PAINWeek Abstract Book 2016

1 Outcomes Associated with a Workers Compensation Population who participated in a Functional Restoration Program

Michelle Zenda, Mark Johnson, Peter Abaci

Bay Area Pain and Wellness Center, Los Gatos, CA, USA

Purpose

Historically, opioid medication has been the treatment of choice for chronic pain conditions. Long-term use of these medications result in a fall-out of symptoms including medication dependency, constipation, decline of physical abilities, cognitive impairment, and psychological sequelae, all of which perpetuate the problem. While, preventing a patient from progressing to a chronic or worsening condition is warranted, identifying symptoms and subjective information to assist health care providers in developing an alternative choice of treatment is more ideal. Given the current common practice of administering opioids to manage pain, and the growing awareness that opioids are contra-indicated for long term chronic pain management, there is a need to increase knowledge and competency in alternative interventions. Greater competency is needed to address the psychosocial sequelae that is often comorbid with chronic pain. There is a need for a model of pain management that addresses fear of movement/pain and the necessity for movement in functional restoration.

Method

Pre- and post-assessment data was collected over an 18-month period from 160 patients who completed a six-week interdisciplinary program focused on functional restoration. Psychological measures included: Patient Health Questionnaire (PHQ-9) [Depression measure], GAD-7 [Anxiety measure], Brief Pain Inventory [Pain Intensity and Pain Interference Measures] (BPI), and the Chronic Pain Coping Inventory [Illness vs. Wellness Focused Coping] (CPCI).

Results

Paired samples statistics of pre-post mean score changes revealed that there was statistically significant improvement on all metrics except for the “pacing” and “seeking social support” behaviors in the CPCI inventory.

Conclusions

An interdisciplinary functional restoration program is an effective model of pain management. Patients demonstrated improved physical functioning including walking, strength, reduced fear of movement, reduced disability, improved ADL function; as well as reductions in anxiety, depression, pain intensity, pain interference; as well as decreased illness-focused coping behaviors and increased wellness-focused coping behaviors.

2 Pediatric Patient, Parent, and Nurse Perceptions of Satisfaction with Pain Management

Alexandra Adams, Lauren Moore, Carol Tringali

Penn State College of Medicine, Hershey, Pennsylvania, USA

Purpose

This study examines congruence of perceived pain control and perceived satisfaction with pain management between three vital team members of pediatric patient care: the parent/guardian, patient, and nurse.

Method

A survey adapted from Bozimowski (2012) assessed perceived pain control and satisfaction with pain management. It was administered to patient, parent, and nurse triads and analyzed for differences among group members. Eligible patients were 10-18 years of age, admitted to general medical-surgical level of care for at least 24 hours at Penn State Health Children’s Hospital, were experiencing pain, and had a parent/guardian present. Participants needed to speak and read English. Triad questionnaires were completed at the same point in time.

Results

Thirty-one triads completed surveys. Mean patient age was 14.2 years and included 19 females, 11 males, and one unspecified gender. Based on paired t-tests, nurses perceived patients to have significantly lower pain scores by 0.96 points out of 10 (p=0.01). Patients and parents did not score pain differently (p=0.69). In addition, parents rated overall satisfaction higher by 0.43 out of 5 than nurses perceived (p=0.02). Patients gave higher satisfaction scores by 0.35 out of 5 than nurses; however, these results were not significant (p=0.12).

Conclusions

In this small sample, nurses underestimated perceived pain compared to patient pain scores. Patients and nurses did not differ in perceived satisfaction with pain management, although parents gave higher scores than nurses. Nurse underestimation of pain control did not impact satisfaction with the care received. These trends should be explored in larger studies.

3 Bioequivalence of Cyclobenzaprine Hydrochloride Extended-Release Capsule When Taken Intact or Sprinkled Over Applesauce

Liat Adar¹, William Zarycranski², Laura Rabinovich-Guilatt³, Jill B. Conner⁴, Jeffrey Dragone³, Lindsay Janka⁵, Michael Tillinger³

¹Teva Pharmaceuticals, Netanya, Israel, ²Teva Pharmaceuticals, North Wales, PA, USA, ³Teva Pharmaceuticals, Frazer, PA, USA, ⁴Teva Pharmaceuticals, Overland Park, KS, USA, ⁵Teva Pharmaceuticals, West Chester, PA, USA

Purpose

Swallowing pills is difficult for up to 40% of the US population (Size, Shape, and Other Physical Attributes of Generic Tablets and Capsules, Food and Drug Administration [FDA] Guidance, June 2015). This can lead to noncompliance with pain medication regimens and a lack of pain control. Inappropriately altering or manipulating tablets or capsules to ease swallowing can cause multiple problems, such as underdosing, overdosing, or dose dumping (Argoff et al. Curr Med Res Opin. 2014). Manipulation of extended-release (ER) formulations may enhance these problems. Cyclobenzaprine hydrochloride ER capsule (AMRIX®; Teva Pharmaceuticals USA, Inc.) is a once-daily muscle relaxant indicated for adjunct care secondary to rest and physical therapy for muscle spasms associated with acute, painful musculoskeletal conditions. The purpose of this study was to assess the pharmacokinetics and safety of cyclobenzaprine ER 30-mg capsule in healthy subjects after sprinkling the capsule contents over applesauce, compared with ingesting an intact 30-mg capsule, in accordance with FDA guidance (Food-Effect Bioavailability and Fed Bioequivalence Studies, FDA Guidance, December 2002).

Method

This single-center, open-label, single-dose, 2-way crossover study randomized 32 healthy subjects to 1 of 2 sequence groups: AB or BA (A=intact cyclobenzaprine ER 30-mg capsule; B=cyclobenzaprine ER 30-mg capsule contents sprinkled over a tablespoon [15 mL] of applesauce). The doses were separated by a washout period of ≥14 days to prevent any carryover effect of the study drug between treatment periods. Calculated pharmacokinetic parameters included maximum observed plasma drug concentration (C_max), time to maximum observed plasma drug concentration (T_max), time to first quantifiable plasma drug concentration (t_lag), area under the plasma drug concentration-time curve from time 0 extrapolated to infinity (AUC_0-∞), and area under the plasma drug concentration-time curve from time 0 to the time of the last measurable drug concentration (AUC_0-t). Bioequivalence was to be concluded if the 90% confidence interval (CI) of the geometric least squares (LS) mean ratios of log-transformed C_max, AUC_0-t, and AUC_0-∞ of the sprinkled dose to the intact capsule were within a range of 80.00%-125.00%. Safety assessments included adverse events (AEs) and change from baseline in clinical laboratory values.

Results

A total of 32 subjects were enrolled in the study and all were evaluable for pharmacokinetics and safety; 1 subject did not return for the follow-up visit. Mean plasma concentration vs. time curves were similar when cyclobenzaprine ER was administered either intact or with the capsule contents sprinkled over applesauce. Bioequivalence between treatments was demonstrated, as measures of exposure (C_max, AUC_0-t, and AUC_0-∞) were contained within the predefined 90% CI bioequivalence bounds of 80.00%-125.00% (C_max: 91.96%-100.76%; AUC_0-t: 96.18%-103.50%; and AUC_0-∞: 95.70%-103.07%). The mean T_max was not significantly different between the intact ER capsule and the ER capsule contents sprinkled over applesauce (P>0.05). Mean t_lag values were the same for both treatments (1 hour). Overall, 4 subjects each reported 1 AE during the study. All reported AEs were mild, and all resolved by the end of the study. No clinically meaningful trends in mean changes from baseline were observed in any clinical laboratory result.

Conclusions

This study demonstrated that cyclobenzaprine ER capsules can be administered sprinkled over applesauce without any expected impact on the efficacy or safety profile. Based on these results, the product’s package insert was revised to allow cyclobenzaprine ER capsule contents to be administered sprinkled on a tablespoon of applesauce and swallowed immediately without chewing (AMRIX Prescribing Information, May 2016). This option offers patients with musculoskeletal pain who have difficulty swallowing capsules an alternative method of administration.

4 An Evaluation of the FDA-Recommended Abuse Potential Questions in Chronic Pain Patients Without a History of Recreational Opioid Use

AC Palsgrove¹, JC Cole², B Trivedi², T Alfieri³, TJ Mayne³

¹PPD, Inc, Rockville, MD, USA, ²PPD, Inc, San Diego, CA, USA, ³Purdue Pharma L.P., Stamford, CT, USA

Purpose

The FDA Guidance for the Assessment of Abuse Potential of drugs requires that abuse potential be assessed in subjects who are “recreational users” and able to “discriminate the effects of the positive control from the placebo.” (1) This is normally accomplished using 20mg IV morphine versus saline. Subjects who qualify are subsequently administered the target opioid and asked three key questions: 1) “How high do you feel?”; 2) “Do you like this drug?”; 3) “How much would you like to take this drug again?” Positive responses are deemed to indicate abuse potential. While abuse potential in recreational users is important information, opioids are labeled for the treatment of pain, and long-acting opioids to treat chronic pain. It would advance pain medicine to understand abuse potential in chronic pain patients who are not recreational opioid users, i.e., the drug’s target population. However, questions on “liking” and desire to “take again” are confounded in pain patients, as they may like and desire the drug for pain relief, and not for euphoric effects. The goal of this study was to conduct cognitive debriefing interviews with chronic pain patients who are not recreational opioid users, testing both the original questions and modified versions of the questions, separating “liking” and desire to “take again” by “pain relief” vs. “other ways the drug makes you feel.”

Method

Adults (≥18 years) confirmed to have been prescribed an opioid ≥30 days to ≤180 days and without a history of opioid abuse were recruited from pain clinics in the east Atlanta area. An IRB-approved protocol guided qualitative data collection and analysis. Structured, one-on-one, audio-recorded interviews with eligible participants were conducted by an experienced qualitative researcher utilizing cognitive debriefing methodology. In addition to the originally worded questions on “euphoria”, “liking” and “desire to take again”, we added two new questions each on “liking” and “desire to take again.” These were: “My liking for this drug due to pain relief is?”; “Excluding pain relief, my liking for this drug is?”; “I would like to take this drug again for its pain relief…?”; “Excluding pain relief, I would like to take this drug again…?” Participant responses were provided on a visual analog scale (VAS), tracked and coded to evaluate clarity, understandability, appropriateness, and validity of concepts.

Results

Thirty participants meeting the study inclusion criteria completed cognitive debriefing interviews. Demographic characteristics of participants were as follows: 46.0 years average age; 22 female, 8 male; 26 African-American, 3 White, 1 Hispanic; and 2.9 months average time on a prescribed opioid. Interview participants were prescribed: Lortab (n=12), Percocet (n=6), hydrocodone (n=5), Vicodin (n=4), oxycodone (n=2), and Dilaudid (n=1). Participants responded positively to the “drug liking” items that were separated into “due to pain relief” and “excluding pain relief”, and rated the “due to pain relief” and “excluding pain relief” items on the positive and negative sides of the VAS, respectively. Patients reported that separating the “liking” and “take again” questions improved their understanding of the question. Additionally, participants were able to define “I am feeling high” in a consistent manner, using phrases such as “euphoria”, “drunk”, “a different state of mind”, “numb”, and “altered”. A second set of confirmatory interviews is being conducted.

Conclusions

Cognitive debriefing interviews with chronic pain patients recently prescribed opioids and without a history of abuse demonstrate that: 1) these patients readily understand what “high” means; 2) the concepts of “drug liking” and “desire to take again” are improved when they are apportioned by “pain relief” and “other effects.” Studies of abuse potential in non-recreational users should use these revised questions or risk contaminating the assessment by confounding pain relief effects with euphoria and other non-therapeutic or hedonic effects. In general, we suggest that researchers carefully examine all instruments designed for abusers when they are applied to pain patients.

5 Immersion in Cardboard VR Compared to an Oculus Rift for Playing a Pain Management Game

Ashfaq Amin, Diane Gromala

Simon Fraser University, Surrey, Canada

Purpose

Virtual Reality (VR) has been demonstrated as a successful method for mitigating pain in numerous though small research studies in health research applications. VR simulation, typically designed as a game, can help distract patients from their physical pain and reduces their perceived pain as well as related anxiety. With the proliferation of mobile technologies in the last decade, it is important to research the potential of Mobile Virtual Reality in this same context. To understand the potential of low-cost Mobile VR, the study, described in this article, aims at finding the difference in levels of immersion between a Cardboard VR and a traditional Head-mounted Display (HMD)–the Oculus Rift DK2. Compared to higher-end VR devices like Oculus Rift, the cardboard is significantly less expensive, therefore, has the potential for mass consumer use. It relies on a user’s smartphone, which the user inserts into the cardboard viewer. The authors are interested in the potential use of Cardboard VR as means to a more accessible pain management, which, the patients will be able to use themselves with their smartphones at a more affordable cost. In order to find out Cardboard VR’s effectiveness in pain management it is important to study its level of immersion first. That is why this study is important to understand the immersion level the Cardboard is capable of providing compared to a traditional HMD.

Method

The study was a between-subjects comparison of immersion across three platforms - Cardboard VR, Oculus Rift and a desktop display. There were three groups of participants-the experimental group used Cardboard VR, control group-1 used the Oculus Rift and, control group-2 used the desktop display. Participants played Cryoblast, a game designed for pain-management, on their respective display for 10-15 minutes. Thereafter, the participant filled out the Immersive Experience Questionnaire based on the experience of playing the game. Built in Unity3D, Cryoblast is a First Person Shooter (FPS) 3D-VR game. The player needs to shoot at “enemy” characters, which were designed as metaphors for the biological process of pain. The ammunition is a metaphor for pain drugs. The idea is to shoot drugs at the agitated characters to calm them down. The player also has to collect as many coins as possible. 30 participants, aged between 22-19, were randomly assigned to one of the three groups. All participants had previous experiences of playing games on smartphones. For the experimental group, a Google LG Nexus 5 smartphone and a Dodocase Virtual Reality Kit 1.2, a standard version-1 of Cardboard VR commercially manufactured and sold by Dodocase, was used. An elastic head strap, attachable to the Cardboard viewer with Velcro, was used for head mounting. For the control groups, Oculus Rift Development Kit 2 (DK2) and an Alienware desktop PC was used. The desktop PC had an Acer GD235Hz HDMI LCD display. All the three groups for sound used full Size Headphones.

Results

Immersion in the different displays was analyzed using one-way between-subjects ANOVA. The analysis revealed a significant effect of immersion for the three different displays at p<0.05 [F(2, 27)=8.7824, p=0.0012]. Post hoc analysis using the Tukey HSD indicated the mean scores for the Oculus Rift (M = 115.5, SD = 18.08) and the Cardboard VR (M = 109, SD = 21.48) were significantly different than that of the Desktop display (M = 85.6, SD = 7.51). However, the Cardboard VR did not significantly differ from the Oculus Rift (p = 0.6658) in this study. The results indicate that the Cardboard VR, despite its simplicity and small screen size, is capable of providing an acceptable level of immersion compared to Oculus Rift’s larger screen size.

Conclusions

Cardboard VR works as a more accessible albeit new kind of virtual reality gaming platform. It has the potential to grow a large consumer base because of its affordable cost. More importantly, it can potentially be used for the large numbers of patients who might use it to alleviate their pain. The simplicity of Cardboard VR, if coupled with a carefully designed pain management game, can ensure the ease of use for chronic pain patients. For this reason, the next phase of the study aims at finding if and how Cardboard VR may be effectively used for pain management.

6 Efficacy and safety of naldemedine for the treatment of opioid-induced constipation in subjects with chronic non-cancer pain receiving opioid therapy: Results from two Phase 3 clinical trials

Martin Hale¹, James Wild², Jyotsna Reddy³, Tadaaki Yamada³, Juan Camilo Arjona Ferreira³

¹Gold Coast Research, L.L.C., Plantation, FL, USA, ²Upstate Clinical Research Associates, Williamsville, NY, USA, ³Shionogi Inc., Florham Park, NJ, USA

Purpose

Opioids effectively treat pain but their use is limited by side effects, including opioid-induced constipation (OIC). Naldemedine is an oral, peripherally-acting µ-opioid receptor antagonist that is being evaluated for the treatment of OIC. We discuss 2 identically designed Phase 3, double-blind, randomized, placebo-controlled 12-week studies that evaluated the efficacy and safety of naldemedine.

Method

In both studies, subjects 18 to 80 years of age, with chronic non-cancer pain and OIC, taking opioids for ≥3 months and on a stable regimen of ≥30-mg morphine-equivalent for ≥1 month, not on laxatives, who had ≤4 spontaneous bowel movements (SBMs) in a 14-day qualifying period and ≤3 SBMs/week in any given week of that qualifying period, with symptoms of OIC in ≥25% of bowel movements, and meeting all other eligibility criteria, were randomized (1:1) to receive naldemedine 0.2 mg taken orally once daily or matching placebo for 12 weeks. The primary objective was to evaluate the efficacy of naldemedine versus placebo as assessed by the proportion of responders. A responder was defined as a subject who had ≥9 positive-response weeks (PRWs) out of the 12 weeks and 3 PRWs out of the last 4 weeks of the 12-week treatment period. A PRW was defined as a week with ≥3 SBMs and an increase of ≥1 SBM/week from Baseline. Key secondary objectives assessed the change from Baseline to Week 1 in the frequency of SBMs/week, and changes from Baseline to the last 2 weeks in the frequency of SBMs/week, complete SBMs/week, and SBMs/week without straining. The safety and tolerability of naldemedine was also assessed. Studies were approved by an Institutional Review Board prior to randomization of subjects, and conducted in accordance with Good Clinical Practice guidelines (ClinicalTrials.gov identifiers: NCT01965158, NCT01993940).

Results

In study 1 (COMPOSE-1), 547 subjects were randomized (naldemedine, 274; placebo, 273), and in study 2 (COMPOSE-2), 553 subjects were randomized (naldemedine, 277; placebo, 276). In both studies, there was a significantly greater proportion of responders with naldemedine compared with placebo (COMPOSE-1: 47.6% vs 34.6%, respectively, P=0.002; COMPOSE-2: 52.5% vs 33.6%, P<0.0001). A significantly greater increase in the frequency of SBMs/week from Baseline to Week 1 was observed with naldemedine compared with placebo (P<0.0001 in both studies), and this difference remained generally stable between the 2 groups throughout the 12-week study period. The naldemedine group also showed greater increases from Baseline to the last 2 weeks of the study period in the frequency of complete SBMs and the frequency of SBMs without straining, compared with the placebo group. Summary measures of treatment-emergent adverse events (TEAEs) were generally similar between the naldemedine and placebo groups in both studies. The TEAEs reported for >5% of subjects, and at a higher frequency in naldemedine compared with placebo, were abdominal pain and diarrhea. In both studies, treatment with naldemedine was not associated with signs or symptoms of opioid withdrawal, and the analgesic effect of opioids was not affected.

Conclusions

Results from these 2 identically designed Phase 3 studies demonstrated a consistent efficacy and safety profile of naldemedine as a treatment for OIC in subjects with chronic non-cancer pain. Naldemedine treatment resulted in a significantly greater proportion of responders compared with placebo, with improvement in the frequency of SBMs/week observed at Week 1 that was sustained throughout the 12-week treatment period. Naldemedine was generally well tolerated in both studies.

7 Long-term safety and efficacy of naldemedine for the treatment of opioid-induced constipation in subjects with chronic non-cancer pain receiving opioid therapy: Results from a 52-week Phase 3 clinical trial

Lynn Webster¹, Srinivas Nalamachu², Tadaaki Yamada³, Jyotsna Reddy³, Yuko Baba³, Juan Camilo Arjona Ferreira³

¹PRA Health Sciences, Salt Lake City, UT, USA, ²International Clinical Research Institute, Overland Park, KS, USA, ³Shionogi Inc., Florham Park, NJ, USA

Purpose

Opioids can be effective for treating chronic pain in select patients; however, their use is associated with multiple side effects, including opioid-induced constipation (OIC). Naldemedine is an oral, peripherally-acting µ-opioid receptor antagonist that is being evaluated for the treatment of OIC. This is a report of a Phase 3, multicenter, randomized, double-blind, placebo-controlled study (COMPOSE-3) that evaluated the long-term safety and efficacy of naldemedine for 52-weeks.

Method

Subjects 18 to 80 years of age, with chronic non-cancer pain for ≥3 months, taking opioids, with self-reported OIC, and on a stable regimen of ≥30-mg morphine-equivalent for ≥1 month, who may or may not have been on laxatives, were randomized (1:1) to receive naldemedine 0.2 mg taken orally once daily or matching placebo for 52 weeks. Further, subjects were included only if they had ≤4 spontaneous bowel movements (SBMs) in a 14-day qualifying period and ≤3 SBMs/week in any given week of that qualifying period, in addition to meeting all other eligibility criteria. The primary objective was to evaluate the long-term safety and tolerability of naldemedine compared with placebo. The primary analysis population was the safety population, defined as randomized subjects who took at least one dose of study drug. Secondary endpoints evaluated the efficacy of naldemedine compared with placebo as assessed by the frequency of BMs/week over time, effect on opiate withdrawal scales, and effect on opiate-mediated analgesia. This study was approved by an Institutional Review Board prior to randomization of subjects, and conducted in accordance with Good Clinical Practice guidelines (ClinicalTrials.gov identifier: NCT01965652).

Results

After 52 weeks of treatment, naldemedine was generally well tolerated. The safety population included 620 subjects in each treatment group. Comparable treatment-emergent adverse events (TEAEs) were reported for both the naldemedine and placebo groups-68.4% versus 72.1%, respectively. Other summary measures of adverse experiences were also reported, with a similar frequency in both treatment groups. Treatment-emergent adverse events that were reported for >5% of subjects, and at a higher frequency in naldemedine compared with placebo, were abdominal pain (8.2% vs 3.1%, respectively), diarrhea (11% vs 5.3%, respectively), and vomiting (6.0% vs 3.1%, respectively). Treatment with naldemedine was not associated with signs or symptoms of opioid withdrawal, as assessed by the subjective opioid withdrawal scale and the clinical opioid withdrawal scale. Further, the analgesic effect of opioids was not affected, as assessed by the numerical rating scale. Treatment with naldemedine for 52 weeks was associated with greater improvements from baseline in the frequency of BMs/week compared with placebo, and were statistically significant at Weeks 12, 24, 36, and 52 (nominal P≤0.0001).

Conclusions

In this 52-week Phase 3 study, in subjects with OIC and chronic non-cancer pain, treatment with naldemedine was generally well tolerated, with an incidence of TEAEs similar to placebo. Gastrointestinal TEAEs were more frequently reported with naldemedine than with placebo, which is expected, given the mechanism of action of naldemedine. Naldemedine was not associated with opioid withdrawal and did not alter the analgesic effect of opioids-in-line with a peripheral-only mechanism of action. Treatment with naldemedine resulted in a significantly greater improvement from baseline in the frequency of BMs than placebo that was durable over the 52-week period.

8 Results of a phase 1, open-label study evaluating the pharmacokinetics of gabapentin administered as gabapentin immediate release, gabapentin gastric retentive, and gabapentin enacarbil in healthy adult subjects

Gerald Aronoff¹, Joseph Shurman², Dennis Swearingen³, Richard Kim⁴, Praveena Raman⁴, Ritu Lal⁴

¹Carolina Pain Associates PA, Charlotte, NC, USA, ²Scripps Memorial Hospital, La Jolla, CA, USA, ³Celerion, Tempe, AZ, USA, ⁴XenoPort Inc., Santa Clara, CA, USA

Purpose

Gabapentinoids are 3-substituted derivatives of the neurotransmitter γ-aminobutyric acid (GABA). They selectively block the calcium channels on the dorsal root ganglion; these channels are voltage dependent and contain the α2δ1 subunit. Gabapentinoids stabilize neurogenic electrical activity, thereby reducing neuropathic pain. Gabapentin immediate release (GBP-IR), gabapentin gastric retentive (GBP-GR), and the prodrug gabapentin enacarbil (GEn) are approved for the management of postherpetic neuralgia (PHN) in adults, which is an intensely painful complication of herpes zoster. In many instances, PHN resolves over time, but there is no known cure. When left untreated, the circadian pattern of PHN is such that the intensity tends to increase throughout the day, peaking at approximately 8:00 PM.

Despite the common classification, these three gabapentinoids are not interchangeable. There are variations in dosing and pharmacokinetic (PK) parameters such as absorption, bioavailability, Tmax, Cmax, and steady state. PK profiles are important in determining individualized treatment plans, as a key objective in pain management is to provide treatment that acts quickly and consistently. Although each drug’s PK profile has been characterized previously, here we present the first direct comparison of all three gabapentinoids using consistent dosing and standardized meals.

Method

This open-label, single-sequence study investigated steady-state PK of GBP-IR 600 mg TID, GBP-GR 1800 mg QD, and GEn 600 mg BID in healthy adults. The study consisted of a 3-day lead-in period, with subjects initially receiving GBP-IR 600 mg capsules QD, which was escalated to TID by the third day. This was followed by 5 days of treatment with GBP IR TID, then 5 days with GBP GR QD, then GEn BID. The final phase was a 7-day taper period during which subjects received 600 mg GEn QD. There was no washout between treatment periods as PK assessments for GBP GR and GEn were conducted ≥7 half-lives (~5-7 hours) after the last dose of the previous treatment; thus, any carryover effect was negligible.

Results

Fourteen healthy adults, including 7 men and 7 women (13 white [9 Hispanic/Latino], 1 black/African American), received all scheduled doses and completed the study. The subjects had a mean age of 46.8 years [SD 7.60], and mean BMI of 26.69 kg/m2 [SD 1.73]. Prior to dose normalization, the area under the curve (AUC) was 29% higher for GBP-GR than GEn, and Cmax for GBP-GR was 56% higher than GEn. Following dose normalization (GEn 1200 mg contains 626 mg gabapentin), AUC0-24 (ng*hr/mL) ±SD was 129.0±23.2 for GEn, 91.0±17.8 for GBP-IR, and 58.4±13.9 for GBP-GR. Plasma gabapentin peak-to-trough concentration ratio was lower for GEn (1.46±0.40) than for GBP-IR (2.36±0.60) or GBP-GR (6.32±2.12). Plasma gabapentin peak-to-Cmin and peak to-trough concentration ratios and percent fluctuation were approximately 2-4 times higher with GBP-GR than with GEn.

Plasma gabapentin concentration-time profiles were analyzed over 24 hours following multiple-dose administration of GBP-IR 600 mg TID, GBP-GR 1800 mg QD, and GEn 600 mg BID. GEn demonstrated the most consistent levels, with sustained plasma gabapentin levels observed throughout, particularly at the end of the 24-hour period; median Tmax was documented at 18.5 hours. For GBP-GR, a single peak was observed at 7 hours post-dose, followed by a steady decline in concentration. For GBP-IR, there were three distinct peaks at hours 3, 9, and 16 (median Tmax). Plasma gabapentin peak to-trough concentration ratio and percent fluctuation were approximately 4-fold higher following GBP-GR vs GEn.

The most frequently reported treatment-emergent adverse events across treatment groups were headache (3 subjects, 21%) and somnolence (3 subjects, 21%). No safety concerns were observed in clinical laboratory, vital signs, or Columbia Suicide Severity Rating Scale assessments.

Conclusions

GEn provided stable, sustained gabapentin exposure throughout the day with the lowest peak-to-trough ratio and the highest bioavailability of the three gabapentinoids. Considering the importance of PK properties in in personalizing treatment, as well as the circadian nature of PHN pain, these data suggest GEn potentially provides optimal pain management compared with GBP-IR and GBP-GR.

9 Methadone prescribing patterns for pain at an academic health system

Gene H. Hur¹, Parisa Karimian¹, Kathy Hollenback¹, Kyle Edmonds², Rabia Atayee^1,2

¹UC San Diego Skaggs School of Pharmacy, La Jolla, California, USA, ²Doris A. Howell Palliative Medicine Program at UC San Diego Health, La Jolla, California, USA

Purpose

Methadone, a long-acting synthetic m-opioid agonist, is most widely known for pharmacological treatment of opioid addiction. Due to its low cost and unique pharmacokinetic and pharmacodynamics properties, methadone has gained considerable interest in the management of chronic pain. Unlike other opioids, methadone acts on two different receptors. It consists of a racemic mixture, an l-isomer that activates the m receptor and the d-isomer, which inhibits the N-methyl-D-aspartate (NMDA) receptor. This dual mechanism of action gives methadone a distinct advantageous option as an analgesic for both neuropathic and nociceptive pain.

Despite its benefits, methadone’s pharmacology raises concern for serious and life-threatening side effects. As a result of its variable elimination half-life of 12-150 hours, potential to prolong correct QT interval, increased risk of harmful drug interactions patients may be at higher risk of morbidity and mortality. Consequently, providers should be aware of appropriate dosing and monitoring. The purpose of this study is to identify inpatient methadone prescribing patterns and monitoring considerations of methadone in an effort to create a guideline for safer practice.

Method

University of California, San Diego Human Research Protections Program granted institutional review board approval. This retrospective data analysis evaluated adult hospitalized patients who received oral methadone during their hospitalization from January 1, 2013 to January 1, 2015 at a two-hospital single academic health system. Patients were further stratified for methadone new start for pain management. Patient demographics such as age, ethnicity, race, primary diagnosis and indication for methadone were collected for all patients who received oral methadone during hospitalization. Additional data was collected for patients that were initiated on methadone during the hospital stay. They included prior opioid therapy, medical services, hospital length of stay (LOS), discharge plan for methadone. Clinical considerations of QTc, electrolyte, drug interaction monitoring were also collected. Statistical analyses that were performed included Chi-square, Fisher exact, analysis of variance, Kruskal-Wallis, and odds ratio with 95% confidence interval as appropriate and listed in below.

Results

Of the 387 patients who received methadone, 103 were new starts and 100 of those patients continued on methadone long enough for data analysis. Three patients were excluded because they expired unrelated to methadone and data were incomplete. Of the 100 new starts, the average age was 45 and there were more men than woman (43% were women and 57% men). Most were non-cancer (60%) with unspecified pain (50%). The majority of methadone were initiated by medicine service (37%), followed by burn service (27%), and trauma (10%). Forty-two percent of the patients were being followed by the palliative care team, primarily for the medicine patients (80%). The most common opioid prior to methadone new start was hydromorphone (n=67, 67%). Patients on the burn service had significantly higher OME (X2 = 10.6, p=0.01) and longest LOS (X2 37.9, p=0.0001). Patients on medicine service were significantly more likely to have an outpatient discharge plan for methadone starts in the hospital (OR= 3.7, CI: 1.4,9.7). Only 45% of patients had an EKG checked 7 days prior to methadone start and 37% of those have a measured QTc of greater than 450 msec. Electrolytes (potassium and magnesium) were not consistently checked and for those who did have lab values in the 24 hours prior, 14/93 (15.1%) had abnormal potassium value and 14/68 (20.5%) had abnormal magnesium value. There was an average of 2.6 severe or major drug interactions per patient related to methadone, with the most common being related to concomitant sedatives and other medications that prolonged the QTc.

Conclusions

In our study the medicine service more likely to provide an outpatient discharge plan for methadone when they consulted palliative care. Patients on the burn service had the longest length of hospital stay after methadone was started. The majority of patients did not have an EKG or monitor liver function and a third did have appropriate electrolytes checked prior to start. There were approximately 2.5 severe drug interactions per patient. Based on our study there was room for improvement in approach to safer methadone prescribing with proposed guidelines involving the pain and palliative care services.

10 Title: Comparison of venlafaxine and duloxetine: measuring clinical impact of time to therapeutic dose (TTD) among patients achieving therapeutic dosing for pain

Kelsie Flynn, Timothy Atkinson, Jennifer Baker

VA Tennessee Valley Healthcare System, Murfreesboro, TN, USA

Purpose

Purpose: Chronic opioid therapy remains controversial, however, there is consensus among treatment guidelines that adjunct medications should be utilized first. A meta-analysis revealed serotonin-norepinephrine reuptake inhibitors (SNRIs) venlafaxine and duloxetine to be equally efficacious in the treatment of neuropathic pain and recommend them as first-line therapy. There are no head-to-head studies, therefore the clinical impact of drug selection in terms of percentage of patients achieving therapeutic dose, TTD, and adverse effect profiles need to be evaluated. The purpose of this study is to evaluate the clinical impact of drug selection as measured by percentage of patients achieving therapeutic dose and time to therapeutic dose for neuropathic pain with either venlafaxine or duloxetine.

Method

Methods: This was a single center, retrospective, observational analysis. New start prescriptions for either venlafaxine or duloxetine between January 1, 2011 and January 1, 2014 were identified. Through data warehouse extraction the following was collected: age, gender, weight, height, race, comorbidities, prescriber, and concomitant antidepressants and anticonvulsants on date of initiation. Manual data collection through the Computerized Patient Record System (CPRS) was then utilized to determine veteran eligibility as well as if therapeutic dose was achieved, TTD, as well as discontinuation rates and cause.

Results

Results: 682 charts were reviewed to identify 302 patients, 151 in each group. The duloxetine group had 120 patients achieve therapeutic dose compared to 82 in the venlafaxine group (p<0.0001). Median TTD for duloxetine was 7 days (0-44.25, IQR) compared to venlafaxine 31.5 days (10-115, IQR). Side effects were reported in 37% of patients in venlafaxine group compared to 22% of duloxetine group (p=0.0053). Of note, 117 (77%) of the duloxetine patients had a previous trial of venlafaxine therapy.

Conclusions

Conclusions: Patients taking duloxetine are significantly more likely to achieve therapeutic dose and experience fewer adverse effects even if they have previously failed venlafaxine therapy.

11 Case Report: Femoral Nerve Injury Following Cooled Radiofrequency Lesioning for the Treatment of Hip Pain Despite Ultrasound Guidance and Motor Testing

Stephen Austad, Jeremy Hackworth, Isaac Gooding, Erik Voogd, Carter Sigmon

Naval Medical Center San Diego, San Diego, CA, USA

Purpose

Percutaneous radiofrequency ablation (RFA) of the articular branches of the obturator and femoral nerves can be an effective method for treating hip pain. No major neurovascular complications have been reported using this technique. In Cooled RFA, the temperature of the probe is reduced with circulating water, allowing for more energy use, and creation of a larger burn lesion. The larger burn area is purported to better account for the variability in the anatomic location of the target nerves and increase the efficacy of the procedure. We present a case where despite the use of recommended safety measures cooled radiofrequency lesioning at the hip resulted in severe femoral nerve injury and quadriceps paralysis.

Method

This is a 25 y/o female who presented with chronic right hip pain secondary to Femoroacetabular impingement syndrome She had no other significant PMH. She underwent hip arthroscopy one year previously which improved but did not eliminate her pain. Her pain continued despite extensive post op physical therapy, chiropractic treatment, and acupuncture. Her medications included only NSAID’s prn. She was 5‘8”, 117lbs, and had a BMI of 19. She had no focal neuro deficits.

Following effective diagnostic blocks of the intended nerves, Cooled RFA was performed. Safety measures employed included ultrasound imaging to locate neurovascular structures and marking 1cm wide margins on the skin, a lateral approach to pass under the neurovascular bundle, and motor testing to 2V at 2Hz without evidence of motor stimulation.

Results

Despite the safety measures employed, the patient developed quadriceps weakness immediately following the procedure with numbness along the femoral and saphenous nerve distribution. These symptoms persisted and physical exam 3 days later revealed 0/5 right knee extension. EMG performed at 6 weeks demonstrated no voluntary motor unit action potentials consistent with severe femoral neuropathy. There was no significant functional recovery over several months of physical therapy, gait training, and external muscle stimulation.

Pt was ultimately referred to Neurosurgery, and a nerve transfer vs grafting is planned.

Conclusions

In this case multiple safety measures were used, but nerve injury still occurred bringing in to question the safety of cooled RF lesioning for hip pain. Exactly how the injury occurred is unclear, but with cooled RF it may be that the burn size extends beyond the area tested with motor stimulation providing a false reassurance of safety. Measures to minimize risk in the future when performing RFA for hip pain include verifying final needle position with ultrasound prior to treatment, limiting local anesthetic volume, and considering pulsed or traditional RFA in patients with low BMI’s.

12 Analysis of Pre-Screening Data from Pediatric Pain Trials

Stacy Baldridge, Laura Wallace, Tyler Folta

Purdue Pharma L.P., Stamford, CT, USA

Purpose

In order to design and implement appropriate, feasible and generalizable clinical trials for pediatric pain patients, it is important to have an understanding of regular clinical practice related to pediatric patients receiving opioids. In addition to the evaluating descriptive statistics of subjects who participate in clinical trials, it can be informative to describe the characteristics of patients who were considered for a study, but deemed ineligible or did not consent to participate. This information can help investigators and clinicians to better understand the study’s context and generalizability to the underlying patient population, as well as to inform future studies within the same population. The population of interest for this study was pediatric pain patients age 7-16, considered for enrollment in the clinical trial, An Open-label, Multicenter Study of the Safety, Pharmacokinetics, and Efficacy of Buprenorphine Transdermal System (BTDS) in Children from 7 to 16 Years of Age, Inclusive, Who Require Continuous Opioid Analgesia for Moderate to Severe Pain. The primary objectives of this study were to:1. Describe the demographic and clinical characteristics and pre-study treatments of pediatric pain patients who did and did not enroll in an opioid clinical trial. 2. Describe reasons for ineligibility or non-consent among patients who did not enroll

Method

To help investigators more accurately identify which patients would be most likely to qualify for enrollment into the clinical trial, a self-reported and voluntary patient identification process (prescreening) was instituted. Over the course of three years, over 3000 patients were prescreened. Pre-screened patients were selected by an investigator based on the patient’s medical history, level of persistent pain, and use of opioid analgesics. Once selected for pre-screening, patients were further evaluated for entry into the screening phase of the study based on age, presence of persistent pain, opioid requirements, and protocol eligibility criteria. The clinical trial was conducted in the United States with investigators specializing in various pediatric specialties from children’s hospitals, academic institutions, and private practice

Based on these pre-screening data, we used descriptive statistics to evaluate the demographics (age and sex), prior treatments (including drug, dose, and duration of use), and medical conditions of patients pre-screened for inclusion in the trial. Pain conditions of interest included: acute pain, chronic pain, burn, surgery, trauma, malignancy, orthopedic condition, other pain, and not specified. All analyses were stratified by whether or not patients went on to enroll in the study.

Results

Approximately 3000 pediatric pain patients were pre-screened; 70 patients were screened, and 41 were enrolled into the trial.

Enrolled and non-enrolled patients differed with respect to age, sex, and pain condition. The prescreening database included potential subjects ranging in age from 0 to 30 years, though the vast majority were within the study-specified age range Subjects who enrolled were older (mean age 13.9, SD 1.96) than patients who did not enroll (mean age 12.04, SD=5.14).

There were only slight differences between those who enrolled and those who did not by sex. In both cases, the majority were female (63% for those who enrolled vs. 55% for those who did not), based on those who had data provided for sex.

Patients who enrolled in the study had different pain conditions compared to those who did not. The most common pain etiologies among enrolled subjects were pain related to underlying sickle cell disease (17%), chronic low back pain (17%), migraine (15%), rheumatologic conditions (12%), traumatic injury (7%), surgery (5%), and other chronic pain conditions. The most common etiologies for patients who did not enroll were surgery (16%), sickle cell disease (8%), acute pain conditions (9%), and cancer (6%) for those who had data provided for condition.

The most common reason for not participating in the trial was the failure to meet the protocol specified inclusion criteria for age or expected duration of opioid treatment, with approximately 60% of potential patients excluded for this reason. The majority of patients excluded due to age or duration of treatment had acute pain, pain related to a surgical procedure, sickle cell disease, or malignancy. The use of protocol-restricted concomitant medications excluded 20% of the prescreened population. The most common pain conditions excluded due to protocol-restricted medications were surgery, oncology, and gastrointestinal disorders.

Conclusions

A very large population of patients needed to be pre-screened to identify sufficient suitable patients to enroll in a pediatric opioid trial. Less than 2% of those pre-screened were eligible and willing to be included in the trial. The high numbers of required pre-screened patients to reach enrollment goals reinforce the difficulty of conducting clinical trials for pain in pediatric patients and the need for careful consideration of study criteria to maximize both the feasibility of study completion and the generalizability of the study’s findings.

13 The Impact of Nausea on Pain and its Relief

Randy Bender¹, Bernard Schachtel², Dennis Revicki¹, Anne Rentz¹, Jacqueline Kwong³, Elizabeth Marrett³

¹Evidera, Bethesda, MD, USA, ²Charleston Laboratories, Inc., Jupiter, FL, USA, ³Daiichi Sankyo, Inc., Parsippany, NJ, USA

Purpose

Opioid-induced nausea and vomiting (OINV) is a common condition associated with the use of opioids to treat moderate-to-severe acute pain. The presence and severity of these opioid-associated side effects can lead to suboptimal pain therapy and patient dissatisfaction, adversely affecting patient well-being. However, the relationship between OINV and pain control has not been previously well-studied. The objective of this analysis was to examine the relationship between 2 patient-reported outcomes, nausea intensity and pain severity.

Method

A post-hoc analysis was performed using data from a randomized, double-blind, phase 3 study evaluating the efficacy and safety of CL-108 (hydrocodone 7.5 mg/acetaminophen 325 mg (HC/APAP) with rapid-release promethazine 12.5 mg) compared to HC/APAP and placebo in patients with moderate-to-severe pain following surgical extraction of at least two impacted 3^rd molars.

Patients received the first dose of study medication after randomization and then self-dosed, as needed, every 4-6 hours, for a maximum of 6 doses over 24-hours. Antiemetic or analgesic rescue medications were allowed as needed. The Nausea Intensity Scale (NIS) assessed nausea intensity using a 0-to-10 numeric rating scale anchored as ‘no nausea’ and ‘severe nausea’. A Categorical Pain Intensity Scale (PI-CAT) assessed current pain severity using a 4-level scale of no pain to severe pain. Subjects completed both assessments at baseline, half-hourly from 0.5-6 hours in clinic post-initial dosing, and hourly at 7-24 hours as outpatients (while awake). Rescue medication use was also recorded.

Pooled data from 211 patients receiving CL-108 and 205 patients receiving HC/APAP were analyzed. Growth Curve Modeling (GCM) was used to examine the relationship between patient-reported nausea intensity and pain severity. Individual models for the trajectory of pain using the PI-CAT, and the trajectory of nausea using the NIS across the 24-hour treatment period were estimated while controlling for a time-varying covariate for rescue medication use, and covariates for age, gender, and the number of opioid doses used over 24 hours.

Results

The GCM modeling showed a significant positive association between patient-reported nausea intensity and pain severity scores (p<0.001). Patients who experienced more intense nausea reported higher pain severity. Similarly, lower levels of nausea intensity were associated with lower levels of pain severity. This positive association was significant at all assessment time points across the 24-hour period (all p<0.001). Nausea intensity ratings and the number of opioid doses taken were the strongest determinants of pain severity scores at 24 hours, accounting for 6.5% and 6.2% of the model variance, respectively. Younger age (p<0.05) and female gender (p<0.05) were also significant predictors of pain severity, accounting for 1.5% and 1.1% of variance.

The positive association between nausea intensity and pain severity scores was most evident at hour 10, with nausea intensity accounting for 10.2% of the variance and number of opioid doses taken accounting for 14.7% of the variance in pain severity ratings.

Conclusions

The model results showed a strong and consistent positive relationship between the level of nausea and the level of pain after oral surgery. At 24 hours, the nausea intensity score and number of opioid doses taken had nearly the same effect size with regard to prediction of a patient’s pain score. Efforts to reduce the occurrence and intensity of nausea in patients receiving opioids for moderate-to-severe acute pain should improve pain reduction, facilitate recovery and enhance patient satisfaction.

14 In vitro tampering assessment of the novel prodrug combination, benzhydrocodone/acetaminophen (APADAZ^TM), compared to hydrocodone/acetaminophen

Bindu Bera¹, Sven Guenther¹, Christopher Lauderback¹, Jason Heimsoth², Leonard Rosik², Julia Gremaud², Travis Mickle¹

¹KemPharm, Coralville, IA, USA, ²EAG Laboratories, Columbia, MO, USA

Purpose

Benzhydrocodone is a prodrug of hydrocodone with inherent physicochemical and pharmacological properties designed to deter certain non-oral forms of abuse on a molecular level rather than through formulation. Benzhydrocodone has been formulated with acetaminophen (APAP) in a novel immediate-release (IR) combination product as benzhydrocodone/APAP tablets (APADAZ^TM). The objective of these studies was to assess the ease of manipulation and tampering with APADAZ tablets compared to hydrocodone bitartrate (HB)/APAP tablets.

Method

The ability to extract hydrocodone from APADAZ compared to HB/APAP was examined with 26 ingestible and non-ingestible solvents that spanned a broad range of pH and polarity. Tests were conducted in both large volumes (amenable for oral or intranasal administration) and small volumes (amenable for intravenous or intranasal administration), and under agitating and stressing conditions to simulate methods an abuser may use to extract hydrocodone from the two products.

Results

In large volume extraction experiments under non-stressing conditions, no hydrocodone (i.e., <5%) was released from APADAZ in 23 of 26 solvents. The maximum amount of hydrocodone that could be extracted was 37%, accomplished with an extremely acidic solvent after 6 hours. In contrast, 85% of hydrocodone could be extracted from HB/APAP with water or Cola within 5 minutes. More than 50% of hydrocodone was extracted from HB/APAP in 19 of 26 solvents, and >80% of hydrocodone was extracted in 14 of 26 solvents. When APADAZ was subjected to agitating and stressing conditions, >60% hydrocodone was released in only 2 of 20 solvents but required heating to 80°C for at least 4 hours. For HB/APAP, nearly half of the test solvents extracted >90% of hydrocodone when heated. In small volume extraction experiments, no hydrocodone was released above the limit of quantitation from APADAZ under any of the 164 test conditions, whereas all 164 conditions released hydrocodone from HB/APAP. With attempts to selectively remove APAP from the tablet by cold-water extraction, only 36% of inactive benzhydrocodone was recovered from APADAZ, whereas 64% of active hydrocodone was recovered from HB/APAP.

Conclusions

These findings indicate that APADAZ provides physicochemical barriers that may make manipulation for intranasal and intravenous abuse inefficient and difficult compared to currently available IR hydrocodone combination products.

15 Lower Serum Cortisol Levels in Patients with Arachnoiditis and Chronic Intractable Pain (CIP)

John Bilello¹, Forest Tennant¹

¹Ridge Dx Labs, Research Triangle Park, NC, USA, ²Veract Intractable Pain Clinic, West Covina, CA, USA

Purpose

Patients with chronic pain often display a dysregulation of the hypothalamic-pituitary-adrenal axis, and changes in the stress system may contribute to the patient’s suffering and pain-related disability. We were interested in whether serum cortisol levels were impacted in severe, chronic pain states such as arachnoiditis and CIP.

Method

We measured the level of cortisol in patents with documented Arachnoiditis (n=26), centralized CIP (n=90) and in a series of 86 normal subjects without symptoms of acute or chronic pain. Each study subject provided a blood sample, which was processed to collect serum. Serum Cortisol was quantified using a competition ELISA (Monobind, Lake Forest, CA). It is well known that serum cortisol levels undergo a diurnal variation. In order to control for this variation, we developed a method to convert all cortisol values to a noon-time equivalent using a concentration time curve derived from studies of diurnal variation of serum cortisol in normal subjects.

Results

Both arachnoiditis and CIP patients had highly significantly lower serum levels of cortisol than normal subjects. Arachnoiditis patients had a mean serum level of 6.52± 4.06 µg/dL with a median of 5.8 µg/dL (range 1.4-14.7 µg/dL) while normal subjects had a mean of 12.58±4.78 with a median of 11.9 (p=<0.0001). CIP patients had a mean cortisol of 10.72±7.1 vs with a broader and lower distribution of values as compared with normal subjects (CIP range 1.7-36.2 median 8.4 µg/dL: normal 2.9-30.8 median 11.9 µg/dL) p=0.046.

Conclusions

Our results indicate that serum cortisol levels were lowest in patients with arachnoiditis. This is consistent with chronic pain states causing the body to modify its metabolic eventually leading to maladaptive responses triggering, the amplification and/or the persistence of the pain. We hypothesize that unresolved severe pain in patients’ with arachnoiditis or CIP, overstimulates and later impairs the HPA axis to the point that cortisol secretion is reduced, often to levels which require aggressive supplementation.

16 Patterns of Chronic Inflammation in Extensively Treated Patients with Arachnoiditis and Chronic Intractable Pain (CIP)

John Bilello¹, Forest Tennant¹

¹Ridge Dx Labs, Research Triangle Park, NC, USA, ²Veract Intractable Pain Clinic, West Covina, CA, USA

Purpose

To use serum biomarkers to gain insight into and gauge the residual (post-treatment) level of inflammation in two groups of intensively treated patients.

Method

Three study groups were analyzed, and included: (i) patients (n=90) with centralized chronic intractable pain (CIP), (ii) patients (n=26) with chronic pain and MRI-documented arachnoiditis and (iii) normal subjects without a diagnosis of chronic pain 9n=86). Each study subject provided a blood sample, which was processed to collect serum. Serum levels of Myeloperoxidase [MPO], and soluble Tumor Necrosis Factor alpha receptor type II [sTNFR2]), were measured by validated individual quantitative ELISA. A1AT concentrations were measured by an analytically validated immunoturbidimetric assay.

Results

Patients treated for arachnoiditis or CIP had higher serum levels of A1AT and MPO than normal untreated subjects without a diagnosis of chronic pain. Arachnoiditis patients had an A1AT mean serum concentration of 167.9±41.9 mg/dL as compared to 148.9±35.2 mg/dL for normal subjects (p=0.023). CIP patients had the highest mean serum A1AT level 182.5±39.8 mg/dL with p values of <0.0001 or 0.11 when compared to normal subjects or arachnoiditis patients respectively. Arachnoiditis patients had an MPO mean serum concentration of 344.6±227.9 ng/mL as compared to 188.2±107.5 ng/mL for normal subjects (p=<0.0001). CIP patients had a similar mean serum MPO level of 354.9±166 ng/mL with p values of <0.0001 or 0.79 when compared to normal subjects or arachnoiditis patients respectively. In addition, we noted a difference in the pattern of MPO expression in patients with arachnoiditis in that 34% had levels of MPO at normal or below and 31% had levels 2 fold or greater than normal.

Conclusions

CIP patients had the highest serum levels of A1AT, MPO and sTNFR2 with p values lower than 0.0001 when compares to normal non-pain subjects. Myeloperoxidase was the predominant inflammatory marker elevated above normal in treated patients with diagnosed arachnoiditis. We have suggested that one difference between acute and chronic pain, is that in the latter, the inflammatory factors are never completely cleared from the system despite extensive and complex treatment regimens.

17 Evaluation of the Relative Intranasal Abuse Potential of a Hydrocodone Extended-Release Tablet Formulated With CIMA® Abuse-Deterrence Technology Platform in Nondependent, Recreational Opioid Users

Mary Bond¹, Kerri Schoedel², Laura Rabinovich-Guilatt¹, Maciej Gasior¹, William Tracewell³, Richard Malamut¹, Yuju Ma¹, Lynn R. Webster⁴

¹Teva Pharmaceuticals, Frazer, PA, USA, ²Altreos Research Partners, Inc., Toronto, ON, Canada, ³Teva Pharmaceuticals, West Chester, PA, USA, ⁴PRA Health Sciences, Salt Lake City, UT, USA

Purpose

The increasing emphasis in the medical community on reducing the potential for abuse of opioid medications is giving rise to the development of abuse-deterrent formulations. As a result, hydrocodone extended release (ER) was reformulated with CIMA® Abuse-Deterrence Technology (ADT) platform to resist rapid release of hydrocodone when the tablet is manipulated or taken with alcohol. We evaluated the relative abuse potential, pharmacokinetics, and safety of intranasal hydrocodone ER in healthy nondependent adults with a history of recreational, intranasal opioid use.

