid users had a slightly higher pain score than non-opioid users (OA: 6.45 vs 6.32; p = 0.17 and CLBP: 6.81 vs 6.23; p < 0.001 on a 0–10 point numeric rating scale). Opioid users in both the OA and CLBP groups reported lower levels of satisfaction for pain impact on life and side effects of their treatments, compared to respondents who had not used opioids (p < 0.001 for all comparisons).

A total of 694 (35%) respondents had used non-pharmacologic treatments in the past 12 months. For both OA and CLBP, people who used non-pharmacologic treatments indicated a higher level of satisfaction with pain relief compared to those who did not use these treatments (p < 0.001). However, OA respondents who used non-pharmacologic treatments reported lower levels of satisfaction with treatment side effects (p = 0.015).

Conclusions

The patient experience with chronic pain is complex and satisfaction with treatment is dependent on many factors. We chose to assess satisfaction with pain treatment using three patient-reported measurements; pain relief, pain impact on life, and treatment side effects. Switching of medications was associated with lower ratings of satisfaction with pain relief in OA but not in CLBP. Use of opioid medications was associated with lower ratings of satisfaction with pain impact on life and side effects for both OA and CLBP groups. Opioid users did not report significantly higher levels of satisfaction with pain relief, in either OA or CLBP, compared to non-opioid users. Non-pharmacologic therapy use was associated with increased satisfaction in pain relief in both OA and CLBP but was negatively associated with satisfaction with side effects in the OA group. For people with OA and CLBP in this study, the measurement consistently associated with the lowest rating of satisfaction was the impact of pain on the participant’s life.

152 A Functional Restoration Program for Active Duty Service Members with Chronic Pain: An Examination of Physical Function Assessments

Emmanuel Espejo, Wade Dowling, Jennifer Muir, Tara Sheridan, Kathleen McChesney

Naval Medical Center San Diego, San Diego, CA, USA

Purpose

Chronic pain conditions are common among active duty service members (ADSM), contributing to significant physical limitations, lost productivity, and early termination of military careers. The Functional Restoration Pain Program (FRPP) at Navy Medical Center San Diego (NMCSD), which incorporates a biopsychosocial approach for treating chronic pain, has demonstrated high success at returning ADSM with chronic pain to ‘fit for full duty’ status with over 80% of treatment completers being deemed ‘fit for full duty’ by the team of providers at the completion of treatment. The current report is an examination of the physical functioning of FRPP participants at the beginning and end of treatment. The objectives of the current study are: 1) to characterize the level of physical functioning among FRPP participants at the outset and completion of treatment and 2) to quantify the improvement in physical functioning experienced by FRPP participants over the course of treatment.

Methods

The current study includes 80 ADSM with chronic pain who participated in the FRPP between May 2014 and June 2017. The NMCSD FRPP is an intensive, medically supervised interdisciplinary outpatient program that combines optimization of medication management, utilization of psychological therapy techniques, patient-focused education on understanding and coping with chronic pain, and quantitatively directed progressive exercise rehabilitation. Healthcare was delivered over eight weeks, 20 hours per week by an integrated, interdisciplinary pain team and included weekly individual and group sessions with a psychologist and physical therapist, as well as biweekly appointments with a pain physician. Objective quantification of physical functioning was assessed by the Functional Movement Screen (FMS), Five Times Sit-to-Stand Test (FTSST), the Harvard Step Test (HST) and the Progressive Isoinertial Lifting Evaluation (PILE). The FMS challenges an individual’s ability to perform fundamental movement patterns that reflect combinations of muscle strength, flexibility, range of motion, coordination, balance and proprioception. The FTSST is a measure of lower extremity strength and functional mobility. The HST simulates stairs/ladder wells and assesses a person’s capacity for strenuous physical effort. The PILE is a dynamic strength test that measures lifting capacity. These tests were chosen based on its use in prior studies, low cost, minimal time requirements, and functional application to the patient population’s work requirements. All tests were performed by a licensed physical therapist during the initial and final week of FRPP.

Results

FRPP participant scores on the physical function assessments were compared to previously established norms for each measure in other populations. On the FMS, 95% of FRPP participants scored below 14, a score previously associated with an increased risk for injury, at treatment initiation. At the end of treatment, less than 39% of FRPP participants scored below 14, with the average participant score increasing by 5.50 (SD = 4.13, p < .001) over the course of treatment. On the FTSST, 39% of FRPP participants scored above 12 seconds, a score previously associated with an increased risk for falling. By the end of treatment, only 5% of FRPP participants scored above 12 seconds, with the average participant time decreasing by 4.63 seconds (SD = 3.98; p < .001) over the course of treatment. On the HST, 82% of participants scored in the ‘poor’ range at the initiation of treatment. At the end of treatment, 67% of participants scored in the ‘poor’ range, with the average participant score increasing by 21.11 (SD = 32.14, p < .001) over the course of treatment. On the PILE – Total Work, 0% of FRPP participants performed at the ‘normal’ level at treatment initiation. At the end of treatment, 29% of FRPP participants performed at or above ‘normal’ with an average improvement for all treatment completers of 42.61 (SD = 35.71, p < .001). On the PILE – Final Force, 1% of FRPP participants performed at the ‘normal’ level at treatment initiation. By the end of treatment, 28% of participants performed at or above ‘normal’ with an average improvement of 28.80 (SD = 28.80, p < .001) by the end of treatment.

Conclusions

The assessment of physical functioning of participants in the FRPP at NMCSD at the outset of treatment revealed that almost all participants scored in a range consistent with increased risk for injury and below normal in comparison to previously established norms. By the end of treatment, the majority of participants were no longer scoring in the range of increased risk for injury (on the FMS) or falling (on the FTSST). Though a considerable percentage of participants moved above the ‘poor’ (HST) and ‘below normal’ ranges on the HST and PILE, respectively, over two-thirds of participants still scored in the ‘poor’ and ‘below normal’ range. Because over 80% of FRPP participants were deemed ‘fit-for-full duty’ at the conclusion of treatment, this may reflect that the established norms for the HST and PILE do not generalize to this ADSM population or do not accurately simulate their physical work requirements. Importantly, FRPP participants demonstrated significant improvements on all five measures of physical functioning over the course of treatment, signifying broad improvements in muscle strength, range of motion, functional mobility, balance, and endurance. The results support the utility of FRPPs in military medical settings as a treatment for chronic pain.

153 Retrospective Analysis of Opioid Prescription Surrounding Treatment with Hylan G-F 20 in Patients with Osteoarthritis of the Knee

David Webner¹, Michael J. Langworthy², Wilson Ngai³, Lichen Hao⁴, Charles D. Hummer, III⁵

¹Crozer-Keystone Health System, Suburban Philadelphia, Pennsylvania, USA, ²Southcoast Health Systems, New Bedford, Massachusetts, USA, ³Sanofi, U.S. Medical Affairs, Bridgewater Township, New Jersey, USA, ⁴Sanofi, Real World Evidence, CMO, Bridgewater Township, New Jersey, USA, ⁵Premier Orthopaedics and Sports Medicine, Media, Pennsylvania, USA

Purpose

Hylan G-F 20 is a hyaluronic acid viscosupplement that is used to reduce pain in patients with mild to moderate osteoarthritis of the knee (OAK). Hyaluronic acid alleviates pain from OAK through its joint lubrication and shock absorption effect, while recent findings suggest anti-inflammatory and chondroprotective effects may play a role. Hylan G-F 20 can delay the need for total knee replacement in patients with OAK. Alternative treatments to alleviate the pain associated with OAK include the use of opioids, NSAIDS, or anti-inflammatory intra-articular (IA) corticosteroids. Opioids were commonly prescribed to treat the pain associated with OAK, although opioid prescription frequency for treatment of OAK in the U.S. has markedly decreased in recent years due to the realization of significant opioid overuse. Opioid analgesics are associated with a high risk of addiction and are not appropriate for long-term or routine use. Evidence reveals the potential for side-effects such as dizziness, constipation, and respiratory depression which can result in death. We, therefore, examined opioid prescriptions among patients treated with Hylan G-F 20 to investigate how viscosupplement treatment affects the prescription of opioids, both in patients who did and did not receive an opioid prescription prior to Hylan G-F 20 treatment.

Methods

This retrospective study was conducted using a national claims database, Truven MarketScan®. A case cross-over study design was utilized in which opioids prescribed for adult patients in the 6 months prior to Hylan G-F 20 treatment was compared to opioids prescribed in the 6 months following Hylan G-F 20 treatment (required study baseline and follow-up periods, respectively). To account for different prescribed opioid medications, opioid dosages were converted to morphine milligram equivalents (MME) based on guidelines developed by the Center for Medicare and Medicaid Services (CMS) and the Centers for Disease Control and Prevention (CDC). Adult patients with a diagnosis of OAK, and who were treated with Hylan G-F 20 between July 1, 2007 and June 29, 2017 were included in the study. Patients were excluded from the study if they had a confounding condition (e.g. fibromyalgia, rheumatoid arthritis), received a viscosupplement other than Hylan G-F 20, received antidepressants, or underwent major procedures which may require pain medications. Two patient populations were investigated: 1) patients who were prescribed opioids before Hylan G-F 20 treatment (baseline period); 2) patients who were prescribed opioids both before and after Hylan G-F 20 treatment (baseline and follow-up periods). The study outcome was opioid prescriptions measured both as the average total MME per patient and the average MME per patient day.

Results

There were 29,395 patients who met study criteria. Of these patients: 6,609 patients were prescribed opioids prior to Hylan G-F 20 treatment (baseline); 3,320 patients were prescribed opioids both before Hylan G-F 20 treatment (baseline) and also following Hylan G-F 20 treatment (follow-up). Among patients who received an opioid prescription prior to Hylan G-F 20 treatment, there was a significant 14.0% decrease in the average total MME per patient after Hylan G-F 20 treatment vs. prior to treatment (2272.8, baseline; 1955.5, follow-up; p < 0.0001). Among this same patient population, there was a significant 14.2% decrease in the average MME per patient day after Hylan G-F 20 treatment vs. before (12.6, baseline; 10.78 follow-up; p < 0.0001). Forty-nine percent of patients who received an opioid prescription for pain control in the baseline, did not require opioid prescriptions after Hylan G-F 20 treatment. Among patients who received an opioid prescription both before and after Hylan G-F 20 treatment, there was no significant difference in the average total MME (3760.7, baseline; 3892.8 follow-up; p = 0.1930) or MME per patient day (20.8, baseline; 21.5 follow-up; p = 0.1980) for opioids before vs. after treatment with Hylan G-F 20.

Conclusions

Among patients who were prescribed opioids prior to Hylan G-F 20 treatment, there was a significant reduction in both average total MME per patient and average MME per day after Hylan G-F treatment vs. before. Forty-nine percent of patients with opioid prescriptions filled prior to Hylan G-F 20 treatment did not receive an opioid prescription afterwards, suggesting that Hylan G-F 20 treatment was effective in treating pain associated with OAK. Future studies should include patient pain scores in order to confirm the reduction in opioid prescriptions is related to improvement in patient-reported pain.

154 Retrospective Analysis of Intra-Articular Corticosteroid Injections Surrounding Treatment with Hylan G-F 20 in Patients with Osteoarthritis of the Knee

David Webner¹, Michael J. Langworthy², Wilson Ngai³, Lichen Hao⁴, Charles D. Hummer, III⁵

¹Crozer-Keystone Health System, Suburban Philadelphia, Pennsylvania, USA, ²Southcoast Health Systems, New Bedford, Massachusetts, USA, ³Sanofi, U.S. Medical Affairs, Bridgewater Township, New Jersey, USA, ⁴Sanofi, Real World Evidence, CMO, Bridgewater Township, New Jersey, USA, ⁵Premier Orthopaedics and Sports Medicine, Media, Pennsylvania, USA

Purpose

Osteoarthritis (OA) is a leading cause of disability contributing 17.1 million years lived with disability between 1990 and 2010, with osteoarthritis of the knee (OAK) accounting for 83% of the OA burden. Inflammation associated with OAK can be treated with NSAIDs and intra-articular (IA) corticosteroid injections. Long-term use of NSAIDs, however, is associated with risk of adverse events such as gastric bleeding, renal dysfunction, and cardiovascular events. Long-term repeated use of IA corticosteroids, on the other hand, is linked to gross cartilage damage. Hylan G-F 20 is a viscosupplement that is indicated for the treatment of pain in knee osteoarthritis (OA) patients who have failed to respond adequately to conservative nonpharmacologic therapy and simple analgesic. It alleviates the symptoms through its joint lubrication and shock absorption effects. The present study was conducted to determine whether treatment with Hylan G-F 20 may affect the number of IA corticosteroid injections received by patients with OAK before vs. after treatment with Hylan G-F 20.

Methods

This retrospective study was performed in adult patients diagnosed with OAK in a national claims database, Truven MarketScan®. A case cross-over study design was utilized where the number of IA corticosteroid injections received in the 6 months prior to Hylan G-F 20 (required baseline period) was compared to the number of IA corticosteroid injections received in the 6 months after Hylan G-F 20 treatment (required follow-up period). Adults treated with Hylan G-F 20 between July 1, 2007 and June 29, 2017 were included in the study. Patients were excluded from the study if they had a confounding condition (e.g. fibromyalgia, rheumatoid arthritis), received a viscosupplement other than Hylan G-F 20, received antidepressants, or underwent major procedures which may require pain medications. The following patient populations were analyzed: 1) patients who received at least one IA corticosteroid injection before Hylan G-F 20 treatment (baseline); 2) patients who received at least one IA corticosteroid injection before Hylan G-F 20 treatment (baseline) and at least one IA corticosteroid injection after Hylan G-F 20 treatment (follow-up).

Results

There were 29,395 patients that met study criteria. Of these patients: 11,162 patients received at least one IA corticosteroid injection prior to Hylan G-F 20 treatment (baseline); 2,810 patients received at least one IA corticosteroid injection before Hylan G-F 20 treatment (baseline) and at least one additional IA corticosteroid injection following Hylan G-F 20 treatment (follow-up). Among patients treated with IA corticosteroids prior to Hylan G-F 20 treatment, there was a significant 72.6% decrease in the average number of IA corticosteroid injections after Hylan G-F 20 treatment vs. before treatment (1.3, baseline; 0.4 follow-up; p < 0.0001). Only 25.2% of patients that received an IA corticosteroid injection before Hylan G-F treatment, received an IA corticosteroid injection afterwards. Among patients who received at least one IA corticosteroid before Hylan G-F 20 treatment (baseline) and at least one additional IA corticosteroid injection following Hylan G-F 20 treatment (follow-up), there was a significant 4.1% decrease in the average number of IA corticosteroid injections comparing baseline to follow-up (1.5, baseline; 1.4, follow-up; p = 0.0043).

Conclusions

Among all patient populations analyzed, there was a significant reduction in the number of IA corticosteroid injections after Hylan G-F 20 treatment vs. before. Seventy-five percent of patients who received IA corticosteroids at baseline did not receive IA corticosteroids after Hylan G-F 20, suggesting Hylan G-F 20 treatment might reduce the need for IA corticosteroid injections to manage OAK inflammation. Future studies should include patient pain scores in order to confirm the reduction in IA corticosteroid injections is related to improvement in patient-reported pain.

155 A Randomized Placebo-Controlled pilot Study of a Topical Herbal Analgesic for the Management of Chronic Musculo-skeletal Pain.

Winston Parris^1,2, Benjamin Johnson³, Ike Eriator⁴

¹Department of Anesthesiology, Duke University Medical Center,, Durham, North Carolina, USA, ²Saint Lucia Pain Institute, Castries, Saint-Lucia, ³Department of Anesthesiology, Vanderbilt University, Nashville, Tennessee, USA, ⁴Department of Anesthesiology, University of Mississippi Medical Center, Jackson, Mississippi, USA

Purpose

To compare the topical analgesic effects of a purified coconut based topical analgesic with diclofenac and a placebo in chronic musculoskeletal pain.

Methods

Following approval by the ethics board, we performed a randomized placebo-controlled pilot study with a purified coconut based topical agent (Test drug), Diclofenac ointment (FDA-approved NSAID) and a placebo (Jasmine oil). The inclusion criteria included axial musculo-skeletal pain of greater than 6 weeks duration in adults 18–75 years of age. Exclusion criteria included history of spinal surgery, prior use of opioids or NSAIDS in the past 7 days, active cancer, gastrointestinal disorders, heart attack, stroke, uncontrolled blood pressure, active skin lesions or use of topical agents in the past one week.

One hundred and ninety six (196) participants were enrolled and randomized to the 3 groups using the nQuery Advisor version 7.0 software protocol. The primary outcome measure was the reduction in pain across the three groups. Follow up was by telephone contact at weeks 2 and 12, and a clinic visit at week 4.

The primary outcome measure was analgesic effects, measured by the change in numerical pain score from baseline, compared using the chi square test or the Krustal wallis rank test.