Method

This double-blind, quadruple-dummy, placebo-controlled, randomized, 5-period, crossover study enrolled subjects who could tolerate a 45-mg intranasal dose of hydrocodone active pharmaceutical ingredient (API) powder and discern the subjective effects of hydrocodone from those of placebo. All subjects received intranasal milled hydrocodone ER 45 mg, intranasal hydrocodone API 45 mg, intact oral hydrocodone ER 45 mg, intranasal milled Zohydro ER 45 mg (hydrocodone ER capsule commercially available at the time of the study), and placebo. Abuse potential was assessed using bipolar visual analog scales (VAS) for “at the moment” Drug Liking (over a period of 48 hours after study drug administration) and Overall Drug Liking (over a period of 24 hours after study drug administration), using the parameter of peak score (maximum effect [E_max]). These VAS scales ranged from 0 (strong negative response) to 100 (strong positive response), with 50 as a neutral midpoint. Nasal effects were assessed with the Ease of Snorting VAS (0=very easy to 100=very difficult) and with E_max and area under the effect curve from 0 to 8 hours (AUEC_0-8h) of the Subject-Rated Assessment of Intranasal Irritation (SRAII) scales (0=not observed/no problem to 5=very severe problem/”as bad as can be”): Burning, Need to Blow Nose, Runny Nose/Nasal Discharge, Facial Pain/Pressure, and Nasal Congestion. A subject’s willingness or desire to take the drug again was assessed with the Take Drug Again Assessment (TDAA) scale (0=definitely would not to 100=definitely would). Pharmacokinetic parameters were calculated for each active treatment, and safety was assessed.

Results

Pharmacodynamic data were available for 34 subjects through 48 hours after study drug administration. Mean (SD) E_max of “at the moment” Drug Liking was significantly (P≤0.004) lower for intranasal hydrocodone ER (72.8 [13.7]) vs. hydrocodone API (80.2 [12.6]) and intranasal Zohydro ER (83.2 [11.9]) and significantly (P<0.001) higher vs. intact oral hydrocodone ER (57.3 [11.0]) and placebo (58.6 [11.3]). Mean (SD) E_max of Overall Drug Liking was also significantly (P≤0.004) lower for intranasal hydrocodone ER (68.5 [19.3]) vs. hydrocodone API (77.1 [14.7]) and intranasal Zohydro ER (79.8 [15.9]) and significantly (P≤0.001) higher vs. intact oral hydrocodone ER (57.8 [15.7]) and placebo (57.7 [13.9]). Ease of Snorting VAS was significantly lower (easier) for intact oral hydrocodone ER (the intranasal “dummy” treatment; 29.2) vs. intranasal hydrocodone ER (42.2; mean difference 12.58; P=0.017). Effects on SRAII scales were generally modest for all treatments; most scores ranged from 0 (not observed/no problem) to 2 (mild/slight problem). As assessed by the TDAA, subjects were significantly (P≤0.005) less likely to want to take intranasal hydrocodone ER (67.5) vs. hydrocodone API (75.5) and intranasal Zohydro ER (78.9). Willingness to take placebo (56.4) or intact oral hydrocodone ER (56.1) was significantly (P<0.001) lower than willingness to take the intranasal treatments. For each treatment, plasma concentration-time profiles paralleled “at the moment” Drug Liking over time. The overall incidence of adverse events was 18% for placebo, 24% for intact oral hydrocodone ER, 53% for hydrocodone API, 52% for intranasal hydrocodone ER, and 61% for intranasal Zohydro ER. No new safety signals were observed.

Conclusions

Abuse potential of milled hydrocodone ER formulated with ADT via the intranasal route was significantly lower than that of the non-abuse-deterrent hydrocodone API and Zohydro ER. When administered intact orally (as intended), liking scores of hydrocodone ER were similar to those of placebo. The results of this intranasal abuse potential study, along with those of a previous oral abuse potential study, demonstrated significantly lower abuse potential with hydrocodone ER tablets formulated with CIMA® ADT platform compared with hydrocodone controls via the 2 most common routes of hydrocodone abuse. Drug liking measures reflected the observed pharmacokinetics (plasma concentration-time profiles).

18 Evaluation of the Abuse Potential of a Hydrocodone Extended-Release Bitartrate Tablet Formulated With CIMA® Abuse-Deterrence Technology Platform in Nondependent, Recreational Opioid Users

Mona Darwish¹, Mary Bond², Yuju Ma², William Tracewell³, Philmore Robertson, Jr³, Lynn R. Webster⁴

¹Sci-Med Bridge, LLC, Malvern, PA, USA, ²Teva Pharmaceuticals, Frazer, PA, USA, ³Teva Pharmaceuticals, West Chester, PA, USA, ⁴PRA Health Sciences, Salt Lake City, UT, USA

Purpose

The increasing prevalence of recreational use of prescription pain relievers is evident in the rising number of emergency department visits and deaths related to misuse/abuse of these agents over the past 10 years. These observations have prompted development of abuse-deterrent formulations. This study assessed the abuse potential, pharmacokinetics, and safety of finely crushed and intact hydrocodone extended-release (ER) tablets formulated with a CIMA® Abuse-Deterrence Technology platform vs. immediate-release (IR) hydrocodone.

Method

This randomized, double-blind, triple-dummy, placebo-controlled, crossover study was conducted in healthy adults with histories of nondependent, recreational opioid use. Subjects able to tolerate a dose of IR hydrocodone 45 mg and differentiate its effects from those of placebo were randomized to treatment. All subjects received finely crushed hydrocodone ER 45-mg tablet, intact hydrocodone ER 45-mg tablet, IR hydrocodone 45-mg powder in a noncarbonated beverage, and finely crushed placebo. The primary endpoint was maximum effect (E_max) of “at the moment” Drug Liking based on the Drug Liking and Effects Questionnaire (question 1), and a key secondary endpoint was Overall Drug Liking over 24 hours after study drug administration; both were scored on a 100-point visual analog scale (0=strong disliking, 50=neutral, and 100=strong liking). A subject’s willingness or desire to take the drug again was assessed with the Take Drug Again Assessment (TDAA) score (0=definitely would not to 100=definitely would). Pharmacokinetic parameters and safety were also evaluated.

Results

In total, 45 subjects were evaluable for relative abuse potential. Significantly lower mean E_max for “at the moment” Drug Liking was observed after administration of finely crushed hydrocodone ER (66.9) compared with IR hydrocodone (85.2; P<0.001). Overall Drug Liking was also significantly lower for finely crushed hydrocodone ER (59.0) compared with IR hydrocodone (75.0; P<0.001). Findings were similar for comparisons of drug liking between intact hydrocodone ER and IR hydrocodone. “At the moment” Drug Liking was significantly lower for intact hydrocodone ER (53.9) compared with IR hydrocodone (85.2; P<0.001), and Overall Drug Liking was significantly lower for intact hydrocodone ER (49.2) compared with IR hydrocodone (75.0; P<0.001). Drug liking after administration of placebo was comparable to that after administration of intact hydrocodone ER (“at the moment” Drug Liking: 53.2 vs. 53.9; Overall Drug Liking: 51.1 vs. 49.2). TDAA scores were significantly lower for intact and finely crushed hydrocodone ER vs. IR hydrocodone (46.4 and 58.7 vs. 75.2; P<0.001), indicating that subjects were significantly less likely to want to take either hydrocodone ER formulation again compared with IR hydrocodone. TDAA scores were comparable in subjects administered intact hydrocodone ER and placebo (46.4 vs. 47.2; no statistical comparison was conducted). The 72-hour plasma concentration-time profile for each treatment paralleled its respective “at the moment” drug liking over time profile (ie, pharmacokinetic and pharmacodynamic profiles were qualitatively similar for each treatment). No unexpected safety signals were observed.

Conclusions

Assessments of “at the moment” Drug Liking and Overall Drug Liking over 24 hours showed that the abuse potential with oral use of hydrocodone ER, the most common route of abuse for hydrocodone products, is significantly lower for finely crushed and intact tablets developed with CIMA® Abuse-Deterrence Technology platform compared with IR hydrocodone in nondependent, recreational opioid users. Hydrocodone ER administered orally intact had liking scores similar to those for placebo. Pharmacokinetic profiles are consistent with and supportive of the drug liking measures.

19 Cebranopadol, a Novel First-in-class Analgesic: Results From a Study in Patients with Moderate to Severe Pain Following Bunionectomy

John Bothmer¹, Andreas Scholz¹, Kornelia Höschen², Stephen E. Daniels³

¹Grünenthal GmbH, Research - Translational Science & Strategy, Aachen, Germany, ²Grünenthal GmbH, Data Sciences - Statistics, Aachen, Germany, ³Premier Research, Austin, Texas, USA

Purpose

Cebranopadol is reported to act via nociceptin/orphanin FQ peptide (NOP) receptor and opioid receptor agonism. The objective of this study was to evaluate the analgesic efficacy, safety and tolerability in patients with pain following bunionectomy.

Method

This study was a randomized, multi-center, double-blind, placebo- and active-controlled, parallel group, single dose, double-dummy trial in patients with moderate to severe post-operative acute pain and conducted according to the requirements of Good Clinical Practice with IRB approval. Subjects who underwent unilateral first metatarsal bunionectomy with osteotomy and internal fixation were assigned to 1 of 3 cebranopadol doses (200 µg, 400 µg or 600 µg), morphine 60 mg CR or matching placebo. Subjects received a single oral dose of cebranopadol or placebo 1 h before the end of the sciatic block, and a single dose of morphine CR or placebo 1 h after the end of the sciatic block. Rescue medication (1st line: acetaminophen, 2nd line: diclofenac) was allowed 1 h after the stop of the sciatic block. Pain was measured by an 11-point numerical rating scale (NRS). The primary endpoint was the sum of pain intensity (SPI) on the NRS between 2 and 10 hours after first intake of investigational drug (SPI_2-10). The mean SPI windows from 2 - 6 h to 2 - 24 h were defined as secondary efficacy outcomes.

Results

258 patients were randomized to placebo, 60 mg morphine CR, or cebranopadol 200 µg, 400 µg or 600 µg. The mean SPI_2-10 was similar for the cebranopadol 400 μg (36.62) and cebranopadol 600 μg (36.95) groups, and different from the cebranopadol 200 µg (47.84), morphine (43.82) and placebo (48.19) groups. Pairwise comparisons of SPI_2-10 between both treatment groups and placebo based on an ANOVA and LOCF imputation resulted in mean (95% CI) differences of -11.4 (-19.30, -3.54), -11.1 (-18.66, -3.53), -4.6 (-12.42-3.20), and -1.27 (-8.97; 6.44) for the cebranopadol 400 ug, cebranopadol 600 ug, morphine CR, and cebranopadol 200 ug groups, respectively.

For reference periods longer than 2 - 10 h, the two highest cebranopadol dose groups and morphine showed similarly lower mean SPI results than the placebo group and the cebranopadol 200 μg group.

The frequency of subjects with at least 1 treatment emergent adverse event (AE) was highest in the morphine group (92.0%). The frequency was lowest in the cebranopadol 200 µg group (67.3%) and in the placebo group (68.1%). The cebranopadol 400 μg and 600 μg groups experienced frequencies of 77.6% and 84.2%, respectively. The most frequently reported AEs were nausea, vomiting and dizziness. No systematic effects on ECG, vital signs or laboratory parameters for any of the treatment groups were observed.

Conclusions

This Phase II trial showed that single dose administration of cebranopadol was safe and well tolerated with a dose dependent analgesic efficacy in patients experiencing moderate to severe post-operative pain due to bunionectomy. When considering the whole assessment period, cebranopadol 600 µg and 400 μg showed similar efficacy to morphine 60 mg CR but was better tolerated.

20 Development and Implementation of Multimodal Pain Treatment Strategies: Surgical and Non-Surgical Protocols

Jeffrey Bush¹, Laura Cullum², Leslie Masem³

¹1West Florida HCA Parallon Supply Chain Solutions, Largo, Florida, USA, ²St. Petersburg General Hospital, St. Petersburg, Florida, USA, ³Memorial Hospital of Tampa, Tampa, Florida, USA

Purpose

There is an abundance of data that supports the need for a movement away from the unnecessary prescribing of prescription opioids. Statistics provided by The Centers for Disease Control (CDC) show that sales of prescription opioids and overdoses related to prescription opioids have significantly increased by four times the amount since 1999. Over half of all opioid overdose deaths in the United States are due to a prescription opioid. With the advent of CDC’s guidelines on opioid use in chronic pain, and the Food and Drug Administration’s (FDA) requirements for opioid medication labeling, a nationwide focus has been put on a reduction of opioid use to reduce the incidence of addiction and adverse events related to these medications. One of the solutions to these issues is integrating multimodal analgesia into the practice of pain management.

Multimodal analgesia is the use of a variety of analgesic medications and techniques that target different mechanisms of action in the peripheral and/or central nervous system. Multimodal analgesia has many demonstrated results, including shortened mean length of stay (LOS), lower visual analogue scale (VAS) scores, less patient controlled analgesia (PCA) use, and reduced incidence of chronic neuropathic pain.

Hospital Corporation of America (HCA)’s West Florida Division developed a comprehensive set of tools to aid in the implementation of multimodal analgesia. With use of these tools, we anticipate a reduction in opioid use and side effects such as opioid induced respiratory depression throughout the facilities while achieving superior pain management for our patients.

Method

This project involves a two-phase rollout; the first phase included development of order sets and a complete toolkit; second phase will be to collect outcome data surrounding protocol use to determine the efficacy of using a multimodal therapeutic approach for pain control.

The phase two outcome data will include analysis of trends in naloxone use, average VAS pain scores, mean LOS, and quantitative opioid consumption.

Results

New treatment plans were developed for use in both surgical and non-surgical patient populations. Surgical protocols followed guideline recommendations on multimodal analgesia from the American Pain Society for total knee arthroplasty, total hip arthroplasty, cesarean section, spinal fusion, and open laparotomy procedures. The same principles of multimodal pain therapy were applied to the development of the non-surgical protocols in order to achieve optimal pain management based on FDA definitions of opioid exposure. To facilitate a successful deployment of these standard protocols, a complete toolkit containing support resources around opiate education, protocol awareness, and implementation timeline was also developed.

Conclusions

Rapid adoption of the order sets demonstrated a need in the facilities for a comprehensive multimodal approach to pain management. This has led to the development of an interdisciplinary team approach which has been advantageous in the implementation of the protocols. This multifaceted team has been responsible for broadening knowledge in the field of pain management across various healthcare disciplines such as pharmacists, physicians, nurses and physical therapists. Data collection for phase two is ongoing.

21 Analysis of morphine milligram equivalents of opioids prescribed in a large urban safety net system

Kelley Carroll¹, Thomas Northrup¹, Villarreal Yolanda¹, Mohammad Zare¹, Reed Brian², Klawans Michelle¹, Stotts Angela¹

¹University of Texas Houston McGovern Medical School, Houston, TX 77030, USA, ²Baylor College of Medicine, Houston, TX 70030, USA

Purpose

Over the past 20 years there has been a dramatic increase in opioid-related accidental overdoses and deaths in the U.S. In addition, chronic use of opioids creates other risks to patient safety including abuse, addiction, transition to heroin use, diversion, and accidents. In response to these alarming trends, the Centers for Disease Control and Prevention (CDC) published guidelines for the use of opioids in chronic, non-cancer, non-palliative pain in March 2016. In its guidelines, the CDC discussed opioid dosage selection and explored levels with low risk and higher risks of opioid related adverse events as measured by morphine milligram equivalents per day (MME/day). Doses under 20 MME/day have the lowest risk. Patients on opioid doses over 50 MME/day are at the highest risk of adverse events and doses exceeding 90 MME/day should be avoided. In this study, we analyzed characteristics of prescription orders of the 3 most commonly prescribed opioids (hydrocodone, codeine, and tramadol) in a large urban safety net system, Harris Health System.

Harris Health System is the safety net health care system for Harris County, Texas. Houston’s metropolitan area has 1.2 million uninsured patients and a large portion of these patients receive care in the Harris Health System. In its network of 3 hospitals, 18 community health centers, 5 school-based clinics, and 13 homeless clinics, Harris Health cares for over 300,000 unduplicated patients with over one million outpatient visits per year.

Method

As part of a system-wide quality improvement project on pain management, Harris Health created a database to monitor the three most frequently prescribed opioids (hydrocodone-acetaminophen, acetaminophen-codeine [T3], and tramadol), with the intention of improving quality of care.

This retrospective chart review utilized database entries from February 1, 2016 through January 31, 2016. In previous reviews of the database, we found a dramatic reduction in hydrocodone prescriptions following the reclassification of hydrocodone in November 2014, while prescriptions for T3 and tramadol increased. Providers clearly shifted to less potent opioids; however, it was unclear what MME/day was being prescribed. In this study, the MME/day for the orders in the database was calculated in order to determine the safety of prescribed dosages. Prescriptions from emergency centers and outpatient facilities were included and inpatient prescriptions were excluded. Number of tablets prescribed was multiplied by the milligrams of opioid and multiplied by the associated MME conversion factor (multipliers: hydrocodone=1; codeine=0.15; tramadol=0.1) to generate total MME (per prescription). Total MME was divided by the number of days the opioid was supplied to yield MME/day. For example, a 30-day supply of tramadol 50 mg (n=60 tablets) would yield MME/total (60 tablets x 50 mg x 0.1 conversion factor)=300 and an MME/day (300/30 days)=10. Chronic use of opioids is commonly defined as opioid use for 3 or more months (out of 12 months); we provide data on the number of patients with 3 or more prescriptions in this 12-month chart review, as well as additional frequency data.

Results

When excluding inpatient data, 53,956 patients were dispensed opioids over the 12-month study period. Sixty-seven percent of patients received 2 or fewer opioid prescriptions in 12 months, while 33.3% (n=17,939) received 3 or more opioid prescriptions providing an approximation of the chronic opioid definition. Further analyses will be conducted to evaluate the proportion of these patients receiving opioids for non-palliative, non-cancer chronic pain.

The median MME/day was 18.75 MME/day, while the 75th percentile was 22.5 MME/day, the 95% percentile was 40.0 MME/day, and the 99th% percentile was 60.0 MME/day. Fifty-nine percent of patients were on less than 20.0 MME/day, 39% were on 20-49.99 MME/day, and 2.0% were on a dose equal to or greater than 50.0 MME/day.

In its guidelines, the CDC specifically discussed elderly populations and opioid safety. Patients over 65 have an increased risk of opioid accumulation due to reduce renal clearance and consequently have a smaller therapeutic window. In light of this, we analyzed the MME/day by age. Sixty-six percent of the prescriptions were prescribed to patients aged 45-64, while 25.8% were prescribed to patients under age 44, and 8.2% were prescribed to patients over age 65. Patients over age 65 were more likely to receive doses under 20 MME/day (66.6%) compared to 45-64 year olds (59.0%) and those under 44 years of age (56.8%). Two percent of patients of all ages received prescriptions over 50 MME/day.

Conclusions

In this large urban safety net system, the majority of patients prescribed opioids were not chronic users. However, almost 18,000 patients met our definition of chronic use. Additionally, the majority of prescriptions were less than 20 MME/day, the dose of opioids least likely to result in accidental overdose and death. Elderly patients, who are at highest risk of opioid-related adverse events, were the least likely to receive prescriptions over 20 MME/day. Further analyses will be conducted to distinguish differences among prescriber departments and to determine if sociodemographic characteristics impact opioid prescriptions and MME/day.

22 Use of an Ultrasound-Guided Diagnostic Block and Pulsed Radiofrequency Ablation for Treatment of Meralgia Paresthetica in a patient with a CAM and Pincer Impingement: A Case Report

Hamilton Chen, Paul Chan, Douglas Grover

UC Riverside, Riverside, CA, USA

Purpose

Meralgia paresthetica (MP) is a neuropathic disorder of the lateral femoral cutaneous nerve. It occurs due to entrapment of the nerve at the inguinal canal, but can be caused by compression anywhere along its course. This causes paresthesia and pain of the anterolateral thigh. Symptoms typically worsen with standing and walking and are relieved by sitting. The Symptoms may present similarly to pathology in the hip joint. Due to its similar presentation, an ultrasound-guided block of the lateral femoral cutaneous is a useful diagnostic tool to diagnose the disorder. We present a unique case of a patient with a CAM and Pincer hip impingement presenting with anterolateral thigh pain where an ultrasound-guided diagnostic block of the lateral femoral cutaneous nerve diagnosed meralgia paresthetica. A subsequent pulsed radiofrequency ablation was subsequently performed and successfully treated the patient’s symptoms.

Method

A 31-year-old overweight male with history of lumbar stenosis, presented to our outpatient pain management clinic with symptoms of left hip pain. The hip pain has been ongoing for approximately 1 year and the pain has been worsening over time. The pain was described as sharp and burning in nature and occasionally radiated to the left lateral thigh. The patient was evaluated by an orthopedic surgeon, where the patient was diagnosed with a CAM and Pincer hip impingement on imaging and was recommended possible surgery. On examination, there was slight weakness in the left hip flexor, and sensation was intact to light touch. Due to suspicion for meralgia paresthetica, a diagnostic left lateral femoral cutaneous block was performed with ultrasound guidance using 3mL of 1% lidocaine and 40mg of Depo-Medrol. The injection provided approximately 3 days of complete pain relief. A left lateral femoral cutaneous PRF was performed under ultrasound guidance as a follow up treatment to his positive response to the diagnostic nerve block.

Results

At 6 weeks status post PRF, the patient reported 80% pain relief and was able to resume his daily activities. The diagnostic block and subsequent PRF allowed the patient to avoid surgical intervention of his hip.

Conclusions

Our case illustrates the utility of ultrasound guided nerve blocks for diagnosis of meralgia paresthetica. Since symptoms of meralgia paresthetica may present similarly to hip pathology, ultrasound guided nerve blocks of the lateral femoral cutaneous nerve are a useful tool to confirm the diagnosis. The case further illustrates how pulsed radiofrequency can be a novel therapy for treatment of this disorder.

23 Cebranopadol, a Novel First-in-class Analgesic: Efficacy, Safety, Tolerability in Patients with Mixed Chronic Low Back Pain

A Christoph¹, M Eerdekens¹, M Kok¹, G Volkers¹, R Freynhagen^2,3

¹Grünenthal GmbH, Aachen, Germany, ²Benedictus Krankenhaus Tutzing, Zentrum für Anästhesiologie- Intensivmedizin- Schmerzmedizin & Palliativmedizin, Tutzing, Germany, ³Technische Universität München, Klinik für Anästhesiologie, München, Germany

Purpose

Reportedly, Cebranopadol acts via nociceptin/orphanin FQ peptide (NOP) receptor and opioid receptor agonism. It is currently in development for the treatment of chronic pain conditions.

Method

Randomized, multi-center, double-blind, double-dummy, placebo- and active-controlled, parallel group, multiple dose trial in moderate to severe chronic mixed low back pain, conducted according to GCP and with IEC approval. Forced titration to the allocated dose over 2 weeks was followed by 12 weeks of maintenance.

Results

641 patients were randomized to placebo, tapentadol ER 200mg BID, or QD cebranopadol 200µg, 400µg or 600µg. the mean (SD) baseline pain score was 7.1(1.26) on an 11-point numerical rating scale (NRS). All cebranopadol doses significantly reduced pain according to MMRM analysis and multiple comparison procedure, (change from baseline to week 12 of maintenance on average 24-hour NRS; p value versus placebo): -2.95 (p=0.0095), -2.95 (p=0.0122), -3.18 (p=0.0021) for cebranopadol 200µg, 400 µg, 600µg, -3.05 and -2.16 for tapentadol and placebo, respectively. Cebranopadol’s effect appeared within the first 2 weeks. 36.5%, 40.6%, 38.9%, 43.8% and 27.5% of patients respectively reported ≥50% pain reduction.

All doses of cebranopadol were safe, without systematic effects on ECG, vital signs or laboratory parameters. 85.7% of patients on cebranopadol experienced treatment-emerged adverse events (TEAE), compared to 79.4% and 65.1% on tapentadol and placebo. The most common TEAEs across active groups were nausea, constipation, vomiting, dizziness, and somnolence.

Conclusions

In this trial, Cebranopadol was effective, safe and well tolerated in a chronic mixed low back pain population. Titration will be optimized in subsequent studies.

24 Analysis of Pain Education Deficiencies Among Student and Recent Graduate US Pharmacists

Jacqueline Cleary^1,2, Joni Carroll^2,5, Jeffrey Fudin^2,3, Scott Strassels⁴

¹Albany College of Pharmacy and Health Sciences, Albany, NY, USA, ²Stratton VA Medical Center, Albany, NY, USA, ³Remitigate LLC, Delmar, NY, USA, ⁴Optum Hospice Pharmacy Services, Clayton, MO, USA, ⁵University of Pittsburgh School of Pharmacy, Pittsburgh, PA, USA

Purpose

Approximately 100 million Americans live with chronic pain as compared to the 61 million Americans being treated for diabetes, coronary heart disease, and cancer conditions combined. The Centers for Disease Control and Prevention report that approximately 50 million inpatient surgical procedures occur each year, creating an additional pool of patients who experience perioperative pain. It is imperative that new pharmacy graduates are equipped with the proper clinical skills and knowledge in pain management to provide safe and effective direct patient care and possess the skillset to employ proper opioid risk management strategies in collaboration with the healthcare team. Currently there are only 13 ASHP accredited specialty pharmacy residency programs which provide additional post-graduate training in pain management and palliative care. Comparatively, there are 122 ASHP accredited specialty pharmacy residency programs in ambulatory care and 77 programs in infectious diseases. Due to the few opportunities for post-graduate training in pain management and the rampant epidemic of opioid abuse and misuse in this country, it is vital for student pharmacists to receive comprehensive pain management education during their didactic pharmacy school training.

The purpose of this project was to develop a questionnaire to survey student and newly graduated pharmacists regarding quality and quantity of the pain education, hours of instruction, basic knowledge, and opioid risk mitigation education received in pharmacy school.

Method

An electronic survey was created using Google Forms. We gathered information on the number of didactic hours in formal PharmD curricula spent on pain risk stratification, urine drug screen interpretation, post-surgical pain management, and the treatment of cancer and non-cancer pain. Additional information surrounding student perspective on their comfort levels and levels of understanding regarding the aforementioned topics and preferred method of opioid conversion were collected. Participation was solicited by providing a link to the survey via social media platforms, including Facebook and Twitter, and via professional organization e-mail lists and message boards. The target audience of the survey was pharmacy graduation classes of 2014-2016. Student pharmacists could only participate if they had completed all of their didactic years of study. The survey was open for completion from March 13, 2016 through April 20, 2016.

Results

Overall, 137 responses were received. The majority of the participants graduated from or were attending a pharmacy school in an Eastern Time zone (77%). Only 17 participants stated that they had a pain elective at their school (12%) and 14 participants were unsure if the option was offered (10%). Eighty-six responders (62%) reported zero hours of opioid risk stratification education in their curriculum. Ninety-five responders (69%) reported zero hours spent in their curriculum on urine drug screens in general. Overall the majority of responders stated that throughout their education they spent 3-4 hours on pain education in the classroom (56 responses (n=137), 41%) and when asked overall if they had received enough education on the topic of pain management, 113 responders stated ‘no’ (82%) versus 8 ‘yes’ (6%) and 16 ‘not sure’ (12%).

Further analyses of survey responses are forthcoming. Consideration will also be given to reopening the survey in the future to obtain a larger sample size.

Conclusions

A preliminary review of survey responses show that recent pharmacy school graduates and current students feel that they are receiving inadequate education surrounding pain management and risk mitigation relative to other subjects within their PharmD curriculum. In light of the growing opioid epidemic, pharmacy schools should reevaluate their current curriculums to include more didactic hours spent on pain management and opioid risk mitigation strategies.

25 Injection Resistance of an Immediate-Release Oral Oxycodone Hydrochloride Product With Abuse-Deterrent Properties

Torben Elhauge¹, Edward J. Cone², August R. Buchhalter², Jeffrey M. Dayno¹, Karsten Lindhardt¹

¹Egalet Corporation, Wayne, PA, USA, ²PinneyAssociates, Bethesda, MD, USA

Purpose

OXAYDO® (5 and 7.5 mg; Egalet Corporation; Wayne, PA) is an immediate-release (IR) oral oxycodone-based product that contains excipients expected to deter abuse. These excipients include sodium lauryl sulfate, which irritates nasal passages and is expected to deter abuse via nasal insufflation, and excipients with gelling properties, which are expected to resist preparation for injection. A comprehensive series of Category 1 studies of OXAYDO was designed and conducted in accordance with the 2015 final US Food and Drug Administration guidance for determining the abuse-deterrent (AD) properties of opioids. Here we present results of studies on syringeability, which assess abuse deterrence via the intravenous route of administration. OXAYDO was evaluated by testing the difficulty of dissolving it into small volumes of solvent and drawing the oxycodone into a syringe and expelling it. Because no other AD IR oxycodone formulation is currently marketed, Roxicodone® 15 mg, a non-AD IR oxycodone formulation, was used as the comparator product.

Method

The syringeability of OXAYDO and Roxicodone, intact or ground to a fine powder, was determined by testing both simple and more complex procedures that could be used to prepare the products for injection. Initial syringeability studies included wetting, mixing, and phase separation of OXAYDO in small volumes of water (2, 5, and/or 10 mL) at room temperature. Syringeability was assessed by using a syringe fitted with different gauge needles. Standard syringeability studies of single or multiple tablets of OXAYDO 5 and 7.5 mg were conducted in small volumes of injection solvents under a variety of conditions (eg, temperature, agitation, incubation times). Syringeability was tested using syringes fitted with 18-, 22-, 25-, or 27-gauge needles. Syringeability of Roxicodone was similarly assessed. Syringeability was also studied with OXAYDO using prolonged extraction from 1-24 hours at room temperature in water or saline. The amount of solvent and oxycodone that were successfully drawn into a syringe was assessed.

Results

In total, 48 different syringeability conditions (solvents, volumes, temperatures, single/multiple tablet, ground/intact, pretreatment) were tested with OXAYDO. Nine conditions were tested with Roxicodone and it was proven to be easily loaded into a syringe, even in the smallest volume tested and with needle sizes typically used by abusers. Although OXAYDO, as an IR product, is readily crushed and rapidly dissolves in small aqueous volumes, it forms a highly viscous gel that resisted preparation for injection. Eighteen of nineteen conditions tested were unsuccessful with OXAYDO; only 1 met the success criteria of drawing up a defined amount of oxycodone (≥5 mg) into a syringe. The “successful” method required 5 tablets and only allowed 19% of the oxycodone to be loaded into a syringe. In addition, much larger needle sizes were necessary to overcome the high viscosity of the OXAYDO solution. Therefore, it is deemed unlikely that OXAYDO will be attractive for injection by abusers.

Conclusions

OXAYDO demonstrated robust resistance to preparation for injection, whereas the comparator was easily prepared for injection. These results suggest that OXAYDO presents significant AD barriers to injection via the intravenous route.

26 Does Weather Affect Outpatient, Pain Management Clinic Attendance? A Five-Year Longitudinal Analysis

David Cosio¹, Amy Demyan¹

¹Jesse Brown Veterans Affairs Medical Center, Chicago, IL, USA, ²University of La Verne, La Verne, CA, USA

Purpose

Adherence to appointments has been found to be a strong predictor of successful chronic disease self-management, yet up to 30% of health appointments are missed. Many factors have been found to influence attendance, including not having enough time, transportation issues, lack of childcare, administrative errors, and inclement weather. Patients with chronic, non-cancer pain often attribute nonadherence to prescribed treatment regimens to weather indices. Chronic pain patients frequently report that their pain is influenced by temperature, barometric pressure, humidity, and wind speed. Pain diagnoses such as rheumatoid arthritis, osteoarthritis, fibromyalgia, headaches/migraines, sickle cell, and low back pain are reported to be especially sensitive to weather changes. The current study investigated weather indices as possible factors of missed pain management treatment appointments. Therefore, the aims of this five-year study was twofold: to investigate if weather the day before, the day of, and/or the day after a scheduled pain education class affected attendance and, if so, to identify the specific measures of weather change that predicted attendance. Informed by the literature on weather and pain, it was hypothesized that attendance would be significantly influenced by weather indices. Since, to our knowledge, this is one of the first studies to examine the influence of actual weather indices in a sample of chronic pain patients, we made no predictions regarding which weather indices would influence attendance.

Method

A total of 911 Veterans Patients had mixed idiopathic chronic, non-cancer pain conditions, including back pain (75%), neck pain (13%), extremity pain (7%), head pain (3%), and fibromyalgia/soft tissue pain (2%), participated in the Pain Education School program at the Midwestern U.S. VA medical center between November 6, 2009 and October 31, 2014. Most patients were African American (64%), male (85%), and between the ages of 55 to 64 years old (40%). The program met once a week for 11 weeks. Participants received education about pain management from 12 program modules. Attendance was tracked and weather indices were recorded for the day before, the day of, and the day after class. Of the 260 calendar weeks, 14 classes were cancelled due to national holidays, resulting in 246 possible classes. Overall, the average patient attended 6/12 classes, with 14% of patients only attending the introduction class. The average attendance for each class was 25 patients and approximately 182 patients participated in the education program each year. Since we used archival data, attendance records were analyzed as a ratio of attendees versus non-attenders and demographic information was recorded by group and, thus not individually linked to attendance.

Results

Of the 260 calendar weeks, 14 classes were cancelled due to national holidays, resulting in 246 possible classes. A stepwise linear regression was conducted to evaluate which measures of weather change were necessary to predict attendance in a pain education program. At step 2 of the analysis, temperature change for the day after class and the wind-chill for the day of class were significantly related to attendance, F(2, 240) = 6.93, p = .01. The multiple correlation coefficient was 0.23, indicating approximately 5.5% of the variance of the attendance rate could be accounted for by these variables. The temperature change for the day after class had a shared contribution of 3.5% and a unique contribution of 3.4%; and the wind-chill for the day of class had a 3.0% shared and a 2.9% unique contribution. The remaining variables (i.e., mean temperatures, precipitation, snow depth, visibility, and mean wind speed) did not enter into the equation at step 3 of the analysis. No significant differences were found for season or class module on patient attendance in the pain education program, F(3, 197) = 2.04, p = 0.11; F(12, 197) = 0.25, p = 0.99, respectively.

Conclusions

This study found support for the influence of cold temperatures (wind chill) on nonattendance to a pain education program for the day of class. Results also offered some support for weather sensitivity in chronic pain patients, as change in the temperature (up or down) for the day after class increased nonattendance. There was, however, no influence of season on attendance. These findings have the potential to help enhance treatment compliance such as using cold weather forecasts as a prompt to make patient reminder calls—a supported method for appointment adherence—to help minimize this barrier to treatment.

27 Delivery of Pain Education through Picture-Telephone Videoconferencing for Veterans with Chronic, Non-cancer Pain

David Cosio, Erica Lin

Jesse Brown VA Medical Center, Chicago, USA

Purpose

Almost a quarter of Veterans nationwide live in rural communities, which may negatively impact their health‐related quality of life compared to their counterparts in urban areas. The incidence of chronic pain is higher in rural areas because the population is often older, obese, and impoverished. Social factors also play a role, such as limited access of pain specialists, transportation issues, unstable housing, poor education, and unemployment. The high rates of chronic pain amongst rural Veterans coupled with the barriers found in these areas complicate the delivery of pain self‐management interventions. Thus, clinical care at a distance is progressing as a model and is being used more frequently to treat disease in rural areas. Dial-up phones and videocassette recording devices are both examples of technologies that have become obsolete, but new, amazing devices and applications are coming on the market every day that allow services to be provided at a distance. Technology-assisted treatments, or “telehealth,” may provide a comparable alternative to face-to-face interventions. The Pain Education School program has been shown to positively impact Veterans stage of change, their experience of pain, and their mood. The purpose of the current feature is to propose the feasibility and potential efficacy of using picture-telephone (PICTEL) videoconferencing technology to disseminate a pain education program to rural Veterans with chronic, non-cancer pain.

Method

The current study used a retrospective outcome design with a sample of 463 Veterans aged 18-88 years old with mixed idiopathic, chronic, non-cancer pain conditions who participated in the Pain Education School program either face-to-face (N=350; 76%) or via PICTEL (N=113; 24%) at a Midwestern VA Medical Center between January 8, 2010-November 4, 2011. Veterans were referred to the Pain Education School program by their primary care provider. The investigators would receive the consult through the computerized patient record system and determine the closest location to the Veteran. The Veteran was then sent a letter two weeks before the scheduled appointment about the location, time, and place of their appointment. The participant then attends their first one-hour class session after the introduction class. The participant is scheduled and encouraged to attend 11 subsequent weeks of one-hour classes led by guest speakers from 23 different disciplines within the VA. The program provides a menu of treatment modalities-the presenters rotated on a schedule, not the Veterans. Presenters from each discipline shared information about chronic, non-cancer pain from their perspective, available treatments within their service, and how to access their respective clinics. As a part of quality management, measures were completed by participants of the face-to-face and PICTEL interventions at the introduction and conclusion of the program. The assessments included a battery of measures, including the Readiness Questionnaire, the Patient Pain Questionnaire, and the Patient Health Questionnaire.

Results

Preliminary findings from the current study propose there was no significant difference between the face-to-face and PICTEL interventions on any of the outcome measures aforementioned, including the stage of readiness to adopt a self-management approach, F (1,429)=0.01, p=0.92; knowledge level about pain, F (1,429)=0.56, p=0.46; experience of pain, F (1,429)=0.03, p=0.87; and the frequency of depression, F (1,429)=0.99, p=0.32. However, the preliminary findings from the current study support past research which has found a significant difference between the pre- and post-measures of the participants’ stage of readiness to adopt a self-management approach, F (1,429)=29.81, p=0.00; their experience of pain, F (1,429)=17.49, p=0.00; and the frequency of their depressed mood, F (1,429)=11.19, p=0.01, regardless of how the intervention was delivered. These results suggest the Pain Education School telehealth program had a moderate effect in increasing participants’ readiness to adopt a self-management approach. In addition, the current findings suggest the telehealth program had a small to moderate effect in decreasing the negative experience of pain. Finally, the results suggest the telehealth program had a small to moderate effect in decreasing depressive symptoms. The preliminary findings mirrored those of previous non-cancer pain research in which Veterans participating in a pain education program did not evidence increased pain knowledge. A prior research study found that the addition of audience response systems to the pain education program at a VA demonstrated significantly greater increases in pain knowledge compared to those locations without the technology by facilitating active learning. The current presentation will also detail logistics and considerations, the PICTEL technology used, technology troubleshooting, best practices and etiquette, and how to capture workload. Several lessons were learned through this process, including the importance of making partnerships, having support from administration, marketing, and obtaining knowledge about the healthcare system in order to have a successful telehealth program.

Conclusions

The current program may prove to be an avenue by which rural Veterans can bypass identified barriers and realize self-management goals. There are merits to the videoconferencing format, but a lot of the recent studies on mobile health and internet-based training programs may better address transportation and time-related barriers. Despite these advancements, there continues to be issues related to trust, quality, security, privacy, and reimbursement with these newer formats. Therefore, videoconferencing may serve as the best option for telehealth care in the current healthcare system. Before such programming can be widely disseminated, more large-scale, multisite, and scientifically-rigorous evaluations are needed.

28 Effects of Eluxadoline on Abdominal Pain in Patients with Irritable Bowel Syndrome with Diarrhea: Results of Two Phase 3 Clinical Trials

Anthony J. Lembo¹, Leonard S. Dove², David A. Andrae³, Lisa Turner², Paul S. Covington²

¹Beth Israel Deaconess Medical Center, Boston, MA, USA, ²Former employee of Furiex Pharmaceuticals, Inc., an affiliate of Allergan plc, Parsippany, NJ, USA, ³Allergan plc, Parsippany, NJ, USA

Purpose

Eluxadoline is a locally active, mixed µ-opioid receptor (OR) and κ-OR agonist and δ-OR antagonist which was shown to improve the symptoms of irritable bowel syndrome with diarrhea (IBS-D) in two Phase 3 trials. The purpose of this study was to perform additional prospective analyses to further examine efficacy with respect to abdominal pain in IBS-D.

Method

Two double-blind, placebo-controlled, Phase 3 clinical trials (IBS-3001 and IBS-3002) enrolled patients meeting Rome III criteria for IBS-D to twice-daily treatment with eluxadoline (75 or 100 mg) or placebo. Both clinical trials had identical designs through 26 weeks of treatment. The primary endpoint was a composite response based on simultaneous daily improvement in worst abdominal pain (WAP) and stool consistency over Weeks 1-12 (Food and Drug Administration [FDA] endpoint) and Weeks 1-26 (European Medicines Agency [EMA] endpoint). Additional prospective analyses of WAP (scale of 0-10) included: Cochran-Mantel-Haenszel (CMH) assessments of WAP responders, defined as patients with ≥50% of days with ≥30% improvement (at the study level and pooled); longitudinal analyses (LA) of WAP response rates and LA of WAP daily scores at specific time points; assessment of pooled data using CMH analyses of WAP responders over the two intervals based on 40% and 50% improvements in pain; and analysis of covariance (ANCOVA) assessment of change from baseline (CFB) in WAP daily scores of the pooled data at specific time points.

Results

2428 patients with IBS-D were enrolled across the two trials. Significantly more patients receiving eluxadoline (75 and 100 mg) were FDA and EMA responders compared with patients receiving placebo (p<0.005), with the exception of eluxadoline 75 mg in IBS-3002, which was not statistically significant. Although no significant differences were seen for WAP responders (i.e. >30% pain improvement for >50% of days), significant differences between eluxadoline- and placebo-treated patients were present for LA of WAP response rates at Week 26 for eluxadoline 75 mg in both IBS-3001 (87.0% vs. 80.0%, p=0.016) and IBS-3002 (83.0% vs. 75.0%, p=0.013), and for eluxadoline 100 mg in IBS-3002 (87.0% vs. 75.0%, p<0.001). Likewise, LA of WAP scores at Week 26 achieved significance for eluxadoline 100 mg compared with placebo in both IBS-3001 (2.66 vs. 2.97, p=0.022) and IBS-3002 (2.50 vs. 2.93, p=0.003). CMH analyses from the pooled data showed significant differences for eluxadoline 100 mg over placebo for WAP responders at both the >40% (44.2% vs. 37.7%, p=0.008) and >50% (38.7% vs. 32.5%, p=0.009) pain improvement levels. Findings were similar for the ANCOVA CFB WAP score analysis of the pooled data for eluxadoline 100 mg and placebo (-3.4 vs. -3.0, p=0.002).

Conclusions

Results from two Phase 3 clinical trials demonstrated that eluxadoline showed statistically significant improvement in treating the abdominal pain component of IBS-D. This was particularly evident for eluxadoline 100 mg, with ≥40% pain improvement definition for responders. This was further supported by results of the LA of pain response rates and LA of pain scores at the study level and ANCOVA CFB analyses from the pooled data.

29 Pharmacodynamic Effects From a Category 3 Oral Human Abuse Potential Study of an Abuse-Deterrent, Extended-Release Morphine Product Candidate in Nondependent, Recreational Opioid Users

Michael D. Smith¹, Lynn R. Webster¹, John Lawler², Karsten Lindhardt², Jeffrey M. Dayno²

¹PRA Health Sciences, Salt Lake City, UT, USA, ²Egalet Corporation, Wayne, PA, USA

Purpose

Abuse-deterrent (AD) technologies deter manipulation of opioid tablets to limit misuse and abuse via alternate routes of administration. Novel morphine AD, extended-release (ER) injection-molded tablets (morphine-ADER-IMT) were developed using proprietary Guardian^TM Technology (Egalet Corporation, Wayne, PA). Morphine-ADER-IMT were evaluated for abuse potential in comparison with a marketed formulation of morphine ER and placebo after manipulation and oral administration.

Method

Volunteers aged 18-55 years who were nondependent, recreational opioid users received intact morphine-ADER-IMT (60 mg), manipulated morphine-ADER-IMT (60 mg), manipulated morphine ER (60 mg), and placebo in a single-center, double-blind, triple-dummy, 4-way crossover study. Pharmacodynamic outcomes included peak effect (E_max) on the Take Drug Again Assessment (TDAA) Visual Analog Scale (VAS), Overall Drug Liking VAS, and responses to the Drug Effects Questionnaire (DEQ).

Results

A higher level of effort was needed to manipulate morphine-ADER-IMT compared with morphine ER tablets. 38 subjects completed the study.

TDAA VAS median E_max scores:

• Intact morphine-ADER-IMT vs manipulated morphine ER: 56.0 vs 68.0; P<0.001

• Manipulated morphine-ADER-IMT vs manipulated morphine ER: 61.5 vs 68.0; P=0.054

Overall Drug Liking VAS median E_max scores:

• Intact morphine-ADER-IMT vs manipulated morphine ER: 57.0 vs 67.5; P=0.001

• Manipulated morphine-ADER-IMT vs manipulated morphine ER: 63.5 vs 67.5; P=0.128

DEQ for “I can feel good drug effects” median E_max scores:

• Intact morphine-ADER-IMT vs manipulated morphine ER: 17.5 vs 52.0; P<0.001

• Manipulated morphine-ADER-IMT vs manipulated morphine: 25.5 vs 52.0; P=0.003

Adverse event profiles of morphine-ADER-IMT and morphine ER were similar; no serious adverse events occurred.

Conclusions

Results suggest that manipulated morphine-ADER-IMT may have lower abuse potential compared with manipulated morphine ER when taken orally, even after greater effort was required to manipulate morphine-ADER-IMT. Additionally, the hardness of morphine-ADER-IMT makes them difficult to chew, presenting another significant barrier to misuse and abuse via the oral route compared with currently available ER morphine products.

30 Second Generation Automated Oxidant and Specific-Gravity Adulteration Detection Reagents for Sample Integrity Detection in Conjunction with DOA Testing

Jerry Denney

Vision Diagnostics, Inc., Branford, Florida, USA

Purpose

The primary purpose of this presentation is to present new research and product development of more effective automated adulterant testing and methods and reagents. A secondary purpose is to enhance awareness of the limitations of currently used detection methods and the consequences of these limitations.

Method

Oxidant Adulterant Detection - We have defined markers present in all human urine which are subject to oxidation in parallel to the destruction of DOA in urine samples. The markers include uric acid, ascorbic acid, cystine, cysteine all of which are detected between 600-850 nm with the alkaline phosphotungstate reagent of the new Oxidant History test. The markers were measured in parallel with Oxidant Adulterants including hydrogen peroxide/peroxidase (Stealth Type), laundry bleach, and potassium nitrite (Klear & Whizzies) using a commonly used oxidant detection reagent, 3,3’,5,5’ tetramethylbenzidine.

The sample measurements were made at time of collection and adulteration, at ten minute intervals following adulteration, and hourly for 24 hours.

Automated Specific Gravity - Newly developed Enzymatic reagents measuring total sodium and potassium in urine for Specific Gravity Index (SGI) were characterized to determine a lower cut-off level for sample dilution and a high cut-off level for adulteration.

Validation for detection of dilution: Urine samples were first assayed for creatinine level and then diluted with water to achieve creatinine levels of 10, 20 (dilution cut-off for creatinine), and 30 mg/dL. The samples were then assayed with the new Enzymatic Specific Gravity reagent using 1.0030 as the lower cut-off for dilution. The pre-dilution creatinine range was 31-253 mg/dL.

Validation for adulteration: Urine samples were spiked with 1-5% Sodium Carbonate (baking soda), liquid drain opener, Potassium Nitrite and Sodium Chloride. The samples were then assayed with the new Enzymatic Specific Gravity reagent using 1.0350 as the upper cut-off level for adulteration.

Results

Oxidative Adulteration - Urine samples spiked with the Oxidant Adulterants hydrogen peroxide/peroxidase (Stealth), laundry bleach, and potassium nitrite (Klear & Whizzies) using a commonly used oxidant detection reagent, 3,3’,5,5’ tetramethylbenzidine showed progressive decrease in detection and values, in terms of Nitrite Equivalents, and fell below the cut-off of both the 200 and 500 μg/mL for the test within as little as 30-60 minutes and were all below the cut-off level in 24 hours and remained low for several days.

The markers measured in the new Oxidant History test showed virtually identical decline rates and remained below the cut-off level of 15 mg/dL uric acid equivalents with all of the adulterated samples and continued to remain low for several weeks following adulteration.

Enzymatic Specific Gravity Index - All samples diluted to 10 mg/dL creatinine produced values below 1.0030 with an average SGI of 1.002 SGI which is below the dilution cut-off SGI of 1.003. Samples having diluted creatinine levels of 20 mg/dL gave average SDI values of 1.003 with a Standard deviation of 0.0007.

All samples spiked with 1% baking soda, liquid drain opener, Potassium Nitrite and Sodium Chloride were above the SGI cut-off for adulteration of 1.035 with values 10-84% above the 1.035 cut-off for adulteration. Samples spiked with 5% adulterant gave values from 186-2,288% above the adulteration cut-off.

The new Enzymatic SGI may be more indicative of dilution than Specific Gravity by weight per unit (W/UV) volume as the SGI correlates with creatinine levels which SG does not.

Conclusions

The new automated Oxidant History test is effective in determining that an oxidant has been added to the urine sample. Importantly, the prior oxidant adulteration can detect the oxidant adulteration for several weeks following collection; consequently, discrepant results between screening labs and confirmatory labs can be eliminated.

The new SGI is effective in detecting both dilution and both chloride and non-chloride salt addition. The non-hazardous enzymatic reagents can replace hazardous reagents used to measure chloride as a SG indicator.

31 A Randomized Control Trial Evaluating Perioperative Music Therapy on Postoperative Pain for Women Undergoing Surgical Treatment for Breast Cancer

Sharon Secord, Sara Whitmore, Sarah Derman, Jaswinder Gill, Ozge Goktepe

Fraser Health, Surrey, British Columbia, Canada

Purpose

Introduction and Background

Poor pain control is a major factor in contributing to delayed discharge after ambulatory surgery (Mattila & Hynynen, 2009). Listening to music is a simple, easy to implement, non-invasive, inexpensive, non-pharmacological intervention that has been shown to reduce post-operative pain in some surgical populations (Binns-Turner et al.2011; Nilsson et al. 2001, 2003, 2005; Engwall & Duppils, 2009; Economidou et al. 2012).

Previous studies have involved heterogeneous populations, inpatient procedures, limited exposure to music (i.e. intraoperative, or Post anesthetic care unit only), and measured immediate post-operative pain scores only.

Studying a more homogenous population, women undergoing surgery as outpatients for breast cancer, this study examined if continuously listening to music throughout the perioperative period (pre operatively, intra operatively and immediately post operatively) resulted in less opioid use, lower reported pain scores and shorter lengths of stay for women undergoing day surgery, compared to women in a placebo group (headphones with no music).

The purpose was to examine the effect of listening to music throughout the perioperative period had on pain scores and opioid consumption compared to a control group.

Method

A randomized controlled trial design with a placebo (headphones with no music) and having the health practitioners blinded was used to examine patients’ post-operative pain scores, opioid consumption and length of stay.

Additionally, data from follow up phone calls 24 hours after the surgery were reviewed to see if any difference in opioid consumption or pain scores continued after discharge from the outpatient center.