Results

One hundred and ninety six participants were enrolled following appropriate consent. Twenty-six did not respond to follow up (14 in the placebo group, 7 in the diclofenac group and 5 in the herbal medication group). The mean age of the participants was 52 years (SD 12.7) with no statistically significant differences between the groups. Median numerical rating score at enrollment was 65 (placebo group), 70 in the diclofenac and herbal medicine groups, on the scale of 0–100. There were no statistically significant differences in baseline pain (Kruskal-Wallis P = 0.3243). Median change in pain from baseline to 3 months showed a decrease of 37.5%, 30% and 40% for the Treatment, Diclofenac, and Placebo groups respectively. All 3 groups showed significant decreases in pain scores from baseline to 12 weeks. There was no statistically significant difference between groups on magnitude of pain scores or any change in pain scores, and this was the case in both the as-randomized analysis and the as-treated analyses. Jasmine oil, which was the placebo in this study, has an antispasmodic quality, and is often used over the counter for pain and as an aphrodisiac. This could also have favored the placebo and help to explain why there was no statistically significant difference between the trial agent and the placebo.

Conclusions

Chronic musculo-skeletal pain is very common in the society and warrants the search for a safe and effective analgesic. This placebo-controlled, randomized pilot study showed that the test drug was similar in effectiveness to topical diclofenac. Essential oils and herbal preparations have been around for decades. Properly prepared, their analgesic effects may be comparable to FDA approved agents.

156 The association of sarcopenia with low back pain and lumbar spine degeneration

Yu Jin Seo¹, June Hong Bae², Hyun Ho Kong¹, Kyoung Hyo Choi¹, Won Kim¹

¹Asan Medical Center, University of Ulsan College of Medicine, Department of Rehabilitation Medicine, Seoul, Korea, Republic of, ²University of Waterloo, waterloo, Canada

Purpose

There were few studies about on the association between low back pain (LBP) and lumbar spine degeneration (LSD) with sarcopenia. In particular, there were few published descriptions of the effects of sarcopenia on LBP and LSD simultaneously. The aim of this study is to investigate the association of low back pain and lumbar spine degeneration with sarcopenia using nationwide survey in men over 60 years old.

Methods

We conducted a cross-sectional study using the 5th Korea National Health and Nutrition Examination Survey (2010–2011). Men ≥ 60 years of age were included. Skeletal muscle mass index (SMI) and body composition were evaluated using Dual-energy X-ray absorptiometry. We defined sarcopenia as a modified SMI (ASM/ht2) value less than 20% of the participants. LSD was evaluated using a modified version of the Kellgren–Lawrence (KL) grade and was defined if the modified KL grade was 2. The risk of LBP and LSD with sarcopenia were investigated with multivariate logistic regression analyses. Model 1 was adjusted by age group. Model 2 was adjusted by age group, obesity, occupation, and physical activity. We also adjusted for LSD.

Results

Of 1032 participants, 849 participants had no LBP and 183 participants had LBP. Sarcopenia was associated with increased risk of LBP (OR = 2.08; 95% CI 1.39–3.11) (OR = 2.03; 95% CI 1.36–3.02 and OR = 2.23; 95% CI 1.38–3.59, respectively for model 1 and 2). This increased odds ratio was maintained after adjusting for LSD (OR = 2.16; 95% CI 1.43–3.25 and OR = 2.37; 95% CI 01.45–3.86, respectively for model 1 and 2). However, sarcopenia was associated with decreased risk of LSD in multivariated analysis (OR = 0.62; 95% CI 0.42–0.93 and OR = 0.61; 95% CI 0.40–0.92, respectively for model 1 and 2).

Conclusions

Our Results suggest that sarcopenia was associated with increased risk of LBP in men ≥ 60 years old. It was also maintained after adjusting for LSD. However, sarcopenia was associated with decreased risk of LSD.

157 Relationship between obesity and lumbar spine degeneration

Sang Yoon Lee¹, Won Kim², Shi-Uk Lee¹, Kyoung Hyo Choi²

¹Seoul National University Boramae Medical Center, Seoul, Korea, Republic of, ²Asan Medical Center, University of Ulsan College of Medicine, Department of Rehabilitation Medicine, Seoul, Korea, Republic of

Purpose

Although several studies have shown that obesity affects low back pain (LBP), the relationship between degenerative lumbar spine (LSD) and obesity has not been fully investigated. This study evaluated whether obesity is independently associated with LSD in the general population.

Methods

This cross-sectional study used public data from the Fifth Korean National Health and Nutrition Examination Survey (2010–2012). Subjects aged ≥50 years who had completed surveys were included (3,668 men and 4,966 women). Obesity was classified by body mass index and LSD was assessed by radiographs of the lumbar spine. The independent associations of obesity to LSD or LBP were determined using odds ratios (OR) adjusted by two regression models.

Results

The prevalence of obesity was more frequent in women than in men (38.27% vs. 33.97%, P < 0.001). Compared to normal-weight women, the risk of LSD was increased in overweight and obese women after adjustment (OR 1.227, 95% confidence interval [CI] 1.019–1.477 and OR 1.217, 95% CI 1.024–1.446, respectively). When obesity was subdivided, the obese II group showed higher odds for LSD in women (OR 1.797, 95% CI 1.287–2.510). However, obesity was not correlated with LSD in men. There were no significant associations between obesity and LBP in either men or women.

Conclusions

Compared to normal-weight women, the risk of LSD was increased in overweight and obese women, especially, those in the obese II subgroup. These findings suggest that maintaining normal body weight may be one of the factors preventing LSD.

158 Radiation Protection Effect of Lead Curtain during Fluoroscopic Guided Procedure

Woong Ki Han, Pyung Bok Lee, Francis Sahngun Nahm

Seoul National University Bundange Hospital, SeongNam, Korea, Republic of

Purpose

C-arm (fluoroscopy) guided procedures are commonly performed by pain physicians to treat various pain disorders while minimizing potential complications. As a result, physicians performing c-arm guided procedures are susceptible to frequent and high dose radiation exposure. We made a lead curtain on the procedure table to further protect radiation hazard that may cause harm to the pain physician and examined the efficacy of the lead curtain on reducing radiation dose to the interventionist relative to distance from the table.

Methods

The lead curtain consisted of 19 shielding fabrics of lead equivalent thickness of 0.5 mm with each having dimensions of 59 × 10 cm. We measured the radiation dose of the x-ray on the physician with and without the lead curtain. The c-arm procedure table was set at 80cm height from the ground, the primary X-ray was generated at 90 kVp, 10.0 mA, and the detector of the C-arm unit was set at three distances from the table: 50 cm, 70 cm, and 90 cm. We measured the radiation exposure at different heights starting from 30 cm to 170 cm, checking at every 10 cm. The radiation exposure was measured by an electrical dosimeter (Hitachi electronic pocket dosemeter Mydose mini PDM-227C-RH). Recorded radiation exposures on the pain physician were an average of two measurements.

Results

There was a significant difference between the dose rate of X-ray with and without lead curtain. The lead curtain proved to be very effective below 100 cm height.

Conclusions

Lead curtain on a c-arm procedure table can effectively reduce radiation exposure to the pain physician and could be an effective tool in reducing the radiation exposure below the waist level of interventionists.

159 Promoting Physical Activity and Movement for Arthritis Patients through a Virtual Reality Game

Xin Tong¹, Frederico Machuca¹, Noel Feng¹, Diane Gromala¹, Linda Li², Gabriela Aceves-Sepulveda¹

¹Simon Fraser University, Surrey, BC, Canada, ²The University of British Columbia, Vancouver, BC, Canada

Purpose

Rheumatoid Arthritis (RA) is a chronic systemic inflammatory disease typically involving joints on both sides of the body (hands, wrists, feet, and knees). Virtual Reality (VR) shows great promise in creating systematic human testing and treatment environments where virtual representations of real environments can be precisely controlled and guided according to therapy needs. VR can provide real-time feedback to a person doing physical therapy and can act as a motivator for many situations. Furthermore, gaming factors can help the subject distract their attention outward and focus on the game task. Game mechanics have been demonstrated to generate greater motivation for adults when using VR environment. Few prototypes or research studies have been designed in VR with a body-sensing system to motivate RA patients to adhere to arthritis-specific Range of Motion (RoM).

Methods

In this study, we included both patients and non-patients as our participants to compare their differences in playing the VR game, performance and their feedback.

A mixed-method study was conducted with quantitative measures and qualitative semi-structured interviews. Inclusion criteria: (1) healthy adults who are older than 19 years old; or (2) arthritis patients who have rheumatoid arthritis and are older than 19 years old.

Measurements include capturing real-time heart rate data, and the Rating of Perceived Exertion Scale (RPE).

Study procedure First the participants were given a tutorial on playing the game, and then they set out to explore the virtual world themselves. Meanwhile, the participants’ real-time heart rate data was captured by the system as they played the game. After the participants experienced the game for around 20 minutes, they were asked to fill in the Rating of Perceived Exertion Scale (RPE) questionnaire. Finally, they had a semi-structured interview with the researchers regarding their experience playing the VR game. The interviews were audiotaped with consent acquired from participants. The entire study took 40–50 minutes for each participant.