Results

Seventy women participated in this study, with 34 in the intervention group (headphones with music) and 36 in the placebo group (headphones but no music). The mean differences in pain scores and opioid consumption between the two groups was statistically significantly less in the intervention group at 2 of the 4 time periods and trending in that way in the other 2 periods.

Conclusions

This was a small pilot study which showed lower opioid consumption in the intervention group and lower reported pain scores. Although the use of headphones for both the placebo and intervention group allowed for blinding of the health professionals, it did alter the “standard of care”, and it may be possible that the placebo group actually received benefit from the headphones (i.e. blocking out other noises) that may not be fully captured in this study. Overall there does appear to be benefit to listening to music throughout the perioperative period, although the amount of benefit may be minimal.

32 Changes in nonmedical use of OxyContin® after reformulation with abuse deterrent properties

Angela DeVeaugh-Geiss, Paul Coplan, Howard Chilcoat, Nelson Sessler, Richa Singh

Purdue Pharma L.P., Stamford, CT, USA

Purpose

To estimate trends in nonmedical use (NMU) of OxyContin® (oxycodone HCI extended-release tablets) before and after reformulation with abuse deterrent properties in Aug 2010, using data from the National Survey on Drug Use and Health (NSDUH). Past-year initiation and past-month NMU were estimated adjusted for population and prescriptions of 1) OxyContin and 2) extended-release (ER) oxycodone, including generic versions of OxyContin, which comprised 18% of ER oxycodone prescriptions pre-reformulation in 2009 but <1% post-reformulation.

Method

The NSDUH uses a complex design to assess drug use from a sample of approximately 60,000 individuals age 12+ each year in the US. Respondents are shown images of brand OxyContin and queried about NMU in past year and past month. IMS National Prescription Audit (NPA) data was used as a measure of total prescriptions dispensed from retail, long-term care, and mail-order sources. Changes in rates were estimated from the pre-reformulation period (2009) to each year post-reformulation (2011-2014) with 2010 as a transition.

Results

Changes in OxyContin NMU varied by type of adjustment. Past-year initiation declined from the year prior (2009) to each year post-reformulation (2011, 2012, 2013, 2014) for population-adjusted rates (-19%, -38%, -28%, -51%, respectively) and OxyContin prescription-adjusted rates (-14%, -27%, -11%, -36%) but changes varied for ER oxycodone-adjusted rates (2%, -11%, 8%, -23%). Past-month NMU generally declined adjusted for population (-16%, -31%, -6%, -33%)and for OxyContin prescriptions (-11%, -19%, 16%, -13%) but generally increased when adjusted for ER oxycodone prescriptions (6%, -1%, 41%, 6%).

Conclusions

The magnitude of change in OxyContin NMU varied by adjustment. Because the NSDUH does not explicitly query about NMU of generic ER oxycodone in addition to brand OxyContin, declines observed in population- and OxyContin prescription-adjusted rates are likely more valid than estimates adjusted by ER oxycodone prescriptions.

33 Monitoring internet postings for mentions of an extended-release (ER) hydrocodone formulation with abuse-deterrent properties

Angela DeVeaugh-Geiss¹, Howard Chilcoat¹, Paul Coplan¹, Venkatesh Harikrishnan¹, Andrea Besharat², Jody Green²

¹Purdue Pharma L.P., Stamford, CT, USA, ²Denver Health RADARS System, Denver, CO, USA

Purpose

The first single-entity (SE) extended-release (ER) hydrocodone formulation with abuse deterrent characteristics, Hysingla ER, was approved by FDA in November 2014 and launched in January 2015. Because of the potential for abuse of opioids it is important to understand the interest of potential abusers. Therefore, internet mentions of Hysingla were examined before (3-4Q14) and after (1-3Q15) launch.

Method

Over 150 million websites (eg, public social media websites, forums, blogs) worldwide were searched using a commercially available web monitoring platform (operated by the RADARS® System Web Monitoring Program). All posts that mentioned Hysingla ER, regardless of content, were identified. Trained coders reviewed posts to characterize salient themes and identify posts related to misuse, abuse, addiction, overdose, death, route of administration, and source of drug acquisition. Additionally, because understanding availability during this time is important for context, monthly prescriptions dispensed were also examined using IMS Xponent data.

Results

The highest number of posts about Hysingla occurred prior to launch, increasing from 70 in 3Q14 (385 themes) to a peak of 1,293 in 4Q14 (4,920 themes). After launch, the number of posts was low: 149 posts (319 themes) in 1Q15, 120 posts (347 themes) in 2Q15, and 49 posts (149 themes) in 3Q15. After launch, the most common theme for posts (>90%) was opinion or sharing experience. Few posts mentioned abuse/misuse (3Q14-1Q15: 0%; 2Q15: <1%; 3Q15: 6.1%) and none mentioned addiction, overdose, death, or route of administration. During this time, dispensed prescriptions increased from approximately 8,000 in 1Q15 to over 25,000 in 3Q15.

Conclusions

There was a peak in internet discussion after FDA approval in anticipation of the launch, though overall discussion of Hysingla has been low with few posts mentioning abuse or misuse.

34 Sustained Response Outcomes from a Phase IIA, Randomized, Double-blind, Placebo-controlled Study of LY2951742, a Monoclonal Antibody to Calcitonin Gene-related Peptide for the Prevention of Migraine: A Post-hoc Analysis

David Dodick¹, Peter Goadsby^2,3, Vladimir Skjlarevski⁴, Margaret Ferguson⁴, Tina Oakes⁴, Yoko Tanaka⁴, Xiao Ni⁴, Qi Zhang⁴, Michael Due⁴, James Martinez⁴, Matthew Sexson⁴

¹Mayo Clinic, Phoenix, AZ, USA, ²King’s College of London, London, UK, ³University of California San Francisco, San Francisco, CA, USA, ⁴Eli Lilly and Company, Indianapolis, IN, USA

Purpose

At the endpoint of a recently reported study of LY2951742 vs. placebo various levels of response are reported. Two important clinical issues include how long early responses (at month 1) are maintained, and whether a subsequent clinically significant response occurs in initial non-responders at 1 month. We sought to examine sustained response outcomes for month 1 responders, and to determine subsequent response outcomes for non-responders at month 1.

Method

Post-hoc analyses from a phase 2a proof-of-concept study in patients aged 18-65 years with 4 to 14 migraine headache days per month who were randomly assigned to LY2951742 or placebo (NCT01625988) identified the proportion of patients with ≥50%, ≥75%, and 100% reduction in migraine headache days from baseline at month 1 who sustained those response levels for month 2 and month 3 (defined as ‘sustained response”). For non-responders at month 1, the proportions of patients with ≥50%, ≥75%, and 100% response at month 2 and 3 were identified.

Results

A total of 217 patients were randomized and received LY2951742 (n=106) or placebo (n=110). The proportion of LY2951742- vs. placebo-treated patients meeting ≥50%, ≥75%, and 100% sustained response were 47% vs. 25%, 22% vs. 13%, and 11% vs. 2%, respectively. Subsequent response outcomes for non-responders at month 1 will be reported.

Conclusions

These post-hoc analyses further characterize response outcomes from a single phase 2a trial of LY2951742 in migraine prevention. It is encouraging for patients and physicians that a significant proportion of responders continue their improvement out to three months.

35 Comparative Simulated Use Study of a Novel Auto-Injector and Nasal Delivery Device for Naloxone Administration

Evan Edwards¹, Eric Edwards¹, Glen Kelley¹, Nicole Fink², Emily Dissinger², Adam Shames²

¹kaleo, Inc., Richmond, VA, USA, ²Core Human Factors, Inc., Bala Cynwyd, PA, USA

Purpose

Administration of naloxone hydrochloride injection by trained emergency medical personnel has been the standard-of-care for reversal of life-threatening opioid-induced respiratory depression and overdose since 1971. In the early 2000s, emergency medical personnel developed pre-hospital intervention protocols for off-label intranasal administration of parenteral formulations of naloxone. In addition, harm reduction organizations, attempting to address the growing opioid overdose crisis, began distributing improvised naloxone intranasal delivery systems (NXN) to opioid users, social service agency staff, and family and friends of opioid users.

EVZIO®, a naloxone auto-injector (NAI) approved by the FDA in 2014, included design and development processes that utilized human factors engineering to optimize the user interface by considering user populations, non-medical setting use environments, and emergency use scenarios. With the availability of different naloxone delivery devices (NDDs), it is important to understand potential device use-related hazards that may result in ineffective use during a suspected opioid emergency.

The study objective was to compare the usability of two NDDs, NAI and an NXN, for naloxone administration during a simulated opioid overdose emergency. The primary endpoint was successful administration of a clinically meaningful naloxone dose into a mannequin without committing a critical task use error. A critical task use error occurred if a participant unsuccessfully performed a task such that a clinically meaningful dose of naloxone would not be delivered. Secondary endpoints were the use of NAI or NXN according to the instructions-for-use (IFU), use errors, time to completion of naloxone administration, and participant preferences.

Method

This single-site, randomized, open-label study included three different stages. During Stage 1, participants were briefly oriented to the testing environment and study materials, but not trained on the use of NAI or NXN, nor exposed to the products prior to testing. Participants could use the instructions found on or with the NDDs, however no additional instructional materials were provided. The testing environment consisted of a home-like setting with the mannequin randomly facing up or down on a couch. Participants used each NDD in randomized order to administer naloxone to the simulated patient experiencing a simulated opioid overdose. Stage 2, conducted on the same day as Stage 1, included a 30-minute training session by a registered nurse on the use of each NDD. Participants then demonstrated correct use of each NDD to the nurse. In Stage 3, conducted at least seven days after Stage 2, the participants used each NDD in randomized order, without additional training, to administer naloxone to the simulated patient experiencing a simulated opioid overdose, relying solely on their memory of training that occurred approximately one week prior. During Stages 1 and 3, participants provided feedback on each NDD’s usability and indicated NDD preferences.

Results

This study enrolled 41 participants age 18-64 years. Participants used NAI to successfully administer a clinically meaningful naloxone dose both before (97.6%) and after training (100%). No participants (0.0%) successfully used NXN before training and 43.9% were successful after training, p <0.0001.

Participants committed more critical task use errors while using NXN versus NAI in both Stages. The average per participant critical task use error was 0.0 for NAI in both Stages, and 3.8 and 1.0 for NXN in Stage 1 and 3, respectively. NXN critical task use errors were committed by all participants during Stage 1 and by the majority of participants in Stage 3.

In both Stages, 92.7% of participants used NAI in accordance with IFU. No participants (0%) and 31.7% of participants used NXN in accordance with IFU in Stage 1 and 3, respectively, p<0.0001.

Time to completion of critical tasks was calculated without regard to successful administration of naloxone. In Stage 1, mean time to completion was 1.0 minute for NAI and 7.0 minutes for NXN. In Stage 3, mean time to completion was 0.7 minutes for NAI and 1.8 minutes for NXN. (p-values<0.0001)

NAI was preferred over NXN in all characteristics measured in both Stages. Over 97% of participants preferred NAI to NXN overall.

Post hoc analysis was performed using these study results combined with results from a previous usability study with identical methodology and endpoints. A significant difference between the studies was that participants in the current study did substantially better completing tasks per IFU in Stage 3 for NXN. Combined study results showed mean time to successful naloxone administration in Stage 1 was 0.9 minutes for NAI and could not be calculated for NXN. In Stage 3, mean time for successful naloxone administration was 0.6 and 1.5 minutes for NAI and NXN, respectively.

Conclusions

This comparative usability study further validated the ability for laypersons to safely and effectively administer NAI in a potentially life threatening opioid emergency in the home or other non-medical settings. A substantially greater number of both trained and untrained participants were able to use NAI to successfully administer naloxone during a simulated opioid emergency compared to NXN.

The design and assembly of NXN may result in individuals not using NXN correctly during a highly stressful opioid emergency, even after focused individual training by a healthcare professional as demonstrated by this usability study.

36 Cebranopadol, a Novel First-in-class Analgesic: Efficacy, Safety, Tolerability in Patients With Pain Due to Diabetic Peripheral Neuropathy

M Eerdekens¹, ED Koch¹, M Kok¹, M Sohns¹, T Forst²

¹Grünenthal GmbH, Aachen, Germany, ²Profil Institut für Stoffwechselforschung GmbH, Medical Sciences, Neuss, Germany

Purpose

Reportedly, cebranopadol acts via nociceptin/orphanin FQ peptide (NOP) receptor and opioid receptor agonism. It is currently in development for the treatment of chronic pain conditions. We explored the effects of cebranopadol in diabetic peripheral neuropathy (DPN).

Method

Randomized, multi-center, double-blind, double-dummy, placebo- and active-controlled, parallel group, multiple dose, exploratory trial in moderate to severe chronic pain due to DPN. Rapid titration (2 weeks) to allocated dose was followed by 6 weeks of maintenance. The primary measure was pain assessed on an 11-point numerical rating scale (NRS).

Results

314 patients were analyzed in placebo, pregabalin 300 mg BID, or QD cebranopadol 100 µg, 300 µg or 600 µg treatment arms. Mean (SD) baseline pain score was 6.83 (1.26) on the NRS. A clinically relevant difference of at least -0.7 points NRS compared to placebo on change from baseline was shown with all cebranopadol doses with higher doses showing a larger difference. Cebranopadol 600µg significantly reduced pain according to MMRM analysis (difference compared to placebo in change from baseline to week 6 of maintenance on average 24-hour NRS): -1.01 (p=0.0153). All doses of cebranopadol were safe without systematic effects on ECG, vital signs or laboratory parameters. Among patients treated with cebranopadol, 73.4%, 82.0% and 85.5% of those taking 100 µg, 300 µg or 600 µg, respectively, experienced treatment-emerged adverse events (TEAE), compared with 75.4% and 69.4% on pregabalin and placebo. The most common TEAEs across all cebranopadol groups were nausea, dizziness, vomiting, fatigue, and somnolence.

Conclusions

In this trial cebranopadol was effective, safe and well tolerated in a population with pain due to DPN. Titration will be optimized in subsequent studies.

37 Supplementation of Tapentadol to Chronic Pain Patients on Buprenorphine Maintenance

Daniel Feldman

Integrated Sports and Spine, Lafayette, CO, USA

Purpose

Introduction: Buprenorphine is a semisynthetic opioid that functions as a mixed partial agonist opioid receptor modulator that can be used to control pain in low to moderate dosages while managing addiction in higher dosages. Tapentadol is a centrally acting opioid analgesic with a dual mode of action as an agonist of the mu-opioid receptor and as a norepinephrine reuptake inhibitor.

Objective: While it is known that buprenorphine, at doses used to treat chronic pain, both activates and blocks mu opioid receptions, it is unknown if patients receive additional analgesia from the addition of immediate release tapentadol for break through pain.

Method

An observational chart review series was performed, identifying five patients in a busy suburban interventional pain medicine practice, who were maintained with buprenorphine via a transdermal patch.

Results

Five patients were included. These patients had previously failed to respond to oral oxycodone or hydrocodone while on buprenorphine. The median VAS on buprenorphine alone was 8.6. With the addition of immediate relief tapentadol, in dosages ranging from 100 to 200 mg/day, the average VAS decreased to 3.0, a 64.4% reduction.

Conclusions

All five treated with a transdermal buprenorphine long acting opioid responded favorably to the addition of tapentadol once or twice daily for break through pain. Larger, prospective studies could be conducted to evaluate the potential benefit of tapentadol in combination with mu-blocking agents compared with traditional opioid pharmacological agents for pain management.

38 Interim Analysis of Practice Changes Following Participation in Online and Live ER/LA Opioid REMS CME/CE Programs from the CO*RE Collaborative

Thomas Finnegan¹, Piyali Chatterjee¹, Cynthia Grimes¹, Cynthia Kear², Tom McKeithen³

¹Medscape Education, New York, NY, USA, ²California Academy of Family Physicians, San Francisco, CA, USA, ³Healthcare Performance Consulting, Statesboro, GA, USA

Purpose

The epidemic of prescription opioid drug abuse, misuse, and addiction is well established. In April 2011, the Office of National Drug Control Policy (ONDCP) released an action plan to address the national prescription drug abuse epidemic. In response, the U.S. Food and Drug Administration (FDA) announced in 2012 the elements of a Risk Evaluation and Mitigation Strategy (REMS) that would require all manufacturers of extended-release and long-acting (ER/LA) opioids to ensure that education is provided to prescribers of these medications. The provision for education was designed to ascertain that the benefits of ER/LA opioid analgesics outweigh the risks in appropriate candidates. In response to this, the Collaborative for REMS Education, (CO*RE) consisting of 13 organizations, partnered to promote individual and population health and public safety through evidence-based and outcomes-oriented interprofessional education related to the comprehensive management of pain, addiction, and their comorbidities. CO*RE has received REMS Program Companies (RPC) grants since 2013, which has resulted in the development and delivery of more than 500 CME/CE activities, educating more than 170,000 clinicians across the U.S. in accordance with the FDA Blueprint. A subset of CME-certified activities on the topic of safe and appropriate use of ER/LA opioid analgesic therapies were specifically designed to include an assessment of changes in practice behavior among participating learners. The current interim analysis was designed to determine the effect of the first 30 CME/CE-certified RPC-supported activities on planned and implemented changes involved in the safe and appropriate prescription of ER/LA opioid analgesics.

Method

A total of 505 US-based health care professionals (HCPs) participated in the post-activity survey that formed the basis of the planned change assessment (PCA). Of the 30 activities included in the interim analysis, 25 were live meetings, 4 were webinars, and 1 online enduring CME activity. The release of the first activity included in the interim analysis was in May 2013 and the most recent activity took place in December 2015. The impact of each activity on self-reported practices related to the safe and appropriate prescription of opioid analgesics was measured using intent to change, a validated surrogate measure for actual changes in clinical practice. An email invitation to participate in the planned change assessment follow-up survey was sent to all respondents 6 weeks to six-months after the activity. This follow-up email served to remind the respondents of the program, and of their commitment to changes in their practice. The follow-up survey asked additional questions as to whether changes in practice were made, and about barriers to change if the change was not made. Survey participants’ stated intentions were compared with reported actual changes in performance, and barriers to implementing changes were assessed. Interim data for the 505 HCPs were collected through April 2016 and evaluated.

Results

The population of responders included in the interim analysis consisted of 50% physicians, 32% PAs, 16% advanced practice nurses (APN), and the remainder from other clinical professions. Among the respondents, 58% were primary care clinicians (PCP), 33% were non-pain specialists, and 8% were pain specialists.

• For all respondents, the most commonly reported change implemented into practice was “counseling patients and caregivers about the safe use of ER/LA [opioid analgesics]” (21%), whereas “initiating, modifying, or discontinuing treatment with ER/LA opioid analgesics” was the least frequently implemented (14%).

• For respondents who could prescribe medication, most commonly reported implemented changes were: “counseling patients and caregivers about the safe use of ER/LA [opioid analgesics]”(21%), “assessing patients for treatment with ER/LA opioid analgesic therapy” (19%), and “managing risks of patients prescribed ER/LA opioid analgesics” (18%).

• For non-prescribers, the most commonly reported implemented changes were: “referring patients when appropriate”(22%), “counseling patients and caregivers about the safe use of ER/LA [opioid analgesics]”(21%), and “managing risks of patients prescribed ER/LA opioid analgesics” (17%).

• PCPs reported both the largest average number of planned changes (3.2) and largest number of average implemented changes (2.5), whereas health care providers categorized as non-pain specialists had the lowest average number of planned changes (2.7) and average implemented changes (1.7). When assessed by profession, APNs reported the largest average number of planned changes (3.5), but the lowest average number of implemented changes (1.3). Although physician and PAs reported a different number of average planned changes (3.2 vs 2.6, respectively), they both reported the same average number of implemented changes (1.7).

• Barriers to the implementation of practice changes across all participants were: diversion (13%), cost of therapy (9%), participant concern regarding the potential for dependency or addiction to opioids (10%), and patient concern regarding the potential for dependency or addiction to opioids (8%).

Conclusions

The interim analysis of educational activities by CO*RE on the safe and appropriate prescribing of opioid analgesics indicated a strong likelihood that health care professionals were implementing what they learned into practice. Participants reported making changes regarding counseling on, and assessing patients for, opioid analgesic therapy. Further efforts should be aimed at increasing the number of health care professionals who report implementing changes on the initiation, modification, and/or discontinuation of opioid analgesics. In addition, future educational initiatives should address barriers preventing health care professionals from more effectively implementing practice changes.

39 An Assessment of Opioid Abuse Risk and its Relationship With Healthcare Resource use in Long-Term Opioid Users with Chronic Non-Cancer pain

Anna Coutinho¹, Kavita Gajria², Rupali Fuldeore¹, Pamela Landsman-Blumberg¹, Sanjay Gandhi²

¹Xcenda, Palm Harbor, FL, USA, ²Teva Pharmaceuticals, Frazer, PA, USA

Purpose

Abuse of prescribed opioids is a serious public health concern, with prescription opioid abuse estimated to account for $56 billion in annual societal costs in the United States. Opioid abuse rates vary and identified abuse risk factors differ depending on the population studied. Approximately 1 in 7 chronic pain ambulatory visits results in an opioid prescription, yet information on the rates and risk factors of opioid abuse, particularly in patients using long-term opioid therapy for chronic pain, is limited. Therefore, a better understanding of the risk factors for opioid abuse in this population is important when attempting to balance the benefits of pain relief with adverse outcomes of opioid use. The study objective was to examine evidence of a sub-population at risk of opioid abuse among long-term opioid users with chronic non-cancer pain (CNCP) and examine differences in all-cause health care resource use (emergency room [ER] visits and hospitalizations) based on identified risk criteria.

Method

A retrospective cohort study using the Truven Health MarketScan® medical and pharmacy claims databases (2006-2012) was conducted. The study index was the date of the first opioid prescription fill during 2007-2011, following the first of 3 medical claims for at least 1 of 5 types of CNCP (ie, low back, neck, osteoarthritis, neurologic, and fibromyalgia). Only long-term opioid users (≥90 days’ supply) were included in this analysis. The 1-year period prior to the first pain diagnosis was used to characterize the study sample at baseline. A 1-year follow-up period beginning at index was used to evaluate prevalence of opioid abuse (ICD-9-CM: 304.0, 304.7, 305.5, 965.0x excluding 965.01) and all-cause healthcare resource use. A Classification and Regression Tree (CART) analysis was used to examine evidence of a sub-population at risk for opioid abuse in the identified sample. An a priori list of 20 variables for the CART analysis was developed from the available claims data and scientific literature. Patients were classified into at-risk or low-risk groups based on the criteria developed using CART results. T-tests and chi-square tests were used to compare baseline characteristics. Comparisons of healthcare resource use were conducted for the at-risk vs low-risk and opioid abuse vs low-risk sub-populations using multivariable models with adjustment for baseline demographic and clinical characteristics.

Results

Among 21,072 CNCP patients with long-term opioid use, 455 (2.2%) had an opioid abuse claim. Age, average daily dose of opioid in mg morphine-equivalent dosing (MED), and total days’ supply of opioids were found to be important predictors of opioid abuse risk. A little over one-quarter of patients (26.9%, n=5,348; sensitivity=70.3%, specificity=74.1%; positive predictive value=5.6%) were identified as a possible sub-population at risk of opioid abuse. Patients at low risk (n=15,269) were significantly older (57.4±12.6 years) and less likely to be male (46.5%) relative to the at-risk cohort (n=5,348; 40.5±12.8; male=54.6%; both P<0.001) and those diagnosed with opioid abuse (n=455; 41.1±13.3; male=55.8%; both P<0.001), respectively. The low-risk cohort had significantly lower average daily dose (37.0±27.9 mg MED) and total opioid days’ supply (228.3±93.2 days) vs. the at-risk (80.5±78.1 mg MED and 310.3±86.1 days; both P<0.001) and opioid abuser cohorts (92.5±81.5 mg MED and 305.2±82.9 days; both P<0.001). As the low-risk cohort did not have any patients aged 18-30 years, all healthcare resource use analyses were conducted in patients aged ≥31 years (n=19,738). In the first year after opioid initiation, a significantly higher proportion of the at-risk cohort and opioid abusers relative to the low-risk cohort had ER visits (37.4% and 52.8% vs. 32.3%; both P<0.001) with adjusted odds (95% CI) of 1.14 (1.03, 1.26; P=0.009) and 2.14 (1.70, 2.70; P<0.001), respectively. Opioid abusers had significantly higher proportions of patients with a hospitalization relative to the low-risk group (42.4% vs. 30.4%; P<0.001) with adjusted odds of 2.33 (1.83, 2.96; P<0.001). The at-risk cohort had a significantly lower proportion of patients with a hospitalization (25.1% vs. 30.4%; P<0.001); however, after controlling for baseline characteristics, the adjusted odds indicated no significant difference (1.01 [0.90, 1.13]; P=0.864).

Conclusions

This study demonstrated that there is a sub-population at risk of opioid abuse among long-term opioid CNCP users. The identified at-risk criteria demonstrated limited sensitivity and specificity which could be attributed to limited information available in claims data and reinforces the importance of physician discretion in individual patient-level treatment decisions. While there were differences in ER visits, the inability to demonstrate differences in hospitalizations based on identified risk groups, highlights the need for developing more robust criteria with data sources that include factors used by clinicians in making decisions on patient care.

40 Use of a Core Set of Chronic Pain Questions within the Electronic Health Record to Evaluate Patient Reported Outcomes from an Individual and Population Health Perspective

Atiq Rehman¹, Marsha Cordts¹, Christopher Gillette², Tom Wolfe², Steve Faulkner²

¹Millennium Pain Center, Decatur, IL, USA, ²Pfizer Inc, New York, NY, USA

Purpose

Given the gaps in consistent electronic data capture for chronic pain, it is often difficult for physicians to systematically assess and monitor patients effectively during each office visit. Additionally, the inability to capture data on chronic pain at a population health level creates challenges for health care organizations (Integrated Delivery Networks, Medical Groups, physician practices) to understand its prevalence, provider management strategies, and the impact of treatment decisions. As a result of these challenges, health care organizations find it difficult to manage chronic pain and are unable to generate data to help guide the development of targeted solutions to address specific issues impacting the chronic pain patient population. The recently introduced Electronic Chronic Pain Questionnaire (eCPQ) was developed to help address these challenges by providing a solution for longitudinal pain management evaluation at an individual patient level and also to help collect population health data on patients suffering from chronic pain conditions. The eCPQ can be incorporated into most Electronic Health Record systems and has been developed to help providers capture relevant chronic pain data. The questions assist providers in systematically collecting discrete patient level data on chronic pain. The use of these questions determines the presence of chronic pain (defined as pain that persists for at least three months), and assesses pain intensity, location, and pain-related interference with function, sleep, and mood among patients with chronic pain. It provides physicians with an electronic record that can guide their “real time” clinical evaluation and track patient progress over time.

Method

A pain assessment form was created within GE Centricity and integrated into the patient visit workflow at a busy pain practice in the Midwest. The following electronic pain questions were added:

• Have you had pain most days or every day in the past 3 months? (Y/N)

• What was your pain over the past week? (NRS: 1-10)

• Where is your pain? (anatomical location of reported pain)

• How much did pain interfere with your daily activities? (NRS: 1-10)

• How much did pain interfere with your sleep? (NRS: 1-10)

• How much did pain interfere with your mood? (NRS: 1-10)

The responses to these questions were then displayed longitudinally so that the provider could quickly assess the patient’s pain and functioning during the current visit and could also observe responses over time. One year following implementation, August 2015, pain data was abstracted and analyzed from a population (pain clinic) perspective.

Results

Over the course of 1 year, 1,669 patients answered the electronic pain questions. Of those, 1,624 reported that they pain most days/every day for the past 3 months (chronic). There were more females (63.1%) in the pain population and the average age was 56.3 yrs. The top three pain diagnoses were back problem (87.3%), other connective tissue (40.9%), and other joint disease (40.0%) based on clinical classification system. Patients reported 3.9 pain locations per visit on average with low back, hip trochanter, and hip buttock being the most prevalent. Patient cohorts were divided by number of visits to the pain clinic in the year for subsequent results; 1 visit (418), 2 visits (320), 3 visits (255), 4 visits (232), and 5 or more visits (391). The first visit pain score (1-10) varied from 6.7 to 7.1 by cohort. From first to last visit, 21.7% to 30.3% by cohort experienced a ≥30 percent reduction in pain score, and 12.3% to 20% by cohort experienced a ≥50 percent reduction. A total of 25.6% to 32.9% by cohort reported a ≥30% improvement and 13.8% to 26.3% by cohort reported a ≥50% improvement in daily activities. A ≥30% improvement in mood was seen in 28.2% to 36.6% patients by cohort and 19% to 24.3% by cohort reported a ≥50% mood improvement. Finally, a ≥30% improvement in sleep was seen in 25.9% to 34% by cohort and a ≥50% sleep improvement was reported in 16.9% to 24.8% by cohort.

Conclusions

The inclusion of the eCPQ into the workflow of a pain practice in the Midwest has served to close the gaps in systematically capturing chronic pain data and has provided a wealth of information on chronic pain prevalence, provider management strategies, and the impact of treatment decisions. The integration of the eCPQ created minimal disruption in practice workflow and allowed providers to quickly assess the patient’s pain and functioning during the current visit, as well as, allowing them to observe responses over time.

41 Effects of hepatic or renal impairment on the pharmacokinetics of extended-release hydrocodone

Errol M. Gould¹, Christopher M. Rubino^2,3

¹Pernix Therapeutics, Morristown, NJ, USA, ²Institute for Clinical Pharmacodynamics, Latham, NY, USA, ³School of Pharmacy and Pharmaceutical Sciences, SUNY University at Buffalo, Buffalo, NY, USA

Purpose

Traditionally there has existed a need to consider hepatic and renal function when dosing opioid medications, because hepatic and renal dysfunction may impact the ability to metabolize and excrete opioids and may thus affect pharmacokinetics. Single-entity extended-release hydrocodone bitartrate (Zohydro® ER) (HC-ER) is indicated for the management of pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate. In this study, we have examined the influence of hepatic or renal dysfunction on hydrocodone pharmacokinetics in subjects treated with HC-ER.

Method

The pharmacokinetics, bioavailability, and safety of a 20-mg HC-ER dose in subjects with hepatic or renal impairment were evaluated in two open-label, single-dose, parallel-group design studies. In one study, subjects with mild or moderate hepatic impairment were enrolled (n=10/group), and in the other subjects with mild, moderate, or severe renal impairment were studied (n=9-10/group). Both studies included matched healthy control subjects. Non-compartmental pharmacokinetic parameters were derived from plasma and urine concentrations of hydrocodone and its metabolites norhydrocodone and hydromorphone.

Results

Minimal impact on hydrocodone pharmacokinetics was seen in patients with mild or moderate hepatic impairment after administration of HC-ER. Mean (±SD) area under the concentration-time curve from time zero to infinity (AUC_0-∞) was 440 (±124) and 509 (±157) ng•h/mL in subjects with mild or moderate hepatic impairment, respectively. These values were 10% and 26% higher, respectively, compared with control subjects (391±74 ng•h/mL). Maximal plasma concentration (C_max) of hydrocodone was also higher in patients with mild or moderate hepatic impairment; 8% (24±5 ng/mL) and 10% (25±5 ng/mL) higher, respectively, compared to control subjects (22±3 ng/mL). Mild and moderate hepatic impairment increased the hydrocodone terminal half-life (t_1/2) by 15% (9.1±1.6 hr) and 25% (9.9±2.1 hr), respectively, compared with control subjects (7.9±1.5 hr) while percent hydrocodone dose excreted in urine was increased 12% (8.3±2.4%) and 28% (9.5±2.5%), respectively, compared with controls (7.4±2.5%). Time to peak concentration (T_max) of hydrocodone was unchanged by hepatic status (6 hr). Norhydrocodone AUC_0-∞ (20% and 23%) and C_max (13% and 30%) values were reduced in patients with mild or moderate hepatic impairment, respectively.

Hydrocodone AUC_0-∞ values were 15% (391±122 ng•h/mL), 57% (547±184 ng•h/mL), and 44% (487±123 ng•h/mL) higher in subjects with mild, moderate, and severe renal impairment, respectively, compared with control (343±105 ng•h/mL), and C_max values were 15% (21.3±5.1 ng/mL), 48% (27.5±7.5 ng/mL), and 41% (25.8±6.0 ng/mL) greater than in control subjects (18.5±4.4 ng/mL). Similar trends were seen for the norhydrocodone metabolite.

Concentrations of the hydromorphone metabolite were low in both studies, often times below the lower limit of quantification, confounding interpretation of results. HC-ER was well tolerated in all subjects.

Conclusions

The observed differences in hydrocodone exposure between healthy subjects and those with either mild or moderate hepatic or mild renal impairment were not clinically meaningful. Thus there is no reason for a priori dose adjustment of HC-ER (Zohydro® ER) in patients with chronic pain. However, patients with moderate or severe renal impairment or severe hepatic impairment should be started on low doses of HC-ER, titrated slowly, and monitored for adverse events.

42 Accidental unsupervised ingestions of Nucynta ER in children less than six years-old: Frequency and risk of severe outcomes

Jody L. Green, Scott Kreider, Stevan Geoffrey Severtson, Richard C. Dart

Rocky Mountain Poison & Drug Center, Denver Health, Denver, CO, USA

Purpose

Nucynta® ER is an extended release (ER) formulation of tapentadol, a Schedule II opioid analgesic used for the treatment of moderate to severe chronic pain. Though intended to deter abuse via unintended routes of administration (e.g. injection), the crush-resistant properties may also be effective in reducing the severity of outcomes among pediatric accidental unsupervised ingestions. A tablet that is more difficult for children to chew could prevent ingestion, making it safer than other opioids. Rates of single substance accidental unsupervised ingestions and rates of severe adverse events (SAEs) among these exposures are calculated for Nucynta ER and compared to other ER opioids, and IR opioids. Rates are calculated per gram of drug dispensed.

Method

Data from the Researched Abuse, Diversion and Addiction-Related Surveillance (RADARS®) System Poison Center Program were used to assess unintentional general exposures in children less than 6 years involving either Nucynta ER, other ER opioids, and/or IR opioids from 3rd quarter 2011 to 1st quarter 2016. ER opioids include ER oxycodone, ER oxymorphone, ER hydrocodone, ER hydromorphone, and ER morphine. IR opioids include IR morphine, IR hydrocodone, IR hydromorphone, IR oxycodone, and IR oxymorphone. SAEs are defined as exposures resulting in death, a major medical outcome, or admission to a heath care facility. Analyses were restricted to single substance cases with known medical outcomes to control for potential confounding effects of multi-substance. Grams dispensed data were obtained from IMS Government Solutions. Rates of exposures and SAEs per gram of drug dispensed were compared using Poisson regression analysis.

Results

There were 22 accidental unsupervised ingestions involving only Nucynta ER compared to 867 involving an ER opioid other than Nucynta ER and 6,409 involving an IR opioid. Five Nucynta ER exposures resulted in an SAE. In contrast, there were 351 other ER opioid exposures and 288 IR opioid exposures that resulted in an SAE. The relative risk (adjusted for grams dispensed) of an exposure to other ER opioids and IR opioids was significantly higher than Nucynta ER (RR=2.37; p-value<0.001; RR=5.65; p-value<0.001, respectively). The relative risk of SAEs per gram of drug dispensed was significantly higher for other ER opioids than for Nucynta ER (RR=4.22; p-value=0.001) but no difference was noted between IR opioids and Nucynta ER (RR=1.12; p-value=0.807).

Conclusions

The risk of accidental unsupervised ingestions of other ER opioids is over 2 times higher and for IR opioids is almost 6 times higher than Nucynta ER (adjusting per gram of drug dispensed). There is also a 4 times higher risk of SAEs per gram of opioid dispensed for other ER opioids than for Nucynta. These risks should be considered when prescribing pain medication to patients with young children in the home.

43 Tampering and Medical Outcomes in Poison Center Abuse and Misuse Nucynta® ER Exposures

Jody L. Green, Marie-Claire Le Lait, Stevan Geoffrey Severtson, Richard C. Dart

Rocky Mountain Poison & Drug Center, Denver Health, Denver, CO, USA

Purpose

Nucynta® ER is an extended release formulation of tapentadol, a Schedule II opioid analgesic used for the treatment of moderate to severe chronic pain. It was released in the US in September 2011. Nucynta ER incorporates a crush-resistant technology intended to deter abuse via unintended routes of administration (e.g. inhalation, injection). This analysis compares the relative risk of tampering with Nucynta ER compared to non-abuse deterrent formulation (non-ADF) ER opioid tablets/capsules among abuse and misuse cases. Also examined were the proportions of abuse and misuse cases resulting in a major medical outcome or death for these two drug groups.

Method

Data from the Researched Abuse, Diversion and Addiction-Related Surveillance System (RADARS®) Poison Center Program from third quarter 2011 through first quarter 2016 were used. This study examined intentional abuse and misuse exposures involving either Nucynta ER or non-ADF ER opioid tablets/capsules (hydrocodone, hydromorphone, morphine, oxycodone, and oxymorphone). Products with FDA approved abuse deterrent labeling (OxyContin®, EMBEDA®, Hysingla® ER, Targiniq® ER, Zohydro® ER) were excluded. The analysis was restricted to single substance exposures and cases with a known medical outcome and route of administration. Use via any route other than ingestion alone was categorized as tampering. The relative risk (RR) of tampering with Nucynta ER compared to non-ADF ER opioid tablets/capsules was calculated with the 95% confidence interval (CI). Fisher’s exact test was used to examine the proportion of cases that resulted in a major medical outcome or death between the two groups.

Results

Among the intentional abuse and misuse exposures identified, 36 involved Nucynta ER and 526 involved non-ADF ER opioids tablets/capsules. Of these, 4 (11.1%) Nucynta ER cases and 151 (28.7%) non-ADF ER opioid tablet/capsule cases involved tampering. Non-ADF ER opioid tablet/capsule cases were 2.58 (95% CI: 1.02, 6.57) times more likely to involve tampering than Nucynta ER. None of the Nucynta ER cases reported major medical outcome or death while 70 (13.3%) non-ADF ER opioid tablet/capsule cases resulted in a major medical outcome or death (p-value=0.019).

Conclusions

Nucynta ER abuse and misuse cases reported to poison centers are less likely to report tampering compared to non-ADF ER opioid tablet/capsule cases. There were no reports of a major medical outcome or death among intentional abuse and misuse cases involving Nucynta ER. Prescription opioids with abuse deterrent properties may reduce abuse and misuse as well as severity of medical outcomes and should be considered one approach to addressing this significant public health issue.

44 Serious Game for Serious Disease: Diminishing Stigma of Depression via Game Experience

Weina Jin, Diane Gromala

Simon Fraser University, Surrey, Canada

Purpose

Stigma is a serious issue for patients suffering from depression. Patients will easily get moral judgements as being “lazy” or “weak”. Stigma prevents patients from getting timely treatment thus leading to serious consequences such as suicide. In this study, we aim to design a 2D platform video game to solve such problem.

Method

In the game, a stone is designed to tie to the avatar symbolized the depression burden. With the depression stone, the player experiences the disempowerment brought by disease condition.

In the beginning of the gameplay, when the player tries to pursue happiness and interest, his/her movement becomes extremely slow. Such behaviour is an instance of how one is easily led to moral judgement of the player as slow, lazy, and weak-willed.

Soon player will notice an overwhelming stone (metaphor of depression) tied to his/her body, which explains player’s slowness. The appearance of the stone explains the contradiction between ordinary task and unreasonable behavior, and stops player from directly judging the patient.

In the 4 challenge stages, the player fully interacts with the depression stone. Before the player gives up the seemingly unattainable goal (which is the usual scenario in depression), a supportive pickup will show up to help. Such experience conveys the message that getting support will dramatically alleviate the patient’s suffering and fasten the way to recovery.

By the end of the game, the depression stone will disappear, thus the play achieves his/her full potential, and eventually reaches the depression-free state. The game experience strengthens the message: “depression cannot define who you are; it simply defines what you are suffering”. The player learns to treat depression as other physical diseases without bringing in any moral prejudice. Thereby the stigma of depression will be diminished.

Results

In the game experience, the player goes through a heroic recovery journey, the player may undergo cognitive changes to reach the idea that depression, like heart disease, diabetes, cancer, or any other serious physical diseases, simply defines what player is suffering, rather than who the player really is.

Conclusions

Although the game is initially designed for patients with depression and their families to overcome stigma, by bringing the game to public domain, it may also serve a larger purpose: to diminish stigmatization associated with mental diseases on larger societal levels.

45 A Virtual Reality Game for Chronic Pain Management: A Randomized, Controlled Clinical Study

Weina Jin, Amber Choo, Diane Gromala, Chris Shaw

Simon Fraser University, Surrey, Canada

Purpose

Although the nature of chronic pain poses significant differences, the pain-attenuation effect of Virtual Reality(VR) from acute pain studies is nevertheless favorable for chronic pain management. Because of its immersive characteristic and analgesic effect, VR may serve as a potential non-pharmacological intervention to fulfill the treatment gap of chronic pain from either long-term management or short-term relapse control. There are still too few research papers available to confirm VR’s effectiveness for chronic pain relief. Therefore, our study adapts what was learned from previous research on the analgesic effects of VR for acute pain, and builds on these findings specifically for chronic pain patients. We designed an immersive virtual reality game called Cryoslide, and conducted a clinical study to determine if it may prove effective as a short-term intervention for chronic pain management.

Method

In the game design of Cryoslide, we employed pain distraction strategies. In the game, the player could interact with different creatures in the icy environment by hitting them with snowballs. The player’s aim is to calm down these agitated creatures with snowballs to earn as many points as possible.

We performed a randomized, controlled crossover clinical study to evaluate the analgesic effect of Cryoslide. Subjects who were 18 years of age or older with the diagnosis of chronic pain were eligible for enrollment. Chronic pain was diagnosed by the pain specialist with the following criteria: ongoing pain lasting longer than 3 months. Participants who had a high risk of motion sickness, or severe pain around the HMD contact regions were excluded from the study. We used Visual Analog Scale (VAS) to collect pain intensity data. Additional questions regarding distraction experience were also incorporated into the questionnaire. Subjects first filled out the Intro Questionnaire which collects the baseline data. They then were randomly assigned to undergo either the VR intervention or the self-mediated control group for 10 minutes, followed by a washout period of 5 minutes. After that they crossed over to the other group for another 10 minutes.

During the washout period, subjects filled out the Post-Intervention Questionnaire, which was used to collect pain intensity data at present and during the past 10 minute.

Results

Of the 23 eligible subjects enrolled, 3 subjects dropped out because of personal time constraints or nausea. The statistical analysis was performed on data of 20 subjects. Four were male (20%) and 16 were female (80%). Their age varied from 30 to 75- years-old.

Pain intensity during and after the interventions was measured. For pain intensity after the interventions, the two groups of the VR intervention and self-mediated control were not significantly different using repeated measures ANOVA (F(2, 38) = 1.377, p = 0.265). However, for pain intensity during the intervention, there was a significant difference between the VR intervention and control groups (F(2, 38) = 21.473, p < 0.001, r = 0.505). Mauchly’s sphericity test was not violated (χ2(2) = 3.726, p = 0.155).

Compared to the baseline, there was a 36.7% reduction in pain intensity during the VR intervention using Bonferroni post hoc tests (95% confidence interval [CI], -31.443 to -11.657; p < 0.001). Compared to control group, the VR intervention group also had a significant reduction in pain intensity (95% confidence interval [CI], -27.397 to -6.953; p = 0.001). There was no significant difference between the baseline and control group in pain intensity (p = 0.336).

In comparison to the control group, subjects in the VR intervention group reported a 56% reduction in the amount of time thinking specifically about their pain (p < 0.001, r = 0.75); subjects also reported a statistically significant effect on losing track of time (p < 0.001, r = 0.78) in the VR intervention compared to the control condition. Subjects also found themselves less frequently thinking unrelated things (p = 0.07, r = 0.57) and thinking inwardly (p = 0.47, r = 0.48) in the VR intervention, but their differences with the control group did not show a statistical significance.

Conclusions

The study result demonstrated that during the VR session, Cryoslide could significantly reduce the perception of pain intensity for chronic pain suffers in comparison to the baseline. Compared with self-mediated interventions such as reading, listening to music, or playing mobile games, our VR game gained more analgesic effect on chronic pain patients’ suffering; it also significantly distracted patients’ attention from their daily pain.

46 Interlaminar Cervical Epidural Steroid Injection with Contrast Vascular Spread: A Case Report

Hamilton Chen, Douglas Grover, Paul Chan

University of California Riverside, Riverside, CA, USA

Purpose

An epidural steroid injection is a popular non-surgical treatment option for patients with persistent radicular pain. Although considered generally safe, one complication of concern is injecting into vasculature instead of the epidural space. Intravascular injections of particulate steroids may lead to the rare catastrophic complication of hemorrhage or infarction of the brain, brainstem, or spinal cord. Vascular spread is more commonly described as a complication of a transforaminal approach, especially in the cervical region. One study demonstrated the incidence of vascular spread using the transforaminal approach in the cervical spine was 19.6%. The incidence of intravascular spread with an interlaminar approach is relatively unknown and less common. The purpose of this report is to discuss a rare incidence of a 48-year-old male who underwent an interlaminar cervical epidural steroid injection with intravascular contrast spread at C7-T1, despite negative aspiration.

Method

A 48-year-old male with history of lumbar and cervical stenosis presented to our pain management clinic with symptoms of neck pain that radiated to the upper extremities. The pain has been ongoing for over 15 years, and the patient had undergone conservative measures, including physical therapy, acupuncture, and medications with continued pain. An MRI of the cervical spine demonstrated moderate spinal stenosis at multiple levels. An interlaminar cervical epidural steroid injection at C7-T1 was attempted. During the procedure, a loss of resistance technique using a glass syringe and saline was utilized to locate the entrance of the epidural space. After negative aspiration, contrast was then injected to confirm appropriate placement in the epidural space before administering glucocorticoids.

Results

Once the contrast was introduced at C7-T1, a vascular pattern of contrast was visualized. This continued to be present despite reintroducing and turning of the needle. The C7-T1 level was aborted and the procedure was completed successfully at T1-T2 without a vascular dye pattern.

Conclusions

This case demonstrates an uncommon incidence of visualizing intravascular spread with an interlaminar cervical epidural. It emphasizes that negative aspiration of the syringe is not a reliable indication of intravascular needle placement. Due to the potential consequences from intravascular injection of particulate steroids and/or local anesthetic, providers should be aware of the possibility of intravascular needle placement with interlaminar cervical epidural injections. Providers should also be aware that negative aspiration of the syringe is an unreliable technique for detecting intravascular needle placement and live fluoroscopy with contrast dye should be utilized for detecting intravascular spread for all cervical epidural injections.

47 Decreased Pain and Opioid Use Following Use of a Compounded Topical/Transdermal Analgesic: Third Interim and Preliminary Control Group Results from the Optimizing Patient Experience and Response to Topical Analgesics (OPERA) Observational Study

Jeffrey Gudin¹, Edmund Harris², Michael Brennan³, Peter Hurwitz⁴, Derek Dietze⁵

¹Englewood Hospital and Medical Center, Englewood, New Jersey, USA, ²Safe Harbor Compliance and Clinical Services, LLC, Austin, Texas, USA, ³The Pain Center of Fairfield, Fairfield, New Jersey, USA, ⁴Clarity Research and Consulting, LLC, Austin, Texas, USA, ⁵Metrics for Learning, LLC, Queen Creek, Arizona, USA

Purpose

Up to 40% of patients treated for chronic pain do not attain adequate analgesia. Opioid pain therapies have significant side effects. Evaluation of opioid-sparing treatments, including topical/transdermal compounded formulations, is critical to identify safer approaches to pain treatment. This pre-planned third interim analysis of an observational study (IRB-approved, informed consent obtained), evaluated the efficacy of topical/transdermal analgesics in reducing Brief Pain Inventory (BPI) Severity and Interference scores and opioid use in patients experiencing neurologic or musculoskeletal pain. In addition, preliminary results for the control group of patients not using a compounded topical/transdermal analgesic over the same time period are reported. Lastly, subgroup analysis was used to identify any differences in BPI scores for patients using diclofenac-containing as compared to ketoprofen-containing compounded topical/transdermal analgesics.

Method

Following IRB approval and patient consent, data were collected beginning in 2014 via paper survey forms completed by study participants from 85 physicians who treat patients with chronic pain. The top four physician specialties were: anesthesiology, general medicine, pain management, and podiatry. Physician practices were in 12 different states across the USA. 631 adult patients experiencing chronic neurologic or musculoskeletal pain received a topical/transdermal analgesic containing compounds such as flurbiprofen 20%, amitriptyline 5%, magnesium chloride 10%, gabapentin 6%, bupivacaine 2%, ketoprofen 5%, diclofenac 20% for a mean of 76 days. Surveys were administered at the first (pretreatment) and third patient visit, with pain levels assessed by BPI (Short Form). Primary complaints/symptoms were recorded, along with any side effects, use of oral pain medications, and general satisfaction with the use of study topical/transdermal analgesics. The preliminary analysis of control group results includes 17 patients who completed the pretreatment questions (Survey 1) and Survey 3 at ~3 months, but did not receive treatment. For the subgroup analysis also reported here, 115/631 paired records were identified for patients using a ketoprofen-containing compounded topical/transdermal analgesic, and 307/631 paired records for patients using a diclofenac-containing compounded topical/transdermal analgesic.

Results

Paired data from 383 females and 248 males were collected during 2014-2015. Reductions in pain following a mean of 75.5±22.5 days of treatment were found for 11/11 BPI items. Mean BPI Severity score decreased 31% (4.8 to 3.3/10; P<.001), and mean BPI Interference score decreased 40% (4.5 to 2.7/10; P<.001). Mean number of primary complaint categories decreased from 2.1 to 1.8 (P<.001). Use of OTC, anti-inflammatory, and opioid medications decreased significantly (51%, 64%, and 28% respectively, P<.001 for each). No side effects were reported by 99.5% of patients, with 0.5% (3) reporting a rash—none were serious adverse events. 92% were very (50%) or somewhat (42%) satisfied overall with the topical/transdermal analgesic, with 76% preferring it over an oral medication. In the control group (preliminary analysis, n=17), mean number of complaint categories increased (1.9 to 3.4), mean BPI Severity scores increased (4.2 to 4.5), and mean BPI Interference scores increased (3.2 to 4.7), while OTC oral pain medication use stayed the same (94% to 94%), anti-inflammatory use increased (6% to 59%), and opioid use increased (6% to 18%). 65% of control group respondents kept their medication and dosage the same in the past 3 months, 24% decreased dose of medication, and 12% increased dosage. Data from a larger number of control group patients may be available for reporting in the poster. In the subgroup analysis, mean BPI Severity and Interference score decreases were greater for patients using diclofenac-containing (-1.7 and -2.2/10) as compared to ketoprofen-containing (-1.2 and -1.2/10) compounded topical/transdermal analgesics (P=.028 and .001). Also, for patients using the diclofenac-containing topical/transdermal analgesics, mean decreases in BPI Severity and Interference scores for patients 30 to 41 years of age (-2.1 and -2.7/10) were greater than those for patients 53 to 64 years of age (-1.5 and -2.0), P=.040 and .042.

Conclusions

Test group results suggest that topical/transdermal analgesics used in this study may reduce BPI scores for adult patients with neuropathic and musculoskeletal pain, reduce the number of primary pain complaints for arthritis, neuropathy or radiculopathy, and myofascial/musculoskeletal pain or spasm, and reduce use of oral OTC, anti-inflammatory and opioid analgesics. No changes or increases in these same results were found for the 3-month control group. Overall patient satisfaction with topical/transdermal analgesics was high—they were safe and well-tolerated. Findings consistent with previous interim analyses. Diclofenac-containing compounded topical/transdermal analgesics may have a more positive effect on BPI scores than ketoprofen-containing topical/transdermal analgesics.