The game was designed by the researchers, and we implemented aesthetic and mechanic immersion to enhance the players’ motivation. We also included 3 older arthritis patients in the participatory design phase. In the game, two different types of tasks were included as the interventions for promoting the patients’ motivation and RoM. The first one is to draw lines with different shapes, which requires the participants to move at a slow speed according to their performance. The second task is ‘connecting the dots’ in 3D space. The participants were asked to stay in the environment for up to 20 minutes.

Results

A total of 28 participants participated (Female = 15, Male = 13, M = 37.63, SD = 18.89). Twenty were younger than 50 years old and eight were older than 50 years old, while five had the diagnosis of RA. The results showed that for our patients, who are mostly older people with limitations of movement because of arthritis, could enjoy and benefit from this Virtual Reality game as much as participants from a younger demography. In the post-test survey, participants reported that they perceived no physical exertion while playing the VR game. However, their real exertion measured by the heart rate sensor showed a significantly different level of physical activity, compared to their normal resting state. The overall awareness of physical activity was low, indicating that the users were immersed in the system so much that they did not notice they sustained a moderate aerobic state. All of the participants felt safe and comfortable while immersed in this VR game.

As for the accuracy of their performance, as hypothesized, the older group (M = 49.07, SD = 20.79) has less accuracy in completing the tasks in the VR game compared to the younger group (M = 68.43, SD = 16.4). When analyzing their heart rate data during gameplay, we found an increase in HR variation (maximum HR minus minimum HR) as participant’s age increases.

From the qualitative interview, we found patients liked the immersive aspect of our VR game and the overall gameplay design. The interview results were categorized into themes:

Colors A lot of the participants made positive comments regarding the colors of the game world (environments, objects, lighting).

Exploration. The environments were interesting and participants wanted to look around and see new things. No participants reported feeling nauseated or dizzy.

Instructions Almost all participants would like more instructions. They would prefer being guided for a little bit longer so they felt more familiar with the game before having to figure out interactions on their own. This was especially important to the older participants.

Input Simplicity A lot of participants mentioned they would prefer if the inputs required to interact with the game world were simpler somehow.

Memorizing the actions associated with specific controller buttons sometimes was a problem for the older participants and patients compared to non-patients.

Conclusions

Virtual Reality games and environments show significant potential as a tool not only for entertainment but also for mental and physical health applications. Therefore, to enhance older adults’ motivation to move and to test the efficacy of such approaches, in this research, we designed a VR game prototype according to the design needs of arthritis patients and then conducted a study with them in a laboratory context. Results showed great promise for using such technology to promote motivation for sustained RoM.

160 FitViz-Ad: A Non-Intrusive Reminder to Support and Encourage Rheumatoid Arthritis Patients with Physical Activity

Xin Tong¹, Tim Bodyka Heng¹, Ankit Gupta¹, Chirs Shaw¹, Diane Gromala¹, Linda Li²

¹Simon Fraser University, Surrey, BC, Canada, ²The University of British Columbia, Vancouver, BC, Canada

Purpose

Regular physical activity and non-sedentary lifestyle are important for 300,000 Canadians who suffer from Rheumatoid Arthritis (RA). A non-sedentary lifestyle improves their condition and reduces the risk of other comorbidities. Physiotherapists and rheumatologists often prescribe a physical activity plan for patients with RA. However, it is hard for patients to keep a detailed record of their physical activity and non-sedentary behaviour throughout the day. Wearable devices can help, but existing consumer devices like Fitbit do not allow any modification, such as customizing the physical activity plan to suit the physical abilities of a patient with mobility issues.

Methods

We developed a new technology that repurposes the online advertisement space with reminders for each patient to maintain a non-sedentary lifestyle.

We developed a Chrome extension which identifies the advertisements on websites such as Facebook, YouTube and Amazon, and replaces those advertisements with personalized reminders to be active.

The FitViz web application downloads a patient’s Fitbit data and determines progress towards non-sedentary goals. The progress is then sent to the FitViz-Ad extension which replaces the online advertisements with reminders to move throughout the day.

We conducted an initial 2-week usability study with 14 healthy individuals as participants. Participants were randomly assigned to one of the two groups: the control group and the intervention group. The control group did not use the Chrome extension. The intervention group, on the other hand, used the Chrome extension for two weeks.

At the end of the study, we compared the change in step counts and the number of hours in a day spent as non-sedentary. We also conducted a semi-structured interview to better understand the experience of using the FitViz-Ad Chrome extension.

Results

We did not observe a significant change in the step counts before and after the study between the control group (M = 7508.93, SD = 2423.88) and intervention group (M = 6625.48, SD = .1891.63); t(10) = −0.7, p = 0.5). The non-sedentary hour data was not normally distributed and the Wilcoxon test revealed no significant difference in the number of non-sedentary hours W(1) = 32.5, Z = −0.965, p = 0.295.

Participants reported an increase in awareness about Physical Activity. One participant said:

“[…]But when I started using the app [extension] and I was working, like it was reminding me on a constant basis that I’m not moving. So I knew… like I was aware and I think it’s important to just know and like sometimes ’oh I’m so tired but cause I didn’t get up.”

All except 2 participants in the intervention group found the reminders to be non-intrusive. However, participants expressed a desire to be able to customize the reminder pop-up. Current efforts focus on improving the design of the FitViz ads and enabling patients to choose the type of reminder. A second usability study that involves RA patients is planned.

Conclusions

Our results show that the design of the FitViz-Ad can be a non-intrusive reminder for rheumatoid arthritis patients to remind and support their Physical Activities.

161 Wearable Transcutaneous Electrical Nerve Stimulation is Associated with Improved Objective Sleep Measures in Poor Sleepers with Chronic Knee Pain

Shai Gozani¹, Thomas Ferree¹, Xuan Kong¹, Dawn Chesher², Taara Madhavan³

¹NeuroMetrix, Inc., Waltham, MA, USA, ²GlaxoSmithKline, Weybridge, Surrey, United Kingdom, ³GlaxoSmithKline, -, Singapore

Purpose

Most people with chronic pain complain of disturbed sleep and daytime lethargy. Polysomnography studies show that chronic pain patients have shorter sleep duration, lower sleep efficiency and greater numbers of periodic leg movements compared to healthy controls. Compromised sleep increases pain sensitivity, possibly through an impairment of descending pain inhibition. In addition, inadequate sleep is associated with poor health including cardiovascular disease, diabetes and obesity. Chronic knee pain is one of the most common forms of chronic pain. Osteoarthritic knee pain, in particular, may be worse at night leading to sleep abnormalities.

Transcutaneous electrical nerve stimulation (TENS) is a non-invasive low-risk treatment for chronic pain. Conventional TENS is delivered through surface electrodes to generate a strong, nonpainful sensation. The resulting stimulation of large diameter, deep tissue afferents produces pain relief by decreasing central excitability and increasing central inhibition. General purpose TENS has typically not been used while sleeping.

Wearable TENS is an emerging form of TENS in which the stimulator is designed for a predetermined location, such as near the knee. A specific site enables development of wearable devices that can be safely used during sleep, which is not feasible with general purpose TENS devices. Another benefit of wearable devices is the integration of physiological sensors. These measurements can provide objective feedback for therapy optimization. For example, accelerometer readings from the leg may be used to objectively track activity and sleep.

Prior studies have demonstrated that wearable TENS use is associated with improvement in self-reported measures of sleep in multi-site chronic pain and chronic low back pain. However, patient reported outcomes are susceptible to bias and vulnerable to non-specific effects. A recent study showed that wearable TENS use is associated with improvement in objective measures of sleep in a subset of subjects with chronic low back pain. The aim of the present study was to evaluate the relationship between wearable TENS use and objective sleep measures in individuals with chronic knee pain in a real-world setting.

Methods

This retrospective, observational study evaluated users of a wearable TENS device (Quell®, NeuroMetrix, Waltham, MA) over a 10-week period. The device is placed on the upper calf, just below the knee, and provides semi-continuous stimulation (typically 60 minutes every other hour). The device and companion smartphone app collect demographics, pain characteristics, pain ratings, treatment adherence data (by device) and objective activity and sleep data (from an accelerometer embedded in the device) that are stored in a cloud database. The pain ratings are provided at the user’s discretion and include pain intensity and pain interference with sleep, activity and mood on an 11-point NRS modeled after the Brief Pain Inventory. The pain ratings are global and therefore are not specific to an anatomical site. Device users with the following data recorded in the database were included: 1) age, gender, height, and weight; 2) pain duration >3 months, 3) pain frequency ≥ several times a week, 4) baseline pain rating, 5) self-reported knee pain, 6) ≥10 weeks of wearable TENS use and 7) device use for at least 3 nights during weeks 1–2 and weeks 9–10.

The objective sleep measurements included time in bed (TIB, measured in minutes), total sleep time (TST, time within TIB spent sleeping measured in minutes), sleep efficiency (SE, defined as TST/TIB), and the periodic leg movement index (PLMI, defined as number of periodic leg movements per hour of sleep). The initial assessment was the median of nights during weeks 1-2 of the study period. The final assessment was the median of nights during weeks 9–10. Participants were allocated to a low sleep (LS) group if TST ≤ 360 or to an adequate sleep (AS) group if TST > 360, based on the initial assessment. Differences between groups or between the initial and final assessments were evaluated by the two-sample t-test for means or by the two-sample Wilcoxon rank-sum test for medians. Differences among proportions were evaluated by the Pearson chi-square test.

Results

A total of 189 device users met the inclusion criteria; 53 (28%) in the LS group and 136 (72%) in the AS group. The two groups had similar demographic and pain characteristics. Both groups had multi-site pain in addition to knee pain, with no difference in the total number of pain sites; 6.1 ± 2.8 (LS) vs 5.7 ± 2.3 (AS), p = 0.308. There was no difference in baseline pain interference with sleep; 6.0 ± 3.3 (LS) vs 5.7 ± 2.8 (AS), p = 0.619.

There were statistically significant differences in sleep metrics between the groups at the initial assessment. TST was 319 ± 33 (LS) compared to 442 ± 53 (AS), p < 0.001. TIB was 372 ± 45 (LS) compared to 492 ± 62 (AS), p < 0.001. SE was 86.3 ± 6.8 (LS) compared to 89.9 ± 5.6 (AS), p < 0.001. There was no difference in the PLMI, which was 8.6 ± 9.2 (LS) compared to 8.0 ± 8.7 (AS), p = 0.680. The number of recording nights during the initial assessment were 8.6 ± 7.6 (LS) compared to 10.2 ± 3.2 (AS), p = 0.002.

There were statistically significant differences in activity and gait between the groups at the initial assessment. Hourly step count while wearing the device was 311 ± 200 (LS) compared to 380 ± 199 (AS), p = 0.033. Stride variability (%) was 3.8 ± 1.2 (LS) compared to 3.4 ± 1.2 (AS), p = 0.057. Step cadence (steps/minute) was 101 ± 10 (LS) compared to 104 ± 11 (AS), p = 0.043.

Treatment variables were similar in the two groups. Utilization (percent of days using device) was 92 ± 10 (LS) compared to 91 ± 14 (AS), p = 0.595. Weekly therapy (hrs/week) was 59 ± 19 (LS) compared to 57 ± 21 (AS), p = 0.786. The median stimulation intensity (ratio of stimulation to sensation level expressed in decibels) was 5.3 (LS) compared to 5.5 (AS), p = 0.304. Overnight utilization (percent of nights using device) was lower in the LS group (58 ± 20) compared to the AS group (69 ± 23), p = 0.001.

There were statistically significant changes in sleep metrics from the initial to final assessment. In the LS group, TST increased by 43 ± 68 (p < 0.001), TIB increased by 38 ± 77 (p < 0.001), SE increased by 2.3 ± 5.8 (p = 0.006) and PLMI increased by 3.3 ± 10.4 (p = 0.023). In the AS group, SE decreased by 1.2 ± 6.2 (p = 0.025) with the remaining parameters unchanged. The relative change in TST was 14.5 ± 21.7% (LS) compared to −1.5 ± 13.6% (AS), p < 0.001. Among participants with follow-up pain ratings, the median decrease in pain interference with sleep was 40% (LS) compared to 25% (AS), p = 0.070.

Conclusions

In this study, about 30% of participants with chronic knee pain were classified as having low sleep duration (≤6 hours) based on objective sleep measurements. Participants in the LS and AS groups had similar demographics and pain characteristics. The LS group was less active than the AS group.

The primary study finding was that wearable TENS use was associated with improved objective measures of sleep duration and efficiency in participants with low sleep duration at baseline. The reason for the increase in PLMI in the LS group is unclear. Participants with adequate sleep at baseline maintained their sleep duration. Consistent with these results, self-reported pain interference with sleep showed a trend towards greater improvement in the LS group. The study population had high wearable TENS utilization, including overnight. Therefore, the study findings may not apply to low utilization cohorts.

Study limitations were lack of a control group with which to evaluate the contribution of non-specific effects and the lack of a true baseline because the initial sleep assessment was coincident with the first two weeks of treatment. Study strengths included use of objective sleep measurements and estimation of sleep variables from multiple nights to mitigate regression to the mean effects.

162 Clinical and Treatment Variables Associated with Effectiveness of Wearable Transcutaneous Electrical Nerve Stimulation in Individuals with Chronic Knee Pain

Shai Gozani¹, Xuan Kong¹, Dawn Chesher², Taara Madhavan³

¹NeuroMetrix, Inc., Waltham, MA, USA, ²GlaxoSmithKline, Weybridge, Surrey, United Kingdom, ³GlaxoSmithKline - Singapore

Purpose

About one-quarter of adults suffer from frequent knee pain, which limits function, decreases mobility and impacts quality of life. Osteoarthritis, which affects 30 million adults in the U.S., is the most common cause of chronic knee pain. Patients with chronic knee pain are often managed with pharmacological agents, including opioids and oral non-steroidal anti-inflammatory drugs. However, these medications may have limited efficacy, cause adverse events and, in the case of opioids, can create addiction risk. For these reasons, there is a need for non-pharmacological options for chronic knee pain.

Transcutaneous electrical nerve stimulation (TENS) is a non-invasive low-risk treatment for chronic pain. Conventional TENS is delivered through surface electrodes to generate a strong, nonpainful sensation. The resulting stimulation of large diameter, deep tissue afferents produces pain relief by decreasing central excitability and increasing central inhibition. General purpose TENS devices have been used for knee pain, including for pain caused by osteoarthritis, for several decades. Recent meta-analyses have been inconclusive on the benefits of TENS in this application.

Wearable TENS is an emerging form of TENS in which the stimulator is designed for a predetermined location. A known target site enables development of wearable devices that can be used for extended time without disrupting daytime activity or sleep, which is not feasible with general purpose TENS devices. For example, the design of the device can be optimized for a specific anatomical location such as the vicinity of the knee. Another benefit of wearable devices is the integration of physiological sensors. These measurements can provide objective feedback for therapy optimization. For example, accelerometer readings from the leg may be combined with a lower extremity biomechanical model to quantitatively track activity, falls, gait, range of motion and sleep, which are all influenced by knee pain. The objective of the present study was to determine clinical and treatment variables that are associated with the effectiveness of a wearable TENS device, located on the upper calf, in individuals with chronic knee pain in a real-world setting.

Methods

This retrospective, observational study evaluated users of a wearable TENS device (Quell®, NeuroMetrix, Waltham, MA). The device is placed just below the knee and provides semi-continuous peripheral nerve stimulation (typically 60 minutes every other hour). The device and companion smartphone app collect demographics, pain characteristics, pain ratings, treatment adherence data (by device) and objective activity and sleep data (from an accelerometer embedded in the device) that are stored in a cloud database. The pain ratings are provided at the user’s discretion and include pain intensity and pain interference with activity, sleep and mood on an 11-point NRS modeled after the Brief Pain Inventory. The pain ratings are global and therefore are not specific to an anatomical site. Device users with the following data recorded in the database were included: 1) age, gender, height, and weight; 2) pain duration >3 months, 3) pain frequency ≥ several times a week, 4) baseline and follow-up pain ratings, 5) baseline pain intensity ≥4, 6) self-reported knee pain and 7) ≥10 weeks of wearable TENS use. A valid baseline pain rating occurred on the first day of device use or within the prior 6 days (latest one used). A valid follow-up pain rating occurred between weeks 9 and 15 following start of device use (median of all ratings within time window were used).

The primary study outcomes were the baseline to follow-up change in pain intensity and pain interference with function (defined as average of the three pain interference values). The relationships between predictor variables and the outcomes were determined using multivariable linear regression. Variables with p < 0.05 were retained as statistically significant outcome predictors. The following variables were modeled: age, gender, BMI, baseline pain intensity and pain interference, number of self-reported pain sites, number of self-reported painful health conditions, specific pain sites and painful health conditions, pain duration, constant versus intermittent pain during the day, weather sensitivity and treatment data. The latter included daily utilization (%24-hour periods with ≥30-minutes stimulation) and overnight utilization (% nights with ≥30-minutes stimulation), sensation threshold (in milliamps) and stimulation intensity (ratio of stimulation to sensation level expressed in decibels).