48 Decreased Opioid Use and Pain Scores After 5 Months Using a Compounded Topical/Transdermal Analgesic: Fourth Interim and Preliminary Control Group Results from the Optimizing Patient Experience and Response to Topical Analgesics (OPERA) Observational Study

Jeffrey Gudin¹, Edmund Harris², Michael Brennan³, Peter Hurwitz⁴, Derek Dietze⁵

¹Englewood Hospital and Medical Center, Englewood, New Jersey, USA, ²Safe Harbor Compliance and Clinical Services, LLC, Austin, Texas, USA, ³The Pain Center of Fairfield, Fairfield, New Jersey, USA, ⁴Clarity Research and Consulting, LLC, Austin, Texas, USA, ⁵Metrics for Learning, LLC, Queen Creek, Arizona, USA

Purpose

Up to 40% of patients treated for chronic pain do not attain adequate analgesia. Opioid pain therapies have significant side effects. Evaluation of opioid-sparing treatments, including topical/transdermal compounded formulations, is critical to identify safer approaches to pain treatment. This pre-planned fourth interim analysis of an observational study (IRB-approved, informed consent obtained), evaluated the efficacy of topical/transdermal analgesics in reducing Brief Pain Inventory (BPI) Severity and Interference scores and opioid use over a 5-month period in patients experiencing neurologic or musculoskeletal pain. In addition, preliminary results for control groups of patients not using a compounded topical/transdermal analgesic over 3-month and 6-month time periods are also reported.

Method

Following IRB approval and patient consent, data were collected beginning in 2014 via paper survey forms completed by study participants from 40 physicians who treat patients with chronic pain. The top four physician specialties were: general medicine, podiatry, and general or foot/ankle surgery. Physician practices were in 9 different states across the USA. 158 adult patients experiencing chronic neurologic or musculoskeletal pain received a topical/transdermal analgesic containing compounds such as flurbiprofen 20%, amitriptyline 5%, magnesium chloride 10%, gabapentin 6%, bupivacaine 2%, ketoprofen 5%, diclofenac 20% for a mean of 164 days. Surveys were administered at the first (pretreatment) and sixth patient visit, with pain levels assessed by BPI (Short Form). Primary complaints/symptoms were recorded, along with any side effects, use of oral pain medications, and general satisfaction with the use of study topical/transdermal analgesics. The preliminary analysis of control group results includes 37 patients who completed the pretreatment questions (Survey 1) but did not receive treatment, 17 of which also completed the Survey at ~3 months (3-month control group), and 20 of which completed the Survey at ~6 months (6-month control group).

Results

Paired data from 93 females and 65 males were collected during 2014-2015. Reductions in pain following a mean of 164.3±24.0 days of treatment were found for 11/11 BPI items. Mean BPI Severity score decreased 43% (4.7 to 2.7/10; P<.001), and mean BPI Interference score decreased 52% (4.2 to 2.0/10; P<.001). Mean number of primary complaint categories decreased from 2.3 to 1.8 (P<.001). Use of OTC, anti-inflammatory, and opioid medications decreased significantly (51%, 71%, and 45% respectively, P≤.001 for each). None of the patients reported any side effects. 99% were very (60%) or somewhat (39%) satisfied overall with the topical/transdermal analgesic, with 85% preferring it over an oral medication. In the 3-month control group (preliminary analysis, n=17), mean number of complaint categories increased (1.9 to 3.4), mean BPI Severity scores increased (4.2 to 4.5), and mean BPI Interference scores increased (3.2 to 4.7), while OTC oral pain medication use stayed the same (94% to 94%), anti-inflammatory use increased (6% to 59%), and opioid use increased (6% to 18%). 65% of control group respondents kept their medication and dosage the same in the past 3 months, 24% decreased dose of medication, and 12% increased dosage. In the 6-month control group (preliminary analysis, n=20), mean number of complaint categories increased (1.5 to 2.4), mean BPI Severity scores stayed the same (4.5 to 4.5), and mean BPI Interference scores increased (3.6 to 4.5), while OTC oral pain medication use increased (45% to 90%), anti-inflammatory use increased (0% to 40%), and opioid use increased (10% to 15%). 40% of control group respondents kept their medication and dosage the same in the past 6 months, 20% decreased dose of medication, and 30% increased dosage. Data from a larger number of control group patients may be available for reporting in the poster.

Conclusions

Test group results suggest that the topical/transdermal analgesics used for 5 months in this study may reduce the use of oral OTC, anti-inflammatory and opioid analgesics, reduce BPI scores for adult patients with neuropathic and musculoskeletal pain, and reduce primary pain complaints for arthritis and neuropathy/radiculopathy. No changes or increases in these same results were found in the 3-month and 6-month control groups. Overall patient satisfaction with topical/transdermal analgesics was high–they were safe and well-tolerated. Findings were consistent with previous interim analyses (n=631). Further analysis with a larger control group is planned—results may be available for the poster.

49 The Long-term Analgesic Effectiveness of Opioid Therapy in Chronic Non-Cancer Pain Patients: A Literature Review of Randomized Controlled, Open-label, and Epidemiologic Studies

Jeffrey Gudin¹, Srinivas Nalamachu², Laura Wallace³, Rayna Matsuno⁴, Paul Coplan^3,5

¹Pain Management and Palliative Care, Englewood Hospital and Medical Center, Englewood, NJ, USA, ²Pain Management Institute, Overland Park, KS, USA, ³Medical Affairs Strategic Research, Purdue Pharma L.P., Stamford, CT, USA, ⁴Henry M. Jackson Foundation, Naval Health Research Center, Military Population Health, San Diego CA, USA, ⁵Adjunct assistant professor, University of Pennsylvania School of Medicine, Philadelphia, PA, USA

Purpose

Pain, a major cause of suffering and disability, is a frequent reason for physician visits and taking medications. With recently issued guidelines (eg, by CDC) and mandates (eg, by state medical boards), there is increased opposition to the use of opioid analgesics to treat chronic pain, with many stating that there is a lack of scientific evidence that these agents are effective long-term (>3 months to 1 year). FDA’s Guidance for Industry on developing medicines for analgesic indications recommends that chronic pain studies are of at least a 3-month duration. Maintaining placebo controls in longer-term trials (>3 months) would present a challenge, and some may question the ethics of treating moderate to severe pain with placebo. Consequently, there are no “long-term” placebo-controlled RCTs evaluating opioid efficacy.

However, single-arm open-label (OL) studies, open-label extension (OLE) studies, and epidemiology studies, many of which are ≥6 months, represent a source of useful information to assess the effectiveness of long-term opioid treatment. These measure longitudinal changes in pain and functional outcomes. Patients in OL studies and the subset of patients in RCTs that elect to continue into OLE studies may reflect the real world patients who are maintained on chronic opioid therapy. The objective of this study is to provide an up-to-date review of the literature and summarize changes in pain scores and function from pre-treatment to 3 months, and to ≥6 months of opioid analgesic treatment as reported in RCTs, OL, OLE, and epidemiologic studies among chronic noncancer pain (CNCP) patients.

Method

A literature search was conducted of published studies of long-term opioid treatment (LOT) in CNCP. Studies were identified using the search terms “opioid,” “long*,” and/or “therapy” in MedLine, EMBASE, Biosis Previews, and PubMed through May, 2016. Additional articles were identified through review of consensus statements, clinical guidelines, literature reviews and meta-analyses. Studies were included regardless of the specific opioid analgesic under study or the route of administration, to maximize coverage of the topic.

Each abstract identified through this search was reviewed by two authors to determine if it met the inclusion criteria. Only original, full-text, English-language articles were included. The review was restricted to studies that were ≥6 months in duration, which ensured that long-term effects were being observed. In addition to RCTs, the review included OL clinical studies (single-arm treatment), OLEs (studies in which RCT participants continue in an unblinded study extension during which both active and placebo groups receive active treatment) and epidemiology studies (observational cross-sectional or cohort studies utilizing registry or insurance claims data). Descriptive studies, such as those for which a relationship between LOT and a selected outcome was not evaluated (e.g., case series), were excluded. If an OL, OLE, or epidemiology study included both cancer and CNCP patients and presented results for the groups separately, the study was included, but only results for the CNCP group were evaluated and presented. RCTs with both cancer and CNCP patients were excluded. Outcomes of interest, including changes in pain score, function, and drop-out rates were extracted.

Results

Two hundred sixty articles representing 268 studies on long-term opioid therapy were identified. Of these, 82 were not original studies, 2 were published in a language other than English, 43 did not evaluate a CNCP population, 63 were less than 6 months in duration, and 7 did not evaluate analgesic effectiveness. After exclusions, there were 70 studies included in the current report: 8 RCTs, 33 OL trials, 14 OLE studies, 11 cohort studies, and 4 cross-sectional studies. The 55 RCTs, OL studies, and OLE studies represented 13,686 patients and 11,808 person-years of opioid treatment experience. The 15 epidemiologic studies represented 5,492 patients and 4,478 person-years of opioid treatment experience.

Forty-nine studies had data for percent change in pain scores from study baseline to end of study. Of these, 18 were 6 to <12 months in duration and 31 were ≥12 months in duration. The average change in pain scores showed a 2% to 82% improvement from baseline. A ≥25% reduction in pain scores from baseline to the end of the study was reported in 43 (86%) studies. Thirty-seven (75%) of these studies reported a ≥30% reduction in pain scores from baseline to the end of the study. Thirteen (26%) of these 49 studies (1 RCT, 10 OLs, 1 OLE and 1 epidemiology study) exhibited a ≥50% decrease in pain score. Study duration (6 to <12 months versus ≥12) did not affect the proportion of studies demonstrating a ≥25% and ≥50% reduction.

A smaller number of studies evaluated measures of function; 10 of 11 (91%) studies that included these data demonstrated a positive correlation between clinically significant changes in pain and physical function scores. Data on mental function were more limited.

Conclusions

Continued analgesic benefit for a substantial percentage of chronic pain patients treated for ≥6 months with opioids was shown amongst those patients who remained in the studies. The data indicated that reductions in pain reported in ≤3 month RCTs were maintained long-term in patients who participated in RCT, OL, OLE, and epidemiological studies ≥3 months. Seventy-five percent of these studies reported a ≥30% reduction in pain scores, usually accepted as meaningful improvement and reflective of real-world patient experience with opioids. Few studies reported functional status outcomes, suggesting the need to incorporate these efficacy measures in future studies.

50 DNA Verified Sample Authenticity for Urine Drug Testing Results from early commercial experience with a new method for matching submitted urine samples to specific patients

Wenjing Guo, Robert Rhodes, Paul Samilpa

Genotox Laboratories, Austin, Texas, USA

Purpose

Widespread growth in the use of opioid analgesics has resulted in serious unintended consequences. According to a recent report by the Centers for Disease Control and Prevention (CDC), there has been a 200% increase in the rate of opioid-related overdose deaths between 2000-2014, prompting the agency to call for an intensification of efforts to ensure safe prescription of opioids.¹

Medication & sobriety monitoring via urine drug screening and testing (UDT) is the primary tool available for helping Providers identify aberrant behaviors which signal a patient is headed in the wrong direction during treatment with prescription painkillers. Due to the potential for abuse and misuse of prescribed medications, it is essential that the Provider have accurate, timely and valid test results to make certain patients are following their treatment plan.

There are, however, several risks to the usefulness of UDT test results that, until now, have been very difficult to identify and quantify. If a sample is mislabeled – how do you know? If a patient has a friend or family member provide them with a “clean” urine sample – how do you know? If a patient goes online, orders and uses one of the many synthetic urine products available – how do you know? Indeed, without some reliable method of urine sample authentication, it is quite possible that the results relied upon by the provider to properly manage a patient’s care have no relevance whatsoever.

Presented here are the findings from early commercial use in nearly 2,700 samples.

Method

The ToxProtect DNA-verified sample authenticity method was developed by Genotox Laboratories, and has been validated to be an accurate, sensitive and specific test for matching patients to the urine samples submitted for testing. The ToxProtect service is available to all customers sending samples to the lab. All samples are analyzed in accordance with the laboratory-developed protocol for matching urine samples to buccal cell samples.

Upon initial enrollment in the program, a patient submits both a urine and buccal cell sample. DNA is extracted, amplified and analyzed according to protocol. Three outcomes are possible: 1) Indeterminate (IND) – the sample(s) yielded insufficient DNA to enable an accurate call, 2) Negative Match (NM) – the urine sample does not match the buccal cell sample or 3) Positive Match (PM) – the urine and buccal samples are from the same person. After enrollment, the buccal cell data are stored and compared to subsequent urine samples to confirm sample authenticity.

Once analysis is completed and results have been communicated to the ordering provider, all data is de-identified and entered into a database to monitor and track real-world experience with indeterminate, positive and negative match rates. Commercial participation was opened on January 1, 2016 and data were collected through July 8, 2016.

Results

During the data collection period 2,677 samples were submitted from 36 clinical sites. The smallest sites submitted only 1 sample and the largest site submitted 765 samples. The Indeterminate rate was 6.3% with a range by site of 0% to 17%. The “Negative Match” rate was 1.3% with a range of 0% to 18% (one site that submitted one sample that was a negative match had a 100% negative match rate). Preliminary analyses suggest that Negative Match rates are highest amongst 20-30 year old patients.

Additional analyses and surveying of users indicates two different approaches to use of ToxProtect in clinical practice. Twelve of the 36 sites accounting for 91.5% of samples submitted are using the verification method with all of their samples submitted. This group has and IND rate of 6.2% and a negative match rate of 1.0%. Twenty-four of the 36 sites are using ToxProtect on “selected” patients. The IND rates in this group 7.5% and the negative match rate is 4.0%

Conclusions

Urine drug tests provide critical information necessary for ensuring proper and effective use of prescription pain medications. A large industry exists for selling products to facilitate fraud in urine drug testing. It is also possible that errors in labeling and handling urines samples occur. Knowing the importance of accurate and valid drug test results, and the consequences of not catching aberrant behaviors immediately, it becomes readily apparent that the results of UDT must include a highly reliable and robust method for making certain the sample analyzed and the results reviewed do, in fact, belong to the patient in question.

51 Efficacy of Avazzia BEST^TM Microcurrent Stimulation Device For Pain and Symptoms Associate with Pain

Tammy Lahutsky, Devyn Pontzer, John Hache

Avazzia, INC., Dallas, TX, USA

Purpose

Electro-stimulation devices are prescribed for the treatment of acute and chronic pain. The purpose of this survey was to examine patient perceptions of the effectiveness and safety of treatment with Avazzia Biofeedback Electro-Stimulation Technology (BEST^TM) microcurrent devices for relief and alleviation of pain.

Method

Patients who received an Avazzia BEST device through their doctor to use at home for acute or chronic pain were invited to participate in a survey. Participants voluntarily chose to respond to a questionnaire. Responses were received from 41 participants who had an Avazzia BEST-Pro 1 or BEST-RSI device. The questionnaire had 24 questions to evaluate the effectiveness of Avazzia technology for treating pain and symptoms of pain. Not every question applied to each patient, so some questions were not answered. Data was analyzed using descriptive statistics. In addition to analysis related to pain reduction, questions related to decrease in medication and improvement in sleep were included.

Results

Participants reported effectiveness in pain reduction (97 percent), improved range of movement (100 percent) and improved ability to return to daily activities (94 percent) after using BEST devices for treatment. In addition, 56 percent reported using less or significantly less medicine and 73 percent reported bettor or much better sleep after using BEST therapies.

Based on the survey of patients from 2009 to 2011, there were no reported side effects of Avazzia BEST devices. No negative claims have been reported through Avazzia regarding side effects of the Avazzia BEST devices.

Conclusions

Respondents perceived the Avazzia BEST devices as effective and safe treatment for alleviation of pain. Avazzia BEST devices can be used to provide patients with a safe, non-invasive, non-pharmacological treatment for pain.

(The technology of BEST devices and their results have improved significantly with the introduction of the ProSport devices in 2015 though that data isn’t fully available yet).

52 Shoulder Pain: Effectiveness of Pro-Sport^TM Microcurrent Electro-Therapy for Pain in a Single Outpatient Visit with Patients Exhibiting Shoulder pain and/or symptoms consistent with Shoulder Pain: PRO-SPORT Open-Label Shoulder Pain Study

Thomas Lenahan¹, Tammy Lahutsky¹, Devyn Pontzer¹, John Hache¹

¹Avazzia, INC, Dallas, TX, USA, ²Cornerstone Wellness Center, Plano, TX, USA

Purpose

Microcurrent electrical stimulation for pain has been researched and reported effective in a number of recent studies. The purpose of this preliminary study is to document educational training modules in the use of Avazzia technology for reducing shoulder pain in a diverse population of patients with varying degrees of pain, and limited mobility. Self-reported chronic pain levels associated with shoulder pain symptoms, and increasing range of motion were measured and reported indicating effectiveness of the microcurrent therapy using the Avazzia PRO-SPORT^TM device, a non-invasive hand-held microcurrent device that utilizes microchip and interactive technology to produce an electrical current with the skin as a conduit, cleared by the US FDA for treating pain.

Method

The study was designed as an open-label study. The patients were seen over a single 60-minute visit at the office of Thomas Lehanan, DC. Each patient had a treatment diagnosis ICD-9 code consistent with frozen shoulder or symptoms associated with frozen shoulder or chronic shoulder pain. All participants presented with a history of chronic pain of at least three months and a limited range of motion in the affected shoulder of varying degrees of pain.

For this study, two forms of measurements were used to compare before and after treatments. They were a self-reported VAS score to determine the strength of the pain, and measurement of the range over which the pain occurred.

Each patient received four microcurrent therapies in a single outpatient visit using the PRO-SPORT^TM device in a designed protocol. The Avazzia PRO-SPORT^TM device is a US FDA cleared microcurrent electro-neurostimulation medical device with Reaction data cleared for indication of use for pain relief that delivers a pulsed, high-voltage, damped, biphasic asymmetric sinusoidal waveform with frequencies ranging from 0.5Hz to 2500Hz and variability of power intensity.

Outcomes measured were self-reported pain levels prior to treatment using numeric visual analog scales, initial reaction and ongoing reaction data obtained using the PRO-SPORT^TM device during treatment, and self-reported pain levels post-treatment using numeric visual analog scales.

Results

After the single outpatient microcurrent treatment was administered, 100% of patients reported a reduction in pain score, and 100% of patients reported an increase in range of motion before feeling pain indicating that over a range, all participants experienced a complete relief of pain. There were no adverse side effects reported with the use of this treatment.

5.64 out of 10 was the average Initial Pre-Treatment VAS Reading. The average Post-Treatment VAS Reading was 2.50 out of 10. These results represented an average pain score reduction of 59.5% across the patient population.

After treatment, total range of freedom of movement indicates that every participant reported increased range of motion. 100% of the participants experienced a noticeable increase in shoulder extension range of motion, and 57% of the participants experienced a 50% or more increase in shoulder flexion.

Conclusions

The Avazzia PRO-SPORT^TM device can reduce pain levels in patients with various degrees of chronic pain. The statistically significant reduction in pain of this degree in a single treatment indicates there is a high probability (>90%) of these results being replicable over a larger pain population and an increased reduction of chronic pain with extended use. However, the sustainability of the beneficial effect over an extended period of time and larger population will need to be considered to further conclude the effectiveness of this treatment.

53 Utilization of the Proove Opioid Risk Profile in Clinical Care

May Hafez, Sapana Kabaria, Ashley Brenton, Svetlana Kantorovich, Brian Meshkin

Proove Biosciences Inc, Irvine, CA, USA

Purpose

The purpose of this study was to determine the clinical utility of the Proove Opioid Risk Profile, an algorithm-based decision tool designed to assess risk associated with opioid use. Specifically, we sought to assess how physicians were using the profile and how guided or unguided treatment affected patient outcomes.

Method

A prospective, longitudinal study was conducted to assess the utility of genetic testing in 4,692 patients across 76 clinics in the USA. The research sites were stratified into four different specialty groups: Family Medicine/Primary Care/Internal Medicine, Neurology/Psychiatry, Orthopedic Surgery, and Pain Medicine/PMR/Anesthesiology. Using a patent-protected, validated algorithm combining specific genetic risk factors with phenotypic traits, patients were categorized into low, moderate and high risk for opioid use. Physicians that ordered genetic testing were asked to complete patient evaluations and document their actions, decisions, and perceptions regarding the utility of the genetic tests.

Results

Physicians rated the benefit of the profile on making clinical decisions an average of 3.5 on a 5-point scale (1 indicating no benefit and 5 indicating significant benefit). 80% of clinicians felt the test exhibited some benefit to their patient care, with 30% indicating they felt the test provided significant benefit. Although the average benefit varied by clinical specialty, the benefit to physicians was reported to be greater in high risk than low or moderate risk patients. Decisions/actions that provided the most benefit to physicians included changing the opioid prescribed, feeling more confident with the treatment regimen, changing the frequency of urine toxicology monitoring, and discontinuing of opioid treatment. Regarding patient outcomes, physicians who took action based on the test result rated its benefit to patient outcomes 0.71 points higher than controls on a 5-point scale and saw a 29% increase in patient improvement within 60 days.

Conclusions

The Proove Opioid Risk Profile influences physician decision-making and results in improved patient outcomes. Further, those patients at high risk benefited the most by guided treatment decisions.

54 An Observational Study of the Impact of Genetic Testing for Pain Perception in the Clinical Management of Chronic Non-Cancer Pain

May Hafez¹, Sapana Kabaria¹, Ashley Brenton¹, Maneesh Sharma², Svetlana Kantorovich¹, Brian Meshkin¹, Steven Richeimer^3,4

¹Proove Biosciences, Inc, Irvine, CA, USA, ²Interventional Pain Institute, Baltimore, MD, USA, ³University of Southern California Keck School of Medicine, Los Angeles, CA, USA, ⁴University of Southern California Departments of Anesthesiology and Psychiatry, Los Angeles, CA, USA

Purpose

Pain levels are a key metric in clinical care. However, the assessment of pain is limited to basic questionnaires and physician interpretation, which yield subjective data. Genetic markers of pain sensitivity, such as single nucleotide polymorphisms in the catechol-O-methyltransferase gene, have been shown to be associated with pain perception and been used to provide objective information about a patient’s pain. The goal of this study was to determine if physician treatment adjustments based on genetic tests of pain perception resulted in improved outcomes for patients.

Method

A prospective, longitudinal study was conducted with 134 chronic non-cancer pain patients genotyped for pain perception-related catechol-O-methyltransferase haplotypes. Physicians were provided with patients’ results and asked to document 1) their assessment of benefit of the genetic test; 2) treatment changes made based on the genetic test; and 3) patient clinical responses to changes implemented

Results

Based on genetic testing results, physicians adjusted treatment plans for 40% of patients. When medication changes were made based on genetic testing results, 72% of patients showed improvement in clinical status. When non-pharmacological actions were performed, 69% of physicians felt their patients’ clinical status improved. Moreover, physicians believed the genetic test results were consistent with patient pain levels in 85% of cases.

Conclusions

These results demonstrate that providing personalized medicine with genetic information related to pain perception affected physician clinical decision-making for a substantial proportion of patients in this study, and that the availability and utilization of this information was a contributing factor in clinical improvement.

55 Nitromedicine

Salaheldin Halasa, Juseph Purita, Zidi Berger

Nitromedicine, Easton, MD, USA

Purpose

Managing Oxidative Stress Related Diseases (OSRDs) and enhance Stem Cell Therapy.

Method

It has been known since the discovery of the biological role of NO in the 1980s, that supplying NO donors such can have many beneficial effects in different conditions by stimulating stem cells and modulating the immune response, however, there also exists a substantial risk of side-effects with long-term use. Excess NO can inhibit mitochondrial metabolism by binding to cytochrome c oxidase (CCO) and can also produce reactive nitrogen species (Peroxynitrite) by interacting with reactive oxygen species (ROS).

To avoid these potential damaging side-effects we propose to combine the use of NO donors with four additional components.

Initially, we believe that the addition of antioxidants such as Thiols, Polyphenols and Vitamins can neutralize ROS and RNS.

Secondly, we believe that application of appropriate wavelengths and dosages of light (blue, red or near infrared depending on the exact condition being treated) will dissociate NO from CCO (and other storage sites) thus restoring mitochondrial ATP production and stimulating healing in many situations.

Thirdly, we think detoxification will remove the pathological free radical generators and increases the nitric oxide bioavailability.

Lastly, by delivering electrons to the body through electrotherapy, we might help to saturate the free radicals with electrons, thus eliminating underlying oxidative stress, stabilizing mitochondria, preventing further formation of pathological free radicals and increasing the nitric oxide bioavailability.

Results

This combination therapy may be applied to treat and prevent large variety of oxidative stressed related diseases such as degenerative diseases, immunological diseases, chronic infectious diseases, cancers and a broad range of unmet medical needs involving chronic inflammation with an emphasis on pain management.

Conclusions

Nitromedicine is a new medical specialty, focused on modulating Nitro-Redox Sensitive Biochemical Pathways to managing Oxidative Stress Related Diseases (OSRDs) and enhance Stem Cell Therapy.

56 Parenteral Methadone: Friend or Foe

Levi Hall^1,2, Annas Aljassem¹

¹Beaumont Health, Beaumont Hospital - Royal Oak, Royal Oak, Michigan, USA, ²Oakland University William Beaumont School of Medicine, Rochester, Michigan, USA, ³Eugene Applebaum College of Pharmacy and Health Sciences, Detroit, Michigan, USA

Purpose

The pharmacological treatment of acute pain for opioid-tolerant patients requiring high doses of opioids (greater than 500 mg of oral morphine equivalent per day) can be challenging, suboptimal, and is often based on expert opinions and consensus. Methadone is a mu-opioid agonist, antagonist at the N-Methyl-D-aspartate receptor, and inhibits the reuptake of serotonin and norepinephrine. Methadone is indicated for the treatment of moderate to severe pain which is poorly controlled, despite high doses of opioids. The use of methadone may have particular benefits over other opiates, specifically in patients with a significant opioid tolerance or in patients with neuropathic pain. Patients who are poorly responsive to other opiates or have contraindications to treatment with opiates may have improved analgesia with rotation to methadone. Methadone may be useful for patients with a component of neuropathic pain, for patients who have poorly controlled pain despite appropriate use of other opioids (either due to refractory pain or intolerable side effects), or for patients with a true morphine allergy. Due to incomplete cross-tolerance with other opiates, reduction in dose is required when rotating from another opiate. Several published conversions exist for opioid rotation to methadone, making the calculation more challenging. This requires introduction of more clinical experience and judgment. Here, we evaluate the final dose titration (parenteral and oral formulations) required to comfort, compared to empiric published dosing recommendations.

Method

We have completed a longitudinal case-series of the first 8 adult patients at our institution from July 2015 - July 2016 who required greater than 500 mg of oral morphine equivalents, and were transitioned to IV methadone for acute pain stabilization with subsequent conversion to oral methadone for chronic pain management by the interdisciplinary palliative care service. Outcome measures included total daily dose of oral morphine equivalent required at the time of conversion, initial and final IV methadone regimen, initial and final oral methadone regimen, pertinent drug-drug interactions, EKG monitoring, and self-reported pain scores (numeric rating scale). Final titrated parenteral and oral dose required for pain stabilization will be compared to the empiric dose recommendations from the consensus guideline on parenteral methadone use in pain and palliative care.

Results

Data collection and analysis are currently being conducted; final results and conclusions will be presented at the 2016 PAINWeek Conference.

Conclusions

Parenteral methadone dosing guidelines were developed and successfully implemented at a large, tertiary, academic hospital. The mechanisms of action for methadone as compared to traditional opioids provide a unique medical treatment for patients with high opioid-requirements not reaching their therapeutic goal. The pharmacokinetic profile, including variations between oral and parenteral formulations, present significant challenges to prescribers in providing this effective therapy. Supervision, experience, and teamwork make the use of this medication a powerful tool in providing relief from uncontrolled pain for patients that may not otherwise find comfort.

57 Discriminating between Neuropathic Pain and Sensory Hypersensitivity using the Chronic Pain Questions (CPQ)

Karin Coyne¹, Brooke Currie¹, Joseph Cappelleri², Rozelle Hegeman-Dingle², Andrea Alexander², Lucy Abraham², Alesia Sadosky², Marina Brodsky²

¹Evidera, Bethesda, MD, USA, ²Pfizer Inc., New York, NY, USA

Purpose

Chronic pain is a disabling and costly health concern that affects a significant number of adults globally. Three main types of pain pathophysiology-nociceptive, neuropathic (NeP), and sensory hypersensitivity (SH) also known as centralized pain or central sensitivity syndromes-are thought to be responsible for the majority of clinical presentations of chronic pain. As these different types of pain respond differently to pharmacotherapy, collecting data that helps elucidate pain type may help guide appropriate treatment selection. The 14-item Chronic Pain Questions (CPQ) was developed for use in clinical practice to help primary care physicians collect data on chronic pain to support efficient screening and monitoring of patients. The CPQ can be administered electronically (as eCPQ) and integrated into the electronic health records. The CPQ includes questions that: identify presence of chronic pain (yes/no); assess pain intensity (0-10 numeric rating scale [NRS]) and location (body map); measure pain interference with usual activities, sleep, and mood; and assess trouble with thinking/remembering and sensitivity to lights/noises/smells (each on a 0-10 NRS). The CPQ also includes the ID Pain, an independently validated tool that differentiates between nociceptive and non-nociceptive pain. Furthermore, patients’ responses to the CPQ, together with their medical history, may help detect the presence of SH pain, however, it is not known if the CPQ can differentiate between patients with SH and patients with other types of chronic pain. The purpose of this study was to examine the ability of the CPQ to discriminate between patients with NeP and those with SH.

Method

In this cross-sectional study, five US-based clinical sites recruited adults with a physician-confirmed diagnosis of either a NeP or SH condition to participate. For the SH group, a mix of conditions were recruited: fibromyalgia (FM), irritable bowel syndrome (IBS), interstitial cystitis (IC), chronic fatigue syndrome (CFS), and temporomandibular joint (TMJ) disorder. Study participants completed paper versions of the CPQ, Pain Outcomes Questionnaire - Short Form (POQ-SF), Short Form Health Survey 36 (SF-36), Hospital Anxiety and Depression Scale (HADS), Medical Outcomes Study Sleep (MOS-S) scale, Fibromyalgia Survey Questionnaire (FSQ) and a sociodemographic form. Clinic staff completed a form which captured a participant’s clinical diagnosis and basic medical information.

Descriptive statistics were used to summarize demographic and clinical variables while group comparisons were performed to examine subgroup responses to the CPQ. Continuous variables were compared with independent t-tests; categorical variables were compared with chi-square analyses. Two series of exploratory logistic regressions were performed to explore cutoff values for CPQ questions to be potentially predictive of SH. The models varied by the inclusion of either the total ID Pain score (Model 1) or the inclusion of the individual symptoms of the ID Pain scale (Model 2). For each model, the following covariates were included: age, gender, number of body areas with pain, mood impact, difficulty thinking/remembering, and sensitivity to lights/noises/smells. For each model, receiver operator characteristic (ROC) curves and concordance (c) indices were calculated to evaluate the discriminative ability of each model and Hosmer-Lemeshow goodness-of fit-tests were performed to evaluate model fit.

Results

98 (68 SH, 30 NeP) patients participated; 73.5% were Caucasian, 81.6% female; mean age was 54.8. SH participants had significantly more females than NeP participants (94.1% vs. 53.3%, p<0.0001). Large proportions of both groups reported arthritis (48.5-50.0%), hypertension (44.1-60.0%), and depression (30.0-47.1%), though anxiety was reported more frequently by SH participants (41.2% vs. 16.7%, p=0.018).

Compared to NeP participants, SH participants had significantly lower Vitality (26.3 ± 20.6 vs. 39.3 ± 20.8, p=0.005), Mental Health (55.9 ± 22.1 vs. 69.2 ± 21.2, p=0.007), and Mental Component Summary scores (39.2 ± 11.8 vs. 47.8 ± 11.3, p=0.001) on the SF-36. No significant group differences were seen for the HADS or MOS-S scales. No significant differences were noted in the POQ-SF subscales or total score, with exception of the Negative Affect subscale where SH participants had higher mean scores (24.5 ± 12.9 vs. 16.4 ± 13.9, p=0.006). SH participants had significantly higher scores (p<0.001) across all FSQ subscales indicating higher levels of impairment than NeP participants.

The results above generally support findings related to CPQ. Differences in CPQ responses between groups were statistically significant (p<0.05) for seven items and ID Pain total score with NeP participants reporting higher total scores (3.4 vs. 2.3). SH participants had significantly higher scores for “trouble thinking/remembering” (5.3 vs. 3.0) and “sensitivity to lights/noises/smells” (4.8 vs. 2.7). No significant differences were noted between groups in pain intensity, “pain made worse with touch,” “pain limited to joints,” or pain interference with “usual activity,” “sleep,” or “mood.”

Results were comparable among all logistic regressions with slight variations in which covariates were significant. Results demonstrated high c-indices for all models (range: 0.89 to 0.97). Consistent findings across models demonstrated that younger age, female gender, and scores >6 for “sensitivity to lights/noises/smells” were all predictive of SH.

Conclusions

These findings suggest that the CPQ is able to discriminate between patients with NeP and those with SH conditions, and that the CPQ may be useful in identifying the presence of SH. Additional research is needed to further evaluate the predictive value and usefulness of the CPQ in identifying chronic pain patients with different types of pain pathophysiology and its ability to support improved management of patients with chronic pain in clinical practice.

58 Patients Treated with CL-108 Over a 5-day Post-Operative Period Use Less Antiemetic Medication for Opioid-Induced Nausea and Vomiting (OINV) than Patients Treated with Standard Hydrocodone/Acetaminophen

Elliot V. Hersh¹, Bernard Schachtel²

¹University of Pennsylvania School of Dental Medicine, Philadelphia, PA, USA, ²Charleston Laboratories, Inc., Jupiter, FL, USA

Purpose

CL-108 is a formulation containing hydrocodone 7.5 mg/acetaminophen 325 mg (HC/APAP) and rapid-release promethazine 12.5 mg. In a phase 3 study, patients who used CL-108 for moderate-to-severe postoperative pain had significantly less opioid-induced nausea and vomiting (OINV) than patients who used commercially available HC/APAP (p <0.001). Because the use of antiemetic medications is an objective outcome measure for OINV, indicating patients’ response to their nausea/vomiting, we analyzed patients’ use of antiemetic medications in this trial.

Method

This was a randomized, double-blind, active- and placebo-controlled multi-site study in patients with moderate-to-severe pain following oral surgery [Clinicaltrials.gov NCT01780428]. Patients were randomized to CL-108, HC/APAP, or placebo and self-dosed as needed for pain every 4-6 hours over 5 days. Supplementary (rescue) analgesic and antiemetic medications were taken according to patient need.

Results

Over 5 days, 39.8% of CL-108-treated patients (n = 211) reported moderate or severe nausea, compared to 60.5% of HC/APAP-treated patients (n = 205) and the incidence of vomiting was 13.3% for CL-108-treated patients, compared to 26.3% for HC/APAP-treated patients (both p <0.001). Antiemetic medication was taken by 11 (5.2%) patients who used CL-108 compared to 42 (20.5%) patients who used HC/APAP, representing a 75% relative reduction in the number of patients using antiemetics (p <0.001). Patients treating pain with HC/APAP also required antiemetics earlier in the course of analgesic therapy than CL-108-treated patients (p <0.001).

Conclusions

Compared with the use of HC/APAP, the use of CL-108 for moderate-to-severe pain resulted in significantly less use of antiemetic medications for OINV.

59 The costs and cost drivers of opioid misuse by diagnosis: abuse, dependence, and overdose/poisoning

Jaren Howard¹, Noam Kirson², Lauren Scarpati², Aliya Dincer², Jessica Hanway², Miriam Zichlin², Howard Birnbaum²

¹Purdue Pharma L.P., Stamford, CT, USA, ²Analysis Group, Inc., Boston, MA, USA

Purpose

The existing scientific literature estimating the healthcare burden of opioid misuse disorders often combines all patients within the broad category of “opioid abuse” as defined as opioid abuse, dependence, or overdose/poisoning. Collectively, these can significantly increase healthcare costs among commercially insured patients. Existing studies estimate that these costs range from approximately $10,000 to $20,000 per-patient-per-year. Real world medical coding practices present challenges to researchers aiming to separately analyze excess costs by diagnosis, though combining these diagnoses may mask some variation in excess costs. Furthermore, little is known about the specific drivers of excess costs at the diagnosis-level.

This study contributes to the literature by assessing the excess costs and primary cost drivers for each of the three opioid-related diagnoses separately, among a commercially insured population.

Method

Using de-identified data from OptumHealth Reporting and Insights, a large national commercial claims database, we selected patients ages 18-64 whose first observed diagnosis of opioid abuse [ICD-9-CM diagnosis codes: 304.0x, 304.7x, 305.5x, 965.00, 965.02, 965.09] occurred in Q1/2012-Q1/2015. The study period was defined as the 12-month period centered on the first abuse diagnosis and was preceded by a 6-month baseline period. Abusers were matched to non-abuser controls using propensity score methods. Excess costs were calculated as the mean difference between healthcare costs of abusers and controls. Primary cost drivers were identified by grouping medical claims at the 3-digit ICD-9-CM level, overall and by place of service.

Results

1-year mean healthcare costs were $27,194 for patients with incident opioid dependence diagnoses and $13,922 for matched controls (N=7,390 pairs; 79.1% of sample), resulting in mean excess costs of opioid dependence of $13,271 (2015 USD). 1-year mean healthcare costs were $24,314 for patients with incident opioid abuse diagnoses and $12,629 for matched controls (N=1,099 pairs, or 11.8%), resulting in mean excess costs of $11,686. For overdose/poisoning patients, 1-year mean healthcare costs were $47,591 for patients with incident diagnoses and $15,425 for matched controls (N=853 pairs, or 9.1%), resulting in mean excess costs of $32,166.

The distribution of excess costs across places of service differed across diagnosis categories:

Inpatient claims accounted for 35.1% of excess costs of patients diagnosed with abuse, 31.3% for overdose/poisoning, and 21.0% for dependence. Emergency department claims accounted for 38.2% of excess costs of patients diagnosed with overdose/poisoning, 35.6% for abuse, and 20.2% for dependence. Rehabilitation facility claims accounted for 22.4% of excess costs of patients diagnosed with dependence, 13.0% for abuse, and 2.1% for overdose/poisoning. Outpatient/other claims accounted for 34.0% of excess costs of patients diagnosed with dependence, 22.6% for abuse, and 20.7% for overdose/poisoning. The remaining excess costs were attributable to prescription drugs.

For opioid dependence, claims with an opioid misuse disorder diagnosis code accounted for $4,008 (30.9%) of excess costs. Claims associated with non-opioid drug and alcohol dependence and abuse accounted for $4,355 (33.6%). The remainder of excess costs was attributed mainly to mental health-related diagnoses, back disorders, and other pain. For opioid abuse, claims specific to opioid misuse disorders accounted for $2,398 (19.3%) of excess costs, while non-opioid drug and alcohol dependence and abuse accounted for $3,557 (28.6%). For opioid overdose/poisoning, opioid misuse disorders accounted for $3,435 of excess costs (11.6%). Claims associated with non-opioid drug and alcohol abuse accounted for $1,177 (4.0%).

Conclusions

Diagnosed opioid abuse, dependence, and overdose/poisoning are all associated with substantial excess costs. However, important differences emerge across diagnosis categories in terms of places of service and cost drivers. While excess costs of opioid abuse and dependence are quite similar, overdose/poisoning is associated with substantially higher excess costs, particularly related to care received in inpatient and ED settings. The similarity of excess costs across opioid abuse and dependence diagnoses despite somewhat different place-of-service distributions may be due to different treatment patterns for the two diagnoses, but could also suggest a possible role for place-of-service-specific coding practices.

60 The economic burden of opioid abuse and its drivers: evidence from a payer perspective

Jaren Howard¹, Noam Kirson², Lauren Scarpati², Aliya Dincer², Jessica Hanway², Miriam Zichlin², Howard Birnbaum²

¹Purdue Pharma L.P., Stamford, CT, USA, ²Analysis Group, Inc., Boston, MA, USA

Purpose

Opioid pain relievers can be highly effective in providing relief for patients suffering from pain. At the same time, prescription opioid abuse, dependence, overdose, and poisoning (hereinafter “abuse”) have become a national public health concern. Opioid abuse is also costly: annual societal costs of opioid abuse in 2007 were estimated at $55.7 billion in the US. Payers face a substantial portion of these costs, with previous estimates of the annual excess costs of opioid abuse to payers ranging from approximately $10,000 to $20,000 per patient. Notably, the current literature does not sufficiently address the drivers of these excess costs in terms of diagnoses and places of service. Do the bulk of these additional costs occur in an inpatient setting? Which conditions and ailments drive opioid abuse-related costs?

This study contributes to the existing literature in several ways: first, by providing refined, current estimates of the excess costs of opioid abuse from a payer perspective both before and after the abuse diagnosis; second, by investigating the drivers of these excess costs; and third, by comparing the findings to a similar set of analyses conducted using a comparable, yet different, large employer claims database.

Method

Using the de-identified Truven MarketScan commercial claims database for a large number of employers, we selected patients ages 18-64 whose first observed diagnosis of opioid abuse [ICD-9-CM diagnosis codes: 304.0x, 304.7x, 305.5x, 965.00, 965.02, 965.09] occurred in Q1/2012-Q1/2015. The study period was defined as the 12-month period centered on the first abuse diagnosis and was preceded by a 6-month baseline period. Opioid abusers were matched to non-abuser controls using propensity score methods. Excess costs were calculated as the mean difference between healthcare costs of abusers and controls, in 1-month and 6-month increments. All amounts are in 2015 USD. Primary cost drivers were identified by grouping medical claims at the 3-digit ICD-9-CM level within 6-month increments, overall and by place of service. The MarketScan-based findings were compared to a parallel set of analyses conducted using another large commercial claims database, OptumHealth Reporting & Insights.

Results

92% of abusers in MarketScan were successfully matched to non-abuser controls, for a total of 75,190 matched pairs. While noticeable differences existed between abusers and controls pre-match, post-match groups were well-balanced. 1-year mean healthcare costs were $25,223 for opioid abusers and $13,753 for matched controls, resulting in mean excess cost of abuse of $11,470. 41% of excess costs occurred in a rehabilitation facility setting, 36% in an inpatient setting, 10% in an ED setting, and 7% of costs in an outpatient/office setting. 5% of excess costs were attributable to prescription drug costs. We observe a build-up in excess costs prior to the opioid abuse diagnosis, with monthly excess costs gradually rising to $786. Excess costs peaked during the index month ($3,658), then quickly dropped off thereafter, ranging from $876 to $1,333 in the 5 months following diagnosis.

Four diagnosis categories were most prominent in driving excess costs: opioid abuse, non-opioid substance abuse and dependence, painful conditions, and mental health disorders. Specifically, in the 6 months prior to the index date, claims specific to non-opioid drug abuse and dependence accounted for $554 (18%) of excess costs. Claims associated with back pain and other painful conditions ($370, or 12%) and mental health disorders ($170, or 5%) also contributed to pre-index excess costs. In the 6 months following the index date, opioid abuse-related diagnoses were the largest contributor to excess costs ($2,418, or 31%), followed by non-opioid substance abuse and dependence ($2,149, or 28%). Mental health disorders ($635, or 8%) and back pain and other painful conditions ($349, or 5%) also contributed.

These findings are generally comparable to those derived from the Optum database, though excess costs in Optum were moderately higher, and a larger share of excess costs in Optum were attributable to both opioid and non-opioid substance abuse and dependence.

Conclusions

Opioid abuse was associated with $11,470 in excess costs during the 12 months surrounding an initial abuse episode. Excess costs began increasing well before the initial diagnosis, with non-opioid drug abuse treatment comprising a substantial proportion. Following the incident opioid abuse diagnosis, excess costs were largely driven by the costs of treating opioid abuse (31%) and non-opioid drug abuse (28%). These findings are generally consistent across commercially-insured populations. Our findings highlight the complex nature of opioid abuse, which often occurs in the context of other substance abuse.

61 Early-through-late drug liking of crushed intranasal Morphine ARER (MorphaBond^TM) relative to crushed intranasal ER morphine

Matthew Iverson, Carmela Pantaleon, Eric R Kinzler, Stefan Aigner

Inspirion Delivery Technologies LLC, Valley Cottage, NY, USA

Purpose

Abuse deterrent opioid formulations are designed to increase the hurdles required to intentionally misuse and abuse these potent medications. Thus far, most manufacturers have employed a single approach to provide abuse deterrent properties, such as formulating the product to be physically hard and difficult to manipulate or incorporating and opioid antagonist that is released upon intentional manipulation. Ideally, however, a formulation would incorporate multiple abuse deterrent properties to deter manipulation. The combination of abuse deterrent features should both deter manipulation and illicit administration to provide significantly less opioid bioavailability which translates to less rewarding drug liking or drug high. Morphine ARER, a novel formulation of morphine sulfate, is physically hard, maintains its extended release properties despite intentional manipulation, and forms a non-syringeable material in liquid environments. We have previously shown that Morphine ARER is overall significantly less liked relative to extended release (ER) morphine. To evaluate whether Morphine ARER is less liked at individual time points, especially at very early time points, we performed a post-hoc analysis of drug liking using the area under the drug liking curve (AUE).

Method

This randomized, double-blind, double-dummy, placebo-controlled, 4-way crossover study evaluated the abuse potential and safety of equivalent doses of crushed intranasal and intact oral Morphine ARER (MorphaBond^TM, Inspirion Delivery Technologies, LLC, Valley Cottage, NY) compared with a commercially available extended release morphine sulfate (ER-morphine) formulation in nondependent, recreational opioid users. The treatment period consisted of a single dose of 4 treatments. Treatments included 60 mg of crushed intranasal Morphine ARER, intact oral Morphine ARER, crushed intranasal ER-morphine, and intranasal/oral placebo. The primary variable of interest was to determine the abuse potential of crushed intranasal Morphine ARER relative to crushed intranasal ER-morphine. Drug liking (drug liking effect; E) is measured on a bipolar curve where 50 mm represents neither drug liking nor drug disliking. To accurately evaluate the area under the liking curve (AUE), a post-hoc analysis was performed by subtracting 50 mm from each subjects’ drug liking score at each time point prior to calculating AUE. The area under the effect curve was evaluated at 0.5 hours (AUE_0-0.5h), 1 hour (AUE_0-1h), 2 hours (AUE_0-2h), 8 hours (AUE_0-8h), and 12 hours (AUE_0-12h).

Results

The primary variable of interest was met with statistically significant and clinically meaningful reductions in maximum drug liking (Emax, 45% reduction; P<.0001). Median very early drug liking was 78% lower in the first 30 minutes of dosing for Morphine ARER relative to ER-Morphine (P =.0002). Early drug liking was 84% lower in the first hour (P<.0001) and 58% lower in the first 2 hours (P<.0001). At later time points, drug liking was 36% lower in the first 8 hours (P<.02), and 15% lower in the first 12 hours (P<.05). Drug liking between crushed intranasal and intact oral administration was not significantly different at any time point.

Conclusions

Physical manipulation and intranasal administration is commonly employed by drug abusers to bypass morphine’s significant first pass metabolism in the gastrointestinal tract. Crushed intranasal Morphine ARER was significantly less liked at each of the time points tested, with very large reductions in liking at the earliest times. AUE analyses were similar between crushed intranasal and intact oral administration of Morphine ARER and are consistent with Morphine ARER’s maintenance of its extended release profile despite physical manipulation and intranasal administration.

62 Chronic pain: gaining understanding and empathy through an interactive system

Weina Jin, Xin Tong, Servet Ulas, Diane Gromala, Chris Shaw

Simon Fraser University, Surrey, Canada

Purpose

Although pain is universal, its experience is quite unique to each individual. One major issue accompanied with chronic pain is that this individual suffering is unseen and incommunicable. This makes it difficult for healthcare professionals, family and society to believe and understand chronic pain patients’ sufferings, let alone empathize and support them. Not feeling believed and understood leads patients to confusion, frustration, anger, shame and social isolation (Osborn and Smith, 2015). Furthermore, gaining an empathetic understanding of patients’ experience is not an adjunct, but integral to help patients to move forward alongside their pain (Toye et al., 2013). Therefore, we aim to design an interactive system called “AS IF”, to educate the public, raise awareness and gain empathy with chronic pain.

Method

We built an interactive system to help non-patients gain empathy with chronic pain patients, i.e.: put non-patients into patients’ shoes. In the system, the participant interacts with their altered body image to complete object-oriented motor tasks. The system is developed in Unity3D. We use Microsoft Kinect Sensor as input device to detect and track the participant’s position and movements, a projector as an output device to act as a virtual mirror.

Results

During the interaction, the participant manipulates his/her virtual body image as silhouette in the virtual mirror, and reaches out to connect dots with lines to form a meaningful shape that is related to chronic pain experience. After the participant gets used to the interaction in the “normal body mode”, the system will turn to “chronic pain body mode”. In it pain randomly attacks different part of the body shown by various visual particle motion. The pain will limit the body movement and hinder the participant reaching the dots. The virtual mirror provides a visual simulation of living within the body of chronic pain. The whole interactive experience lasts for 5-10 minutes.

Conclusions

By putting the non-patient into the virtual body of chronic pain sufferer, the interactive application visually shows the altered body schema caused by chronic pain, and allows the participant to gain the experience and empathy of living within a virtual body of chronic pain.

63 Pharmacist-directed Outpatient Pain Stewardship

Brittany Johnson, Joseph Cammilleri, Adrienne DeBerry, Nadia Iwanyshyn

UFHealth Jacksonville, Jacksonville, Florida, USA

Purpose

Opioids are considered the most potent analgesics for the treatment of chronic pain. However, prescribing these medications is not without risk, resulting in 46 deaths daily in the United States. Despite the risk, opioid therapy plays an integral role in pain management for situations where adjuvant therapy has failed. Current literature recommends monitoring patients with urine drug screens, pain agreements, and the state adopted prescription drug monitoring program. However, the disproportionate number of patients to primary care practitioners makes it difficult for physicians to appropriately monitor patients. Clinical pharmacists are a valuable asset to providers facing these challenges due to their expertise in pharmacotherapy and ability to provide more extensive monitoring. The purpose of this study was to evaluate the impact of a pharmacist directed outpatient pain stewardship program on chronic opioid use measured in morphine equivalents dispensed.

Method

This was a retrospective, single center study of chronic pain patients receiving controlled substances from the institution’s ambulatory pharmacy over a two-year period. All patients receiving controlled substances for a chronic pain related diagnosis were included. Pharmacist impact on morphine equivalents dispensed was evaluated utilizing monthly reports from the ambulatory pharmacy. A sub-group analysis of 200 patients was conducted via the electronic medical record to assess the frequency of patients with a urine drug screen, pain agreement, and adjuvant therapy. Incidence of emergency department visits due to overdose or uncontrolled pain were also evaluated.