Results

A total of 367 device users met the inclusion criteria. Study participants had a mean age of 58 (SD 14) years, 62.7% were female and the mean BMI was 31.8 (SD 7.3) kg/m². Participants reported a mean of 5.8 (SD 2.5) pain sites with multi-site pain (≥ 3 sites) reported by 92%. Participants self-reported a mean of 3.5 (SD 2.0) painful health conditions. The most common conditions were arthritis (77%), prior leg injury (50%) and prior back injury (50%). Among those reporting arthritis, 60% specified osteoarthritis. Most participants (79%) reported chronic pain duration of ≥4 years. At baseline, the mean pain intensity was 6.8 (SD 1.6). Mean pain interference with sleep, activity and mood were 6.2 (SD 2.8), 7.3 (SD 2.2) and 6.7 (SD 2.5), respectively. Weather sensitivity was reported by 74% of participants.

Mean daily utilization was 76% (SD 27) and mean overnight utilization was 34% (SD 33). Weekly therapy was 41 (SD 25) hrs/week. The mean sensation threshold was 14.8 (SD 11.5) mA. The mean stimulation intensity was 6.3 dB (SD 5.5).

The mean change in pain intensity from baseline to follow-up was −0.93 (SD 2.3) for all participants and −1.3 (SD 2.3) for 221 adherent (daily utilization ≥ 80) participants (both different from 0 at p < 0.001). The mean follow-up period was 88 (SD 15) days and the mean number of pain ratings forming the follow-up rating was 11 (SD 13). The multivariable regression model identified 7 statistically significant predictors (R² = 0.28, F(20, 346) = 6.87, p < 0.001). Positive independent predictors of reduced pain intensity were age, baseline pain intensity, daily utilization (−0.16 points per 10% increment) and overnight utilization (−0.12 points per 10% increment). Negative predictors were female gender, herniated disc and constant pain.

The mean change in pain interference with function was −1.2 (SD 2.5) for all participants and −1.8 (SD 2.4) for 219 adherent participants (both different from 0 at p < 0.001). The multivariable regression model identified 8 statistically significant predictors (R² = 0.30, F(20, 342) = 7.40, p < 0.001). Positive independent predictors of reduced pain interference with function were baseline pain interference with sleep, activity and mood, daily utilization (−0.24 points per 10% increment) and overnight utilization (−0.15 points per 10% increment). Negative predictors were baseline pain intensity, herniated disc and constant pain.

Conclusions

The participants in this study were older adults, overweight/obese and had moderate to severe pain with substantial interference with function. Knee pain was not an isolated symptom, as most participants had multi-site chronic pain. There were 4 key findings from this study.

1. Pain intensity and pain interference with function improved following 10-weeks of wearable TENS use. The mean changes were at or above the minimum clinically meaningful level of 1-point. The relative contribution of treatment and non-specific effects cannot be estimated.

2. Utilization was a positive predictor for improvement in both outcomes suggesting that frequency of use may be a modifiable factor for wearable TENS effectiveness in individuals with chronic knee pain. The fact that daily and overnight utilization were independently predictive suggests that treatment during sleep may confer distinct benefits.

3. Self-reported disc herniation was negatively predictive of improvement in both outcomes. It is possible that wearable TENS is less beneficial in individuals with concurrent knee pain and disc pathology.

4. Constant pain throughout the day was negatively predictive of improved pain, suggesting that wearable TENS may be more effective for pain that occurs intermittently during the day.

163 The Social and Functional Implications of High versus Low Dose Opioids on Chronic Non-Cancer Pain

Yohei Denawa¹, Will Kurtz², Till Conerman³

¹Icahn School of Medicine at Mount Sinai, New York, NY, USA, ²Washington University in St Louis, St Louis, Missouri, USA, ³Allegheny Health network, Pittsburgh, PA, USA

Purpose

Chronic non cancer pain (CNCP) is a major health concern. Opioids may be a useful treatment option but their use still remains controversial given the significant risks and epidemic of opioid addiction and abuse. There is limited data on whether opioid therapy is an effective treatment option for chronic non cancer pain. This study was a retrospective cohort study using the Short Form 36 health survey (SF36) to assess both physical and emotional dimensions of health for patients on opioid therapy for CNCP.

Methods

182 patients were recruited at the West Penn Pain Institute outpatient pain clinic. 95 patients were recruited in the low dose opioid group (5–30 MME) while 87 patients were recruited in the high dose opioid group (>90 MME). Each patient filled out the SF-36 survey used to assess both the physical and emotional dimensions of their health. We also analyzed patient’s employment status, reasons for unemployment, pain diagnosis, side effects, and compliance issues through the electronic medical record (EMR).

Results

Mean scores on General Health Perceptions for the low-dose and high-dose opioid groups were 50.3 ± 21.6 and 44.4 ± 21.9, respectively (p = .07). Though not reaching statistical significance, high-dose patients had lower item scores, indicating a perception of poorer health. There were no significant differences between the low-dose and high-dose opioid treatment groups on any of the mean scores from the 8 domains of the SF-36.

There was a statistically significant association between opioid treatment group and working status, non-compliance, and the self-reported number of side effects. Patients treated with high dose opioids had significantly higher rates of unemployment (85%) (66%), (χ2(1) = 8.48, p = .004, odds ratio = 2.89 (95% CI 1.39 to 6.01)). Unemployed patients in the high dose treatment group were more likely to list disability as unemployment while retirement was the most common response in the low dose treatment group. Patients treated with high-dose opioids had significantly higher rates of self-reported side effects (46%) than did low-dose opioid patients (21%), (χ2(1) = 12.02, p = .001, odds ratio = 3.08 (95% CI 1.61 to 5.89)). Patients treated with high-dose opioids had significantly higher rates of noncompliance (49%) than did low-dose opioid patients (33%), (χ2(1) = 4.75, p = .029, odds ratio = 1.94 (95% CI 1.07 to 3.54)).

Conclusions

These data suggest that low-dose and high-dose opioid treatment patients do not have significantly different quality of life outcomes. Future studies that incorporate longitudinal data are necessary to examine the temporal relationship between quality of life and opioid therapy.

164 Side Effect Profile of Oral CBD Capsules in a Pain Management Population, 10 month Data Set.

Julian Grove, Peter Kubitz

Pain Consultants of Arizona, Phoenix, AZ, USA

Purpose

The purpose of this study was to evaluate all patients side effects who have chosen to take oral CBD capsules as a means for pain relief at our pain management center. The vast majority of pain medications that are at the disposal of health care providers that treat pain have potentially significant cognitive effect. Those that do not often have end organ system damage including over the counter pain medications including NSAID (GI and Renal) and Acetaminophen (Liver). Separately, the ripple effects of the opioid crisis have highlighted the behavioral side effects that can ultimately be fatal as well. In light of the multitude of side effects that pain physicians have to evaluate (opioids, neuropathic agents, skeletal muscle relaxants, NSAID), the authors wanted to evaluate a 10 month data set using oral CBD capsules ranging from 12.5 mg per day to 100 mg per day (in BID dosing).

We have seen anecdotal data regarding side effects of tinctures of CBD and wanted to evaluate the side effect profile of oral CBD capsules with a 10 month self-reported data set to evaluate CBD risk and benefit profile to a better degree.

Methods

Patients reported side effects upon follow up on a questionnaire at our pain management clinic. Those that were taking CBD followed up at a 1-3 month interval depending on other medications that they were taking and/or followed up by phone questionnaire.

Side effects for patients that were taking multiple medications were noted and only those side effects where each of the other medications were stable were attributed to the cannabidiol product.

We limited our data set to one type of cannabidiol product (both capsules and cream) to eliminate the wide variability that exists in the cannabidiol landscape.

Results

Overall, we saw a limited number of side effects, all less than 1% of our tested subjects. N = 812

The two cases of Maculopapular rash were seen with the CBD Cream, all other side effects were attributed to the capsules.

Generalized Headache: 4 cases (less than 1%)

Dyspepsia/Bloating/Abdominal Discomfort: 6 cases (less than 1%)

Agitation/Nervousness: 3 cases (less than 1%)

Macular Rash: 2 cases (less then 1%)

Maculopapular Rash: 2 cases (less then 1%)

Conclusions

In the armamentarium of medications for pain, we believe that the side effect profile has been a significant and limiting aspect of many of these treatments. Our supposition for this study is that cannabidiol (CBD) potentially had a more advantageous side effect profile than some of the more traditional medications that are used for pain syndromes including tricyclic antidepressants, anti-epileptics, selective serotonin and norepinephrine reuptake antagonists, NSAIDS, skeletal muscle relaxants and opioids.

The data support the theory that CBD taken routinely carries a low side effect profile, with less than 1% self-reported side effects of a transient nature. This appears to warrant further study into the apparent broad safety profile of CBD. While we have no reason to think there are any prominent end organ system issues regarding cannabidiol, we are currently underway with this further evaluation.

165 Use of a specific type of CBD as a method for opioid reduction in patients on chronic opioid therapy, our experience at a pain management center, 10 month data set.