Results

Pharmacist directed pain stewardship was associated with an increase in total morphine equivalents dispensed (p= <.0001) compared to the physician only directed group (mean 1095 vs. 1043, Median 900 for both groups). The frequency of urine drug screens between the pre and post intervention group was 65% vs. 68% respectively (p= 0.6529). There was no difference between groups with regard to compliance with pain agreements (p= 0.7750). The total number of emergency department visits due to uncontrolled chronic pain was 25 in the pre-intervention group and 5 in the post intervention group (p= <.0001). None of the patients from either study group presented to the emergency department due to opioid overdose. The most common chronic pain diagnoses in both the pre and post-intervention groups were lumbago (44% vs. 45%) and cervicalgia (21% vs. 17%). The frequency of prescribing for non-opioid adjuvant pain relievers was 47% in the pre-intervention group, compared to 89% in the post-intervention group (p= <.0001). Additionally, there was an increase across all adjuvant therapy categories between groups (i.e., acetaminophen, anti-inflammatories, muscle relaxers, and neuropathic pain agents) (p= <.0001).

Conclusions

Following the initiation of the pharmacist driven outpatient pain stewardship program patients showed a reduction in the number of visits to the emergency department for uncontrolled pain. There was an association between pharmacist intervention and increase in the total morphine equivalents dispensed, however due to the sample size this study was powered to detect a small difference which may not be clinically relevant. An increase in the frequency of adjuvant therapy prescribed occurred with pharmacist intervention, likely because pharmacists are well versed in these medications. These findings suggest that pharmacists maintain monitoring similar to physicians while reducing emergency department visits.

64 Characteristics of a sample of chronic pain patients who either made significant improvements or deteriorated during treatment at a community based outpatient chronic pain clinic: a retrospective observational study

Lawrence Kei¹, Brenda Lau^2,3, Carson Berry³, Austin Kao³, Curtis May³

¹Department of Physical Medicine and Rehabilitation, UBC, Vancouver, B.C., Canada, ²Department of Anesthesiology, Pharmacology & Therapeutics, UBC, Vancouver, B.C., Canada, ³CHANGEpain Clinic, Vancouver, B.C., Canada

Purpose

CHANGEpain Clinic (CpC) is a unique community-based chronic pain clinic that utilizes evidence based multidimensional care delivered in a layered manner. The layered care approach begins by addressing myofascial pain and enrolling patients in self-management programs for nutrition, relaxation, and sleep. Hence, this model reserves the riskier and more expensive treatments to those that really need them. There is a paucity of studies evaluating patients at community chronic pain clinics outside of major tertiary centers.

We aimed to utilize practice-based research (PBR) to describe medical profiles, treatment course, and outcomes on various validated pain related questionnaires for all the patients who completed initial and follow-up questionnaires. Our goal was to determine how many patients made significant improvements and how many deteriorated while attending a community pain clinic utilizing a multi-layered approach. Based on these results, we collected further data to examine the two groups of patients who made significant improvements or deteriorated. This descriptive data can help identify factors that may be more prevalent in the groups who deteriorated. In addition, we hope that this data demonstrates the feasibility of practice-based research in community-based clinics.

Method

This retrospective observational community-based study collected data on 3367 patients who were seen at CpC from 2013-2015. Of these, 1036 patients completed at least an initial Brief Pain Inventory (BPI) and a follow up BPI questionnaire. Averages and standard deviations for the outcomes were calculated. Furthermore, based on the difference between their initial and follow up scores for both Brief Pain Inventory (BPI) and Numeric Rating Scale (NRS), subgroups were formed consisting of the 30 patients who made significant improvements and the 30 patients who deteriorated during treatment at CPC.

The outcomes collected were recommended by the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) and included the following validated questionnaires: BPI (assesses the intensity and impact of pain on daily functions), NRS (pain intensity), the Patient Health Questionnaire-9 (PHQ-9; indicates a clinical level of depressive symptoms), the Patient Self-Efficacy Questionnaire (PSEQ; assesses confidence in performing activities while in pain), and the Pain-Related Self Statements scale (PRSS; assesses situation-specific aspects of patients’ active coping with pain and level of catastrophizing). In addition, we examined the data on pain referral reasons, the numbers of treatments and classes completed, prior pain related diagnoses, numbers and types of injuries and surgeries.

We calculated averages and standard deviations for the outcomes for the general population (n= 1036), the group who made significant improvements (n=30) and the group who deteriorated (n=30).

Results

3367 patients visited CPC in the study period; 40% (1036) completed an initial and follow-up questionnaire for BPI and NRS. Follow-up was on average 127 days. Mean BPI score at intake was 45/70. 69% of patients had reductions in BPI scores, with BPI average scores significantly reduced (p<0.01).

NRS average score for the general population was initially 5.77; follow-up 5.47. The group that deteriorated initial score was 5.28 (Standard deviation (SD) 2.12); follow-up 6.6 (SD 1.89). The improved group initial score was 6.23 (SD 1.57); follow-up 4.01 (SD 1. 73).

PHQ-9 average score for the general population was initially 13.19; follow-up 11.70. The group that deteriorated initial score was 11.86 (SD 6.71); follow-up 14.4 (SD 6.84). The improved group initial score was 16.1 (SD 6.1); follow-up 9.16 (SD 6.73).

PRSS –CAT average score the general population was initially 2.89; follow-up 2.72. The group that deteriorated initial score was 2.95 (SD 0.94); follow-up 3.12 (SD 0.83). The improved group initial score was 3.38(SD 0.70); follow-up 3.42 (SD 0.82).

PSEQ average score for the general population was initially 29.39; follow-up 31.44. The group that deteriorated initial score was 29.0 (SD 14); follow-up of 28.95 (SD 12.6). The improved group initial score was 27.83 (SD 17.4); follow-up 40.3 (SD 13.0).

Additional numbers were collected for the deteriorated and improved groups including: Mean number of trigger point injection (TPI) appointments (7.56 vs 9.28), mean number of surgeries (2.15 vs. 2.88), and self- reported duration of pain in years (6.54 vs. 9.64).

Conclusions

This study indicates positive outcomes for chronic pain patients using a multi-layered approach to chronic pain in a community setting that theoretically may lower the cost and number of higher risk interventional treatments. However, we also identified that these approaches do not benefit everyone. Our data may highlight characteristics of those of who may deteriorate with multi-dimensional, layered pain care.

65 Pharmacokinetics of 2.0 mg Intranasal and Intramuscular Naloxone HCl Administration and the Impact of Vasoconstrictor Use on the Bioavailability of Intranasal Naloxone HCl

Eric Edwards¹, Catherine Kessler¹, Glen Kelley¹, Arthur Gapasin², Georgeta Mardari², Ronald Goldwater²

¹kaleo, Inc., Richmond, VA, USA, ²PAREXEL International, Baltimore, MD, USA

Purpose

The opioid overdose epidemic in the United States is continuing to escalate. In 2014, there were 18,893 deaths from prescription opioid pain relievers, a 16% increase from 2013. Naloxone hydrochloride (HCl), an opioid antagonist, is now encouraged to be co-prescribed with opioids for patients at increased risk for life-threatening opioid-induced respiratory depression (OIRD).

Naloxone HCl has been used parenterally for over 4 decades by emergency personnel for the reversal of OIRD. In the last decade, intranasal administration of naloxone by first responders using an off-label nasal atomization kit has become more prevalent.

Data in the literature suggest that abnormal nasal physiology, drug interactions and certain diseases may impact the absorption and bioavailability of intranasally administered drugs, including naloxone; however, clinical studies specifically designed to examine this potentially clinically significant concern have not been conducted. As naloxone HCl is used in life-threatening opioid emergencies, it is essential to consider the potential impact of common medical conditions and medications on naloxone absorption and exposure by different routes of administration when prescribing naloxone.

Method

This was a randomized, open-label, single-dose, 3-period crossover pharmacokinetic (PK) study. Key eligibility criteria were men and women 18-55 years of age diagnosed with chronic rhinitis but with no clinically significant nasal abnormalities, surgery, polyps, or trauma and no other clinically significant abnormal findings that would jeopardize the safety of the participants or impact the validity of the study results.

The 3 study treatments were intramuscular administration of 2.0 mg naloxone (1 mg/mL in each thigh) using a standard syringe and needle (IM), intranasal administration of 2.0 mg naloxone (1 mg/mL in each nostril) using the LMA MAD Nasal^TM atomizer (IN), and intranasal administration of 2.0 mg naloxone 30 minutes after intranasal administration of a vasoconstrictor (Oxymetazoline) (V+IN). Blood samples for naloxone concentrations were collected pre-dose through 8-hours post-dose. Standard pharmacokinetic parameters were calculated. Safety assessments included clinical laboratory tests, physical examinations (including nares and injection site evaluations), 12-lead electrocardiograms, vital signs, adverse event (AE) and concomitant medication monitoring.

Results

Thirty-six (36) volunteers completed the study (21 male/15 female; mean age 33.7 years; mean body mass index 25.8 kg/m2).

C_max and total naloxone exposure was greatest after IM compared to IN and V+IN. Mean maximum plasma concentration (C_max, pg/mL) for IM (4539±2089) was greater than IN (1288±622) or V+IN (747±388). Mean area under the concentration-time curve (AUC_0-t, pg-h/mL) for IM (9400±1261) was much greater than IN (1456±457) or V+IN (1112±391). The geometric mean ratio (GMR) for IM/IN was 3.57 for C_max and 6.75 and 6.85 for AUC_0-t and AUC_0-inf, respectively. The V+IN C_max was approximately half the IN C_max (GMR of 0.58) and the GMR for V+IN/IN was 0.76 for both AUC_0-t and AUC_0-inf. During the early critical period of absorption, mean AUC_partial (pg-h/mL) was greater for IN (176±110) than V+IN (94±88). The GMR for V+IN/IN was 0.38, also indicating a lower naloxone exposure following IN in the presence of the vasoconstrictor. Median T_max was 15 minutes for IM and IN and 20 minutes for V+IN.

There were no serious AEs. Three AEs were reported in the study. An AE of mild headache was reported for 2 volunteers. One volunteer experienced a mild, unrelated AE of epistaxis and was discontinued from the study (as epistaxis could impact absorption and confound the study results), and was not included in the PK analyses.

Conclusions

In volunteers with chronic rhinitis, overall naloxone absorption was less for IN and V+IN than for IM. Naloxone absorption was slower in V+IN than IN, resulting in markedly lower C_max and naloxone exposure in the early critical phase. It is reasonable to expect that other IN vasoconstricting agents (e.g., phenylephrine, cocaine) are likely to have similar effects on IN naloxone absorption. The impact of common medical conditions or medications should be considered when selecting the route of naloxone administration to use in treatment of OIRD.

66 In Vitro Evaluation of a Novel Immediate Release Formulation of Oxycodone (RoxyBond^TM) for the Potential for Abuse Via Injection

Eric R Kinzler¹, Ray DiFalco², Carmela Pantaleon¹, Matthew Iverson¹, Stefan Aigner¹

¹Inspirion Delivery Technologies LLC, Valley Cottage, NY, USA, ²Cerovene, Inc., Valley Cottage, NY, USA

Purpose

The introduction of abuse-deterrent formulations of extended release opioids into the market appears to have significantly reduced rates of misuse and abuse of these products but epidemiologic data suggest that abusers of prescription opioids may simply switch to immediate release formulations to circumvent abuse deterrence. A novel abuse-deterrent formulation of immediate release oxycodone, Oxycodone ARIR (abuse resistant immediate release), has been developed to help prevent switching to immediate release opioids. Oxycodone ARIR tablets incorporate a proprietary abuse-deterrent technology that makes tablets difficult to manipulate and resist extraction in widely used solvents. These tablets are difficult to crush and prepare for absorption with most household tools. Even if they are crushed, the resulting particles form a coarse powder that alters the intended release profile and rapidly forms a material that resists passage through a needle when subjected to a liquid environment. Taken together, these unique properties are designed to create significant hurdles to commonly used methods of manipulation and routes of administration for abuse, thereby achieving abuse deterrence while avoiding the potential risk of using opioid antagonist or aversive agents. Because in vivo injectability abuse potential studies are not considered safe for study participants, in vitro tests are commonly employed to characterize their abuse-deterrent properties. To evaluate the potential for abuse of Oxycodone ARIR tablets via injection, a series of in vitro syringeability and small volume extraction studies were performed.

Method

Syringeability and extractability of Oxycodone ARIR 30 mg tablets (RoxyBond^TM, Inspirion Delivery Technologies, LLC, Valley Cottage, NY) relative to commercially available IR-Oxycodone tablets were performed according to a prespecified protocol. Briefly, Oxycodone ARIR tablets (N=5) were either left intact or manipulated (crushed) and placed in glass vials containing either 5 or 10 mL water for 1, 5, 10, and 30 minutes with and without agitation (100 RPM). At each time point, attempts were immediately made to draw the mixture into a 10 cc syringe fitted with 27-, 24-, or 18-gauge needle. Difficulty was assessed by the laboratory technician on a scale of 1 (very easy to syringe) to 10 (impossible to syringe). All tests were completed in an iterative fashion whereby the smallest needles were tested first; if passage through the needle was successful the larger needles were not tested. Finally, if any liquid was syringeable, the volume was recorded and analytically tested for oxycodone.

Results

Crushed IR-Oxycodone was easily syringed into small needles (27 gauge) and released more than 90% of its oxycodone within 1 minute in these extraction experiments. In contrast, manipulated Oxycodone ARIR tablets immediately formed a material that was difficult to syringe and did not produce a meaningful amount of liquid, even through large 18 gauge needles. Subjecting manipulated samples to agitation or adding additional manipulated tablets to the mixture did not increase the oxycodone released or resulted in a completely non-syringeable sample. In some cases, a small amount of liquid was syringeable but contained visible particulate that would not be suitable or safe for intravenous injection. Under ‘optimal conditions’ for extracting and injecting oxycodone from Oxycodone ARIR tablets, a maximum of 19% of oxycodone was released at long 30-minute time points. In general, earlier time points resulted in less oxycodone release. No dose dumping was observed at any time point under any of the conditions evaluated.

Conclusions

Abusers desire immediate access to the active ingredient. In the literature, the average maximum time subjects would be willing to spend tampering with an abuse deterrent tablet was 10 minutes for intranasal use and 16 minutes for intravenous use. Here, the inherent physiochemical properties within Oxycodone ARIR significantly increased the hurdles required to successfully prepare the formulation for injection; even at very long 30-minute time points very low levels of oxycodone were injectable under rigorous laboratory conditions. These data suggest that Oxycodone ARIR has abuse-deterrent properties that may reduce abuse via injection.

67 Cebranopadol, a Novel First-in-Class Analgesic: Optimization of the up-Titration Regimen to Individual Best Dose for Patients Suffering from Moderate to Severe Chronic Pain

Marie-Henriette Eerdekens¹, Sofia Kapanadze², Maurits Kok²

¹Grünenthal GmbH, Development, Aachen, Germany, ²Grünenthal GmbH, Clinical Development, Aachen, Germany

Purpose

Cebranopadol reportedly acts via nociceptin/orphanin FQ peptide (NOP) receptor and opioid receptor agonism. It is currently in development for the treatment of chronic pain conditions. In clinical studies conducted to date, cebranopadol was effective, safe and well tolerated. The majority of discontinuations due to tolerability issues occurred during the titration phase. The purpose of this evaluation is to review the possible impact of various titration schemes on tolerability in these studies to inform a new titration scheme for phase 3 development in chronic non-malignant pain.

Method

This assessment focuses on data gathered from 4 clinical studies in moderate to severe chronic pain resulting from osteoarthritis (OA), low back pain (LBP), diabetic peripheral neuropathy (DPN) and cancer. The evaluation of the titration will focus on the tolerability profile observed in the titration phase of these studies and is limited to the highest targeted doses of cebranopadol in these studies. To evaluate the effect of different starting doses, the lowest doses in the DPN (100 µg/day) and LPB (200 µg/day) study will be evaluated during the initial 2 weeks of treatment.

Patients with LBP and pain due to DPN were forced titrated to 600 µg/day (i.e. LBP study starting at 200 µg/day and increasing the dose every 3 days with 200µg dose incremental steps and DPN study starting at 100 µg/day or 200 µg/day and increasing the dose every 3 days with 200 µg dose incremental steps). In OA and cancer pain trials the patients were allowed to flexibly titrate their dose up from 200 µg/day to the dose range between 400 µg/day and 800 µg/day or to 1000 µg/day respectively. Longer dose intervals were allowed between dose steps as necessary. Flexibility entailed titration to most beneficial dose within the range. A full description of the design of these studies can be found on clinicaltrials.gov (NCT01709214; NCT01725087; NCT01939366; NCT01964378).

Results

In the trials with forced titration, the discontinuation rates during titration due to adverse events (AE) in the 600 µg/day treatment arms were 35.5% and 35.2% in the DPN (n=22/62) and the LBP (n=45/128) study respectively. In the trials with a flexible titration of cebranopadol 18.1% of the patients in the 400-800 µg/day dose arm in the OA study (n=28/155) and 7.7% of the patients in the cancer pain study (n=5/65), discontinued.

Also discontinuations due to the commonly reported AEs during the titration phase were lower when a flexible titration was being used. For nausea, vomiting and dizziness, alone or in combination, the discontinuation percentages were 27.4% (n=17/62) and 30.4% (n=39/128) in DPN and LBP studies respectively, compared to 12.3% (n=19/155) and 1.5% (n=1/65) in OA and cancer pain studies respectively.

Additional information on titration and on tolerability profile can be derived from studies using different starting doses and low dose treatment arms. In the DPN study discontinuation rates due to AEs during the first 2 weeks of treatment with 100 µg/day (100 µg arm) were 6.3% (n=4/64) compared to 13% (n=17/130) on a dose of 200 µg/day in the LBP study (200 µg arm).

Conclusions

The tolerability of cebranopadol during titration could be improved by initiating treatment at a dose lower than 200 µg/day and by allowing longer dose intervals and smaller incremental dose steps, as well as flexible titration to the most beneficial dose for the individual subject.

68 Predictors of Illicit Substance Use In Patients Prescribed Chronic Opioid Therapy

Mancia Ko, Thomas Smith, Patricia Woster

Ameritox, LLC, Baltimore, MD, USA

Purpose

Oral opioid therapy is widely used in pain management. This study evaluated the relationship between patient characteristics and use of illicit substances assessed by urine drug monitoring, in patients prescribed opioid medications.

Method

Urine samples from patients prescribed ≥1 opioid medication were analyzed using liquid chromatography/tandem mass spectrometry. Samples were tested for the presence of illicit substances including: THC (i.e. marijuana), cocaine, heroin, PCP, and MDMA. Adjusted odds ratios (aOR) and 95% confidence intervals (CI) were calculated using multiple logistic regression analysis with the following independent variables: sex, age decade, geographic and primary payer.

Results

Over a two-year period between 2013 and 2015, a total of 450,018 analyzed samples were tested, of which 46,592 (10.4%) were positive for ≥1 illicit. Marijuana (38,158 samples) and cocaine (8,574 samples) were the most commonly detected illicits, whereas heroin was detected in only 1649 samples, and no other illicits were detected >125 samples. Factors most strongly associated with likelihood of detecting an illicit substance were: sex (men 13.1% vs. women 8.2%; aOR, 1.76; 95% CI, 1.73-1.80); age (illicit detection progressively decreased as age increased: from 18.3% among those 20-29 years of age to 0.4% at 80-99 years; compared with 20-29 years, aOR for 80-99 years was 0.02; 95% CI, 0.01-0.03); and primary payer, in whom the illicit rate ranged from high of 16.4% for Medicaid patients to a low of 8.1% for those with Medicare (compared to self-pay patients, who had an illicit rate 12.5%, aOR for Medicaid was 1.34; 95% CI, 1.29-1.38 and aOR for Medicare was 0.63; 95% CI, 0.61-0.65).

Conclusions

Among patients prescribed opioid medications, use of illicit substances was common and varied with patient characteristics. Understanding factors associated with the likelihood of positive urine testing for illicit substances may better inform strategies for using urine drug testing in the clinical management of patients on prescribed opiate therapy.

69 Predictors of Medication Adherence: Relationship with Opioid Dose

Mancia Ko, Thomas Smith, Woster Patricia

Ameritox, LLC, Baltimore, MD, USA

Purpose

Medication monitoring is recommended for patients prescribed an opioid for an extended period. This study evaluated the relationship between the prescribed dose of hydrocodone and the likelihood of finding hydrocodone or its metabolites with urine testing

Method

Urine samples submitted to the laboratory between 2013 and 2015 from patients documented on the laboratory requisition to have been prescribed hydrocodone as their sole opiate medication were analyzed. The first sample obtained from each patient was tested for the presence of hydrocodone and its metabolites using liquid chromatography/tandem mass spectrometry. Samples were classified as positive for hydrocodone if parent drug and/or metabolite(s) were confirmed and negative if neither were detected. Adjusted odds ratio (aOR) and 95% confidence interval (CI) were calculated using multiple logistic regression analysis with the following independent variables: sex, age decade, primary payer, geographic region, year tested, and dose category.

Results

Of 178,582 unique samples analyzed, 28.4% were classified as negative for hydrocodone. Demographic factors most strongly associated with potential nonadherence were age (highest rate for age 20-29 years [37.6%] and lowest rate for age ≥60 years [23.2%]) and payer type (highest rate for Medicaid [36.2%] and lowest rates for workers’ compensation [25.0%] and commercial insurance [25.4%]). The rate of potential nonadherence decreased as prescribed hydrocodone dose increased, from 37.1% for patients prescribed 5 to 20 mg/day to 17.5% for those prescribed 60 to 120 mg/day (aOR, 0.35; 95% CI, 0.34-0.37).

Conclusions

Among patients prescribed hydrocodone, potential nonadherence was common and varied with both patient characteristics and with prescribed dose. Understanding factors associated with potential nonadherence may inform strategies to use urine drug monitoring to better manage patients and improve treatment outcomes.

70 Predictors of Medication Adherence in Patients Prescribed Opioid Medications

Mancia Ko, Monica Fileger, Thomas Smith, Patricia Woster

Ameritox, LLC, Baltimore, MD, USA

Purpose

This study evaluated the relationship between patient characteristics and potential medication nonadherence in patients prescribed opioid medications.

Method

Urine samples from patients prescribed opioid medications were analyzed for the presence of opioids using liquid chromatography/tandem mass spectrometry. Samples were confirmed as positive for opioid medication if parent drug and/or metabolite(s) were detected, and negative if neither were detected. Adjusted odds ratio (aOR) and 95% confidence interval (CI) predicting potential nonadherence were calculated using multiple logistic regression analysis with the following independent variables: sex, age decade, and primary payer. Because data were obtained from a de-identified database, this study was not submitted for IRB review.

Results

Of 447,453 unique samples analyzed (2013 to 2015), 43.0% tested negative for the opioid medication prescribed. Potential nonadherence was slightly lower in men compared with women (41.7% vs 44.0%; aOR, 0.94; 95% CI, 0.93-0.96). Potential nonadherence consistently decreased as the decade of age increased (62.2% [10-19 years], 51.6% [20-29 years] to 34.5% [80-89 years]). Relative to the 20-29 years age group, the aOR of potential nonadherence was 1.50 (95% CI 1.29- 1.73) among the 10-19 years group and 0.48 (95% CI, 0.4- 0.51) among the 80-89 years group. Compared with self-pay patients, potential nonadherence was higher for Medicaid patients (52.0% vs 43.6%; aOR, 1.36; 95% CI, 1.32-1.39), and lower for patients with commercial insurance, Medicare, or workers’ compensation (36.1%-40.8%; aOR ranging from 0.79-0.90) as the primary payer.

Conclusions

Among patients prescribed opioid medications, potential nonadherence was common and varied with patient characteristics. Understanding factors that influence potential medication nonadherence may guide clinicians in patient identification and implementing adherence strategies.

71 The effect of physical manipulation by crushing of Xtampza^TM ER (oxycodone extended-release capsules) compared with the abuse-deterrent version of OxyContin® (oxycodone hydrochloride extended-release tablets)

Ernest Kopecky, Melinda O’Connor, Michael DeGeorge, Alison Fleming

Collegium Pharmaceuticals, Inc, Canton, MA, USA

Purpose

Prescription opioids play an important role in the management of chronic pain. Extended-release (ER) opioid products have several advantages including the convenience of less frequent dosing, decreased fluctuations in plasma levels, more consistent analgesia over the dosing period, and less night-time awakening due to pain. However, as ER opioids contain large quantities of active drug, these analgesics are a target for abuse by physical manipulation and chemical extraction. Abusers frequently attempt to manipulate (eg, cut, crush, chew, or dissolve) these formulations to get an immediate bolus of opioid. In a recent study, 40% of oral abusers of crush-resistant tablets manipulate their ER opioid prior to abusing orally.1 In addition to abuse, misuse of ER opioid medications can occur when patients or their caregivers manipulate such formulations, for example, to facilitate swallowing, not understanding that manipulation of the ER medication can cause release of a fatal dose of opioid.

Xtampza^TM ER (oxycodone extended-release capsules) with the DETERx® technology (Collegium Pharmaceutical, Inc., Canton, MA) is a microsphere-in-capsule, ER, abuse-deterrent (AD) analgesic. The formulation was designed to retain its ER properties following tampering with commonly available utensils as well as more sophisticated methods. The objective of this clinical study was to assess the safety and pharmacokinetics (PK) of Xtampza ER when the capsule was taken intact compared with crushing the capsule contents (microspheres) prior to oral administration. Comparators were OxyContin® (oxycodone hydrochloride extended-release tablets) intact, OxyContin crushed, and an immediate-release (IR) oxycodone tablet formulation that was crushed.

Method

This was an open label, randomized, active-controlled, 5-treatment, 5-period, cross-over comparison study in naltrexone-blocked, healthy subjects (n=41). Subjects were randomized to receive Xtampza ER 36 mg (equivalent to 40 mg oxycodone hydrochloride [HCl]) intact and crushed, OxyContin 40 mg intact and crushed, and oxycodone IR 40 mg crushed. The tools used to crush the formulations are commonly available household tools and were previously identified in product development studies as the most effective tools to reduce the particle size for each respective product. Primary PK endpoints included Cmax, AUC0-t, AUCinf, and Tmax. Abuse quotient (AQ), a measure of rate of rise in blood concentration, suggested to be correlated with abuse potential, was calculated by using Cmax and Tmax (AQ=Cmax/Tmax). Safety was assessed by adverse events, clinical laboratory values, vital signs, oxygen saturation, and physical exam. The study was approved by an IRB; each subject provided informed consent before any study-related procedure/assessment was conducted.

Results

Crushed Xtampza ER capsule contents (microspheres) (Cmax = 61.2±13.1 ng/mL; AUC(inf) = 549±143 hr × ng/mL) were bioequivalent to intact Xtampza ER capsules (Cmax = 56.9±13.4 ng/mL; AUC(inf) = 534±142 hr × ng/mL) with similar Tmax, demonstrating that crushing the contents of Xtampza ER capsules did not alter the ER PK profile. Conversely, crushed OxyContin tablets (Cmax = 79.9±17.9 ng/mL; AUC(inf) = 540±142 hr × ng/mL) were bioequivalent to crushed IR oxycodone tablets (Cmax = 78.1±22.0 ng/mL; AUC(inf) = 497±193 hr × ng/mL) with similar Tmax, demonstrating that crushing OxyContin compromised the integrity of the time-release formulation, transforming the drug-release PK profile from an ER profile to an IR profile. At one hour after dosing, crushed OxyContin resulted in an approximately 5-fold higher mean plasma concentration than taking OxyContin intact and an approximately 4-fold higher mean plasma concentration than crushed oxycodone DETERx. The AQs for intact and crushed Xtampza ER were similar (19.1±9.71 ng/mL/h and 17.4±6.13 ng/mL/h, respectively); the AQ for crushed OxyContin was similar to that of IR oxycodone (56.1±33.7 ng/mL/h and 63.1±47.5 ng/mL/h, respectively). Xtampza ER was demonstrated to be safe and generally well-tolerated in this healthy, naltrexone-blocked adult population.

Conclusions

This is the second comparative clinical trial demonstrating that Xtampza ER maintains its ER properties and does not result in increased drug exposure after crushing, whereas OxyContin fails to retain its ER properties after crushing, resulting in increased peak plasma exposure, shorter time to peak plasma exposure, and bioequivalence to immediate-release oxycodone. Xtampza ER provides clinicians and patients with an alternative AD oxycodone formulation for the treatment of chronic pain. This research was supported by Collegium Pharmaceutical, Inc., Canton, MA

72 Medullary Sponge Kidney: Patient Perspectives on Quality of Life and Occupations

Barbara L. Kornblau, Jessica Leer, Olivia Ehrlich, Jeremy Klimek, Debora Oliveira

Florida A&M University, Tallahassee, USA

Purpose

The purpose of this study was to explore engaged patient’s perspective of quality of life and occupations of people living with Medullary Sponge Kidney (MSK), a chronic condition that causes kidney stones. This study revealed how engaged patients with MSK define quality of life (QOL), symptoms that interfere with QOL, triggers of symptoms, and lack of occupational engagement due to living with MSK, a chronic condition. Engaged patients’ perspectives on QOL can increase quality of care, lower health care cost, and improve QOL for individuals living with chronic conditions (Hibbard & Cunningham, 2008). Knowledge of QOL and occupation revealed how occupational therapists can meet the occupational needs of chronic conditions such as MSK.

Method

This is a qualitative study based on grounded theory. Due to the large number of participants, quantitative data was collected, and analyzed for incidence of chronic pain among participants. Participants included engaged patients with a self-reported diagnosis of MSK, who were 18 years of age or older, U.S. residents, and English speakers. Following IRB approval, engaged patients were recruited from members of closed, online, MSK, Facebook support communities, who consented to take the survey. Participants obtained a link to an online survey of open-ended questions created on Survey Monkey through closed online Facebook MSK support groups, where participants shared patient care experiences. Participants, engaged patients who live with MSK, answered questions about their perceptions of QOL and occupational engagement. Data was collected from members of multiple MSK support groups to ensure rigor and trustworthiness of the data. Multiple researchers, including an experienced qualitative researcher, participated in data analysis to support triangulation. Researchers analyzed the data using grounded theory to produce themes until saturation was reached.

Results

This was the first self-report, large-scale study of individuals diagnosed with MSK. The study collected qualitative and quantitative data from 154 individuals. Of the participants, 99.07% were female and 68% were between the ages of 25 and 44. Saturation was reached at between 30 – 35 participants. Participants defined QOL as participation in desired occupations consistent with the theory of occupational autonomy. Participants reported that MSK caused pain and fatigue, depression and/or anxiety, and interfered with participation in daily life, limiting their QOL. The main triggers of symptoms of MSK identified by participants comprised: physical activity, fluids and food intake, as well as external and internal stressors. The main limitations in occupational engagement due to MSK diagnosis included: working, parenting, leisure activities requiring physical activity, and living without pain. All 154 participants reported experiencing chronic pain. This was the first study that revealed that MSK is associated with chronic pain.

Conclusions

Standard measures of QOL are based on clinically defined QOL measures on the SF-36. Individuals’ voices with chronic conditions are commonly not heard while symptoms of pain, discomfort, and stress escalated negatively affecting health and QOL. Participants need to express their goals and desired occupations in their own voices. Our research shows patients with MSK define QOL in terms of “occupational autonomy,” or the ability to participate in desired occupation when desired. This study supports occupational therapy intervention to address patients’ perceived needs for occupation and participation to support QOL for individuals with MSK, a chronic pain condition.

73 The Impact of New York States Prescription Monitoring Program on Illicit Drug Use

Eric Hirsch¹, Tahir Sheikh¹, Sanwal Mushtaq¹, Erica Glants¹, Tova Baharlias¹, Ranga Krishna²

¹Total Neuro Care, Brooklyn, USA, ²New York Community Hospital, Brooklyn, USA

Purpose

This study aims to assess the impact of New York State’s Prescription Drug Monitoring Program (PDMP) on rates of illicit drug use (IDU) among workers’ compensation patients receiving prescription opioids. Although representing less than 5% of the world’s population, Americans consume 80% of all opioids and nearly two thirds of all illicit drugs. For patients receiving workers’ compensation, rates of IDU are higher and can exacerbate challenges associated with recovery and reentry into the workforce. The use of prescription opioids is also a risk factor for IDU. Studies have shown that while 80 percent of new opioid abusers in the 1960s began with heroin, 75 percent of new opioid abusers in the 2000s began with prescription opioids. (ASPE 2015). When patients are out of work and taking prescription opioids, the risk factor may be multiplied. A previous study at this clinic found that the rate of IDU among workers’ compensation patients receiving opioids (44%) was significantly higher than both the national average (9.4%) and the average for unemployed persons (16%).

On August 27, 2013, New York State implemented its Prescription Monitoring program (PMP). The PMP provides doctors and pharmacists with a comprehensive prescription history, allowing them to identify patterns of abuse. According to the ASPE, initial reports from providers have found a 75% decline in cases of opioid abuse since the implementation of PMP. Although these results are encouraging, there has been little focus in the literature on what effects PDMP has had on the rate of IDU generally.

Method

A cohort of 224 individuals (average age 60 yo) presented for a neurologic consultation by a board certified Neurologist. All subjects were receiving worker’s compensation, and using opioids for chronic pain management. Urine toxicology screenings were performed by Millenium Laboratories using Gas Chromatography- Mass Spectroscopy (GC-MS) methodology. Patients were screened for Heroin, Opioids, Cannabinoids, Methamphetamine, and Cocaine. Results were categorized based on job type; age, gender, LWP, and ID abuse level, which was measured significant against a normal. Statistics were calculated using PASW Statistics program.

Results

Of the 224 subjects screened, 36 were found to be using IDs, approximately 16% of the cohort. While this rate was significantly higher than the national average of 9.4%., it was also significantly lower than the rate found among a similar cohort at this clinic before the implementation of New York State’s PMP (p = 0.0012). The average age was 60. The main worker demographic was construction and extraction, transportation, and maintenance and repair. The IDs used were THC and cocaine. Based on the urine toxicology, 34 patients had used THC and 2 patients had used cocaine.

Conclusions

This study found that the rate of IDU among a cohort of workers’ compensation patients taking prescription opioids has decreased significantly since the introduction of New York state’s PMP. According to the National Institute on Drug Abuse, IDU use costs the United States 120 billion dollars in lost worker productivity and 193 billion dollars annually when healthcare, crime, and lost work productivity are factored together. Reducing IDU among workers’ compensation patients can improve outcomes for recovery and reentry into the work force.

74 Urinary Buprenorphine and Fentanyl Metabolites as a Method of Identifying Deception in Patients Tested for Drugs

Kevin Krock, Joyce Nickley, Amadeo Pesce

Precision Diagnostics, San Diego, CA, USA

Purpose

Urine drug testing is a standard method of identifying compliance in both drug treatment centers and for physicians treating patients with chronic opioid therapy. However, as pointed out by Jung et al [1], physicians have difficulty identifying patients practicing deception to obtain opiate prescriptions. Additionally, Reisfield et al [2] have documented that many physicians are not trained to interpret urine drug test results. One common way of practicing deception is to add parent drug to the test specimen. In these cases, the laboratory report should indicate the presence of parent drug without metabolite. Buprenorphine is used as part of a treatment program for patients subject to substance abuse of opiates. We postulated that the presence of buprenorphine without its norbuprenorphine metabolite was an indication of deception. Additionally, because it is administered as a patch, detection of deception by patients prescribed fentanyl is not usually considered. The purpose of this study was to determine the prevalence of deception using the presence of parent drug without metabolite as an indicator.

Method

A retrospective analysis of 83,205 specimens from pain practices and addition centers were tested by a highly sensitive LC-MS/MS method. The presence of the drug pairs buprenorphine/norbuprenorphine and fentanyl/norfentanyl were determined by use of a dilute and shoot LC-MS/MS method sensitive to 5ng/mL for buprenorphine and for norbuprenorphine and 1ng/mL for fentanyl and 2ng/mL for norfentanyl. This enabled detection of potentially small concentrations of metabolites.

Results

Of the 14218 patients positive for buprenorphine we observed only 153 cases of buprenorphine positive with a negative observation for norbuprenorphine or about 1.08%. In contrast of the 1181 specimens positive for fentanyl or norfentanyl, 50 were found to be positive for fentanyl with no metabolite, or about 4.23%.

Conclusions

These results indicate little or no deception by patients treated with buprenorphine for substance abuse, while patients treated with fentanyl patches have a high incidence of deception. Physicians should be aware of potential deception which in some cases can be detected checking to see both parent drug and metabolite are present.

75 Lower Cutoffs for LC-MS/MS Urine Drug Testing Better Indicate Patient Compliance

Kevin Krock, Amadeo Pesce, Joyce Nickley

Precision Diagnostics, San Diego, CA, USA

Purpose

Urine drug testing is used by health care providers to determine a patient’s compliance to their prescribed regimen and to detect substances which may complicate the treatment plan. However, cutoff levels used by clinical labs were set arbitrarily and do not reflect the needs of the patients served. The goals of this study are to i) outline the way to analyze patient results and estimate a more appropriate cutoff, ii) develop and validate a high sensitivity analytical method capable of quantitating drugs and metabolites at those cutoffs, and iii) determine the number of positive results that would have been missed when using the arbitrary cutoffs.

Method

A high sensitivity (LC-MS/MS) method was developed and validated, capable of quantitating low concentrations of 71 drugs and metabolites important for monitoring medication adherence and substance use disorder.

An estimate of the high sensitivity cutoff levels required were determined by plotting previous patient data on a semilogarithmic plot and using the intersection of an applied trend line and x-axis for each drug or metabolite in Microsoft Excel. The lower limit of quantitation (LOQ) was set at the higher level of the trendline intersection and where S/N ≥ 10.

Results

The lognormal distribution of hydromorphone (Figure 1) shows the typical truncated bell curve found for most drugs analyzed with greater than 100 positive patient results during the study period. The trendline indicated a more appropriate cutoff level of 10 ng/mL. The analytical system was validated to 5 ng/mL for hydromorphone, so it was used instead.

A retrospective analysis of 83,205 anonymized patient results, of which 46,717 had at least one positive analyte, was performed by plotting the concentrations on a lognormal distribution graph for compounds with greater than 100 positive results. The number of positive results with concentrations below the typical industry cutoff level (4,5,14), but above the high sensitivity cutoff level were determined. The ratio of these results to the number of low sensitivity positives were used to calculate the false negative rate.

The distribution of hydromorphone (Figure 2) using the high sensitivity method shows a bell curve that extends further down the normal distribution of results. This demonstrates that a greater proportion of the positive population is being captured by the high sensitivity LC-MS/MS method. The low sensitivity method with a cutoff level of 50 ng/mL has a 37.4% false negative rate. The rate was calculated for all analytes with sufficient positive results and are displayed in Table 2, along with the cutoff levels used for the calculation.

Conclusions

These data show the current industry standard cutoff levels are insufficient to adequately detect and quantitate the majority of common prescription medications and illicit substances. This can result in false negative reports being sent to the treating health care provider. As a consequence, false negative results can lead the health care provider to doubt a patient’s adherence to the prescribed regimen and reduce or not prescribe needed pain medications. Also drug diversion may be incorrectly suspected when cutoff levels are inappropriately set.

76 Implementation of a Strategy to Reduce Acetaminophen Combination Products from Formulary at a Teaching Hospital

Genevieve Kumapley

Saint Peter’s University Hospital, New Brunswick, NJ, USA

Purpose

In 2009, FDA recommended the limiting the dose of acetaminophen in combination products due to the risk of hepatotoxicity as result of unintentional overdoses associated with combination opioid use.¹ Part of the consideration of this recommendation was based on data showing an increase in acute liver failure associated with acetaminophen from 28% in 1998 to 51% in 2003.^1,2 The incidence may be higher in the presence of risk factors such as multiple orders with acetaminophen containing products, chronic liver disease, and older age.³ The National Council for Prescription Drug Program recently published a white paper with recommendations and strategies to decrease the risk of unintentional overdose of acetaminophen in the inpatient setting. Among the strategies, reduction of acetaminophen containing combination products available on formularies was recommended. Our aim was to implement a strategy to eliminate combination acetaminophen products from formulary at our institution.

Method

We implemented an automatic therapeutic substitution protocol as a strategy to decrease the risk of excess acetaminophen administration in our patients. In July 2015, several hospital committees (including the Pain, Pharmacy and Therapeutic and Medical Executive Committees) at our institution considered and reviewed the FDA recommendations and approved the removal of the combination acetaminophen products from the formulary. An automatic substitution protocol was instituted for all orders for patients for Percocet ®, Tylenol #3 ®, Ultracet ® and Vicodin ® to its’ equivalent single opioid agent, unless a physician specifically ordered it as Dispense as Written (DAW).

The process for implementation was over 6 months as the strategy was presented to the various hospital committees for approval. Additionally, all order sets for pain management were amended to reflect the formulary change and the automated medication dispensing cabinets were stocked with only single agent opioid products. The prescribers could order acetaminophen separately as adjuvant therapy when necessary for pain. To enable a smooth transition, education including alerts was provided to prescribers and clinical staff, such as nurses and pharmacists, as part of the implementation process.

Results

Prior to implementation of this strategy, sixty percent of oxycodone orders were for Percocet® and Vicodin ® in the in-patient setting. Six months post the implementation of the protocol, it was noted that less than 0.01% of the orders were for combination products. The overall number of oxycodone orders remained fairly consistent and no negative outcomes were reported.

Conclusions

Based on FDA recommendations, our institution successfully eliminated combination acetaminophen products and implemented an automatic therapeutic substitution protocol of combination acetaminophen containing products to single opioid product for adults. This change met minimal resistance in acceptance and decreased the potential risks for unintentional overdose.

77 Perceived Treatment Effectiveness and Satisfaction in Fibromyalgia Patients Taking FDA-approved Treatments: A Prospective Survey Study

Sandhya Metha¹, Winghan Jackie Kwong², Craig White¹, Jeffrey Niemira¹, Anja Prüfert¹, Kathy Lang¹

¹Quintiles, Cambridge, MA, USA, ²Daiichi Sankyo, Inc., Parsippany, NJ, USA

Purpose

Fibromyalgia (FM) is a chronic pain disorder characterized by widespread pain, and is often associated with other symptoms such as fatigue, sleep and cognitive impairment. Three medications are approved by the United States (US) Food and Drug Administration (FDA) for management of FM: duloxetine, pregabalin, and milnacipran. Previous studies have examined treatment patterns, adherence and health care costs of patients taking FDA-approved treatments using administrative databases; however, patient-reported treatment experiences are not well-studied. The aim of this study was to assess effect of patient reported outcomes measures on perceived treatment effectiveness and satisfaction with FDA-approved FM medications.

Method

A cross-sectional survey was conducted with FM patients recruited via the internet. Patients (≥18 years old) who had taken any of the FDA-approved FM medications at any time within the past 2 years were allowed to participate in the survey. Patients were asked to rate effectiveness (on a scale of 1 to 5, with 1 being “Not at all effective” and 5 being “Extremely effective”) and satisfaction (on a scale of 1 to 5, with 1 being “Extremely dissatisfied” and 5 being “Extremely satisfied”) for each of the FDA-approved medication(s) they were taking or had taken. The survey also included questions on patient demographics, FM-related symptoms, medication side effects and its bothersomeness, and validated patient reported outcomes (PRO) scales including the modified Brief Pain Inventory-Short Form (BPI-SF), Fibromyalgia Impact Questionnaire (FIQR), Work Productivity and Activity Impairment (WPAI), Medical Outcomes Study Sleep Scale (MOS), Hospital Anxiety and Depression Scale (HADS), and EuroQol five dimensions questionnaire (EQ-5D). Multivariable ordinal logistic regression was conducted to assess the effect of PRO measures on perceived treatment effectiveness and satisfaction while controlling for patient demographics, FM medication, medication side effects and its bothersomeness.

Results

A total of 514 patients completed the survey, of which 297 (57.78%), 395 (76.85%) and 89 (17.32%) had used pregabalin, duloxetine and milnacipran, respectively. The majority patients were female (91.83%), white (83.27%) and aged between 35 and 64 years (75.49 %). Only 35.99% patients were actively employed. On average, patients had experienced FM-related symptoms for 12.66 years, had been diagnosed for 8.61 years, and took pregabalin, duloxetine and milnacipran for 2.86 years, 3.45 years and 2.11 years, respectively. No significant differences were observed across the treatment groups with respect to medication side effects, except for weight gain (highest in pregabalin, 38.05%) and weight loss (highest in milnacipran, 13.48%). FIQR, WPAI and BPI-SF interference scores were highly correlated (Pearson r>0.73); therefore, FIQR and WPAI scores were excluded from regression models.

Multivariable ordinal logistic regression showed that patients reporting higher BPI-SF pain severity were less likely to rate their treatment as effective (Odds Ratio [OR]: 0.78, 95% Confidence Interval [CI]: 0.67-0.91). Patients with better health-related quality of life (higher EQ-5D scores) were more likely to rate their treatment as effective (OR: 1.09, 95% CI: 1.01-1.17). Duloxetine patients were less likely to rate their treatment as effective compared to pregabalin users (OR: 0.50, 95% CI: 0.33-0.75).

Patients reporting higher BPI-SF pain severity (OR: 0.86, 95% CI: 0.75-0.99) and BPI interference scores (OR: 0.88, 95% CI: 0.78-0.99) were less likely to be satisfied with treatment. Patients reporting higher EQ-5D scores were more likely to be satisfied (OR: 1.10, 95% CI: 1.02-1.18). Duloxetine users reported lower satisfaction (OR: 0.65, 95% CI: 0.44-0.97) compared to pregabalin users. Female patients were more satisfied than male patients (p<0.001). Bothersomeness of medication side effects significantly reduced treatment satisfaction (P<0.04) but did not affect treatment effectiveness. The effect of MOS or HADS on treatment effectiveness and satisfaction was not significant.

Conclusions

The underlying FM-related pain severity level and its impact on health-related quality of life are important determinants of treatment effectiveness and satisfaction. The study findings highlight the importance of assessing patient reported outcomes in FM patients to understand their unmet needs to help provide tailored treatment regimens and improve the lives of patients with FM.

78 Safety, tolerability, and efficacy of Xtampza^TM ER (oxycodone extended-release capsules) treatment in subjects 65 years and older

Ernest Kopecky¹, Ben Vaughn², Scott Lagasse¹, O’Connor Melinda¹

¹Collegium Pharmaceuticals, Inc, Canton, MA, USA, ²Rho, Inc, Chapel Hill, NC, USA

Purpose

Limited data exist on the effects of oxycodone treatment regimens among elderly patients with chronic pain. This post hoc analysis evaluated the safety, tolerability, and efficacy of Xtampza^TM ER (oxycodone extended-release capsules), a novel oxycodone, microsphere-in-capsule formulation with abuse-deterrent properties, among subjects ≥ 65years.

Method

Data are from an enriched enrollment, randomized withdrawal, Phase 3 study consisting of an open-label Titration Phase followed by a 12-week Double-blind Maintenance Phase in opioid-naïve and opioid-experienced subjects with chronic lower back pain (CLBP). The ≥ 65year subject population was evaluated for efficacy based on average pain intensity numerical rating scale (PI-NRS) scores (11-point scale) at Week 12 and Patient Global Impression of Change (PGIC). The safety and tolerability profile of Xtampza was also evaluated by examining common treatment-emergent adverse events (TEAEs).

Results

Of the 26 subjects ≥ 65years old who were randomized to Xtampza prior to the Double Blind Maintenance Phase, 18 (69.2%) completed the study; only 2 subjects (7.7%) in the Xtampza-randomized group discontinued the study due to AEs. In subjects ≥65years, clinically important pain reduction from Screening Baseline (≥2 points on PI-NRS) was achieved with Xtampza treatment, with a median PI-NRS score at screening of 7.50 and a median PI-NRS score at Week 12 of 2.69 (p<0.0001). All 18 subjects who completed the study reported improvement in their CLBP by the end of the Double-blind Maintenance Phase, with 16 (88.9%) showing ≥30% improvement (p=0.01) and 14 (77.8%) showing ≥50% (p=0.05) improvement in pain intensity at Week 12. The safety and tolerability profiles observed in subjects ≥65 years were as expected with no new or unexpected safety concerns, and the AE profiles were similar between the Titration and Double-blind Maintenance Phases of the study.

Conclusions

Xtampza may offer geriatricians and their patients an effective and safe abuse-deterrent opioid analgesic option for the management of chronic pain. This research was supported by Collegium Pharmaceutical, Inc., Canton, MA

79 Efficacy and Safety of Opioids Compared with Placebo in Chronic Pain: A Systematic Review and Meta-Analysis of Enriched Enrollment Randomized Withdrawal Trials

Diana Meske¹, Roi Treister^1,3, Oluwadolapo Lawal¹, Harrison Elder¹, Lisa Portney¹, Valerie Langberg², Florence Paillard¹, Nathaniel Katz^1,4

¹Analgesic Solutions, Natick MA, USA, ²The Center for Evidence Based Medicine, Brown University, Providence RI, USA, ³Department of Neurology, Massachusetts General Hospital, Boston, MA, USA; Harvard Medical School, Boston MA, USA, ⁴Tufts University School of Medicine, Boston MA, USA

Purpose

The long-term efficacy of opioids to treat chronic non-cancer pain is a subject of continued interest. The use of opioids for management of chronic pain is further complicated by high rates of misuse, abuse and diversion of prescription opioids. In view of recent controversy about the efficacy of long-term opioid treatment of chronic pain, we conducted a meta-analysis of published clinical trials to evaluate the efficacy of μ-opioid receptor agonists in chronic non-cancer pain.

Method

MEDLINE and Cochrane Central Register of Controlled Trials were searched for studies with Enriched Enrollment Withdrawal design (EERW) published in English (≤June 2016) with double-blinded outcomes comparing any opioid to placebo for ≥12 weeks during the study’s randomized blinded treatment phase (RBTP). Study selection criteria were: adult participants; ≥10 patients per arm; any chronic non-cancer pain; all approved μ-agonist opioids (including combinations); oral, transdermal, nasal, sublingual, and transmucosal routes of administration. Risk of bias was assessed based on guidelines from Cochrane Risk of Bias Tool of the SRDR. High quality studies were those with no major methodological flaws fulfilling ≥6 of the 12 internal validity criteria. Primary outcome measure was change in pain intensity (PI) from randomization baseline to study endpoint. Secondary outcome measures included responder rate (≥30% and ≥50% improvement), Patient Global Impression of Change (PGIC), Patient Global Assessment of Study Medication (PGASM), change in function, rescue medication consumption, and Quality of Life (QOL). Safety outcomes collected included proportion of patients with adverse events (AEs), serious AEs (SAEs), and discontinuing due to AEs or withdrawal symptoms. For the primary outcome, the standard mean difference (SMD) in PI from randomization baseline to week 12 was assessed by a binary random-effects model using the restricted maximum likelihood method (REML). Responder rates, PGIC, and PGASM were analyzed using a binary random-effects REML model, with results reported as risk differences.

Results

Fifteen studies met the inclusion criteria. Treatments included hydrocodone (4 studies), oxymorphone, oxycodone, buprenorphine, and tapentadol (2 studies each); hydromorphone, morphine/naltrexone, and tramadol (1 study each). Most studies involved chronic low back pain indications (10 studies). For all studies, the open-label phase lasted between 2 and 8 weeks and 12 weeks for the double-blind maintenance phase. Opioid efficacy was statistically significant compared to placebo for (i) the change in PI score from randomization baseline to week 12 (SMD:-0.416; 95%CI: -0.521 to -0.312; p<0.001); (ii) ≥30% and ≥50% improvement in PI (risk difference estimate: 0.166 and 0.137, respectively; p<0.001); (iii) PGIC (0.163, p<0.001) and PGASM (0.194, p<0.001). There was a statistically significant difference between opioids and placebo in the proportion of patients discontinuing due to an AE (risk difference estimate: 0.021; p=0.011). The overall weighted mean discontinuation rate was numerically higher for placebo (42.1%) than study drug (31.0%), probably due to discontinuation due to lack of efficacy in the placebo group.