Julian Grove, Peter Kubitz

Pain Consultants of Arizona, Phoenix, AZ, USA

Purpose

Our initial purpose and objective was to answer the question: can high quality cannabidiol (CBD) be used for chronic pain and supplant some of the more traditional medications we use for pain.

Due to the ongoing opioid crisis, our authors were interested in addressing the potential for CBD to help with opioid reduction given its pain relieving qualities. As all practitioners realize when we take care of patients on acute and chronic opioid therapy, there are potential and real concerns regarding the side effects and behavioral consequences of opioids including severe constipation, cognitive effects, addiction, dependency, respiratory depression and the possibility of overdose to name a few. We were interested in the possibility of a potentially safer alternative with a different and more benign side effect profile. We created a company over two years ago that was dedicated to the medical application of CBD and addressing separate etiologies of pain including, but not limited to, inflammatory pain, nerve pain, and headache.

Specific to this data set, our primary purpose was to use CBD as an option for patients on chronic opioid therapy who were actively interested in reducing their opioids.

Methods

All patients at our pain management center are offered a comprehensive approach for their specific pain management issue. Often, we use comprehensive and complementary therapies in order to decrease or avoid opioid usage and/or to reduce opioids if the particular pain issue has reduced in severity.

For this particular group we offered cannabidiol (CBD) oral capsules ranging from 12.5 mg per day to 100 mg per day (in BID dosing) for patients that were interested in CBD for their pain complaints to see if this would help in their opioid reduction. During the course of the opioid reduction, all other medications they may have been on remained stable including neuropathic, NSAID, and skeletal muscle relaxant. All treatments such as interventional therapies did not deviate from their previous years treatments.

We followed patients for 10 months (July 2018-May 2019). Over the course of the 10 months, we assessed the opioid intake for our patients and the dose, strength and type of CBD that the physician and patient had jointly chosen. For this particular data set, we limited patients to one brand of CBD as we were able to control the purity and variability of CBD. We excluded patients who were not on opioids or who were on opioids less than two weeks as our focus on this study was for chronic pain patients on chronic opioid therapy and did not want to introduce the issue of acute pain resolving on its own. We also eliminated patients who had a definitive therapy that may significantly decrease their pain (such as a total knee arthroplasty for patient with primary osteoarthritis of the knee).

Results

Percentage of Opioid Reduction – Percentage of Patients

  0%              10%

  >10%             14%

  >33%             20%

  >50%             15%

  >66%             22%

  100%             19%

Overall we are showing 76% of patients achieving greater than 33% reduction in their opioid medications, and 56% of patients achieving greater than 50% reduction in their opioid medications.

Conclusions

In our effort to explore cannabidiol (CBD) as a potential and possible treatment for pain at our chronic pain management center, we felt that a robust test of the efficacy of CBD would, in part, involve its application in helping to reduce opioids in a severely debilitated pain population.

In reference to the data, we feel that that pain relieving properties of CBD have significantly helped a refractory pain population that involves many patients who have been on opioids for decades and have maximized all of our traditional non-opioid pharmacotherapy and adjuvant medications.

Despite the limitations of this study, including a regulatory environment that is exerting pressure on patients to reduce their opioids, we feel that this study merits further look at CBD as an alternative treatment for patients trying to wean off opioid medications and more globally as a real and potentially first line treatment for pain complaints.

166 CBD Use at a Pain Management Clinic, Our Experience With CBD as a Mechanism for Polypharmacy Reduction, 10 month data set.

Julian Grove, Peter Kubitz

Pain Consultants of Arizona, Phoenix, AZ, USA

Purpose

One of the main concerns for our multidisciplinary pain clinic are patients who get referred on a less than ideal pharmacotherapy regimen. This is a primary concern for all healthcare providers who deal with complex pain management patients. While the spotlight and narrative on opioids is an enormous concern, of additional concern to pain practitioners is the additive and sometimes synergistic cognitive and CNS depressant side effects of many of the other medications that we prescribe including: tricyclic antidepressants (pain and sleep), skeletal muscle relaxants (pain, muscle spasm and sleep), Anti-epileptics (nerve pain) and selective serotonin reuptake inhibitors (nerve pain). In addition to the concern for CNS depression, we included the use and elimination of NSAIDS in this group as the anti-inflammatory effect of CBD was a genesis for elimination of NSAID users due to side effects. While many of the applications of these medications have worked for their intended purpose, these authors wanted to explore the growing patient use of CBD to ameliorate some of the cognitive effects and side effects of polypharmacy in a pain management patient.

We specifically wanted to explore the patients use of cannabidiol (CBD) and observe which medications, if any, were reduced or eliminated given the patient reported benefits of CBD.

Methods

This was a partially prospective and partially retrospective 10 month data set from July 2018 to May 2019. Patients were followed during this time period and throughout the study elected voluntarily to try cannabidiol (CBD). We excluded tinctures for this study and this was limited to CBD capsules and cream. This was specifically full spectrum CBD cream and capsules with supplementation for inflammation (Turmeric, Ginger, Piperine), nerve pain (alpha lipoic acid, Vitamin B12), headache (coenzyme Q10, Riboflavin, Magnesium), and sleep (Melatonin, Vitamin D).

We looked at the variety of patients who had taken CBD over the course of the data set. Of this group, we looked at the ratio of those that added CBD to their existing pharmacologic regimen. Over the course of the data set we tracked those patients that had a reduction or elimination in their pain medication (NSAID, skeletal muscle relaxer, neuropathic, and opioid) regimen while on their course of CBD.

Results

Overall, during the course of the 10 month data set, we had reductions in each of the subsets of pain medications as well as patients achieving reductions in multiple subsets of pain medications.

Percentage of patients voluntarily reducing their polypharmacy regimen by at least one strength of one medication: 89%

Percentage of patients voluntarily reducing their polypharmacy regimen that eliminated at least one medication with CBD use: 64%

Percentage of patients voluntarily reducing their polypharmacy regimen that reduced at least two strengths of medications with CBD use: 55%

Percentage of patients voluntarily reducing their polypharmacy regimen that eliminated at least two medications with CBD use: 12%

Breakdown of medications that were voluntarily reduced and/or eliminated:

NSAIDS: 64%

Skeletal Muscle Relaxers: 18%

Antiepileptics: 12%

Tricyclic Antidepressants: 4%

SS/SNRI: 8%

Opioids: 61%

**Note that there were patients that were also reducing benzodiazepam use, however our clinic does not prescribe these medications and this reduced our ability to tract this appropriately.**

Conclusions

Polypharmacy is a significant issue for patients as it applies to drug-drug interactions, cognitive delay, additive and potential synergistic side effects. Given the severe consequences of many of the types of pain medications we prescribe, the authors thought that it would be important to evaluate CBD as a means for patients to pursue pain relief, and a treatment with potentially lower side effect profile. The subsequent ability to reduce their pain medication polypharmacy and overall reduce their global side effect profile and potentially improve cognition and other indices is an important step to safer prescribing.

We conclude that the data supports the thesis that cannabidiol (CBD) is a viable treatment that can reduce and supplant traditional medications we use for pain. Given the open ended aspect of this study, we found patients generally using CBD to reduce or supplant NSAID’s and opioids to the greatest degree, and some of the more adjuvant pain medications to a lesser degree. We suspect the patients decision making process was centered on the current medications that were perceived as giving them unpleasant and unwanted side effects or stigma. We feel this study warrants further evaluation related to CBD use in the pain management community.

167 Patient Satisfaction with Chronic Pain Management and Correlations with Treatment in a Pharmacist-Physician Collaborative Care Model Within Primary Care

Michele Matthews^1,2, Alev Atalay²

¹MCPHS University, Boston, MA, USA. ²Brigham and Women’s Hospital, Boston, MA, USA

Purpose

The opioid overdose epidemic within the United States as well as increasing regulatory changes restricting the prescribing of opioids are causing uncertainty about the approaches for chronic pain management. Studies related to chronic pain management mostly focus on reduction in pain severity, rather than important outcomes such as function, well-being, and satisfaction with treatment. Pharmacist-physician collaboration can optimize pain management and minimize risks of treatment. The primary outcome of this study is to determine correlations for patient satisfaction as it relates to expectations of therapy, treatment type, and overall care for patients with chronic non-cancer pain who are managed within a collaborative care model within a large primary care practice.

Methods

A retrospective chart review and patient self-report surveys to identify parameters including demographics, current pain management therapies, and satisfaction ratings (1 – very dissatisfied to 5 – very satisfied) for patients managed within this collaborative care model at Brigham and Women’s Hospital. Inclusion criteria was age ≥ 18 years old, diagnosis of chronic non-cancer pain, and documentation of at least one follow-up visit with the pharmacist within the past 12 months. Correlations related to select demographics, use of opioids, substance use history, and psychiatric history were evaluated to determine indicators of satisfaction. Regression, two tailed t test and ANOVA test were all used in appropriate context to evaluate the relationship between the two variables.