Conclusions

This meta-analysis of 15 EERW studies demonstrates that opioids are effective for up to 3-months in the treatment of chronic non-cancer pain as measured by pain intensity reduction and patient global evaluations, with minor benefit on physical function. The EERW design allows inferences of efficacy of long-term pre-study treatment. The confirmation of long-term opioid efficacy will help inform continued discussion about the risk-benefit balance of opioid therapy.

80 Bioequivalence and Food Effect of a Novel, Abuse-Deterrent (AD), Extended-Release (ER) Morphine Product Candidate Compared With a Currently Available non-AD, ER Morphine Product

John Lawler, Gwendolyn Niebler, Karsten Lindhardt, Jeffrey M. Dayno

Egalet Corporation, Wayne, PA, USA

Purpose

Abuse-deterrent (AD) formulations of opioids have been deemed an important component of risk mitigation for opioid abuse. Novel morphine AD, extended-release (ER) injection-molded tablets (morphine-ADER-IMT) have been developed using proprietary Guardian^TM Technology (Egalet Corporation, Wayne, PA) utilizing an injection-molding manufacturing process that produces a hard tablet resistant to rigorous physical and chemical manipulations. The bioequivalence of morphine-ADER-IMT were compared to a marketed non-AD, ER morphine and the effect of food was evaluated.

Method

The bioequivalence of morphine-ADER-IMT and a marketed non-AD, ER morphine product was assessed in two phase 1, randomized, open-label, single-dose, crossover studies in healthy adults aged 18-55 years. In study 1 (N=66), fasted subjects received oral morphine- ADER-IMT 30 mg, morphine ER 30 mg, or morphine-ADER-IMT 2 × 15 mg in 3 sequential periods. In study 2, one cohort (n=40) received morphine-ADER-IMT 60 mg or morphine ER (60 mg) under fasting conditions in 2 treatment periods; a second cohort (n=25) received morphine-ADER-IMT (60 mg) under fed conditions in an additional treatment period. In both studies, all subjects received naltrexone 50 mg before and after each study drug administration. Pharmacokinetic parameters for morphine included area under the plasma concentration vs time curve (AUC) from time 0 to the time of the last quantifiable concentration (AUC_0-t), AUC from time 0 extrapolated to infinity (AUC_0-inf), and maximum plasma concentration (C_max). Bioequivalence criteria were from US Food and Drug Administration guidelines.

Results

In study 1 (fasting conditions), bioequivalence was demonstrated among all 3 treatments (morphine-ADER-IMT 30 mg, morphine ER 30 mg, and morphine-ADER-IMT 2 × 15 mg) for all 3 pharmacokinetic parameters. In study 2, bioequivalence (fasting conditions) was demonstrated between morphine-ADER-IMT 60 mg and morphine ER 60 mg; further, the fed/fasted analysis demonstrated no clinically relevant food effect for morphine-ADER-IMT 60 mg. Morphine-ADER-IMT was generally well tolerated with no unexpected adverse events.

Conclusions

Bioequivalence across the dosage range (15 mg, 30 mg, and 60 mg) was demonstrated for morphine-ADER-IMT compared with a non-AD, ER morphine product. In addition, morphine-ADER-IMT have no evidence of a clinically relevant food effect as shown in a fed/fasted study.

81 Optimization of a smoking-simulation technique to investigate smoke-ability of opioids from pharmaceutical formulations

Paul Fort, Amanda Hobe, Jessica Baehr, Chris Altomare, Hongzhe Wang, Daniel Leach, Abdel Halim

DRUGSCAN, Horsham, PA, USA

Purpose

For decades, opioids have been abused by smoking through the technique of sublimation of an opioid contained in natural or manufactured pharmaceutical products.

The FDA 2016 draft guidance “General Principles for Evaluating the Abuse Deterrence of Generic Solid Oral Opioid Drug Products” listed abuse by smoking as one of the abuse-deterrent formulation (ADF) characteristics that need to be evaluated. The FDA guidance suggested to evaluate abuse by smoking via assessing % of opioid sublimation following heating of the product at 233°C as defined by the ignition temperature of paper.

In this poster, we are optimizing a proprietary technology created by DRUGSCAN and Pinney Associates to simulate smoking of an opioid product via heat-induced volatilization of an active opioid ingredient and collection of volatilized ingredient in a pump-induced air suction that mimic inhalation.

Method

To optimize the technology two of the most common active pharmaceutical ingredients (API); Oxycodone (OC) and Hydrocodone (HC) were attempted as free base and as Oxycodone hydrochloride & Hydrocodone bitartrate.

An amount of each material, equivalent to a common tablet content of the active pharmaceutical ingredient (API), was heated at different temperatures (between 160⁰C to 300⁰C), at 20⁰C increments, to cover the melting points of the pure API components. OC was attempted over two heating times; 5 and 10 minutes and HC was attempted for 10 minutes only. Volatilized materials, in addition to remnants post heating, were analyzed on validated LC/MS-MS assays.

Results

Optimization results showed that each free base was volatilized more than the salt form for both OC and HC. When heated for 5 and 10 minutes, about 46 % and 51 % of OC base was volatilized at 300 ⁰C and 260 ⁰C respectively, and about 17 % and 28 % of OC salt was volatilized at 300 ⁰C and 280 ⁰C. About 63 % of HC base and about 25 % of HC salt were volatilized at 300 ⁰C and 260 ⁰C respectively.

Conclusions

Further optimization is ongoing but these results indicate that smoking simulation technique should be optimized at different heating temperatures and, probably, different heating times rather than heating at a fixed temperature as it has been suggested by the FDA guidance. Once optimized conditions have been established, these conditions should be applied to the pharmaceutical product under investigation.

82 Dissolution Studies in the Presence of Alcohol With an Abuse-Deterrent, Extended-Release Morphine Product Candidate

Torben Elhauge, Lene Kristensen, Jeffrey M. Dayno, Karsten Lindhardt

Egalet Corporation, Wayne, PA, USA

Purpose

Some extended-release (ER) opioid formulations may be prone to rapid drug release (dose dumping) when co-ingested with alcohol, potentially causing toxicity, overdose, and even death. Dissolution testing in the presence of various concentrations of alcohol to assess the potential for dose dumping was conducted with a novel product candidate of morphine abuse-deterrent, ER injection-molded tablets (morphine-ADER-IMT). Morphine-ADER-IMT applies proprietary Guardian^TM Technology (Egalet Corporation, Wayne, PA) that uses a novel application of injection-molding for the manufacturing of pharmaceutical tablets.

Method

Dissolution of morphine-ADER-IMT (15, 60, and 100 mg dosages) was evaluated (N=12) at 37ºC±0.5ºC in 900 mL 0.1 N HCl (pH 1.2; reflecting gastric pH) or buffer (pH 6.8; reflecting intestinal pH) media containing 0%, 5%, 10%, 20%, or 40% ethanol, using a standard United States Pharmacopeia apparatus. Morphine release was measured by high-performance liquid chromatography with an ultraviolet detector (285 nm) at 15, 30, 45, 60, 75, 90, 105, and 120 minutes.

Results

All dissolution profiles for morphine-ADER-IMT 15 and 60 mg complied with f2 profile comparison test criteria, indicating comparable dissolution profiles among aqueous (0% ethanol) and ethanol-containing media. The 100 mg dosage demonstrated a significantly slower dissolution in 40% ethanol and, therefore, did not pass the f2 test. Ethanol in concentrations of 5%-20% had no clear effect on dissolution rates in either pH 1.2 or pH 6.8. However, a trend showing a decrease in dissolution rates for all dosages was observed with increasing ethanol concentrations, and a significant decrease in dissolution rate was observed with 40% ethanol.

Conclusions

No evidence of alcohol dose dumping was observed with morphine-ADER-IMT, and slower dissolution rates occurred at higher alcohol concentrations.

83 An Evaluation of the Safety and Efficacy of N1539, a Novel Intravenous Formulation of NanoCrystal Meloxicam, Administered by IV Push in Subjects with Moderate to Severe Pain Following Bunionectomy

Ira J. Gottlieb¹, Deborah R. Tunick¹, Randall J. Mack², Stewart McCallum², Campbell P. Howard², Alex Freyer², Wei Du³

¹Chesapeake Research Group, Pasadena, MD, USA, ²Recro Pharma, Inc., Malvern, PA, USA, ³Clinical Statistics Consulting, Blue Bell, PA, USA

Purpose

Previous studies have identified doses of N1539 from 5-60 mg to be well tolerated when administered as an intravenous (IV) push over 1-2 minutes. The current study was planned to evaluate the safety of N1539 administered as a rapid IV push over 15-30 seconds, compared with placebo, in subjects with acute moderate to severe pain following bunionectomy. Additionally, this study sought to evaluate the efficacy of 60 and 30 mg dose levels of N1539 in an orthopedic pain model. N1539 is a novel IV formulation of NanoCrystal Colloidal Dispersion® meloxicam, being developed for the management of moderate to severe pain.

Method

This was a single-center, randomized, double-blind, placebo-controlled study in male and female subjects, age 18-75 years in otherwise good health, undergoing simple unilateral bunionectomy. Study participation included a screening visit with written informed consent, an inpatient visit including surgery and study treatment, and two follow-up visits after discharge. Subjects underwent a standardized bunionectomy procedure, and were maintained using a popliteal block until Postoperative Day 1, when they were eligible to qualify for randomization. Qualifying subjects with moderate to severe pain were randomized to receive N1539 60 mg, N1539 30mg, or placebo via IV push over 15-30 seconds every 24 hours for two doses, with an option for a third dose prior to discharge. Safety assessments included clinical laboratory tests, vital signs, ECGs, surgical wound assessment, and monitoring of adverse events (AEs) and serious AEs (SAEs). Efficacy assessments included Pain Intensity (PI) assessed using a 11-point numeric pain rating scale (NPRS), rescue analgesia use, and a patient global assessment (PGA) of satisfaction with analgesia, at intervals over the 48-hour double-blind inpatient phase. Rescue analgesia, oral oxycodone, was available for pain not relieved by the study drug. The primary efficacy objective was to evaluate the effect size of N1539 using the summed PI difference from Hour 0 to 48 (SPID₄₈) after dosing. The primary analysis method for SPID₄₈ used a last observation carried forward (LOCF) method, with a 2-hour windowed LOCF (W2LOCF) method included as a sensitivity analysis.

Results

This study evaluated 59 subjects ranging in age from 18 to 72 years. The majority of subjects were female (81.4%) and African American (50.8%), with demographics similar across groups. N1539 was tolerated with no deaths, SAEs, or withdrawals due to an AE. AEs were generally mild or moderate in intensity, and similar in incidence across groups. The most common AEs included nausea, headache, dizziness, pruritus, and vomiting. Administration over 15-30 seconds was well tolerated, with no infusion related AEs, and no infusions were slowed or interrupted.

The estimated effect size for SPID₄₈ was 0.81 and 0.87 using the LOCF method, and 0.88 and 1.01 using the W2LOCF method for the 60 and 30 mg dose groups respectively. This study demonstrated superior efficacy of N1539 at 60 and 30 mg dose levels versus placebo at all evaluated SPID intervals (6, 12, 24, 48, 12 48, and 24-48 hours), using the LOCF and W2LOCF methods via ANCOVA models. Analysis of SPID results at various intervals revealed no difference between the N1539 60 and 30 mg dose levels. The incidence of subjects achieving 30% and 50% improvement in pain intensity within the first 6 and 24 hours post treatment initiation was statistically significant for the N1539 30 mg dose under the W2LOCF analysis compared with placebo; significant differences were not identified for the 60 mg dose or with other analysis models. Time to first use of rescue medication was statistically significantly longer in N1539 60 mg treated subjects; KM median time to first rescue (95% CI) was 3.10 (1.13-6.35) hours for 60 mg, 1.26 (1.02-2.68) hours for 30 mg, and 1.57 (0.85, 2.51) hours for placebo.

Conclusions

This study supports the safety and tolerability of N1539 at a 60 or 30 mg IV dose administered once daily over 15-30 seconds. The efficacy analysis was favorable for both N1539 dose levels compared to placebo with estimated effect size ranged from 0.52 to 1.01 per observed SPID₄₈, and statistically significant differences in SPID intervals throughout the study. As no incremental benefit was identified using a higher treatment dose, this study supports the use of N1539 30 mg administered IV once daily in post-operative settings where patients are expected to have moderate to severe pain.

84 Six-month, open-label study of hydrocodone extended release formulated with CIMA® abuse-deterrence technology platform: safety, maintenance of analgesia, and abuse potential

Martin E. Hale¹, Yuju Ma², Richard Malamut²

¹Gold Coast Research, LLC, Plantation, FL, USA, ²Teva Pharmaceuticals, Frazer, PA, USA

Purpose

The US Food and Drug Administration has identified a need for abuse-deterrent formulations of opioids as a high public priority. As a result, a single-agent hydrocodone extended-release (ER) tablet formulated with a CIMA® Abuse-Deterrence Technology (ADT) platform was developed for the management of pain severe enough to require daily, around-the-clock, long-term opioid treatment when alternative treatment options are inadequate. The ADT platform prevents rapid release of hydrocodone when the tablet is manipulated or taken with alcohol. The compound has demonstrated acceptable long-term (12-month) safety and tolerability in a previously completed study (Hale et al. J Opioid Manag. 2015;11:425-34). Clinical efficacy (Hale et al. J Opioid Manag. 2015;11:507-18) and abuse-deterrent properties (Darwish et al. Pain Med 2016; epub) have also been demonstrated.

Method

This phase 3, multicenter open-label extension study was conducted to evaluate long-term safety and tolerability, maintenance of analgesia, and aberrant drug-related behaviors (drug loss and diversion) with hydrocodone ER in patients aged 18-80 years with moderate-to-severe back pain for ≥3 months. All patients had completed a previous 12-week randomized, double-blind, placebo-controlled study of hydrocodone ER. Patients receiving hydrocodone ER in the previous study continued their identified analgesic dose unless adjustment was needed; those receiving placebo underwent dose titration/adjustment to an analgesic dose (30-90 mg every 12 hours). Analgesic dose was defined as a worst pain intensity (WPI) score ≤6 and an average pain intensity (API) score ≤4 on a numeric rating scale (0=no pain; 10=worst imaginable pain) over the preceding 24 hours and use of rescue medication at no more than 20% of the daily hydrocodone ER dose for 3 consecutive days while on the same dose of study drug. Patients received 22 weeks of open-label treatment. The primary outcome measure was safety, as assessed by adverse events (AEs). Secondary outcome measures included maintenance of analgesia, as assessed by patient-reported WPI and API scores during the 24 hours preceding each study visit, and aberrant drug behavior, as assessed by study drug loss and diversion. In addition, pure tone audiometry was performed 2 weeks after the final study visit.

Results

A total of 182 patients were enrolled at 56 US centers and received ≥1 dose of study drug; 170 had an identified analgesic dose and entered open-label treatment; and 136 completed the study. Of the 182 enrolled patients, 78 received placebo in the previous study. The mean age of patients was 52.1 years (range: 21-79 years), approximately two thirds were white, and 62% were opioid naïve before the previous study. The most common stable pain relief dose of hydrocodone ER overall was 30 mg (33% of patients); the most common dose was 30 mg (39%) in patients who were opioid naïve before the previous study and 90 mg (17%) in patients who were opioid experienced. Doses were stable during open-label treatment, with 4%/4% of patients increasing/decreasing dose. AEs were reported for 65/182 (36%) patients during dose titration/adjustment and 88/170 (52%) during open-label treatment. The most common AEs were nausea (10%) and vomiting and constipation (5% each) during titration/adjustment and constipation (7%) and nausea (6%) during open-label treatment; respiratory depression did not occur during the study. Most AEs were mild to moderate in intensity. No treatment-related serious AEs or clinically meaningful trends in other safety assessments, including physical examination and pure tone audiometry, were noted. Neurosensory deafness was reported as a severe AE in 1 patient (hydrocodone ER 30 mg twice daily) and was considered treatment related. Mean WPI and API scores remained steady without showing loss of effect throughout the 22-week open-label treatment period. The mean changes from baseline to endpoint in WPI scores were 0.0 among patients who were opioid naïve before the previous study and 0.1 among those who were opioid experienced; the respective mean changes in API scores were -0.1 and 0.1. Six (3%) patients reported medication loss, and 5 (3%) reported medication diversion.

Conclusions

Hydrocodone ER 30-90 mg every 12 hours was safe and well tolerated during the 22-week treatment period, with a safety profile that was consistent with that of hydrocodone and other opioids. Hydrocodone maintained its analgesic effect in patients with chronic low back pain during treatment without evidence of the development of tolerance. The incidence of loss and diversion was low. These findings support the chronic use of hydrocodone ER in patients with chronic low back pain, with preserved long-term safety and tolerability despite the addition of an abuse-deterrent formulation.

85 Whose Urine is it? A new approach to identify mislabeled samples and other human or synthetic urine substitution in outpatient medication/sobriety monitoring. Results from a multicenter 902 sample randomized study to prove the validity of a new method for matching urine samples to a specific patient

Matthew McCarty, Keqin Gregg

Genotox Laboratories, Austin, Texas, USA

Purpose

Opioid analgesic use has grown dramatically over the past quarter century. In 2012, health care providers wrote 259 million prescriptions for opioid pain medication.¹ This increase in opioid use has been accompanied by a significant escalation in opioid-related morbidity and mortality. Death from opioid overdose has increased fourfold since the early 1990s.² Now, more than ever, it is critically important for Providers to develop and maintain a strong therapeutic alliance with patients to ensure all clinical decision making is based on accurate diagnostic information.

Urine drug testing (UDT) is the gold standard in sobriety and medication monitoring and an essential tool to help providers make certain patients are complying with the treatment plan. The clinical value of UDT is 100% dependent on knowing the sample analyzed and results reviewed are actually from a specific patient. Published literature documents a 0.1 to 5.0% sample mislabeling rate in processing laboratory samples.³ Additionally, due to the unique reasons why UDT is required, there may be incentive for some patients to attempt to cheat the drug test by submitting synthetic or another person’s urine in order to continue to receive medications even though they are non-compliant with the treatment agreement. Sales of products used to cheat the results of a drug test are believed to be approaching $1Billion. Due to the known presence of labeling errors and the growing industry helping patients fraudulently pass drug tests, it is essential that clinicians have the ability to match each urine specimen to a specific patient.

Method

This study is an IRB-approved, multicenter, double-blind study. All subjects were informed about the nature of the study and signed informed consent forms. Although each study site was encouraged to attempt to enroll all patients undergoing urine drug testing, the informed consent documentation clearly stated that participation in the study was optional.

A urine sample and buccal swab sample were collected from each consenting patient during their regular appointment(s). A total of 902 paired samples were collected from 682 patients at the 10 clinics between July 15, 2015 and December 31, 2015. During the same time period, an additional 986 urine samples were received from the study sites for urine drug testing but not included as part of the study, because the patients declined participation and/or the site failed to screen them for enrollment.

The samples were shipped overnight to Genotox Laboratories via UPS at ambient temperature. Upon receipt at Genotox, the samples were accessioned and sent to a third-party laboratory, where a trained scientist replaced a subset of the samples with known matched, mismatched, or synthetic urine samples, using a randomization plan designed by Novella Clinical. DNA was extracted from the paired buccal and urine samples and analyzed with a proprietary panel of genetic markers. Genotyping results of each urine sample were compared to the corresponding buccal cell sample to determine whether the paired samples matched. After un-blinding, the test results were compared to the expected results, as recorded in the randomization plan, to evaluate accuracy, sensitivity, and specificity.

Results

During the 6-month study (July 15, 2015 to December 31, 2015), a total of 902 urine/buccal cell samples were collected. Of those, a subset of 173 urine samples was replaced with known matched, mismatched, or synthetic urine, per the blinded randomization plan. Six of the 902 samples (4 from the randomized group and 2 from the non-randomized group) were inadvertently mislabeled and therefore excluded from the study. The remaining 896 samples were processed and tested in accordance with the protocol.

The DNA extracted from 3 (1.7%) of the randomly introduced control urine samples (1 matched pair and 2 mismatched pairs) was of poor quality and failed to generate reliable data. These samples were labeled “indeterminate” (IND) and not included in the final analysis. The remaining randomly introduced control samples (n=166) were all tested with 100% accuracy, 100% sensitivity, and 100% specificity.

Out of the 727 non-randomized urine samples, 34 had poor DNA quality and failed to generate reliable data resulting in a call rate of 95.3%. The remaining non-randomized samples (n=693) gave reliable data for sample identification. Eleven (1.6%) of these samples were “Negative Match” meaning the urine sample was not a match to the corresponding buccal cell sample.

Conclusions

Critical clinical decisions are based on the results of urine drug tests. Sample mislabeling and deliberate urine substitution using synthetic or other human urine may lead to clinical choices based on erroneous and inaccurate lab results. The rapidly escalating morbidity and mortality rates associated with widespread opioid analgesic use necessitate a better approach to authenticating sample validity for urine drug testing. DNA-verified sample authentication was demonstrated to be sensitive, specific and accurate at matching urine samples collected with buccal cells for individual patients. Use of this authentication method eliminates the need to ever ask again – Whose urine is it?

86 Are We “In the Weeds”? What Hospice Providers Want to Know About Medical Cannabis

Kelly Mendoza, Mary Lynn McPherson

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

Purpose

Currently, 25 states and the District of Columbia have legalized or decriminalized cannabis (marijuana) for medical use, beginning with California in 1996. With more and more states putting the issue on their legislative ballots, physicians and other healthcare providers are finding themselves in the midst of the cannabis debate. The benefits of medical cannabis have been shown in nausea and vomiting associated with cancer chemotherapy, cachexia associated with HIV/AIDS, and certain kinds of neuropathic pain or treatment-resistant cancer pain. However, it is unclear how comfortable hospice providers are with the concept of medical cannabis. The aim of this study is to determine knowledge, skills, attitudes, and perceived knowledge gaps from hospice providers (physicians, pharmacists, nurse practitioners, chaplains, social workers, etc) regarding medical cannabis. This data will be used to develop training programs on the appropriate, safe, and effective use of medical cannabis in hospice and palliative care.

Method

Working within a large national hospice and palliative care program that has operations in 19 states, an anonymous survey will be used to assess providers’ knowledge, beliefs, concerns, and training needs regarding medical cannabis. Survey results will guide the approach to and content of a training module for the providers regarding best clinical practices of medical cannabis.

Results

Results are pending and will be completed by the PAINWeek conference.

Conclusions

Conclusions will be made once the survey results have been collected.

87 Neuromodulation Therapy for the management of Post Mastectomy Pain Syndrome (PMPS)

Krishna K Mettu¹, Shadi M Haddadin², Srinivas Nalamachu³

¹Sleep Medicine & Neurology, Jefferson City Medical Group, Jefferson City, MO, USA, ²Hematology & Oncology, Jefferson City Medical Group, Jefferson City, MO, USA, ³International Clinical Research Institute, Overland Park, KS, USA

Purpose

Post Mastectomy Pain Syndrome (PMPS) is a type of chronic neuropathic pain that can develop following mastectomy beyond the anticipated healing post-mastectomy period. Incidence reported so far has ranged from 20 to 72%. PMPS is thought to be caused by direct nerve injury and, or from the development of a traumatic neuroma or scar tissue involving neural tissue in the axillary and/or chest wall regions. The pain and discomfort from PMPS can be severe enough to impact daily activities, mood changes, insomnia, diminished social and occupational function, loss of productivity, long-term quality of life and can cause a significant economic burden for the healthcare system.

Current treatment modalities involve physical therapy, desensitization techniques, transcutaneous electrical nerve stimulation (TENS), topical cold packs; pharmacotherapy with use of Alpha 2 delta agonists, SNRIs, Topical agents or NSAIDs. Interventional techniques like nerve blocks or Botulinum neurotoxin type A injections and complementary treatments like acupuncture therapy have also been tried. We present a case report of a patient with PMPS who benefitted with the new non-invasive Neuromodulation device, Chronic Pain (CP) Relief Wand®.

Method

A 40-year-old female presented with chronic pain and discomfort in her left lateral chest wall, axilla, and medial upper arm region for the past 8 yrs. She was previously diagnosed with Ductal Carcinoma In Situ of the left breast, 8.5 yrs ago. Treatment included lumpectomy followed by multiple surgical procedures with complete mastectomy, lymph node biopsies and post reconstruction with implant placement. Over the course of time, she developed chronic pain (described as burning, stinging, tingling and heaviness) and lymphedema. On brief pain inventory scale, reported 6-8/10, almost day to day. This chronic pain interfered with her quality of life affecting daytime functioning, reduction in range of motion, fatigue, and insomnia. Examination showed hypersensitivity, scarring of the surgical region, mild edema, hyperalgesia involving the above mentioned areas and discomfort with movement. She was diagnosed with Post Mastectomy Pain Syndrome (PMPS).

Multiple modalities of treatments were tried with both pharmaceutical and non-pharmaceutical modality measures including Lidoderm patch, Topical lotions, Massage and Physical therapy for pain, lymphedema treatment with use of compression hoses with limited benefit. Gabapentin was offered but she opted for drug-free therapy with the chronic pain relief device.

Results

Treatment was instituted with Neuromodulation therapy on a daily basis for 5-15 minutes per session, applied to the painful areas (Patient-controlled demand use). With this therapy, she reported a significant improvement in her pain severity, frequency and duration. Pain severity reduced to 1-2/10 on a consistent basis for the past 9 months resulting in a significant improvement in general activity, work, sleep, range of motion and overall quality of life. After 6 months of daily usage, continued to report significant reduction in severity and recurrence of pain. As a result, felt lesser need to use stimulation therapy and been using on an average of 2-3 times a week with continued consistent benefit. She did not require any additional pharmaceutical measures or reported significant side effects.

Neuromodulation device delivers Transcutaneous Electrical Nerve Stimulation (Patented technology and FDA cleared for pain relief), when applied over the symptomatic area, by discharging electrical stimulus to underlying nerve-muscle fibers, altering and/or blocking pain signals through sensory fibers to the spinal cord and brain. It is postulated to act on pain-relieving endogenous opioid pathways, inhibit the excitatory neurotransmitters and enhance the inhibitory pathways via the modulation of ascending and descending nerve tracks neurotransmission to restore the central pain modulation through central inhibition. Thus neuropathic pain relief can be achieved with modulation of these both peripheral and central pain relief mechanisms.

Conclusions

This case report illustrates the potential role of a new Chronic Pain Relief Wand® both as a drug-free alternative and/or adjunctive to pharmacologic management for the management of Post Mastectomy Pain Syndrome (PMPS). This modality can be drug sparing, and can be applied easily at home when patient experiences symptoms. (Patient-controlled demand use). It can also offer cost savings in lieu of the medications due to chronicity of this condition. Further studies with a larger sample size will be beneficial to further clarify the role of this device in the management of Post Mastectomy Pain Syndrome.

88 Management of Comorbid Pain and Pain related features of Restless Leg Syndrome (RLS) with a Non-Invasive Neuromodulation Therapy

Krishna K Mettu¹, Manjamalai Sivaraman², Pradeep Sahota²

¹Sleep Medicine & Neurology, Jefferson City Medical Group, Jefferson City, MO, USA, ²Dept. of Neurology, University of Missouri-Columbia, Columbia, MO, USA

Purpose

Restless Leg Syndrome (RLS) has been traditionally described as a serious distressing chronic sensorimotor neurologic disorder usually associated with unpleasant sensations in the deeper tissues. Often a lifelong disease, it can severely affect sleep and quality of life. Management involves correcting deficiency states, avoidance of triggering factors, behavioral modifications and pharmacotherapy (dopamine-receptor agonists, alpha 2 delta calcium-channel ligand agonists, opioid therapy). Medications may help achieve partial control or cause significant complications both on a short term basis (weight gain, mood disturbances, impulse control disorders) and emergence of new problems during long-term treatment (augmentation, loss of efficacy, excessive daytime sleepiness) necessitating either limiting or even discontinuation of pharmacological therapy. In addition, a significant percentage of patients have comorbid Chronic Pain and may continue to be symptomatic despite use of combinational therapy. Some patients may not even prefer drug therapy due to concern for side effects to medications.

There is an emerging recognition that RLS may be a type of chronic painful neuropathic condition. In addition, chronic pain tends to centralize to CNS over the time. These two premises could be factors in a significant percentage of patients who continue to experience intractable RLS and pain like descriptive symptoms despite combinational medical therapy. Based on these considerations, we hypothesize the role of neuromodulation as one of the potential application for the treatment of RLS. We report a case series involving use of Chronic Pain (CP) Relief Wand® that works through neuromodulation technique for the management of RLS and comorbid Chronic Pain.

Method

11 patients mean age of 60.5 yrs., (4 Males, 7 Females) diagnosed with RLS (met ICSD 3 criteria), type (3 Primary, 7 Secondary) after comprehensive evaluation. Severity of RLS assessed with International Restless Leg Syndrome Scale (IRLS), Pain with Brief Pain Inventory Scale (BPI), Day time somnolence with Epworth Sleepiness Scale (ESS), comorbid medical conditions, ongoing response to current pharmacological therapy and preference for their treatment course. Patients were given option to use device with primary outcome for either drug sparing (Drug Sparing Cohort) treatment by either weaning off current medications or reduction in medications vs adjunctive therapy to current pharmacologic therapy (Adjunctive therapy patient cohort). Pain was deemed primarily from RLS related in 2 patients and in 9 patients from combination of RLS and comorbid pain conditions. RLS severity (IRLSS), Pain (BPI), Sleepiness (ESS), clinical response, trend of medications use (reduction in frequency, number, dosage, side effects), were assessed at baseline and after treatment over the course.

Treatment was instituted with neuromodulation therapy on a daily basis for 5-15 minutes per session, applied to the painful areas for pain conditions and to bilateral legs for RLS treatment. Frequency and duration of use was guided according to the patients clinical ongoing symptoms either daytime or early evening or night time including middle to night breakthrough (Patient Controlled Demand Use). Patients were evaluated to assess response to and treatment, medications were adjusted accordingly.

Results

All 11 patients had clinically significant reduction in baseline IRLS scale (mean of 16.5), Pain (mean of 5.6), clinical improvement in pain symptoms, sleep, and quality of life. 4 patients had Drug Sparing response and were able to stop their current medication. 1 had 50% control requiring adjunctive pharmacotherapy. 6 patients in Adjunctive therapy cohort also reported additional clinically significant RLS and pain symptom control with use of device to their pharmacotherapy. Of these 6 patients, 3 were able to discontinue at least one of their current medication and other 3 patients did not require additional medications. There was also significant reduction in ESS with a mean of (5.9) from baseline. 5 patients reported less need for day to day use of device after a period of time and reduced pattern of use to intermittent basis for RLS and Pain related symptoms. The benefits were consistent over an average duration of 10 months. None of them developed significant side effects except for anticipated transient mild local paresthesias during initial device acclimatization phase.

FDA cleared for pain relief, the Chronic Pain Relief Wand® employs neuromodulation in the form of Transcutaneous Electrical Nerve Stimulation (Patented technology). When applied near symptomatic area, it discharges electrical stimulus to reach underlying nerve-muscle fibers altering and or blocking pain signals through sensory fibers to spinal cord and the brain. It is postulated to act on pain-relieving endogenous opioid pathways, inhibit the excitatory neurotransmitters and enhance the inhibitory pathways via the modulation of ascending and descending nerve tracks neurotransmission to restore the central pain modulation through central inhibition. Thus RLS symptoms and pain relief can be achieved with modulation of these both peripheral and central pain relief mechanisms.

Conclusions

This illustrates potential role of Chronic Pain Relief Wand® both as drug-free alternative and or adjunctive to pharmacologic therapy for RLS management. All RLS patients need to be assessed for pain severity as a guide to assess response to treatment in addition to traditional IRLS scale. Ideal for patients with comorbid pain, experiencing side effects, polypharmacy or drug interactions is an issue. Enables daytime symptoms relief without interfering with activities or sleepiness. Can be opioid sparing and avoids need for combination therapy in intractable RLS patients. Economic impact in view of long term medications therapy for RLS and Pain management.

89 Pharmacokinetics and abuse potential of benzhydrocodone, a novel prodrug of hydrocodone, after intranasal administration in recreational drug users

Travis Mickle¹, Sven Guenther¹, Kathryn Roupe², Jing Zhou², Daniel Dickerson³, Lynn Webster³

¹KemPharm, Coralville, IA, USA, ²Worldwide Clinical Research, Austin, TX, USA, ³PRA Health Sciences, Salt Lake City, UT, USA

Purpose

Immediate-release (IR) opioids are commonly abused via the intranasal (IN) route. Benzhydrocodone is a prodrug of hydrocodone with inherent physicochemical and pharmacological properties designed to deter non-oral forms of abuse on a molecular level rather than through formulation. The objective of this study was to compare the pharmacokinetics and abuse liability of equimolar doses benzhydrocodone hydrochloride and hydrocodone bitartrate (HB) following IN administration in non-dependent, recreational opioid users.

Method

This was a randomized, double-blind, two-way crossover study. Study participants included experienced opioid users, male or female, 18 to 55 years of age, who were not currently

physically dependent on opioids. In contrast to most human abuse potential studies, there was no drug discrimination test and therefore the study was not enriched in subjects that could differentiate active drug from placebo. As such, this design made it less likely to demonstrate differences in Drug Liking between the two treatments. Eligible subjects were randomized 1:1 to receive one of two treatment sequences that included IN benzhydrocodone (13.34 mg) and IN HB (15 mg). The primary objective of the study was to compare the rate and extent of absorption of hydrocodone from benzhydrocodone relative to HB. The secondary objective to was compare the IN abuse potential of the two treatments.

Results

Peak hydrocodone plasma concentration (C_max) was 36.0% lower, and total hydrocodone exposures (AUC_last and AUC_inf) were 20.3% and 19.5% lower, respectively, for benzhydrocodone compared to HB (p<0.0001). All partial AUC values were lower for benzhydrocodone, with ≥75% reduction in hydrocodone exposure at all time intervals up to 1 hour post-dose (p<0.0001). Median T_max of hydrocodone for benzhydrocodone was delayed by >1 hour compared to HB. Drug Liking score, as assessed by maximal liking (E_max), was significantly lower for intranasal benzhydrocodone compared to intranasal HB (p=0.004), with 45% of subjects showing ≥30% reduction in Drug Liking E_max compared to HB.

Conclusions

Reductions in hydrocodone exposure, with concomitant decreases in drug liking relative to HB, suggest that the prodrug, benzhydrocodone, may provide a deterrent to intranasal abuse.

90 Local Administration of HTX-011, a Long-Acting Biochronomer-Based Bupivacaine/Meloxicam Combination, in Hernia Repair Provides Similar Initial Results Whether Injected, Instilled, or Both

Peter Winkle¹, Harold Minkowitz², Erol Onel³, Guy Boccia³, Alice Chu³, Neil Clendeninn³, Mary Rose Keller³, Tom Ottoboni³, Sanjay Patel³, Barry Quart³

¹Anaheim Clinical Research, Anaheim, CA, USA, ²Memorial Hermann Memorial City Medical Center, Houston, TX, USA, ³Heron Therapeutics, Inc., San Diego, CA, USA

Purpose

Although local anesthetics have been used for decades in the management of post-operative pain, a major limitation is that their duration of action is short (6 to 12 hours) compared to the pain from surgery (usually several days). This leads to the increased use of opioid analgesics for additional pain relief in the days following surgery, which has been linked to an increased risk of abuse and may directly contribute to the current opioid public health crisis. To address the unmet need of extended non-opioid post-operative pain control, Heron Therapeutics, Inc. is developing HTX-011: an extended release, fixed-dose combination product that contains both bupivacaine, a local anesthetic, and low-dose meloxicam, a nonsteroidal anti-inflammatory drug (NSAID), in a biochronomer-based delivery system. Post-operative pain control is accomplished through wound infiltration of the local anesthetic via injection, instillation, or both at the incision site. Initial data on the efficacy and safety of HTX-011 by these various methods following herniorrhaphy are presented.

Method

This is an ongoing Phase 2 randomized, controlled, multicenter study evaluating the efficacy and safety of HTX-011 in adult patients undergoing elective open inguinal hernia repair. This interim analysis is focused on comparing the techniques for administration of HTX-011. Institutional Review Board approval was obtained at all sites, and then patients provided written informed consent. Following administration of HTX-011 at the end of surgery, pain scores and opioid usage were recorded via patient diaries at pre-specified time points through the first 72 hours after study drug administration.

Results

This analysis includes 17 subjects who received 400 mg HTX-011 via injection, 20 subjects who received 400 mg HTX-011 via instillation, and 17 subjects who received 200 mg HTX-011 by both injection and instillation for a total dose of 400 mg. Subjects had a Summed Pain Intensity score through 24 hours (SPI_0-24) of 74, 79, and 75, respectively; none of these were statistically significantly different from each other. Similarly, total opioid use through 72 hours and median time to first opioid were not statistically different among any of the groups from each other. No deaths, treatment-related serious adverse events, or adverse events leading to early termination were reported.

Conclusions

Given that there were no statistically significant differences in the SPI_0-24, opioid use, or safety, this hernia study showed that HTX-011 could be administered by injection, instillation, or both and still provides similar results. Instillation would avoid the potential for inadvertent intravenous administration reported with other bupivacaine products. HTX-011 is currently in phase 2 testing in humans in several surgical/anesthetic models.

91 Narcotic pain medication and other concomitant medication use before and after buprenorphine maintenance treatment initiation in patients with opioid dependence

Bernd Wollschlaeger¹, Naoko Ronquest², Leslie Montejano³, Tina Willson³, Vijay Nadipelli²

¹Aventura Family Health Center, Miami, FL, USA, ²Indivior Inc, Richmond, VA, USA, ³Truven Health Analytics, an IBM company, Cambridge, MA, USA

Purpose

Over 116 million Americans suffer from persistent chronic pain. Opioid analgesics have been used for centuries, and extensive research has demonstrated their ability to provide effective pain relief and improved quality of life among patients suffering from acute and chronic pain. Prescriptions for opiates in the United States have increased dramatically in the last decade and increasing attention has been placed on the risk of addiction and problematic use of prescription opioids. While most patients with chronic pain do not develop opioid addiction, pain specialists and primary care physicians face challenges in the treatment and management of pain in patients with opioid dependence. Further, many patients with chronic pain and opioid dependence present with other physical and psychiatric comorbidities and recent research highlights the importance of treating these comorbidities as part of a comprehensive treatment program for opioid dependence. A close collaboration between primary care physicians and pain, addiction, and psychiatric specialists is required to ensure optimal outcomes among these patients. To date, little research has addressed how prescription opioids and medications for various comorbidities have been used among patients being treated for opioid dependence. The objective of this study was to compare concomitant medication use, including narcotic pain medication and select central nervous system agents for treating depression, schizophrenia, and anxiety, before and after buprenorphine maintenance treatment initiation in a real-world sample of patients with opioid dependence.

Method

A retrospective analysis was conducted using administrative claims data from the Truven Health MarketScan Commercial Claims and Encounters and Medicaid Multi-State databases. Patients of any age with an outpatient pharmacy claim for buprenorphine (monotherapy or with naloxone) from 2008-2014 were selected from the databases and the date of the earliest buprenorphine claim was set as the index date. To ensure initiation of a new buprenorphine treatment episode, patients were excluded if they had claims for buprenorphine in the 3 months prior to the index date. Patients were required to have a diagnosis of opioid dependence (ICD-9-CM 304.0x, 304.7x, 305.5x) prior to or on the index date and continuous enrollment with medical and pharmacy benefits for 6 months pre-index and post-index. Patients receiving less than 30 days of therapy at an average daily dose less than 4mg/day were excluded from the analysis because they may represent patients using buprenorphine solely for detoxification, as opposed to for maintenance therapy. Patient demographics were measured on the index date and clinical characteristics were examined during a 6-month pre-index period. Concomitant medication use including narcotic pain medications, antidepressants, antipsychotics, benzodiazepines, and other sedative/hypnotics were measured from outpatient pharmacy claims in the 6 months pre-and post-index. Descriptive analyses were conducted to compare the utilization of concomitant medications before and after buprenorphine initiation.

Results

A total of 22,563 Commercial and 7,811 Medicaid patients were included in the analyses. The Commercial patients were majority male (62.7%) with a mean age of 32.6 years. The Medicaid sample was predominantly female (72.0%) with a mean age of 32.3 years. Both patient samples had high rates of comorbid chronic pain conditions (45.2% Commercial, 56.7% Medicaid), depressive disorder (29.6% Commercial, 39.2% Medicaid) and non-opioid substance use disorders (28.6% Commercial, 37.7% Medicaid). The proportion of Commercial patients with a claim for a narcotic pain medication fell from 48.6% prior to buprenorphine initiation to 25.5% in the 6 months following treatment initiation. In the Medicaid sample, a similar decrease in prescription narcotic utilization was observed (63.0% pre-index to 38.8% post-index). The proportion of patients with a benzodiazepine claim decreased slightly from the pre-index to the post-index period (Commercial: 27.9% pre, 21.9% post; Medicaid: 31.8% pre, 28.5% post). Contrarily, use of other sedative/hypnotic agents increased from 22.1% of Commercial patients before treatment to 26.8% after treatment initiation and 22.5% of Medicaid patients pre-index to 27.2% of patients post-index. In the Commercial sample, the proportion of patients using antidepressants increased from 46.2% in the pre-index period to 57.2% in the post-index period. Among Medicaid patients, antidepressant utilization also increased from 48.3% pre-treatment initiation to 57.6% post. The proportion of patients with at least one claim for an antipsychotic increased from 12.7% pre-index to 19.1% post-index in Commercial patients and from 18.6% pre-index to 22.9% post-index in Medicaid patients.

Conclusions

Patients diagnosed with opioid dependence had high prevalence of pain and psychiatric conditions. The rates of narcotic pain medication utilization observed in this analysis highlight the importance of careful management of prescription opioid use among patients with opioid dependence. The increase in non-benzodiazepine sedative/hypnotic utilization is not surprising since these agents are often used during early recovery to alleviate anxiety, but careful dosing and monitoring is needed. The increase in antidepressant and antipsychotic use after starting buprenorphine may indicate the identification of mental health conditions that are often masked by opioid misuse prior to initiating the buprenorphine assisted treatment program.

92 Clinical pharmacist interventions as a member of palliative medicine interdisciplinary team in a community hospital

Dharma Naidu, Kimberly Jones, David Kanyer, John Hausdorff

Community Hospital of the Monterey Peninsula, Monterey, CA, USA

Purpose

This study was conducted to quantify interventions and outcomes achieved by clinical pharmacists assigned with daily responsibilities to the Palliative Medicine Interdisciplinary Team.

Method

The medical records of patients with a palliative medicine consult between November 1st 2013 and October 31st 2014 were retrospectively reviewed. Data was extracted on documented clinical pharmacist palliative care activities. Pain and symptom management outcomes before and after pharmacist intervention were reviewed through examination of clinical notes.

Data on pharmacist recommendations for discontinuation of medications/treatments, participation in family meetings, and advance care planning was also collected.

Results

The palliative medicine pharmacist documented interventions in 487 patients, which represents 57% of all patients with a palliative care consult. Of the 487 patients, 325 were on concurrent pharmacy managed pain protocol where the palliative pharmacist took the lead in pain/symptom management. The remaining 162 were seen by the palliative pharmacist for routine intake and assessments, development of goals of care, including holding family meetings and completing advance health care directives/POLST.

The average pain score reduction (0 to 10 pain scale) was 2.6 points in acute pain patients and 2.8 points in chronic pain patients within 24 hours of pharmacist intervention. In patients who had a documented pain goal, the pharmacist was able to meet the goal in 91% of these patients. Other symptoms managed included anxiety, nausea and dyspnea. There was improvement from moderate/severe symptoms to none/mild symptoms post pharmacist intervention. Pharmacists documented 481 interventions related to discontinuation of medications/treatments not supporting palliative care goals. These included chemotherapy (2.7%), antimicrobials (15%), fluids/oral medications (53%), and laboratory tests (29.3%) with an estimated direct cost savings of $100,000.00.

Conclusions

This study demonstrates the value of a clinical pharmacist aligned with an interdisciplinary palliative care team in a community hospital setting.

93 Levorphanol, Another Choice in Opioid Rotation

Srinivas Nalamachu^1,2, Jeffrey Gudin^3,4

¹International Clinical Research Inst, Overland Park, KS, USA, ²Temple University School of Medicine, Philadelphia, PA, USA, ³Pain Management and Palliative Care, Englewood Hospital and Medical Center, Englewood, NJ, USA, ⁴Icahn School of Medicine at Mt. Sinai, New York, NY, USA

Purpose

Levorphanol is a potent opioid analgesic that has been available for the treatment of moderate to severe pain since 1953. It has a wide range of ascending and descending pain pathway receptor-mediated pharmacological activities including mu, delta and kappa (kappa 1 and 3) opioid agonism, N-methyl-D-aspartate (NMDA) antagonism and mild reuptake inhibition of both norepinephrine and serotonin. Levorphanol’s multimodal profile is quite unique amongst the class and may make it an optimal agent both for initial use, as well as for opioid rotation. Despite possessing many favorable properties, levorphanol has become the “Forgotten Opioid”, with its use largely supplanted by other, more recently approved opioids. With its activities on multiple receptors, levorphanol has the potential for treating diverse conditions including nociceptive, central and neuropathic pain. Further, it has been reported to help patients who have pain syndromes that are refractory to other opioids, such as central and neuropathic pain syndromes, and may also play a role for addressing opioid-induced hyperalgesia.

Method

A literature review was conducted starting with the discovery and development of levorphanol in the late 1940s and 1950s continued to present using search terms that included levorphanol, methorphan, Dromoran (both early names for levorphanol), levorphanol-3-glucuronide, and opioid combined with glucuronide. Other articles were identified through reviews and original publications on levorphanol. The focus of the review was on metabolism, pharmacokinetics (PK), pharmacology, safety, effectiveness and clinical studies on levorphanol.

Results

Levorphanol has a multimodal pharmacological activity profile. PK studies of levorphanol demonstrate that it is readily absorbed orally, has a longer half-life (11-16 hr) and a longer duration of analgesia (6-15 hr) than most opioids. It undergoes rapid hepatic conversion to an inactive glucuronide, which reaches concentrations 5 to 10 times that of levorphanol and is slowly eliminated by renal excretion. Levorphanol accumulates with repeated dosing and reaches steady state in about 3 days (five half-lives). Levorphanol is not metabolized by cytochrome P450 enzymes or dependent on p-glycoprotein for absorption.

The recommended starting dose for levorphanol is 2 mg 3-4 times a day. Levorphanol is approximately 4-8 times more potent than morphine, and when switching to levorphanol the recommended daily dose is 1/15 to 1/12 of the daily equivalent morphine dose. These conversion factors also take into account the potential for incomplete cross tolerance. Dosing interval, maximum daily dose, and interval between dose increases are all influenced by its longer half-life. Therefore, changes to the dosing regimen should be evaluated in 72 hour intervals. As with any opioid, the dose should be individualized for the patient, taking into consideration factors such as comorbidities and age. Adverse events and warnings for levorphanol are similar to other mu opioid analgesics and there are no reports in the literature of levorphanol related QT interval changes.

The effectiveness of levorphanol has been demonstrated in clinical studies for both chronic pain and neuropathic pain. Levorphanol is well-suited as a first-line opioid. It also fits well in opioid rotation, especially for pain refractory to treatment with other opioids and situations where other opioids cannot be used because of potential drug-drug interactions or drug-food interactions. Levorphanol may have utility for the treatment of opioid induced hyperalgesia and neuropathic pain and as a replacement for methadone.

Conclusions

Levorphanol’s action at multiple opioid and NMDA receptors provides a unique multimodal analgesic profile. Its longer half-life compared to many opioids may make levorphanol best suited for chronic pain. The absorption and metabolism of levorphanol is independent of p-glycoprotein and CYP enzymes, respectively, resulting in less potential for drug-drug/food reactions. Levorphanol’s pharmacokinetic, metabolic, and multimodal analgesic profile lends strong support for inclusion in the opioid rotation, especially for treatment-refractory pain with other opioids. Further investigations of levorphanol are warranted, especially for neuropathic pain, opioid-induced hyperalgesia, and as a replacement for methadone.

94 Gabapentin enacarbil to manage neuropathic pain in post-gastric-bypass patients

Hany Nasr

Kaweah Delta Rehabilitation Center, Visalia, California, USA

Purpose

Gabapentin is commonly prescribed for neuropathic pain. As it is primarily absorbed in the upper small intestine, post-gastric-bypass patients may no longer respond to this drug for treatment of neuralgia. The prodrug formulation gabapentin enacarbil (GEn [HORIZANT®, XenoPort, Inc, Santa Clara, CA]) is indicated for moderate-to-severe primary restless legs syndrome and for the management of postherpetic neuralgia in adults. Its absorption pathway is distributed throughout the small and large intestinal tract. Hence, GEn may help to manage neuropathic pain in patients who have undergone gastric bypass and no longer achieve significant benefit from gabapentin. Here, we report the use of GEn for two post-gastric-bypass patients with chronic neuropathic pain to determine whether it would improve neuralgia that was not sufficiently managed with gabapentin.

Method

Two post-gastric-bypass patients with chronic neuropathic pain that had been suboptimally managed with gabapentin were prescribed GEn as add-on treatment. Patient SW is a 44-year-old female 15 years post-bypass with neuropathic pain in all extremities; she has been treated with gabapentin 800 mg three times a day (then twice a day, plus pregabalin) since surgery. Comorbidities include hypertension, hypercholesterolemia, depression/anxiety, and osteoarthritis. Other medications include opioids, muscle relaxant, carbamazepine, and aripiprazole. Patient MB is a 58-year-old menopausal female 2 years post-bypass with cervical-based neuropathic pain treated for 3 years with gabapentin 100 mg 2-3 times daily. Comorbidities include anxiety, asthma, and type 2 diabetes. Other medications include oxycodone/acetaminophen and muscle relaxant. GEn 600 mg/day was added to both patients’ regimens with no other medication changes. Gabapentin and pregabalin were not discontinued.

Results

Both patients reported marked amelioration of neuropathic pain. SW experienced no treatment-related adverse events. After approximately 1 month, she had to discontinue GEn due to cost. She remains on gabapentin and pregabalin and experiences suboptimal pain management. MB also reported marked improvement in pain but experienced nausea, flatulence, and severe diarrhea. She discontinued GEn after 1 week.

Conclusions

As demonstrated in these cases, post-gastric-bypass patients previously treated with gabapentin may experience improvement in neuropathic pain with GEn added to their treatment regimen. This is likely related to the absorption pathway of GEn, which is not limited to the duodenum that is frequently removed in gastric bypass surgery. Clinicians must weigh safety considerations, particularly in patients with multiple comorbidities being managed with other medications.

95 Cebranopadol: a Novel First-in-class Analgesic in Development for Chronic Pain Conditions - Results from a Human Abuse Potential Study in Non-Dependent Recreational Opioid Users

M Sokolowska², R Nemeth¹, E Babich¹, I Szeto³, M Eerdekens¹

¹Grünenthal GmbH, Aachen, Germany, ²Grunenthal USA, Morristown, NJ, USA, ³INC Research, Toronto, Ontario, Canada

Purpose

Cebranopadol is reportedly a nociceptin/orphanin FQ peptide (NOP)/opioid receptor agonist with central anti-nociceptive activity. Our hypothesis is that this novel mechanism of action will lead to lower risk for abuse compared to pure mu opioid receptor agonists. The primary objective of this trial was to evaluate the abuse potential of single doses of cebranopadol relative to hydromorphone immediate release and placebo.