Results

Forty patients met inclusion criteria for the time period analyzed. Twenty seven were females (67.5%) and 13 were males (32.5%). Ages ranged from 26 to 78 years old, with the mean age being 53.4 years old. Over 75% of the patients included had a high school education (n = 31).Ethnicity varied among the group but consisted of 20 Caucasian (50%), 15 African American (37.5%), and 5 Hispanic (12.5%) patients. The most common diagnosis was chronic low back pain. Over half of the patients had a treatment regimen that consisted of one opioid (n = 25). For patients on opioids, the average morphine milligram equivalents (MME) prescribed was 104.85 and the dosing ranged from 8 to 520. No significance difference was found when correlating demographics and patient satisfaction related to treatment regimen as well as overall care. On average, patients were satisfied more so with the care provided by the team in comparison to their expected level of pain relief and treatment plan.

Conclusions

Although the goal of this study was to identify factors that influence patient satisfaction of care, the data collected provides the information necessary to continue advancing medicine in the direction of individualized pain management. It is important to note that there was not a significant correlation between opioid use, MME, and patient perception of care. Therefore, within this population, the use of an opioid or the dose of prescribed had no influence on patient satisfaction with their treatment regimen. This suggests that although patients with severe pain may receive higher doses of chronically prescribed medications, their satisfaction with their therapy cannot be easily predicted by looking solely at opioid use and MME. This aids in better understanding this patient population and further emphasizes the need for individualized care as a group generalization cannot be made at this time. Although there were no statistically significant correlations found in this study, the information provided should still be considered timely and relevant. The results from this study may be used to support expansion of pharmacist integration into primary care to assist with the management of chronic pain, especially for patients who are on or are being considered for opioid therapy.

168 A Challenging Case of Sciatica and the Value of Dynamic EMG

Maryam Hosseini¹, Loren Fishman²

¹Montefiore Medical Center, Bronx, NY, USA, ²Columbia University, New York, NY, USA

Purpose

A 54-year-old man presented with severe bilateral sciatica. MRI revealed Grade I-II anterolisthesis and disc herniation (HNP) at L4 – L5. Conventional electrodiagnostic testing (EMG) demonstrated L4-5 and L5-S1 radiculopathy.

It was unclear whether spondylolisthesis, HNP or stenosis was the predominant pain generator, making it difficult to select optimal treatment. EMG did not relate symptoms to a specific pathology. We supplemented conventional EMG with dynamic testing of the posterior tibial and peroneal H reflexes in lumbar extension. Based upon findings the subject was treated for spinal stenosis (LSS) with exercise in flexion.

Methods

On the more symptomatic right side posterior tibial and peroneal H reflex values increased after 3 minutes in lumbar extension from 31.5 to 33 milliseconds (ms) and 28.6 to 30.0 ms respectively. On the less symptomatic side latencies increased from 30.7 to 32.1 ms and from 27.5 to 28.6 ms. The subject improved by 70% in pain and by 40% in strength after 6 weeks of flexion bias exercise.

Results

Flexion bias exercises are beneficial for LSS and extension bias exercise can be problematic as stenosis increases with bulging of the ligamentum flavum. Cadaveric studies demonstrate 63% narrowing of the spinal canal in extension.

Dynamic EMG with LSS has demonstrated soleus H-reflex latency prolongation after walk-loading subjects. We selected three minutes in extension as prior study by the examiner suggested that for LSS subjects there is at least a one millisecond prolongation of latency after 2.5 minutes in extension. We compared H-reflex latencies in neutral position with those following three minutes of lumbar extension.

Conclusions

Identifying the primary pain generator is important in selecting the most appropriate treatment. Dynamic electrodiagnostic studies can help optimize outcomes in patients with LSS by increasing diagnostic specificity.

169 An Analysis of Biomarkers in Chronic Pain Patients

Joshua Gunn¹, Melissa Hill¹, Bradley Cotten¹, Timothy Deer²

¹Ethos Research & Development, Newport, KY, USA, ²Center for Pain Relief, Charleston, WV, USA

Purpose

Due to the subjective nature of current pain assessments, limited efficacy of treatment options and risks associated with opioid abuse and diversion, the need for objective pain biomarkers to assist with chronic pain management has never been greater. The objective of this study was to determine the prevalence of abnormal findings in a population of chronic pain patients utilizing a novel, pain-specific biomarker panel which can reveal underlying, biochemical causes of pain.

Methods

A novel, pain-specific biomarker test panel which evaluates biomarkers of systemic inflammation, oxidative stress, neurotransmitter turnover and micronutrient status was employed to determine the prevalence of abnormal findings in 17,833 patient samples analyzed at a large, national reference laboratory (Ethos Laboratories, Newport KY). Patient biomarker results were considered abnormal if they were outside of the 95% confidence internal reference ranges established using a healthy population of donors who had no history of chronic pain or opioid use.

Results

77% of chronic pain patients exhibited at least one abnormal biomarker result (n=13,765). The most common abnormal biomarker finding was elevated Quinolinic acid which was observed in 29% of patients (n=5107). Elevated Pyroglutamate, indicative of glutathione depletion was observed in 19% of patients (n=3314). Elevated Xanthurenic acid, indicative of Vitamin B6 insufficiency was observed in 17% of patients (3025). Elevated levels of the acrolein metabolite, 3-hydroxypropyl mercapturic acid (3-HPMA) were observed in 21% of patients (n=3667). Elevated Methylmalonic acid (MMA), indicative of a Vitamin B12 deficiency was observed in 10% of patients (n=1827) while abnormally low levels of neurotransmitter metabolites were observed in 8% of patients (n=1456).

Conclusions

A novel biomarker assay which measures objective correlates to the neurobiological processes underlying chronic pain reveals a high prevalence of atypical biochemistry in a population of pain patients. Abnormal biomarker findings presented here provide objective support for the role of cytokine mediated inflammation, oxidative stress, abnormally low production of neurotransmitters and micronutrient deficiencies in the development or worsening of chronic pain. This unique panel of functional pain biomarkers provides practitioners with novel, objective insight into the underlying causes of pain which will pave the way for truly personalized pain medicine. The importance of these findings cannot be overstated as each abnormal biomarker finding represents a possible underlying cause of pain. Correcting abnormal biomarker findings with targeted, non-opioid therapies to improve patient function and alleviate pain would lessen the opioid burden and drastically reduce healthcare costs.

170 Using Comfort Menu to Impact Pain Experience

Chona Melvin^1,2, Ahlam Jadalla³, Joy Goebel³

¹Cedars-Sinai Medical Center, los angeles, CA, USA, ²Southern California DNP Consortium Program, Fullerton, CA, USA, ³California State University Long Beach, Long Beach, CA, USA

Purpose

The purpose of this Quality Improvement project was to improve patients’ pain experience as measured by pain indicators and LOS in post surgical spine patients through the development, implementation, and evaluation of a comfort menu of non-pharmacological interventions (NPIs).

Methods

A quality improvement (QI) project was implemented at a spine surgical unit from July 16 to September 16, 2018. The comfort menu contained the following 6 NPIs: acupuncture, pet therapy, hot/cold therapy, virtual reality, music therapy, and reiki/meditation. Postintervention assessment of pain scores and documentation of opioid consumption through the hospital’s electronic medical record (EMR) was performed by nursing staff as part of standard of care.

Results

All pain indicators and LOS improved post-comfort-menu implementation. The aggregate mean Numerical Rating Scale (NRS) pain level decreased from 7/10 (baseline sample) to 6/10 (postimplementation sample), which was a percent change of 14.3%. Also, the aggregate mean net opioid consumption from Morphine Equivalent Daily Dose (MEDD_n) decreased from 78.10 mg/day (baseline sample) to 48.53 mg/day (postimplementation sample), which was a percent change of 37.9%. Additionally, HCAHPS pain satisfaction score increased from 71.1% (baseline sample) to 100% (postimplementation sample), which was a percent change of 40.6%. Lastly, LOS decreased from 6.56 days (baseline sample) to 3.67 days (postimplementation sample), which was a percent change of 44.1%.

Conclusions

The implementation of the comfort menu not only improved spinal surgery patients’ pain experience as evidence by an improvement of pain indicators and LOS, it also conformed to The Joint Commission (TJC) 2018 revised pain management requirements. Thus, it is safe to say that the comfort menu of NPIs can be utilized as adjuvant alternative therapy in treating surgical spine pain.

However, a longer project timeline, and in a different patient population may be needed to provide a stronger evidence of efficacy. Also, because of accessibility issues, initiatives should be proposed for making NPIs more accessible to patients. It is hoped that by providing patients tools to reduce their pain and by including them in choosing the type of pain management treatments, patients may feel more empowered to utilize these NPIs to reduce their pain beyond their hospital stay.