Method

The study was a single dose, nested-randomized, double-blind crossover trial in non-dependent recreational opioid users. It was composed of a qualification phase and 7 periods treatment phase (cebranopadol 200µg, 400µg and 800µg, hydromorphone 8mg and 16mg, and two placebos). The primary endpoint was the mean peak (Emax) Drug Liking at the moment, measured by Visual Analog Scale (VAS). Various secondary endpoints (e.g. VAS rating for Good Drug Effects, High, Bad Drug Effects, Take Drug Again, Drug Similarity, and pupillometry) were also investigated.

Results

42 subjects completed the trial. Cebranopadol 200µg and 400µg generally did not separate from placebo on the abuse potential assessments and had responses lower than hydromorphone. Responses associated with cebranopadol 800µg were generally similar to hydromorphone 8mg and lower than hydromorphone 16mg, but the maximum effect on VAS Drug Liking was delayed in comparison to hydromorphone (1.5 hours and 3 hours, respectively).

In this study, administration of cebranopadol was safe, no serious adverse events and trial discontinuation due to Treatment Emergent Adverse Events occurred.

Conclusions

This study suggests that at the doses tested cebranopadol has lower abuse potential than hydromorphone.

96 Cebranopadol: a Novel First-in-Class Analgesic in Development for Chronic Pain Conditions - Effects on Respiration in Healthy Human Volunteers

A Dahan¹, J Hay², GJ Groeneveld², M Neukirchen³, J Bothmer³, E Olofsen¹

¹Department of Anesthesiology, Leiden University Medical Center, Leiden, The Netherlands, ²Centre for Human Drug Research, Leiden, The Netherlands, ³Grünenthal GmbH, Aachen, Germany

Purpose

There are serious concerns regarding the respiratory effects of classical opioid agonists. Cebranopadol is a nociceptin/orphanin FQ peptide (NOP) receptor and opioid receptor agonist with central anti-nociceptive activity. A ceiling effect to respiratory depression has been linked to activation of NOP receptors. This pharmacokinetic-pharmacodynamic study quantifies cebranopadol’s respiratory effects in male volunteers.

Method

Twelve healthy male volunteers received 600 μg of oral cebranopadol. At regular time intervals for 10‐11 hours post dose we measured ventilation at an elevated clamped end‐tidal PCO₂, pain threshold and tolerance to a transcutaneous electrical stimulus train and plasma cebranopadol concentrations. The data were analyzed using sigmoid EMAX (respiration) and power (antinociception) models. The trial was conducted according to GCP and with IEC approval.

Results

Cebranopadol displayed typical opioid‐like effects including miosis, analgesia, respiratory depression and sedation. The blood‐effect‐site equilibration half-life for respiratory depression and analgesia was 1.2 ± 0.4 h (median ± SE) and 8.1 ± 2.5 h, respectively. The estimated effect site concentration causing 50% respiratory depression was 62 ± 3.6 pg/mL reaching a significant ceiling at 4.9 ± 0.7 L/min from a baseline ventilation of 20 L/min; the equivalent concentration causing a 25% increase in currents to achieve the pain threshold and tolerance was 97 ± 29 pg/mL.

Conclusions

This study suggests that cebranopadol likely due to its NOP receptor agonism in combination with traditional opioid receptor agonist activity, produces a ceiling in respiratory depression at 25% of baseline ventilation in contrast to pure MOP receptor agonists that produce apnea at high concentrations.

97 A Sensitive Assay for Urinary Cocaine Metabolite Benzoylecgonine Shows More Positive Results Than Those Using Traditional Cutoffs

Joyce Nickley, Kevin Krock, Amadeo Pesce

Precision Diagnostics, San Diego, CA, USA

Purpose

Cocaine is a drug often used by patients with substance use disorder. Its detection is part of the SAMHSA work place testing program. The screening cutoff detection concentration for the cocaine metabolite benzoylecgonine is 150ng/mL and its confirmatory cutoff is set at 100ng/mL [1]. Studies have suggested that these cutoffs may be set too high and that patients with this substance abuse problem may be missed [2,3]. With the advent of LC-MS/MS technology it is possible to reliably detect and quantify lower concentrations of its metabolite benzoylecgonine [4]. The purpose of the study was to establish if there was a significant increase in cocaine detection using a twentyfold more sensitive cutoff.

Method

A very sensitive dilute and shoot assay for benzoylecgonine was developed using a Sciex 6500 instrument with a lower limit of quantitation of 5ng/mL. To eliminate the possibility of carryover, all concentrations lower than 100ng/mL were repeated in a separate run with no high benzoylecgonine specimens. Determination of the 5ng/mL cutoff was achieved by plotting all the positive cocaine observations as a frequency distribution on a logarithmic scale. The number of positive results with concentrations below the typical industry 100ng/mL cutoff level but above the high sensitivity 5ng/mL cutoff level were determined for 83,205 total specimens analyzed. The ratio of these results to the number of low sensitivity positives were used to calculate the false negative rate.

Results

There were 4252 benzoylecgonine positives above 5 ng/mL. There were 2046 positives above 100 ng/mL, thus 2206 would have been called falsely negative by using the 100 ng/mL cutoff, for a false negative rate of 51.9%. There were 1907 positive results above the screening cutoff of 150 ng/mL, for a false negative rate of 55.2%.

Conclusions

We suggest that positive findings in the range of 5 to 100ng/mL are most likely indicative of the presence of cocaine in the patient’s environment. A second possibility is that for known users, these low concentration findings represents a slow elimination process. The length of time for the slow elimination phase of cocaine metabolites has yielded half-life estimates ranging from 14.6 to 52.4 h [5]. This work is in agreement with other studies that have indicated that the 100ng/mL cutoff is too high and probably misses those patients indulging in cocaine use [2,3].

98 Management of Moderate to Severe Chronic Low Back Pain with Buprenorphine Buccal Film Using Novel BEMA Technology

Joseph V. Pergolizzi^1,4, Robert B. Raffa^5,6, Charles Fleischer⁴, Robert Taylor⁴, Gianpietro Zampogna⁴

¹Johns Hopkins University School of Medicine, Baltimore, MD, USA, ²Temple University School of Pharmacology, Philadelphia, PA, USA, ³Association of Chronic Pain Patients, Houston, TX, USA, ⁴NEMA Research, Inc., Naples, FL, USA, ⁵University of Arizona College of Pharmacy, Tucson, AZ, USA, ⁶Temple University School of Pharmacy, Philadelphia, PA, USA

Purpose

A novel form of buccal buprenorphine (BBUP) has been cleared for market release in the United Sates. This new product uses BioErodible MucoAdhesive (BEMA) technology to allow for a delivery system that employs a transmucosal film (BelbucaTM, Endo Pharmaceuticals, Malvern, PA).

The burden of chronic low back pain (CLBP) is difficult to measure. It is one of the leading causes of years lived with disability (YLD) in every nation surveyed in the Global Burden of Disease Survey of 2013 (n=188) and is a leading cause of disability in most advanced nations.^1,2 Costs associated with CLBP include medical expenditures, lost productivity, and expenses related to indemnity payments and litigation.^3,4 Low back pain cost the U.S. over $90 billion in 2000, making it one of the costliest health conditions known.^5,6 Most patients with acute nonspecific low back pain will have an unremarkable natural course and favorable outcome, with symptomatic improvement in about four weeks.² Patients with subacute low back pain usually improve as well but may take longer, up to 12 weeks. However, a subset of patients will develop CLBP with little to no substantial improvement over time.7

The challenge of treating CLBP involves the management of centralized pain with a prominent neuropathic component. First-line agents include acetaminophen and nonsteroidal anti-inflammatory drugs (NSAIDs). However, these agents carry certain risks (hepatoxicity at high doses, GI symptoms, and cardiovascular risk) and may not be effective in all patients.

Method

Buprenorphine should be considered as an appropriate agent because of its unique pharmacology, its ability to address both nociceptive and neuropathic pain, the fact that it can be taken without dose adjustment in the elderly, and its relatively low potential for abuse.^8-10

The relatively low bioavailability of oral buprenorphine (~15%) has led to formulations utilizing other routes of administration, such as transdermal buprenorphine for pain control and transmucosal buprenorphine for opioid maintenance in dependent patients.¹¹ The BBUP relies on a transmucosal film which offers dosing versatility compared to the transdermal system, ease of administration, and improved bioavailability (46% to 51% over doses).¹² BBUP also achieves steady state in a shorter period of time than buprenorphine transdermal products.¹²

The buccal mucosa is an area of heavily vascularized tissue with vessels that drain into the jugular vein. Drugs that penetrate the epithelium of the buccal mucosa thus enter systemic circulation directly and circumvent first-pass hepatic elimination via the gastrointestinal tract. Transmucosal buccal products are also relatively easy for patients to take, but limitations involve saliva dilution, fluctuations in individual oral pH values, aversion to the taste of the product, and a relatively low absorptive surface compared to the intestines.13 A number of buccal mucosa delivery systems are on the market or in development.

BBUP is available in doses of 75, 160, 300, 450, 600, 750, and 900 µg with a time to maximum serum concentration (Tmax) of about 2.5 to 3.0 hours.14 The mean plasma elimination half-life of BBUP is 27.6 ± 11.2 hours.15

Results

Clinical Effectiveness

Two large multicenter, randomized, double-blind, placebo-controlled studies have evaluated BBUP for the treatment of CLBP. In a study of 749 opioid-naïve cLBP patients, all patients were titrated to receive a dose of BBUP in the range of 150 to 450 µg every 12 hours that they could tolerate well and that provided adequate analgesia.16 Patients were on this therapy for at least 14 days. At that point, patients were randomized to continue with BBUP (n=229) or placebo (n=232) for 12 weeks. Mean daily pain intensity scores at baseline were 7.15±1.05, which was reduced at drug titration to 2.81±1.07. After randomization, placebo patients continued to decrease pain intensity scores and achieved a mean of 1.59±2.04 at 12 weeks, while BBUP patients decreased pain to 0.94±1.85 at 12 weeks (p=0.0012).

Another randomized double-blind, placebo-controlled, withdrawal study evaluated 511 opioid-experienced patients with cLBP.17 In the open-label titration phase of this study patients received BBUP (150 to 900 µg every 12 hours). After 14 days, patients were randomized to receive BBUP or placebo for 12 weeks. Prior to titration, the mean pain score was 6.7±1.30 and following titration the average pain score was 2.8±1.02. Over the course of this study, pain scores increased to 1.92±1.87 and 0.88±1.79 for placebo and BBUP patients, respectively. Significantly more BBUP patients achieved pain reductions ≥30% and ≥50% versus placebo patients (p<0.0001).

Safety

The most common side effects reported with BBUP in opioid-experienced patients are nausea and vomiting. In a safety study, BBUP was associated with slight changes in the QRS interval (≤ 1 millisecond).¹⁸

Conclusions

Patients taking 80 to 220 mg of oral morphine sulfate or equivalent can be successfully rotated to BBUP at 50% of their full dose without increased risk of withdrawal symptoms or inadequate analgesia.19 Concerns about opioid analgesics are important therapeutic considerations in light of opioid abuse, but these concerns should not cause pain to go untreated. Pain control must be viewed as a fundamental human right.^20,21

CLBP is a prevalent and costly condition that may be effectively addressed by a novel BBUP product that offers ease of administration, improved bioavailability, and greater dosing flexibility compared to the buprenorphine transdermal patch.

99 Will the New Opioid Guidelines from the CDC Have Unintended Consequences?

Joseph V. Pergolizzi^1,4, Robert B. Raffa^5,6, Gianpietro Zampogna⁴, Frank Breve⁷, Robert Colucci⁸, William K. Schmidt⁹, Jo Ann LeQuang⁴

¹Johns Hopkins University School of Medicine, Baltimore, MD, USA, ²Temple University School of Pharmacology, Philadelphia, PA, USA, ³Association of Chronic Pain Patients, Houston, TX, USA, ⁴NEMA Research, Inc., Naples, FL, USA, ⁵University of Arizona College of Pharmacy, Tucson, AZ, USA, ⁶Temple University School of Pharmacy, Philadelphia, PA, USA, ⁷Temple University School of Pharmacy, Philadelphia, PA, USA, ⁸Colucci & Associates, LLC, Newton, CT, USA, ⁹NorthStar Consulting, LLC, Davis, CA, USA

Purpose

Opioids are at the heart of a “dual epidemic” which is comprised on the one hand by the well-known crisis of opioid misuse and on the other of patients with a legitimate need for medication to manage their moderate to severe pain. A balance must be sought to ensure access to opioid pain relievers for those who need them, while limiting access to opioids to those who might be at risk for abusing them. This year, the Centers for Disease Control and Prevention (CDC) in Atlanta published official guidelines about opioid prescribing.¹ While efforts to address the dual epidemic are laudable, these guidelines may have unintended consequences in that they may make it more difficult for pain patients to get the prescription opioid pain relievers they legitimately need.

Given the gravitas of the CDC organization, these guidelines will have considerable weight in clinical practice. They may help shape public policy and they will certainly be taken seriously by many non-specialist prescribers. As such, it is important that we evaluate these guidelines for their scientific soundness as well as clinical practicality and relevance.

Method

On September 16, 2015, the CDC hosted an invitation-only webinar to present new guidelines for opioid prescribing. Some of our authors participated in the call-in webinar. Comments but not questions were permitted. Questions from the public were then accepted by the CDC Committee through January 13, 2016. Our authors discussed the guidelines and in some cases compared them with previous guidance and the literature.

In March 2016, the new guidelines were published and the authors again evaluated them in light of the evidence and other guidelines.¹ In particular, we examined these new recommendations, evaluating their relevance for clinicians on the frontlines in making prescribing choices for treating pain. This was not a formal analysis but rather the insights of pain specialists and others involved in the care of pain patients who were familiar with other guidelines.

Results

The CDC arrived at 12 guidelines, some of which were concerning.

Guidelines 1 and 2 added “function” as a metric for assessment of opioid therapy success and made it equivalent to pain control.

Guideline 4 recommends prescribing immediate-release (IR) rather than extended-release (ER) or long-acting (LA) opioids in a generalization that does not address the many specific concerns of individual pain patients.

Guideline 5 states that doses of opioids are not to be increased to ≥ 50 morphine milligram equivalents (MME) per day without a patient reassessment and that doses must not exceed ≥ 90 MME/day for chronic noncancer pain. While it is important to prescribe opioids at the lowest effective doses, there is no scientific evidence in the literature to support these two values as cutoffs.

Guideline 6 says that acute pain should be treated with opioids only for three days. Acute pain should be treated for as long as necessary.

Guideline 10 advocates urine drug testing, but only “at least annually.” While urine drug testing is an established part of opioid therapy, one assay a year is unlikely to provide any benefit.

Guideline 11 recommends that opioids not be prescribed concurrently with benzodiazepines. This guidance makes it seem as if opioids and benzodiazepines are the only potentially dangerous or objectionable drug combination. Polypharmacy is common in chronic pain patients and there are many drug-drug interactions of concern.2-7

Guideline 12 recommends that clinicians offer evidence-based treatment with buprenorphine or methadone in combination with behavioral therapies for patients with opioid use disorder. The guidelines do not define opioid use disorder, nor do they explain what these evidence-based treatments are and how they might be applied. This will likely limit physicians from prescribing opioids, because many physicians may not have confidence in their ability to manage a patient through detoxification and opioid rehabilitation.

Conclusions

The 12 guidelines offered by the CDC carry considerable weight in the clinical community, but they seem to raise more questions than they answer. In some cases, the guidelines seem to be based more on addressing the public health crisis of opioid abuse than on offering the pain control that is necessary for so many patients.

The public health crisis of opioid abuse must not let our fears allow us to apply unscientific standards to medical care or to cause us to lose sight of the pain patients who deserve our help and compassion.

100 Chronic Postsurgical Pain: An Update

Joseph V. Pergolizzi^1,4, Robert B. Raffa^5,6, Charles Fleischer⁴, Gianpietro Zampogna⁴, Taylor Robert⁴

¹Johns Hopkins University School of Medicine, Baltimore, MD, USA, ²Temple University School of Pharmacology, Philadelphia, PA, USA, ³Association of Chronic Pain Patients, Houston, TX, USA, ⁴NEMA Research, Inc., Naples, FL, USA, ⁵University of Arizona College of Pharmacy, Tucson, AZ, USA, ⁶Temple University School of Pharmacy, Philadelphia, PA, USA

Purpose

Pain following surgery is prevalent (reported by over 80% of surgical patients) and 86% describe that pain as moderate to severe or very severe.¹ For most patients, this pain follows a predictable course in which it is most intense in the first postoperative day and diminishes progressively over the following days. However, it is possible for acute postsurgical pain to transition into chronic postsurgical pain (CPSP). CPSP has been defined as pain that persists three or more months after surgery and for which causes other than surgery can be excluded.^2,3 CPSP is surprisingly prevalent; about one-third of surgical patients experience it.²

The transition from acute postsurgical pain to CPSP has not been thoroughly elucidated. The purpose of our review is to raise awareness about CPSP, its possible association with acute postsurgical pain, and therapeutic options to control CPSP.

Method

We searched PubMed for “chronic postsurgical pain” and “chronic postoperative pain” and evaluated those articles and their bibliographies.

Results

Risk factors for CPSP may include preoperative factors (patient’s anxiety, catastrophizing, depression, stress as well as comorbidities and impaired sleep); intraoperative and perioperative factors (the extent of nerve and tissue injury, type of surgery, anesthesia, and analgesia); and the postoperative period (subsequent therapies such as chemotherapy or radiation, psychosocial factors, and surgical revisions).⁴

In the immediate postoperative period, pain intensity should be assessed and pain treated with appropriate analgesic products. Patient-controlled analgesia (PCA) may be appropriate. The new CDC guidelines on opioid prescribing recommend opioid therapy (if appropriate) for only three days following surgery,⁵ but analgesia should continue until the patient no longer needs pain control.

Many products are appropriate for acute postsurgical pain, including transdermal buprenorphine. The transdermal formulation is convenient, buprenorphine is an effective analgesic with a relatively low potential for abuse and misuse.^6-8

The CPSP diagnosis is one of exclusion: other sources for the patient’s persistent pain must be considered and rejected. Patients facing CPSP should be educated about the maladaptive nature of chronic pain, its neuropathic component, and strategies that can help control it. In some cases, patients may be able to manage their pain with nonpharmacological regimens, including exercise, lifestyle modifications, massage, and so on. Pharmacological management may include nonopioid medications (acetaminophen or nonsteroidal anti-inflammatory drugs) or opioids or both. Agents like tramadol with a dual mechanism of action may be considered.

Chronic pain often involves a neuropathic component which may require combination therapy. Neuropathic pain may be addressed by the use of anticonvulsants (such as pregabalin) or by opioids which address both neuropathic as well as nociceptive pain (such as buprenorphine).

In all cases, medications should be provided at the lowest effective dose for the shortest period of time.

Conclusions

CPSP is prevalent, often under-diagnosed, and not optimally treated. Acute postsurgical pain should be aggressively treated to prevent it from transitioning into chronic pain. When patients are diagnosed with CPSP, this pain must be treated.

101 Hydrocodone Rescheduling Revisited

Joseph V. Pergolizzi^1,4, Robert B. Raffa^5,6, Gianpietro Zampogna⁴, Frank Breve⁷, Robert Colucci⁸, William K. Schmidt⁹, Jo Ann LeQuang¹

¹Johns Hopkins University School of Medicine, Baltimore, MD, USA, ²Temple University School of Pharmacology, Philadelphia, PA, USA, ³Association of Chronic Pain Patients, Houston, TX, USA, ⁴NEMA Research, Inc., Naples, FL, USA, ⁵University of Arizona College of Pharmacy, Tucson, AZ, USA, ⁶Temple University School of Pharmacy, Philadelphia, PA, USA, ⁷Temple University School of Pharmacy, Philadelphia, PA, USA, ⁸Colucci & Associates, LLC, Newton, CT, USA, ⁹NorthStar Consulting, LLC, Davis, CA, USA

Purpose

In the summer of 2014, hydrocodone was rescheduled from Schedule III to the more restrictive Schedule II on the controlled substances list.¹ Hydrocodone is a semi-synthetic phenanthrene opioid receptor agonist that is frequently used in fixed-dose combination analgesic products. A single-entity hydrocodone product was approved in 2013 (Zohydro^TM ER, Zogenix, Inc., San Diego, CA) and classified as a Schedule II drug by the U.S Controlled Substances Act. This rescheduling closed the so-called “Vicodin loophole” which treated hydrocodone combination products as Schedule III products, while similar combination products using other opioids fell into the more restrictive Schedule II category.²

At the time of the rescheduling, hydrocodone was one of the most frequently prescribed drugs in America³ with 25 million Americans in possession of an automatic-refill hydrocodone prescription.2 The rescheduling represented an effort to help reduce opioid abuse and misuse in America, but the change affected how this analgesic would be prescribed and dispensed in ways that were unforeseen when the rescheduling went into effect.⁴

Our aim was to consider how the rescheduling of hydrocodone has affected its use in pain treatment.

Method

Nationally, prescriptions for hydrocodone fixed-dose combination products decreased; in the first year after rescheduling, 1.1 billion fewer hydrocodone combination tablets were dispensed.⁵

At a Level 1 Trauma Hospital, a study of usage patterns of various analgesics in the six months before and six months after hydrocodone rescheduling found hydrocodone use decreased markedly after rescheduling (from 225.97 prescriptions per day to 1.2 per day) while during the same time period, tramadol and codeine prescriptions increased (from 60.04 to 91.85 and 5.81 to 98.94 per day, respectively).⁷

In an online survey (n=6420) of hydrocodone patients conducted after the first 100 days subsequent to the rescheduling of hydrocodone, 61% found some barriers in obtaining their prescribed hydrocodone although 82.5% of respondents had been prescribed hydrocodone for a year or more.⁸ The majority of respondents (64.2%) said the change in scheduling resulted in their having to consult with their physicians more often. Most patients did not approve of the rescheduling (88.3%) and of those respondents who worked, 46.2% said they missed work at least once because of the rescheduling and 27.2% said they had had thoughts of suicide since the rescheduling.

Results

Unintended Consequences

Fixed-dose hydrocodone combination products may be the optimal product choice for many patients in the large populations of cancer pain patients, chronic noncancer pain patients, postsurgical patients, dental patients, patients with end-stage renal disease, and patients in palliative care. Limiting their access to these products may either result in untreated pain or the physician needing to switch the patient to a less-appropriate analgesic product. Further, many patients prescribed hydrocodone products may now be faced with more frequent clinic and pharmacy visits to obtain their medication. This can represent a severe hardship for rural patients, those with impaired mobility, or patients without a ready means of transportation. Based on a typical office visit fee of $100 these extra office visits may amount to millions of dollars of incremental costs to Medicare and private insurance programs.²

Nursing home residents frequently are prescribed hydrocodone products; a survey in 2014 reported that 20% of long-term care residents had such a prescription.⁹ Long-term care facilities found Schedule III products provided good pain control and fit well into their workflow. Rescheduling hydrocodone to make it more restrictive places a burden on these facilities in terms of increased record-keeping demands and administrative requirements by the DEA in addition to increased costs.

Now that fixed-dose combination hydrocodone products are Schedule II drugs, it may be that more stringent felony laws are imposed for possession, distribution, or manufacture of these drugs. Depending on the jurisdiction, possession of even one fixed-dose hydrocodone combination product tablet may result in felony charges, significant criminal financial penalties, and incarceration.¹⁰

Rescheduling hydrocodone combination products may cause prescribers and pharmacists to view fixed-dose hydrocodone products in a different light and this may change prescribing practices but not necessarily in a way that reduces abuse.

Conclusions

Clearly, the goal of rescheduling hydrocodone combination products from Schedule III to the more restrictive Schedule II was carried out to prevent abuse. The restrictions of drug scheduling affect prescribers, legitimate users, and pharmacists much more than potential abusers who may not even be aware of the relative scheduling differences of various opioids.

102 Peripherally Acting Mu-Opioid Receptor Antagonists (PAMORAs) for Constipation Associated with Chronic Opioid Therapy

Joseph V. Pergolizzi^1,4, Robert B. Raffa^5,6, Charles Fleischer⁴, Robert Taylor⁴, Gianpietro Zampogna⁴

¹Johns Hopkins University School of Medicine, Baltimore, MD, USA, ²Temple University School of Pharmacology, Philadelphia, PA, USA, ³Association of Chronic Pain Patients, Houston, TX, USA, ⁴NEMA Research, Inc., Naples, FL, USA, ⁵University of Arizona College of Pharmacy, Tucson, AZ, USA, ⁶Temple University School of Pharmacy, Philadelphia, PA, USA

Purpose

Opioid exposure is associated with opioid-induced constipation, a disorder that can affect up to 90% of patients on long-term opioid therapy and can affect patients even on short-term (<1 week) therapy.^1,2 With a growing number of patients taking opioids for pain control, the prevalence of OIC has increased. The Rome IV criteria have added OIC as a separate disorder.³

OIC does not typically respond to conventional laxative therapy. The purpose of this article is to examine some new products-peripherally acting mu-opioid receptor antagonists (PAMORAs)-for treating laxative-refractory OIC.

Method

Mechanisms of OIC

Exogenous opioids affect the mu-opioid receptors of the enteric system, delaying gastrointestinal (GI) emptying, stimulating nonpropulsive motor activity, increasing intestinal tone, increasing fluid absorption (by delaying transit time), and decreasing the secretion of electrolytes and water into the intestinal lumen.⁴ OIC differs from other forms of constipation and in many cases is refractory to treatment with conventional laxatives and lifestyle modifications.

Diagnosis and Treatment

OIC may be reported by patients as a change in bowel habits, in particular related to bowel movement frequency, difficulty passing bowel movements, a sensation of incomplete evacuation, and drier or harder stool consistency.^5,6 Another definition of OIC is that it occurs when a patient has ≤ 3 bowel movements per week or has hard and/or difficult-to-pass stools.⁷ Since patients may be embarrassed to report these symptoms or may not be aware of their association with opioids, clinicians should routinely ask opioid therapy patients about OIC symptoms. Patients do not develop tolerance for OIC over time, as they do for other opioid-associated side effects such as nausea and dizziness.⁸

OIC can be quantified using any of several assessment tools. The Bowel Function Index (BFI) is the only such metric validated specifically for the assessment of OIC.⁹

A bowel regimen and conventional laxative or combination of laxatives may be prescribed as a first-line therapy.^10,11 An observational pilot study of adult OIC patients found 43% did not respond to conventional laxatives.¹²

Results

PAMORAs are agents that treat laxative-refractory OIC.

• The first PAMORA approved by the FDA was subcutaneous methylnaltrexone (Relistor®, Salix Pharmaceuticals).

• Alvimopan (Entereg®, Merck) is a PAMORA indicated in the U.S. for short term use for treating postoperative ileus; long-term use of alvimopan is associated with cardiovascular risk.¹³

• Naloxegol (Movantik®, AstraZeneca) is an oral product that treats OIC.^14,15

• Lubiprostone (Amitiza®, Sucampo AG) is an oral chloride-channel activator.¹⁶

• An oral fixed-dose combination oxycodone/naloxone product (Targiniq, Purdue Pharma, LP) allows the naloxone to negate the effects of oxycodone on the GI tract but naloxone is then inactivated by the hepatic metabolism so as not to impair analgesia.¹⁷ Oxycodone and naloxone can also be offered to patients as “loose doses,” that is, as combination therapy using single-entity agents.

• Linaclotide (Linzess) is a 14-amino-acid peptide that is approved for treating chronic idiopathic constipation and is sometimes prescribed off-label for OIC.¹⁸

The literature contains many studies that show these medications are effective in treating OIC, do not adversely affect opioid analgesia, and are safe.^1,19-35 Side effects have been reported with these agents, the most notable of which is abdominal pain.

Conclusions

OIC is a prevalent condition but one which may be managed with PAMORAs. PAMORAs appear to be effective in managing laxative-refractory OIC with reasonable tolerability and safety. They do not compromise opioid analgesia.

103 Turmeric: Its Potential Role in Analgesia

Joseph V. Pergolizzi^1,4, Ugo J. Eke-Okoro⁵, Frank Breve⁵, Robert Taylor⁴, Robert B. Raffa⁶

¹Johns Hopkins University School of Medicine, Baltimore, MD, USA, ²Temple University School of Pharmacology, Philadelphia, PA, USA, ³Association of Chronic Pain Patients, Houston, TX, USA, ⁴NEMA Research, Inc., Naples, FL, USA, ⁵Temple University School of Pharmacy, Philadelphia, PA, USA, ⁶University of Arizona College of Pharmacy, Tucson, AZ, USA

Purpose

Turmeric, known to Americans as a spice used in curry, has a broad range of folk medicinal uses in its native Southwest India.¹ Turmeric contains curcuminoids and other phytochemicals, volatile oils, proteins, and resins among its many biologically active compounds. Curcumin is believed to be its major therapeutic agent and new investigations into the ancient flavoring are showing it may hold promise for its analgesic properties.¹ As a natural substance with few known adverse effects, turmeric joins a growing number of natural substances being explored in the fight against pain.

Method

Poor absorption and rapid metabolism and excretion give oral turmeric relatively limited systemic bioavailability.² When combined with tumererne (turmeric oil), which blocks its metabolic pathways,³ there is a 10-fold increase in turmeric absorption.⁴ Piperine, which inhibits glucoronidation in the liver and intestine, also increases curcumin bioavailability by 2000% in humans.^5,6 Novel formulations of curcumin, such as nanoparticles or phospholipid complexes, may improve bioavailability by extending the agent’s half-life.^5,7,8

Pharmacodynamics

Curcumin is a selective lipoxygenase and phospholipase A2 inhibitor, but it does not inhibit cyclooxygenase (COX) 1.^9,10 Thus, curcumin produces anti-inflammatory effects without the side effects associated with COX-1 inhibition. Curcumin may also inhibit pro-inflammatory cytokines such as interleukin (IL) 1β, IL-6, IL-8, and tumor necrosis factor-α (TNF-α).¹¹

Results

A curcumin extract (Flexofytol®) was evaluated in an observational study of 820 osteoarthritis (OA) patients with improved pain control, better articular mobility, and enhanced quality of life within the first six weeks. More than half of patients discontinued their analgesic, anti-inflammatory, and chondroprotective drugs. The turmeric product was well tolerated.¹³

In a randomized, double-blind, placebo-controlled study of 50 postsurgical patients found that after three weeks, all curcumin patients were pain free and over the three weeks had consumed significantly less analgesic agents than the placebo group.¹⁴

In a study of 46 men following inguinal hernia repair, patients were randomized to receive either 400 mg of curcumin, 100 mg of phenylbutazone, or 250 mg lactose (placebo) three times daily for five days. Patients were assessed for spermatic cord edema, spermatic cord tenderness, incision pain and tenderness on a pain scale of 0 to 12. Curcumin and phenylbutazone produced similar results, curcumin reduced inflammation to a greater degree and was found to be safer.¹⁵

Drug-drug interactions may occur when therapeutic doses of turmeric are taken along with oral hypoglycemic drugs,^16-18 antacids,^16,18 and blood thinners.¹⁷ It may cause premature uterine contractions and is not recommended for pregnant women.^16,17 It should not be taken by individuals with blood diseases or anemia,19 and it may inhibit conception.20

The FDA lists turmeric as a food on its list of “generally regarded as safe” (GRAS).21 The therapeutic use of turmeric has not been evaluated by the FDA, and it is not FDA indicated for any conditions. Nevertheless, there is a growing interest in turmeric and other natural products as alternatives or adjuncts in the armamentarium against pain. Such agents warrant serious and careful study not only as analgesics in and of themselves, but because they advance our knowledge of how analgesic products can circumvent or blunt pain mechanisms.

Conclusions

Despite advances in pharmacology and pain control, analgesic products are often associated with limited effectiveness, moderate to severe adverse effects, and tolerability issues. The interest in natural products may be a response to finding safer and more tolerable alternatives for pain control. Turmeric has long been associated with home remedies and new studies reveal its curcumin may have unique anti-inflammatory properties that can reduce pain with few side effects. Further study is warranted.

104 The Johnny BellyBreath App: Engaging young children in relaxation breathing and bubble blowing interventions using photoplethysmogram-based biofeedback

Christian Petersen¹, Evgenia Todorova², Eric Zhao¹, Wen-Ling Lin¹, Theresa Newlove², Mark Ansermino¹

¹Dept. of Anesthesiology, Pharmacology and Therapeutics, University of British Columbia, Vancouver, BC, Canada, ²Dept. of Psychology, University of British Columbia, Vancouver, BC, Canada

Purpose

Deep relaxation breathing is widely considered a beneficial coping strategy for children and adults experiencing pain and anxiety. Children are often taught this behavioral intervention through the blowing of real or imaginary soap bubbles.

Widely prevalent mobile technology is an excellent medium to teach and promote relaxation breathing. Many such applications are already available for adults in the mindfulness space. Users of these applications must be self-disciplined in order for the intervention to be effective. The ability to sustain interest and focus on relaxation breathing is difficult for children in the absence of active coaching.

The present work combines a previously developed low-cost smartphone pulse oximeter sensor with a breathing game for young children that integrates a biofeedback reward mechanism. The game encourages children to be compliant with the relaxation breathing protocol. The opportunity to score points and personalize elements of the game encourages prolonged relaxation breathing that maximizes the benefits of this coping strategy.

The first prototype had no biofeedback and featured a bubble-blowing character (Johnny Bellybreath) in an archetypal hot air balloon. An ethics board approved clinical study involving 80 consented children aged 5-17 was conducted to determine the parameters of a biofeedback reward mechanism. Here, we present the second generation of the application based on the results of the biofeedback calibration and the user experience from the first prototype.

Method

The game has been programmed to run on iOS and Android smartphones. As the breathing intervention inherently requires a slow paced game play, animation elements were added to enhance a rising balloon experience: The balloon wiggles in the wind, and the character in the balloon blinks, looks up and down, smiles, and has blowing and breathing motions. In addition, the background changes from a green field to the deep blue of outer space as the balloon rises.

Watching children interact with the first prototype inspired further design efforts. As personalization is a pillar of many successful computer games today, an avatar concept was therefore developed to allow users to pick a favorite character and balloon shape. Different balloon-avatar pairs were designed with consideration to gender, ethnicity and age of the children. The app now has a total of 21 such combinations of balloon and avatar appearances, which combines with facial expressions to form several hundred distinct screen impressions.

The application collects photoplethysmogram (PPG) waveforms with an attached pulse oximeter. Respiratory induced sinus arrhythmia, synchronized to a paced breathing of 6 breaths per minute, was used as a biofeedback trigger. The trigger threshold was programmed based on PPG from the clinical trial. The threshold is re-evaluated on every expiration and inspiration, i.e. at a rate of 0.2 Hz, causing the balloon to rise or fall. The balloon height is adjusted through a low-pass filter to provide a fluid and responsive experience on the screen.

Results

The height of the biofeedback driven balloon was tested by applying the calibrated algorithm to the recorded clinical study PPG data from 80 children of ages 5-7y (n=18), 8-10y (n=20), 11-13y (n=21) and 14-17y (n=21). During spontaneous breathing sessions the balloon reached a normalized average height of 0.07 +/- 0.08, i.e. remained grounded, while during two minutes of paced breathing rose to 0.76 +/- 0.29, near the top of the game world. The balloon took 15.4 +/- 4 seconds to start rising from the beginning of the paced session, corresponding to approximately 1.5 breaths.

Inspection of the raw PPG recordings reveals a variety of responses to the deep breathing protocol. Some subjects exhibit a strong PPG baseline variation, and others a strong amplitude modulation. All subjects in the clinical study had sufficient sinus arrhythmia modulation to achieve a positive synchronous effect during the paced breathing protocol.

Ad hoc testing has also shown the current biofeedback scheme to work poorly in adults, with some failing to raise the balloon. We speculate that this is due to the well-known reduction in sinus arrhythmia with age. A more elaborate biofeedback algorithm that also considers PPG amplitude and baseline modulations may improve performance in older adult subjects.

A second ethics board approved clinical study involving 200 consented children undergoing blood work at BC Children’s Hospital is currently ongoing to investigate the efficacy of the fully programmed game. Preliminary observations confirm that the biofeedback works as intended in real time, and the enhanced customizable graphical environment is very well received by the children.

Conclusions

A smartphone application that combines active and immediate visual feedback in response to relaxation breathing and gaming has been developed. The biofeedback loop has been calibrated based on clinical data, and the app features custom avatars and high score functionality that young children find engaging and fun.

The authors hope to make this technology widely available through the global app stores and reach out on online media to provide new age-appropriate means for children to manage their pain in both hospital and home care settings.

105 Converting from transdermal to buccal formulations of buprenorphine - a pharmacokinetic metamodel simulation

Tony Priestley¹, Arvind Chappa¹, Diane Mould^1,2, Neil Shusterman¹, Steven Passik¹, Vicente Tormo¹, Stephen Camper¹

¹Endo Pharmaceuticals Inc, Malvern, PA, USA, ²Projections Research Inc, Phoenixville, PA, USA

Purpose

Until recently, patients suffering from pain severe enough to require daily, round-the-clock, long-term opioid treatment, for which alternative therapeutic options were inadequate, had only a single FDA-approved buprenorphine therapeutic option, buprenorphine transdermal system (BTDS, BUTRANS®, Purdue Pharma L.P). With the successful approval and subsequent launch of a buprenorphine buccal film formulation (BBF, BELBUCA^TM, Endo Pharmaceuticals Inc.) for pain in February 2016, patients and physicians now have a second buprenorphine option to manage pain in this population. BBF is available in seven dose strengths (75, 150, 300, 450, 600, 750, 900 µg) formulated in a completely bioerodible buccal film and is approved for use in both opioid-experienced and opioid-naive patient populations. It is reasonable to assume that clinicians treating patients with BTDS may consider BBF as an alternative for their patients due to application site reactions, inadequate analgesia or other concerns and this poses a question about how best to manage such a conversion. The aim of the current study was to develop conversion scenarios, based on simulated pharmacokinetic (PK) meta-modeling. The ultimate goal was to provide clinical guidance with respect to dose and timing parameters required for minimal disruption to pain management and without compromising patient safety.

Method

A meta-analysis of available pharmacokinetic (PK) data, extracted from published literature, was performed in order to explore potential conversion scenarios. The time-course of mean buprenorphine plasma concentrations achieved following application of a transdermal patch or buccal film (multiple dose levels for each product) were digitized from available literature and a meta-model was developed using specific PK parameters derived from intravenous and buccal-administered buprenorphine. No clinical studies were conducted to investigate the conversion of a transdermal patch product to a buccal film formulation.

Results

Intravenous and buccal population pharmacokinetics were described using a 3-compartment model with between-subject variability on clearance (CL), central volume of distribution (V1), peripheral volume of distribution (V2) and V1-V2 equilibrium (Q2). The buccal absorption was a simple first-order input. The final transdermal model employed a zero-order input rate that was influenced by patch delivery rate, time after application of the patch (with a decline in rate over time) and patch type (Norspan® vs Butrans®). The transdermal absorption rate constant became zero when the patch was removed. A transition to a 150 µg dose of BBF, 12 hours after removal of a 20 mcg/hr transdermal patch, yielded average plasma levels (C_avg) that were similar to those estimated at the time of patch removal. The C_max excursions for the 150µg Q12hr dose of BBF were below the simulated prior steady-state C_max predicted for the transdermal patch formulation, implying this cautious conversion scheme should not expose patients to unnecessary risk. Subsequent step-wise up-titration in BELBUCA dose to 300 ug Q12hr, using the paradigm described in the BBF prescribing information (PI), would enable patients to attain comparable average buprenorphine exposure - seen at steady-state during transdermal patch application and within a relatively brief period after conversion. If necessary, additional BBF dose titration to achieve optimal therapeutic effect, would also be feasible using the scheme provided in the PI. Additional conversions from lower strengths of BTDS will also be presented.

Conclusions

Using a 20 mcg/hr BTDS as an example, switching to 150 µg BELBUCA, initiated 12 hours following removal of BTDS, appears to represent an optimal starting dose for the conversion with a reasonable balance between C_avg and C_max and subsequent options for patients to be further titrated to desired effect using the predetermined titration scheme described in the BBF prescribing information. Additionally, this modeling further illustrates the wide range of BBF dosing available to achieve plasma buprenorphine exposures above those possible with the maximum BTDS strength, for those patients who require higher doses to achieve adequate pain relief.

106 Modeling Pain as a Control System

Robert B. Raffa^1,2, David Fiumara³, Jonathan Gorky⁴, Prasad S. Dhurjati³, Joseph V. Pergolizzi^5,7

¹University of Arizona College of Pharmacy, Tucson, AZ, USA, ²Temple University School of Pharmacy, Philadelphia, PA, USA, ³University of Delaware College of Engineering, Newark, DE, USA, ⁴Thomas Jefferson University College of Biomedical Sciences, Philadelphia, PA, USA, ⁵Johns Hopkins University School of Medicine, Baltimore, MD, USA, ⁶Temple University School of Pharmacology, Philadelphia, PA, USA, ⁷Association of Chronic Pain Patients, Houston, TX, USA

Purpose

It is well known that there are ascending and descending pathways that transmit and attenuate pain signaling. By connecting the two pathways to form an integrated controlled system, we can employ standard control systems engineering and Fuzzy Logic techniques in order to model a system in which there is a setting for pain-perception. Such modeling might help improve understanding of certain aspects of the reception and perception of pain signaling that remain elusive, despite our growing understanding of neurotransmission systems (e.g., hyperalgesia, allodynia, peripheral and central sensitization, chronification, breakthrough pain, etc.). We wish to design a simple preliminary control systems model of the pain system.

Method

The system was designed recognizing that pain is a subjective measurement which can be influenced by a number of individual and environmental factors. The model used a black-box and fuzzy logic approach (pain as ‘mild’, ‘moderate’, or ‘severe’) to the body’s perception and modulation of pain signals. By modeling the system as a feedback loop in a traditional process control engineering sense, pain is treated as a disturbance to the system. The body’s response to pain is an attempt to return to a steady-state, which may provide insight on the effect of different types of pain and pharmacologic and non-pharmacologic interventions to treat pain.

Results

A model was created that describe the processes connecting pain stimulus to pain perception. The stimulus (input) is imposed on an individual’s Set-point (pain perception homeostasis) and closed-loop feedback-control that incorporates positive (amplification, ascending pathways) and negative (attenuation, DNIC pathways) inputs. A Controller monitors the differential between pain and the Set-point and attempts to reestablish homeostasis. A Transfer Function relates stimulus to intensity. Each aspect of the system can be modeled: the Set-point for example for genetic, environmental, and cultural influences; the Controller for signal sensitivity and transmission fidelity; the Transfer Function (eg, using the Weber-Fechner relationship, or other). Fuzzy Logic can be used to abrogate the lack of biochemical measures of pain perception and vagaries of analog scales.

Conclusions

The reception and perception of pain signals can be modeled as a feedback loop and a hypothesized “pain thermostat” regulating the ascending and descending pain pathways. Then, by using standard control-systems engineering to model the system, the model can be used to better understand pain and may provide insights into different types of interventions.

107 Pharmacokinetics and Safety of Fentanyl Sublingual Spray and Intravenous Fentanyl Citrate in Adult Opioid-Naive Healthy Volunteers: A Randomized, Open-Label, Single Ascending Dose Study

Richard Rauck¹, D. Alexander Oh², Neha Parikh², Christina Cognata Smith², Christian Koch³, Jin Yu², Srinivas Nalamachu⁴, Santosh Vetticaden²

¹Carolinas Pain Institute and The Center for Clinical Research, Winston-Salem, NC, USA, ²Insys Therapeutics, Inc., Chandler, AZ, USA, ³Lotus Clinical Research, LLC, Pasadena, CA, USA, ⁴Pain Management Institute, Overland Park, KS, USA

Purpose

Fentanyl sublingual spray is indicated for the treatment of breakthrough cancer pain in opioid-tolerant patients. Because of fentanyl sublingual spray’s rapid onset of pain relief and less invasive route of administration compared with intravenous opioids, it may provide a reasonable treatment option for acute or postoperative pain. As patients receiving opioids in acute or postoperative pain settings also include opioid-naive patients, it is important to understand the relationship between systemic exposure of fentanyl following the administration of fentanyl sublingual spray and its effect on safety and respiratory function in an opioid-naive population.

Method

This randomized, open-label, single-center, Phase 1 study in opioid-naive healthy volunteers assessed the pharmacokinetics and safety of ascending single-dose fentanyl sublingual spray (100, 200, 400, 600, or 800 mcg) or intravenous fentanyl citrate (50 mcg) in 5 dose cohorts (8 and 2 volunteers per cohort receiving fentanyl sublingual spray and intravenous fentanyl citrate, respectively). Volunteers were dosed after a 10-hour fast, and they continued to fast through 4 hours post-dose. Plasma samples were collected through 24 hours post-dose and assayed by a validated liquid chromatography/mass spectrometry method. Safety assessments were made from the time of dosing through follow-up on Day 7. Respiratory function parameters (respiratory rate, pulse oximetry, capnography) were measured at Day 0 (pre-dose) and at frequent intervals over a period of 24 hours post dose.

Results

Fifty volunteers with a mean age of 33.4 years and a mean body mass index of 25.87 kg/m² met the study criteria. Pharmacokinetics of fentanyl following fentanyl sublingual spray administration was well characterized in this population with a mean maximum plasma fentanyl concentration (C_max) of 0.2 to 2.0 ng/mL at mean time to maximum plasma fentanyl concentration (T_max) of 0.3 to 0.6 h. Analysis of dose proportionality suggested that C_max and total fentanyl exposure (area under the plasma concentration-time curve [AUC]) increased in a linear manner with increase in dose but was slightly greater than dose proportional. All treatments were generally well tolerated. All doses of fentanyl sublingual spray were generally well tolerated. The most common adverse events in this study included somnolence, nausea, and vomiting, which is consistent with the safety profile of fentanyl. No serious adverse events were observed. Episodes of hypoxia were observed at 600 (n=1) and 800 (n=4) mcg doses of fentanyl sublingual spray and were readily managed by verbal stimulation or nasal cannula/face mask oxygenation.

Conclusions

Overall, a single dose of fentanyl sublingual spray ranging from 100 to 800 mcg was generally well tolerated in opioid-naive healthy volunteers. A single dose of fentanyl sublingual spray of up to 400 mcg may be safely administered without the need for supplemental oxygenation in an opioid-naive healthy population in an appropriately monitored and equipped setting.

Supported by INSYS Therapeutics, Inc.

108 Preliminary design and population characteristics of a pharmacy-psychology run chronic pain care clinic for veterans

Eleni Romano¹, Chrisana Olson¹, Allison Schroeder¹, Joseph Frank^2,1, Paul Rozzero¹, Michael Craine^1,2

¹Denver VA Medical Center, Denver, CO, USA, ²University of Colorado School of Medicine, Denver, CO, USA

Purpose

Rates of chronic pain within the veteran population exceed the general population. Approximately 56% of veterans report chronic non-cancer pain, and 12.9% of veterans within the Veterans Affairs Health Care System (VAHCS) during FY 2016 2^nd quarter were prescribed chronic opioid therapy (COT). Due to the risk associated with COT, such as respiratory depression, endocrine and immune dysfunction, opioid misuse, and accidental or intention death, initiatives designed to promote the delivery of safe and effective interventions for chronic pain have been developed within the VAHCS.

The management of chronic pain and COT present a significant burden to primary care providers. PCPs are tasked with managing chronic pain in addition to treating multiple comorbid medical and psychiatric conditions. The Chronic Pain Care Clinic (CPCC) was implemented at the Denver VA Medical Center in August, 2015 to support PCPs in the management of chronic pain. The CPCC is a novel, interdisciplinary team comprised of clinical pain pharmacists and pain psychologists designed to optimize pharmacological management of chronic pain, provide close monitoring through frequent and extended appointment times, deliver psychoeducation about the biopsychosocial model, and promote the use of coping strategies such as relaxation and activity pacing. Providers deliver interventions in group and individual appointments and enrollment in the CPCC requires a commitment of appointment frequency ranging from weekly to monthly visits. The purpose of this program evaluation project is to describe the design of the CPCC and report preliminary descriptive data regarding veterans who are referred, accepted, and enrolled in the CPCC.

Method

Authors reviewed charts of all consults received between November, 2015 and April, 2016 to evaluate the initial impact of the CPCC. Authors gathered the following information through a retrospective chart review: Total number of consults received, referral question, demographic characteristics, percent of those receiving COT, those receiving COT and concurrent benzodiazepines, percent receiving over 200 morphine equivalents per day (MEDD) or higher, percent of consults declined, reason for consult decline, and percent of veterans who attended an Orientation Class and elected to enroll in the CPCC. Morphine equivalence will be calculated using standard opioid conversion metrics. The RIOSORD index will be used to estimate current overdose and respiratory risk level. Veterans who attended an Orientation Class prior to enrollment in the CPCC were asked to complete several baseline, self-report measures of pain and psychological functioning, including the Brief Pain Inventory-Short Form, Pain Self Efficacy Questionnaire-Short Form, Chronic Pain Acceptance Questionnaire-8, and Pain Catastrophizing Scale-Short Form. Means and standard deviations of scores on self-report measures will be calculated using SPSS.

Results

During the initial six months of clinic implementation, 190 veterans were referred to the CPCC. Of those referred, 55% (N = 105) were accepted to clinic. Reasons for discontinuation of the referral included non-PCP referring provider, referral from a community-based outpatient clinic outside of the CPCC service area, active malignancy, scheduled surgery for pain condition, and veteran declining referral. The referral question drop down menu included the following options: Continue with no opioids, continue current opioid regimen without change, rotate opioids to a similar or lower oral morphine equianalgesic dose, taper opioid dose down, and titrate opioids up as deemed appropriate. Further data analysis will be presented at the 2016 PAINWeek conference.

Conclusions

During the initial six months of CPCC, 190 veterans were referred and 55% were accepted in the clinic. The preliminary program evaluation suggests this is an effective model to provide support to primary care in the treatment of veterans with chronic non-cancer pain. A large number of declined consults suggests the importance of providing health care staff with frequent education about the purpose of CPCC and exclusion criteria for clinic. Future program evaluation should seek to identify barriers to enrollment and participation in clinic.

109 National Institutes of Health Pain Consortium Centers of Excellence in Pain Education - The creation of a burning mouth syndrome learning module to instruct future health professionals

Kevin Rowland, Cyril Pandarakalam, McKenzie Ferguson, Chris Herndon

Southern Illinois University Edwardsville, Alton, IL, USA

Purpose

Chronic pain adversely affects millions worldwide. Education of healthcare professionals in regards to chronic pain has been recognized as key in reducing the time to diagnosis, limiting opioid usage and improved overall care (IOM Report, 2011). We have been established as a Center of Excellence in Pain Education (CoEPE) at Southern Illinois University Edwardsville and St. Louis University by the National Institutes of Health. Our CoEPE seeks to create cased-based educational resources to better prepare students of the health professions in the assessment and treatment of pain. We present here our first case scenario involving a sufferer of burning mouth syndrome, a condition characterized by intense burning sensations within the oral cavity, usually localized to the tongue and lips. Individuals with painful, enigmatic conditions, such as burning mouth syndrome, often are evaluated by numerous healthcare professionals sometimes over a period of years before a definitive diagnosis is reached. Following a diagnosis of burning mouth syndrome a multidisciplinary approach for treatment and monitoring is warranted.

Method

Our cased-based learning module consists of pre- and post-tests of knowledge of the learning objectives of the case including: diagnosis and treatment of burning mouth syndrome, head and neck anatomy and differential disorders presenting similarly to burning mouth syndrome. Students of the health professions follow “Beverly” on a computer-based module as she seeks a diagnosis for her condition from a variety of healthcare professionals. The module includes video-recorded descriptions of Beverly’s symptoms. Throughout the module students learn via slides and animations of symptomology, epidemiology, normal anatomy and physiology

Results

Assessment of our content will also focus on the ability of the student to demonstrate clinical reasoning. Upon completion of the module, script concordance tests will present three different clinical vignettes in which the student applies knowledge in order to make clinical decisions and manage a patient under uncertain conditions. Script concordance tests aim to measure the degree of concordance between examinees and an expert reference panel. The test uses a method of combined scores to account for variability in the responses made by an expert panel of clinicians in order to determine the score awarded to the student. The score is calculated according to the number of panel members who chose a particular response.

Conclusions

Over the next year, we plan to assess dental medicine, pharmacy, medical and nursing students in an effort to determine the effect of our educational materials on clinical reasoning. Results from the assessments to be presented at the meeting. Our conclusion is that education of future providers will improve interprofessional practice and prescribing behaviors.

110 Primary care physician attitudes towards opioids analgesics and management of patients with chronic pain: a comparison between 2014 and 2016

Gregory Salinas, Lee Whitworth

CE Outcomes, LLC, Birmingham, AL, USA

Purpose

A major public health problem in the United States, chronic pain has been estimated to affect up to a third of Americans. At PAINWeek 2014, we reported data from a national survey on physician practice patterns and attitudes regarding chronic pain management to identify the factors involved in prescribing opioid analgesics. As education through an extended-release (ER) and long-acting (LA) opioid analgesic REMS (Risk Evaluation and Mitigation Strategy) program has been made available, it is anticipated that physicians’ attitudes and practices have changed since that time. Here, we will present updated results of that survey and changes in the landscape on management of chronic pain. The results of this study will show where educational gaps have been fulfilled and the current needs of the primary care community.

Method

After a thorough literature review and a series of focus groups conducted to ascertain the perception of physicians regarding barriers to prescribing opioid therapies, an online survey was designed and nationally distributed to primary care physicians (PCPs) who see at least 30 patients weekly with chronic pain in February 2014. Data collected from 250 PCPs were compiled for descriptive and inferential analysis. An identical version of the survey was fielded to 250 PCPs in July 2016. Additional analyses will be conducted to determine shifts in perceptions over the past 2 years and whether ER/LA opioid education had any impact on altering physician practice regarding risk assessment, treatment selection, or attitudes toward opioids.

Results

In the previous study, we reported that most PCPs were only somewhat confident in prescribing ER/LA opioid analgesics, educating patients about potential misuse of opioid analgesics, providing patients with relief from moderate-to-severe pain, and treating patients with moderate-to-severe pain. Patient-related factors about which more than half of PCPs were very concerned included patient development of addiction, the potential for misuse of opioid analgesics, and the potential for patient abuse of opioid analgesics. Major physician-related factors that inhibit prescription of opioid analgesics are lack of availability of abuse-deterrent medications, regulatory oversight, and REMS. Almost half of respondents were not familiar with REMS for ER/LA opioids. The primary predictors for physician prescription of opioids include physician confidence in chronic pain management, reduction of patient barriers, and reduction of physician barriers. Familiarity with REMS and chronic pain patient load has no effect on prescribing. Data from the 2016 survey is being collected and will show changes and trends, if any, in the past 2 years. Of particular interest in the analysis will be the awareness of the REMS program, current attitudes toward prescription of ER/LA opioid analgesics, and perceptions of abuse-deterrent therapies.

Conclusions

Appropriate use of opioids is a critical component of chronic pain management. The regression analysis from 2014 implied that increasing overall physician confidence and decreasing physician and patient barriers are key to increasing opioid analgesic prescription. Analysis of current perceptions will enable an understanding of the changes in physician practice as a result of the opioid REMS program and allow refinement of educational messages that should be considered.

111 Synthetic Urine How easy is it to find, order and have synthetic urine delivered?

Paul Samilpa, Lyndsey Langley

Genotox Laboratories, Austin, Texas, USA

Purpose

Urine drug testing is used extensively by Providers to verify that patients receiving prescription pain medications and those in rehab and recovery programs are following the treatment plan prescribed by their physician. The goal of urine drug testing is to identify any aberrant or off plan drug taking (prescription, illicit and/or OTC) behaviors that may be an early signal that a patient is headed for trouble – abuse, addiction or worse.

In order for drug testing to be of value, the testing must be completed with accurate and validated testing methods and sample authenticity must also be confirmed. Numerous laboratories are available with the necessary instruments, methods and expertise to properly analyze and report the results of a urine drug test. But what happens if the sample submitted for analysis is not from the patient? More specifically, what happens if the patient went online or to the local smoke shop and purchased and used one of many readily available substitute urine products available? Substitute urine products are readily available from a variety of sources and the market for urine adulteration products is estimated to be approaching $1Billion. A number of states have passed laws banning synthetic urine; despite this, the market for these products continues to grow.

Just how easy is it to find, purchase and have delivered to your home synthetic urine to facilitate “passing a drug test” when a real sample would not produce a clean test? Very easy.

Method

As part of the development and validity testing of a new DNA-verified authenticity method designed to match urine samples to individual patients, a Laboratory Technician at a clinical testing lab was tasked with identifying and purchasing a variety of substitute urine products from the internet. These products were to be used as part of the known controls introduced into the regular flow of patient samples to determine If the DNA-verified matching method would detect and properly classify any non-human urine.

The process began by typing various searches into a variety of search engines. Key words like “cheating a drug test,” “synthetic urine,” “passing a drug test,” and “substitute urine” were used to find websites and products. A total of 4 hours was spent performing the searches and ordering the products. All products were ordered using a company credit card with delivery instructions to the address of the laboratory.

Results

Entering the term “cheating a drug test” into the search engine Google returns 1,190,000 possible matches in under 1 second. Entering the term “synthetic urine” returned “about 428,000” results in under half a second. Going to amazon.com and entering “synthetic urine” yields 445 results. In just under four hours, more than 25 different synthetic urine or substitute urine products were ordered and within one week all had arrived at the laboratory. Preliminary testing indicated these products were quite effective at defeating the traditional validity measures of creatinine, specific gravity and pH. Products had very well developed packaging and branding featuring brand names such as “U-Pass,” “P-clear,” “Gator Whizz,” “Quick Fix +” and “Clear Choice.” Many of the products included clear instructions on how to use the products to get a “clean” drug test.

Conclusions

People are misusing, abusing and dying from prescription pain medications at an alarming rate in the United States today. Providers prescribing medications to treat pain have a unique challenge and obligation to do everything possible to prevent their patients and their prescriptions from contributing to the epidemic of prescription pain medicine and opium addiction in this country and their community. Urine drug testing is a vital tool to help providers lower the risk of improper use of the medications they prescribe. There is a plethora of very easy to acquire products available to help patients cheat a urine drug test.

112 Actual-Use Study of CL-108 for the treatment of flares of osteoarthritis of the knee or hip

Hessam Aazami¹, Richard M. Glover², Alan J. Kivitz³, David Oliver⁴, Donato R. Ricci⁵, Ronald Surowitz⁶, Bernard Schachtel⁷

¹Hope Clinical Research, LLC, Canoga Park, CA, USA, ²Heartland Research Associates, LLC, Newton, KS, USA, ³Altoona Center for Clinical Research, Duncansville, PA, USA, ⁴Renstar LLC, Ocala, FL, USA, ⁵Accord Clinical Research, LLC, Port Orange, FL, USA, ⁶Health Awareness, Inc., Jupiter, FL, USA, ⁷Charleston Laboratories, Inc., Jupiter, FL, USA

Purpose

Two randomized, double-blind, placebo- and active-controlled phase 3 safety and efficacy trials have demonstrated the relief of moderate-to-severe postoperative pain by CL-108 (hydrocodone 7.5 mg, acetaminophen 325 mg (HC/APAP) and rapid-release promethazine 12.5 mg) with significantly less opioid-induced nausea and vomiting (OINV) than HC/APAP (both p <0.001).^1,2 To observe the safety and effectiveness of CL-108 for moderate-to-severe acute pain in a non-surgical clinical setting, we conducted an actual-use study on patients with flares of osteoarthritis of the knee or hip.

Method

Patients in 17 medical practices in the US who were dissatisfied with their nonsteroidal anti-inflammatory drug (NSAID) treatment for osteoarthritis (OA) of the knee and/or hip were identified by their physicians from patient responses on a satisfaction questionnaire. They were eligible for this actual-use study if they experienced moderate-to-severe pain associated with a flare of a target joint after they discontinued their NSAID therapy. Pretreatment, patients also used standard rating scales to evaluate knee/hip stiffness, general health, and activities of daily living (ADL). Patients with moderate-to-severe pain after a flare of OA took CL-108 1 tablet every 4 to 6 hours as needed for joint pain. Patients continued to rate their joint pain and stiffness and side effects daily when they treated the OA flare. At a follow-up visit 2 weeks later, patients reevaluated their general health, ADL, and satisfaction with the study medication, and each attending physician provided a global evaluation of CL-108 as a treatment for moderate-to-severe acute pain of OA.

Results

Of 178 patients with moderate-to-severe pain associated with acute flares of OA of the knee/hip, approximately 62% were female and the mean ± SD age was 61.2 ± 10.1 years with 36.5% (n = 65) aged ≥65 years. Patients used, on average, 2 CL-108 tablets/day to treat the pain of their OA flares. Compared to pretreatment, 70% of the patients who used CL-108 for acute flares of OA reported significantly improved joint pain, as did 80% of the patients with severe joint pain (n = 95; both p <0.001). CL-108 significantly improved joint stiffness in 65% of all 178 patients and in 87% of patients with severe joint stiffness (n = 67; both p <0.001). All patients reported improvements in ADL, including 39% improvement in the ability to bathe or get dressed and 31% improvement in the ability to walk 1 block (all p <0.001). Physicians assessed CL-108 as a good-to-excellent treatment for 85% of the patients. There were no unexpected opioid-related adverse events, the most common being drowsiness. The incidence of OINV in this actual-use setting was low (2.2%).

Conclusions

Under real-life conditions of clinical use, CL-108 was a safe and effective treatment for acute flares of OA of the knee or hip.

¹J Pain 2014;15:S81. ²J Pain 2016;17:S83.

113 The Efficacy of CL-108 in Preventing Opioid-Induced Nausea and Vomiting (OINV)

Stephen E. Daniels¹, Stephen F. Richardson², Kyle Patrick¹, Steven P. Royall², Emily J. Schachtel³, Mary Beth Lorton³, Bing Zhang⁴, Sunny Cho⁵, Bernard P. Schachtel³

¹Formerly with Premier Research Group, LLC, Durham, NC, USA, ²Jean Brown Research, Salt Lake City, UT, USA, ³Charleston Laboratories, Inc., Jupiter, FL, USA, ⁴MacroStat, Inc., Wilmington, DE, USA, ⁵Daiichi Sankyo, Inc., Parsippany, NJ, USA

Purpose

OINV is a common pharmacologic side effect of opioids. Patients often describe this condition as more annoying than pain, particularly in the postoperative setting. For these reasons a new analgesic, CL-108, is being developed, consisting of hydrocodone 7.5 mg/acetaminophen 325 mg (HC/APAP) with a low dose (12.5 mg) of a rapid-release formulation of the antiemetic promethazine, for the relief of moderate-to-severe pain and the prevention of OINV. A randomized, double-blind, placebo- and active-controlled oral surgery study¹ demonstrated the efficacy of CL-108 over 24 hours for moderate-to-severe pain compared to placebo and for OINV compared to HC/APAP (both p <0.001). To study CL-108 over 48 hours, a randomized, double-blind, phase 3 trial was conducted to evaluate pain intensity reduction by CL-108 compared to placebo and the incidence of OINV compared to HC/APAP in patients following orthopedic surgery.

Method

To improve assay sensitivity, the study population was enriched by identifying patients with a history suggestive of being likely to develop nausea (e.g., previous OINV or motion sickness). After undergoing primary unilateral first metatarsal bunionectomy, patients rated pain intensity on a categorical scale. If they had moderate or severe pain confirmed on a 0-10 numerical pain intensity rating scale (PI-NRS), patients were randomized to CL-108, HC/APAP, or placebo under double-blind conditions. They used the PI-NRS at regular intervals over 48 hours while documenting the occurrence, severity, and frequency of nausea and vomiting. Patients received study medication regularly every 4-6 hours and took antiemetic and supplementary (rescue) analgesic medications as needed. The co-primary endpoints over 48 hours were summed pain intensity differences (SPID₄₈) comparing CL-108 to placebo for analgesia and a composite endpoint of no vomiting or use of antiemetic comparing CL-108 to HC/APAP for OINV prevention.

Results

A total of 552 patients were randomized to CL-108 (n = 252), HC/APAP (n = 250), or placebo (n = 50). There were no differences in demographic characteristics (including age) or clinical features (including baseline pain intensity) among the treatment groups. Patients who used CL-108 had significant pain relief compared to placebo (mean SPID₄₈ of 118.4 vs 53.1; p <0.001) and a 74% reduction in the risk of developing OINV relative to patients who used HC/APAP (OINV incidence of 11.9% vs 45.2%, respectively; p <0.001). Of clinical note: for the prevention of OINV, the number-needed-to-treat (NNT) was 4 (95% confidence interval 3-4). Opioid-related side effects observed with CL-108 were typical for hydrocodone and promethazine (e.g., mouth dryness, drowsiness, confusion, difficulty concentrating) and mostly mild in severity. There were no unexpected serious side effects in patients who received CL-108 or HC/APAP.

Conclusions

We conclude that CL-108 is a safe, effective analgesic for moderate-to-severe pain and the prevention of OINV.

¹Schachtel, B J Pain. 2014.

114 Objective evidence of the efficacy of CL-108 compared to standard hydrocodone 7.5 mg/acetaminophen 325 mg in preventing Opioid-Induced Nausea and Vomiting (OINV)

Elliot V. Hersh¹, Bernard Schachtel², William J. Kozarek², Emily Schachtel²

¹University of Pennsylvania School of Dental Medicine, Philadelphia, PA, USA, ²Charleston Laboratories, Inc., Jupiter, FL, USA

Purpose

CL-108 (containing hydrocodone 7.5 mg, acetaminophen 325 mg [HC/APAP] with rapid-release promethazine 12.5 mg) was formulated to provide analgesia and prevent or reduce opioid-induced nausea and vomiting (OINV). In a Phase 3 randomized, double-blind, placebo- and active-controlled trial CL-108 was shown to be an effective analgesic compared to placebo and to significantly reduce the incidence of moderate or severe nausea, vomiting, and the use of antiemetics compared to HC/APAP (both p <0.001).¹ Another definition of OINV includes only two objective criteria to determine the efficacy of a drug in preventing OINV: any vomiting or use of antiemetics. We used this 2-component endpoint to analyze the results of this study.

Method

After surgical extraction of at least 2 impacted third molar teeth, 466 patients with moderate-to-severe pain were randomized to self-administer double-blind CL-108 (n = 211), commercially available HC/APAP (n = 205), or placebo (n = 50) every 4-6 hours as needed for pain and supplementary (rescue) analgesic and antiemetic medication was allowed as needed. On an hourly basis (while awake) over the first 24 postoperative hours, patients documented the intensity of pain and nausea and, importantly, the frequency of vomiting and use(s) of an antiemetic.

Results

There was 52% less risk of vomiting for patients who used CL-108 over 24 hours compared to HC/APAP-treated patients (p <0.001). More HC/APAP-treated patients (16.6%) used antiemetics than CL-108-treated patients (3.8%), and HC/APAP-treated patients (2.4%) used more repeat doses of antiemetics than CL-108-treated patients (1.0%; both p <0.001). Overall, applying the stringent 2-component definition of OINV to these 24-hour results, 11.4% of patients who used CL-108 experienced OINV compared to 31.7% of patients who used HC/APAP, representing a 64% relative reduction in the risk of developing OINV (p <0.001).

Conclusions

We conclude that patients who use CL-108 for moderate-to-severe pain experience significantly less OINV than patients taking a standard analgesic that contains the same dosages of hydrocodone and acetaminophen.

¹Schachtel B, et al. J Pain. 2014.

115 Updated and Validated Comparison of Plasma and Cerebrospinal Fluid Fentanyl Pharmacokinetics and Bioavailability When Delivered Intranasally or Sublingually

Pete Schmidt, Srinivas Rao

Depomed, Inc., Newark, CA, USA

Purpose

Breakthrough cancer pain (BTPc) is a rapid onset, severe pain of relatively short duration (mean duration of 30 minutes) that occurs despite stable and adequately controlled background pain. Optimal treatment requires medication that exhibits pharmacokinetic and pharmacodynamic properties that match its onset and duration. Transmucosal formulations of fentanyl are the only medications approved by the Food and Drug Administration (FDA) for the treatment of BTPc. The primary objective of this study was to compare two transmucosal formulations of fentanyl (Lazanda® nasal spray and SUBSYS® sublingual spray) with respect to the pharmacokinetics in the central nervous system (cerebrospinal fluid, CSF). We also compared the plasma pharmacokinetics, bioavailability, and safety and tolerability of these formulations versus an intravenous (IV) injection. This report represents an update to data previously reported (Chen et al. PAINWeek 2015).

Method

This was a partially randomized, open-label, 3-way crossover, single-center study in which healthy subjects were randomly assigned in a 1:1 ratio into 1 of 2 arms. Subjects received fentanyl nasal spray, 200 μg (IN) or fentanyl sublingual spray, 200 μg (SL) in crossover dosing sequences on days 1 and 3. All subjects received fentanyl citrate injection, 100 μg IV on day 5. Doses were separated by a 48-hour washout period. Study drugs were administered under a naltrexone block. Blood samples were collected pre-dose, and at 5, 10, 15, 20, 30, 45, 60 minutes and 1.5, 2, 3, 4, 6, 8, 12, 24 hours post IN and SL administration; and pre-dose, and at 2, 5, 10, 20, 30, 60 minutes and 2, 4, 6, 8, 12, and 24 hours post IV administration. CSF samples were collected via a spinal catheter implanted on Day 1 pre-dose and at 5, 10, 20, 30, 45, 60 minutes and 2, 3, 4, and 6 hours post IN and SL administrations. Both fentanyl and its primary metabolite norfentanyl were analyzed in the plasma; only fentanyl was analyzed in the CSF.

A paired t test was used to compare the differences in C_max or AUC ratios between study drugs. A Wilcoxon signed-rank test was used for the comparison of T_max.

Results

Thirteen subjects were randomly assigned in the study. Twelve completed the study and 1 discontinued due to lumbar catheter complications. The safety population included all 13 subjects who received at least 1 dose of study drug. The PK population included all 13 subjects who received at least 1 dose of study drug and had at least 1 evaluable PK parameter. Subject’s mean (SD) age was 41 (12) years and mean (SD) weight was 73 (14) kg.

Plasma

Geometric mean (geometric CV) absolute bioavailabilities for IN and SL were 69.1 (49.2)% and 56.7 (21.7)% respectively. The ratio (IN/SL) of geometric least square means [LSMR] (90% CI, P) for the AUC_{0- tlast} (pg*h/mL) was 1.163 (0.972-1.392, P = .1588). The corresponding ratio for C_max (pg/mL) was 1.428 (1.056- 1.932, P = .0581). There were no appreciable differences between IN and SL in t_1/2 or T_max. The LSMRs for AUC_0-tlast norfentanyl/AUC_0-tlast fentanyl for IN and SL were 0.367 and 0.566, respectively (P = .0005). The LSMRs for C_max norfentanyl/C_max fentanyl were 0.140 and 0.319, respectively (P = .0003).

CSF

The IN/SL LSMR (90% CI, P) for the AUC_{0- tlast} (pg*h/mL) was 1.432 (0.933-2.198, P = .1639) and for C_max (pg/mL) was 1.384 (0.948-2.022, P = .1489). The median (range) T_max (h) was 1.01 (0.75-3.00) hours for IN and 2.00 (0.75-3.00) for SL (P = .0684). In a post-hoc analysis, the concentration of fentanyl in the CSF was significantly higher when administered by nasal spray at 1 hour (the CSF T_max for IN) (P = .04). At the T_max for SL (2 hours), the concentrations were not significantly different.

Conclusions

Systemic exposure was numerically higher when fentanyl was administered IN vs SL, while exposure to norfentanyl was lower. Thus, the ratio of norfentanyl/fentanyl was significantly different indicating a greater extent of metabolism following SL administration.

The ratio of fentanyl in CSF/plasma was relatively low and was comparable between treatments. There was a ~1 hour difference (1 hour vs 2 hours) in CSF T_max for IN vs SL, and this difference approached significance. The concentration of fentanyl in the CSF was significantly higher when administered IN at 1 hour but not significantly different at 2 hours.

116 Comparison of Pharmacokinetics and Simulated Driving Performance in Healthy Volunteers Taking Therapeutic Doses of Gastroretentive Gabapentin, Gabapentin, or Pregabalin

Pete Schmidt, Srinivas Rao

Depomed, Inc., Newark, CA, USA

Purpose

Dizziness and somnolence are among the most commonly observed adverse effects of pregabalin and gabapentin in clinical trials in patients with post-herpetic neuralgia (PHN). These adverse effects have the potential to negatively impact multiple domains of daytime functioning, including driving, which may have serious consequences.

The primary objective of this study was to determine the relative impact of Gralise® [gastroretentive gabapentin (G-GR)], gabapentin (G), and pregabalin (P) on daytime function, as assessed by driving simulator performance and measures of sedation and cognition, and to correlate with subjective impairments. The secondary objective was to compare the relative safety and tolerability of the 3 dosage forms under fed conditions. We also explored the exposure and response relationship following treatment with G-GR, G, and P.

Method

In this double-blind, placebo-controlled, crossover study, healthy volunteers were randomly assigned 1:1:1:1 to a 4 period dosing sequence with a 7-day washout between periods. Dosing consisted of G-GR, or G, or P, or placebo (PBO) at PHN labeled doses, in the evening on day 1, and ending in the morning on day 3, all under fed conditions.

At approximately 2 hours post-treatment on day 3, the following instruments were administered: a Driving Simulator test (DST) that simulated monotonous driving for ~60 minutes, Karolinska Sleepiness Scale (KSS), and Portland Neurotoxicity Scale (PNS).

The primary driving outcome measure was the change from baseline in standard deviation of lateral position (SDLP) on the DST. SDLP, is a stable, validated measure of driving performance with high reproducibility. A larger SDLP reflects greater weaving during simulated driving.

A pharmacokinetic analysis was performed in each treatment period to facilitate an exploratory assessment of the relationship between drug exposure and drug response using pharmacokinetic/pharmacodynamic (PK/PD) modeling. Samples were collected pre-dose (within the 5 minutes prior to dosing) and at 1, 2, 3, 4, 6, 8, 10, and 12 hours post-dose on day 1 and at 1, 2, 4, 6, 7, 8, 10 and 12 hours after the morning dose on day 2.

Results

Thirty-two participants were dosed, 28 completed all 4 dosing periods. The median age was 47.5 years, 75% were male, 38% were white, and 59% were black/African American. The least squared mean difference (LSMD) in SDLP change (feet) from baseline for G-GR (n=28) was 0.255. Corresponding values for G (n=31), P (n=30), and PBO (n=30) were 0.395 (P = .0275), 0.356 (P = .1103), and 0.135 (P = .0611), respectively.

On the PNS, subjects receiving G-GR reported less tremor than for other treatments; reaching statistical significance when compared with G (difference = -0.140; P = .0304) and PBO (difference = -0.171; P = .0083). Visual disturbances were less frequent in subjects receiving G-GR with a significant difference vs G (difference = -0.286; P = .0177). Other PNS parameters were not significantly different.

No statistically significant differences were noted with respect to sleepiness, as measured by the KSS.

Median gabapentin Tmax was 8 hours for G-GR and 6 hours for G; median Tmax was 4 hours for P. Greater fluctuations in plasma concentration-time profiles were observed for G and P, compared with G-GR. AUC0-24 and Cmax did not appear to correlate with SDLP.

No serious adverse events or adverse events (AEs) of severe intensity were reported. Treatment emergent adverse events occurred in 52%, 42%, 21%, and 17% of subjects treated with P, G, G-GR, and PBO, respectively.

Conclusions

In this exploratory study in healthy volunteers initiating gabapentinoids at PHN labeled doses, driving impairment (SDLP increase) was greater for G and P than G-GR, reaching statistical significance versus G. Neurological symptoms, such as tremor and visual disturbances, were less frequent for G-GR than for G. AEs were less frequent for G-GR versus G and P. These differences may reflect the distinct pharmacokinetic profiles of G (dosed TID) and P (dosed BID), compared with G-GR (QD evening dosing). Though not necessarily reflective of clinical practice, these results may inform larger trials to further elucidate the relative impact on daily function.

117 Correlation of Pharmacokinetic (PK) and Subjective Pharmacodynamic (PD) Parameters: An Exploratory Post Hoc PK-PD Analysis from Two Human Abuse Potential Studies With a Hydrocodone Extended-Release Tablet Formulated With CIMA® Abuse-Deterrence Technology Platform

Kerri Schoedel¹, Michael Gillespie², Naama Levy-Cooperman¹, Megan J. Shram¹, Laura Rabinovich-Guilatt²

¹Altreos Research Partners, Inc., Toronto, ON, Canada, ²Teva Pharmaceuticals, Frazer, PA, USA

Purpose

A hydrocodone extended-release (ER) tablet was developed with the CIMA® Abuse-Deterrence Technology (ADT) platform to provide resistance against rapid release of hydrocodone when tablets are manipulated or taken with alcohol. Two studies previously demonstrated the significantly lower abuse potential of hydrocodone ER tablets formulated with the ADT platform compared with hydrocodone controls administered orally and intranasally, the most commonly reported routes of abuse (Darwish. Pain Med. 2016). In both studies, the mean plasma concentration-time curves for each treatment paralleled mean “at the moment” Drug Liking scores over time. Although clinical studies have demonstrated that drug formulations with slower kinetics have potentially reduced abuse potential, pharmacokinetic (PK) and pharmacodynamic (PD) data are often only weakly correlated at the aggregate level and not correlated at the individual level (Quinn. Clin Pharmacokinet. 1997). This exploratory post hoc analysis of the oral and intranasal abuse potential studies of hydrocodone ER was conducted to examine PK/PD correlations in each study.

Method

Both the oral and intranasal human abuse potential studies were single-dose, randomized, double-blind, placebo- and active-controlled crossover studies performed in healthy, nondependent recreational opioid users. In the oral study, subjects received a 45-mg dose of each of the following treatments separated by a ≥14-day washout: intact oral hydrocodone ER, crushed oral hydrocodone ER, hydrocodone active pharmaceutical ingredient (API) powder in solution, and placebo. In the intranasal study, subjects received a 45-mg dose of each of the following treatments separated by a ≥7-day washout: intranasal milled hydrocodone ER, intranasal hydrocodone API powder, intact oral hydrocodone ER, intranasal milled Zohydro ER (hydrocodone ER capsule commercially available at the time of the study [before reformulation with BeadTek® Technology]), and placebo. PD assessments included peak effect (E_max) for the following measures: “at the moment” Drug Liking visual analog scale (VAS), Overall Drug Liking VAS (at 12 and/or 24 hours postdose), and Take Drug Again VAS. Hydrocodone PK measures included maximum observed plasma drug concentration (C_max), time to maximum observed plasma drug concentration (T_max), area under the plasma drug concentration-time curve (AUC_S), partial AUC_S, and the abuse quotient (AQ; C_max/T_max). Associations between individual PK and PD data were examined using Pearson correlation coefficients (r value) and scatter plots for each treatment and for all treatments combined, separately by study.

Results

In the oral study, positive correlations were observed for some parameters for all treatments combined, including plasma concentrations and “at the moment” Drug Liking scores at 4 hours postdose (T_max for crushed oral hydrocodone in previous study; r=0.5206), and “at the moment” Drug Liking VAS E_max vs. hydrocodone C_max (r=0.7135), AQ (r=0.6230), and AUC_0-4h (r=0.7361). Inverse correlations were observed for hydrocodone T_max and E_max for the following PD parameters: “at the moment” Drug Liking VAS (r=-0.6981), Overall Drug Liking VAS (r=-0.5771), and Take Drug Again VAS (r=-0.5635), indicating that an earlier C_max was associated with higher positive subjective responses. There was no correlation between PD AQ (“at the moment” Drug Liking VAS E_max/time to E_max) vs. PK AQ (r=-0.0830). Generally, correlations between PK and PD parameters were lower in the intranasal study than the oral study. Correlations were also generally weaker when examining each individual treatment separately, in particular for the intact oral hydrocodone ER in both studies.

Conclusions

Results showed that lower and later plasma drug concentrations correlate at least moderately with decreased drug liking and willingness to take drug again. Correlations were generally stronger in the oral study, consistent with the influence of non-PK factors (eg, local effects of the formulations) on intranasal abuse potential and liking. These correlations were stronger than reported previously, potentially because of very slow kinetics and lack of abuse-related effects with intact oral hydrocodone ER. These exploratory data from abuse potential studies of hydrocodone ER formulated with CIMA® ADT platform demonstrate that, under some conditions, PK and subjective PD effects are correlated.

118 Onset of Efficacy of LY2951742 in Migraine Prevention: Data from a Phase IIA, Randomized, Double-blind, Placebo-controlled Study of a Monoclonal Antibody to Calcitonin Gene-related Peptide (A Post-hoc Analysis)

Peter Goadsby^1,2, David Dodick³, James Martinez⁴, Margaret Ferguson⁴, Tina Oakes⁴, Yoko Tanaka⁴, Xiao Ni⁴, Qi Zhang⁴, Michael Due⁴, Vladimir Skljarevski⁴, Matthew Sexson⁴

¹King’s College of London, London, England, UK, ²University of California San Diego, San Diego, CA, USA, ³Mayo Clinic, Phoenix, AZ, USA, ⁴Eli Lilly and Company, Indianapolis, IN, USA

Purpose

Despite the availability of preventive medications for migraine, significant needs remain for efficacious and tolerable medications. The development of new medicines offers opportunities to ask clinically relevant questions, such as when does efficacy of an entirely novel preventive approach start. We used a post-hoc analysis of the trial of LY2951742 to determine the time to onset of efficacy of LY2951742, a humanized monoclonal antibody to calcitonin gene-related peptide, for the prevention of migraine.

Method

These analyses were conducted using data from a randomized, double-blind, placebo-controlled, phase 2a study in patients aged 18-65 years with 4 to 14 migraine headache days per month who were randomly assigned to LY2951742 or placebo for 12 weeks (NCT01625988). To assess the onset of efficacy, daily data reflecting if the patient had a migraine headache (“yes” vs “no”) during the 12-week treatment period were aggregated into the number of migraine headache days for each weekly interval. Onset of efficacy was defined as the first week in which LY2951742 was statistically superior to placebo in reduction of migraine headache days per week.

Results

In analyses of both migraine headache days (MHD) and probable MHD, the onset of efficacy of LY2951742 (n=106) was observed as early as week one compared with placebo (n=110). LY2951742 continued to demonstrate statistically significant improvement compared with placebo at the majority of subsequent weeks including endpoint (week 12) for MHD, but not probable MHD at endpoint compared with placebo.

Conclusions

These analyses suggest evidence of onset of efficacy of LY2951742 as early as Week 1.

119 No evidence of increased abuse potential of CL-108, a bi-layered tablet containing hydrocodone/acetaminophen/promethazine, in recreational opioid users

Megan Shram¹, Naama Levy-Cooperman¹, Lynn Webster²

¹Altreos Research Partners, Inc., Toronto, Ontario, Canada, ²PRA Health Sciences, Salt Lake City, Utah, USA

Purpose

CL-108 is an immediate release (IR) tablet containing 7.5 mg hydrocodone (HYD), 325 mg acetaminophen (APAP) and 12.5 mg rapid-release promethazine (PMZ) under development for treating patients who suffer from moderate to severe pain while preventing opioid induced nausea and vomiting (OINV). Promethazine is a histamine (H₁) receptor blocking agent indicated for the prevention and control of nausea and vomiting associated with certain types of anesthesia and surgery; it is associated with adverse events including drowsiness, dizziness, and fatigue. Although non-medical use of PMZ both alone and in combination with opioids has been reported, a formal evaluation of the abuse potential of administering a combination of PMZ with an opioid has not been conducted. This study evaluated the abuse potential of supratherapeutic doses of orally administered CL-108 tablets in non-dependent recreational opioid users compared to equivalent dosages of HYD/APAP and placebo (PBO). This study also assessed the cognitive behavioral effects and safety of orally administered CL-108 relative to HYD/APAP and placebo.

Method

The study consisted of a Dose Selection Phase and Main Study. Because the safety and tolerability of administering higher combined doses of HYD and PMZ orally was unknown prior to study conduct, the Dose Selection Phase evaluated the safety and tolerability of 4 CL-108 doses (up to a maximum dose of 37.5 mg HYD/1625 mg APAP/62.5 mg PMZ) to identify 2 doses for inclusion in the Main Study. The Dose Selection Phase utilized a randomized, double-blind, placebo-controlled dose escalation design in 4 separate cohorts of healthy recreational opioid users (N=12). Following the Dose Selection Phase, the Main Study utilized a randomized, double-blind, PBO- and active-controlled 5-way crossover design. Subjects were healthy recreational opioid users who passed a qualification session to ensure they could distinguish HYD/APAP 30 mg/1300 mg from PBO. Eligible subjects (N=40) received single doses of CL-108 (22.5 mg/975 mg/37.5 mg [low-dose] and 37.5 mg/1625 mg/62.5 mg [high-dose]), HYD/APAP (22.5 mg/975 mg [low-dose] and 37.5 mg/1625 mg [high-dose]) and PBO. Subjective measures (e.g., visual analog scales [VAS]), cognitive measures, pupillometry, and standard safety measures were evaluated over 24 h postdose.

Results

Mean peak (E_max) of Drug Liking VAS (primary endpoint) was significantly higher for both supratherapeutic doses of HYD/APAP compared to PBO (p≤0.001), confirming study validity. HYD/APAP and CL-108 showed significantly higher scores on all subjective measures and pupillometry compared to PBO. For both CL-108 and HYD/APAP, scores on subjective measures for the high-dose treatments were generally higher than the scores observed for the low-dose treatments, indicating assay sensitivity. Comparisons between dose-matched CL-108 and HYD/APAP treatments were not statistically different on the majority of subjective measures, including the primary Drug Liking E_max endpoint. Both doses of CL-108 were associated with greater drowsiness (as measured by the Alertness/Drowsiness VAS) compared to dose-matched HYD/APAP (p<0.01 for both). In addition, maximum pupil constriction was significantly greater for high-dose CL-108 compared to high-dose HYD/APAP (p=0.0014). All treatments were well tolerated, with most adverse events being mild in severity and the most commonly reported adverse events were consistent with expected side effects of opioids and PMZ (e.g., pruritus, euphoric mood, and somnolence). Both supratherapeutic doses of CL-108 were associated with a greater incidence of somnolence compared to dose-matched HYD/APAP.

Conclusions

Oral administration of supratherapeutic doses of CL-108 demonstrated similar subjective effects and safety when compared to dose-matched HYD/APAP. On the whole, results suggest that the addition of PMZ to the combination of HYD and APAP results in no greater abuse potential compared to an IR combination product containing HYD and APAP in the same dosages.

120 Correlating Viscosity and In Vitro Dissolution to In Vivo Pharmacokinetic Profiles of Proprietary Injection-Molded Tablet Formulations With Abuse-Deterrent Characteristics

Nikolaj Skak, Torben Elhauge, Martin Jan Øvergård, Karsten Lindhardt

Egalet Corporation, Wayne, PA, USA

Purpose

Egalet Corporation developed Guardian^TM Technology, based on manufacturing using a proprietary plastic injection-molding process, resulting in tablets that are very hard with extremely low porosity. The tablets have physical properties expected to deter accidental misuse and rigorous attempts at abuse. An extended-release profile is achieved by tablet polymer matrix erosion. The objective of this study was to test the hypothesis that strong abuse-deterrent (AD) features do not limit predictable drug delivery, and that correlations exist between the polymer viscosity, the in vitro dissolution profile, and the pharmacokinetic (PK) profile.

Method

AD features were tested according to US Food and Drug Administration guidance (Category 1). Scanning electron microscopy (SEM) was used to assess tablet porosity. The viscosity of polyethylene-oxide (PEO) in different tablets was measured using standard conditions. Dissolution profiles (the time for 50% drug release) were obtained with a United States Pharmacopeia apparatus I. The PK profiles of tablets with different PEO viscosities were compared in a phase 1 clinical trial (N=30). The correlation coefficient was calculated for viscosities and dissolution rates. Prediction error (PE) was calculated for the dissolution rates, maximum plasma concentration (C_max; in vivo PK), and area under the plasma concentration-time curve (AUC).

Results

Category 1 data were consistent with robust AD features. SEM images documented low porosity of the tablets. Linear correlation was observed for the log polymer viscosity (cP), the dissolution rate (r²=0.9883), and for the dissolution and PK profiles (%PE_(Cmax)= -8.12; %PE_(AUC)= -7.03, average values). This demonstrated a level A nonlinear in vitro/in vivo correlation between in vitro dissolution profiles and PK profiles, providing a correlative link between polymer viscosity and PK profiles.

Conclusions

By determining the viscosity of the polymer applied to tablets manufactured by the proprietary plastic injection-molding technique, the tablet PK profile can be predicted. Importantly, tablet polymer viscosity can be used as a predictive tool in the development of new AD products.

121 INTAC® - a technology platform for extended release, immediate release and fixed-dose combination opioids with abuse deterrent characteristics

Hans-Juergen Stahlberg, Sebastian Schwier, Klaus Wening, Eric Galia

Gruenenthal GmbH, Aachen, Germany

Purpose

Many solid, extended release (ER), immediate release (IR) and fixed dose combinations (FDC) dosage forms containing opioids can be abused by snorting of crushed product or preparation of solutions for subsequent injection. Abuse deterrent formulations (ADF) aim to impede intentional abuse e.g. by pulverization and dissolving.

Method

GRT INTAC® formulations (Test) were investigated in open, randomized, cross-over, relative bioavailability trials against the Reference, marketed opioid formulations. Single oral doses were administered to healthy male subjects under fasted conditions. Serum drug concentrations were determined by validated LC-MS/MS methods. Non-compartmental PK analyses were performed and the usual 80.00 - 125.00% confidence interval acceptance criteria for bioequivalence were used for comparing Test to the Reference.

Results

The 90% confidence intervals for C_max, AUC_0-t, and AUC_0-∞ of Test formulations were within the range usually accepted for confirmation of bioequivalence.

The data demonstrate that INTAC® formulations have comparable in-vivo performance to standard immediate and extended release formulations for single entity as well as for combination products.

Conclusions

Abuse deterrent formulations comprising INTAC® technology may enable physicians to switch patients from conventional to reformulated ADF products.

122 Preclinical and Clinical Assessments of the Abuse Potential of the Kappa-Opioid Receptor Agonist CR845 Suggest Low Abuse Potential

Frédérique Menzaghi¹, David Heal², Catherine Munera¹, Joseph W. Stauffer¹, Robert Spencer¹

¹Cara Therapeutics, Inc., Stamford, CT, USA, ²RenaSci Ltd, BioCity, Nottingham, UK

Purpose

CR845 is a highly potent, peripherally-acting kappa-opioid receptor agonist (KORA) with no affinity for either delta- or mu-opioid receptors and no other detectable off-target activity at other receptors, ion channels, or transporters. CR845 exhibits analgesic effectiveness in clinical studies of acute and chronic pain. Although the analgesic activity of KORAs has been recognized for more than 15 years, their development has been hampered due to central nervous system (CNS)-mediated adverse events, in particular dysphoria and hallucinations. CR845’s hydrophilic, unnatural peptide structure greatly limits its entry into the brain and thus CR845 should be devoid of the centrally-mediated adverse psychoactive effects. Since CR845 lacks affinity of the mu-opioid receptors, it should also lack abuse properties. Here we describe preclinical and clinical studies undertaken to determine whether the compound has the potential for recreational abuse in humans. We investigated whether CR845 would generalize to the discriminative cue elicited in rats by (-)pentazocine, a mixed kappa/delta-opioid receptor agonist and mu-partial agonist. In addition, the ability of CR845 to serve as a positive reinforcer was evaluated in rats that had been trained to self-administer a low dose of heroin. These preclinical findings were reported along with results obtained with CR845 in a drug-experienced human volunteer trial.

Method

Thirty female Lister Hooded rats were trained to discriminate (-)pentazocine (5 mg, intraperitoneally [ip]) from saline on a fixed reward 5 (FR5) schedule for sweetened milk rewards. Separate groups of rats were then challenged with intravenous (iv) doses of pentazocine, butorphanol (a mixed kappa/mu-opioid receptor agonist), or CR845 to validate the model and assess the generalization of CR845 to (-)pentazocine.

Forty male Sprague-Dawley rats were trained to self-administer heroin on an FR5 reinforcement schedule. After saline extinction, separate groups of rats were evaluated with iv doses of CR845 or (-)pentazocine to assess their reinforcing effects.

Forty-four recreational polydrug users who were experienced, but not dependent, on opioid and hallucinogenic drugs were enrolled in a double-blind, single-center, randomized, active- and placebo-controlled, 4-way crossover study assessing the abuse potential of CR845. All subjects could discriminate between iv doses of placebo or pentazocine (Talwin Lactate Injection, 0.5 mg/kg). Subjects were challenged with single bolus iv therapeutic and supra-therapeutic doses of CR845 (5 mcg/kg), CR845 (15 mcg/kg), placebo, and pentazocine (0.5 mg/kg). The doses were administered in a balanced Williams crossover design with 48 hours between doses. Response to each drug was assessed up to 8 hours after each dose using a bipolar Drug Liking Scale in which 0 indicated “strong disliking” and 100 indicated “strong liking.” Additional measures of abuse liability were taken and changes in pupil diameter measured periodically after each treatment provided an objective measure of mu-mediated drug response.

Results

Drug discrimination was validated by dose-dependent generalization of iv (-)pentazocine to the ip (-)pentazocine training cue. A similar response was observed with increasing iv doses of butorphanol, used as a reference comparator. In contrast, CR845 produced low-level, non-dose dependent, partial generalization to (-)pentazocine, a result that is consistent with its potent KORA activity coupled with its poor CNS penetration. Peak plasma concentration (C_max) was in excess of the human plasma concentration at therapeutic doses. Pentazocine also substituted for heroin in heroin-maintained rats at all doses tested demonstrating that it serves as a positive reinforcer. In contrast, CR845 produced no evidence of positive reinforcement at doses in excess of clinical doses.

In humans, maximum possible effect (E_max) for Drug Liking was significantly higher for iv pentazocine than placebo (p<0.0001) confirming the validity of the study. The VAS measure of “drug liking” (E_max and over the entire 8-hour observation period) for CR845 was significantly lower than pentazocine (p<0.0001) with no evidence of dose-related effect. A similar pattern was observed on measures of Any Effects, Good Drug Effects, and Drug High, with small elevations relative to placebo seen after doses of CR845 that were not dose-related and which were significantly lower than scores following pentazocine. In the end-of-session question of Overall Drug Liking and Take Drug Again, subjects who received CR845 reported scores that were not different from placebo; in contrast, there was a strong liking and desire to take pentazocine again. In agreement with these findings, pentazocine showed CNS pharmacological activity (i.e. pupillary constriction) whereas CR845, like placebo, produced no evidence of pupillary constriction, consistent with its lack of mu-opioid agonist activity.

Conclusions

The preclinical results and those of the human abuse potential study provide complementary data that are consistent with the known properties of CR845. All together, these studies did not identify a significant potential of CR845 for drug-seeking behavior relative to the CNS active mixed kappa/mu comparator, pentazocine, a Drug Enforcement Administration Schedule IV drug. These data provide evidence that the selective KORA CR845 is unlikely to be recreationally abused and may represent a new class of non- to low-abusable opioid analgesic.

123 Safety, Tolerability, and Effectiveness of Orally Administered CR845, a Peripherally Acting Kappa-Opioid Receptor Agonist, in Patients with Osteoarthritis of the Knee or Hip

Frédérique Menzaghi, Joseph W. Stauffer, Catherine Munera

Cara Therapeutics, Inc., Stamford, CT, USA

Purpose

CR845 is a potent, selective, peripherally-acting kappa-opioid receptor agonist (KORA) being developed for the treatment of pain and pruritus. In vitro, CR845 has been shown to have 30,000-fold selectivity to kappa-opioid receptors compared with mu- or delta-opioid receptors and no other off-target activity. CR845 is a hydrophilic tetrapeptide and is therefore unable to cross the blood-brain barrier in amounts sufficient to cause CNS-mediated adverse events characteristic of other KORAs that do penetrate the brain, for example dysphoria and hallucinations. In previous clinical studies that demonstrated the analgesic effectiveness of CR845 for treatment of post-surgical pain, CR845 was dosed intravenously. However, for the treatment of chronic pain conditions, oral dosing would be preferred. In this report we describe a clinical trial designed to assess the safety and effectiveness of CR845 administered orally in patients with osteoarthritis of the knee or hip.

Method

Male or female patients ≥25 years old with a body mass index ≤40 kg/m² and osteoarthritis of the knee or hip were eligible to enroll in this single-blind, pilot study provided they reported an average daily pain intensity of ≥4 on a 0 to 10 Numerical Rating Scale (NRS) at screening and for 3 days prior to baseline. Four cohorts of patients were enrolled and were treated sequentially with 0.25, 0.5, 1.0, and 5 mg enteric-coated tablets taken twice daily (q12h) for 14 days. Average daily NRS pain intensity was recorded each evening in each patient’s diary. Venous blood samples were taken from the first 6 patients in each cohort before and during the 12 hours after the morning dose on Day 1 and Day 2 of treatment for assessment of pharmacokinetics. Safety was evaluated by the incidence and severity of treatment-emergent adverse events (TEAEs) and clinical laboratory measurements.

Results

Eighty-one patients (n=20 or 21 per cohort) were enrolled in the study. Mean baseline NRS pain severity score in each cohort ranged from 6.2 to 6.8. Following the initial dose, mean C_max and AUC_0-∞ were proportional to dose. Forty-four percent of patients reported at least 1 TEAE during the study, with the highest incidence being in the 1 mg (50% of patients) and 5 mg (85% of patients) dosing groups. The most common TEAEs were dizziness (12%), headache (7%), and nausea (6%), and the incidence of these TEAEs appeared to be dose-related. The effect of CR845 on joint pain was assessed using an AUC analysis of the NRS daily average severity score. The area under the NRS pain intensity score for the 5 mg dose group was significantly less than the pooled AUC of the other 3 dose groups (P=0.02). The mean percent reduction in NRS daily average pain intensity score seen in the 1 mg (-26%) and 5 mg (-34%) were similar to those reported for other classes of analgesics used for the treatment of chronic pain in patients with osteoarthritis. In addition, the use of rescue medication (acetaminophen 325 mg tablets) was lower in the 5 mg CR845 group compared with its use in the other 3 dosing groups combined at the end of both Week 1 (p=0.039) and Week 2 (p=0.033).

Conclusions

The results of this study suggest that oral CR845 may represent an effective analgesic for with the relief of chronic pain in patients with osteoarthritis. A double-blind, placebo-controlled Phase 2b clinical trial is planned for oral CR845.

124 Content Validity of the Penn Facial Pain Scale: Cognitive Debriefing in Patients with Trigeminal Neuralgia

T Symonds¹, JA Randall¹, D Hoffman², J Zakrzewska³, W Gehringer⁴, JYK Lee⁵

¹Clinical Outcomes Solutions, Folkestone, UK, ²Biogen Inc, Cambridge, MA, USA, ³Eastman Dental Hospital UCLH, London, UK, ⁴Clinical Outcomes Solutions, Tucson, AZ, USA, ⁵University of Pennsylvania, Philadelphia, PA, USA

Purpose

Trigeminal neuralgia (TN) is a condition that causes recurring severe pain in the face, manifesting as intermittent shooting, stabbing, and sharp pain that impacts on activities of daily living, interpersonal relationships, and emotional well-being. The PENN Facial Pain Scale (PENN-FPS) was developed to assess the impact of TN on daily activities (formerly known as the Brief Pain Inventory (BPI)-Facial). It was initially developed as an additional 7-item module to the BPI, but as the PENN-FPS it is now a standalone measure. This study aims to address the measure’s content validity in order to ensure that the PENN-FPS captures concepts that are most important to patients with TN, which is a critical part of measurement development.

Method

Semi-structured qualitative interviews were undertaken with 20 participants (15 US, 5 UK) with confirmed TN diagnosis. The interviews involved both concept elicitation and cognitive debriefing. Concept elicitation requires participants to spontaneously describe the impact of TN on their daily lives, allowing identification of concepts that are most important to patients. Cognitive debriefing tests the extent to which measures capture these concepts of interest. In this study, after the concept elicitation phase, participants were asked to complete the original BPI-Facial, comprised of the 7-item BPI-Pain Interference scale and seven-item TN-specific module. Each of these 14 items assesses the extent to which pain impacts on 14 different daily activities and experiences. Participants were asked to describe impressions of the instructions, questions, recall period, and response options, whilst also highlighting if the 14 items captured all relevant concepts. All interviews were transcribed verbatim and analyzed using thematic analysis in ATLAS.ti version 7.0.

Results

Participants’ age ranged from 43-72 years, 17 were female and the majority, 65% were Caucasian, 25% were African American, and 5% of were American Indian and African American/Hispanic.

Nine themes relating to restricted activities were identified during concept elicitation: “talking,” “self-care,” “eating,” “eating hard foods,” “touching,” “activities with temperature change,” “daily activities,” “mood,” and “relationships.”

During cognitive debriefing three BPI-Pain Interference items were identified as relevant in TN (“mood,” “general activities,” and “relations with others”). Feedback on the 7 TN specific items indicated all concepts were relevant but that minor amendments to some items were required i.e., “eating hard foods,” should be rephrased to “biting and chewing,” and the item “touching your face (including grooming)” should be separated into two items: “self-care (including washing face or hair, shaving and applying makeup)” and “touching your face (including moving stray hairs, hugging, kissing)”. One new item was created related to activities with temperature change, as per the theme identified during concept elicitation.

All participants were happy with the proposed response options, wording, and recall period of the past week.

Consequently, these 12 items were put together to form the new PENN-FPS.

Conclusions

This study supports the content validity of the PENN-FPS. The new 12 item PENN-FPS captures all the concepts identified as relevant by participants with TN during concept elicitation. Psychometric validation of this revised version is now planned.

125 Genetic Metabolic Defects In Severe Chronic Pain Patients On High Dose Opioids

Forest Tennant

Veract Intractable Pain Clinic, West Covina, CA, USA

Purpose

There is a subgroup of severe chronic pain patients who require high opioid dosages to control their pain. Little is known about these patients. This survey was done to determine if genetic metabolic defects were prevalent in a group of severe, intractable pain patients who maintained on a minimal opioid dosage of 100 mg equivalence of morphine (MED) a day.

Method

One Hundred One (101) intractable pain patients who were in on-going medical management and required over 100 mg (MED) a day were tested for genetic defects in three cytochrome 450 (CYP450) enzymes; 2 D 6, 2 C 9, and 2 C 19. Forty-five of these same patients were also tested for opioid receptor mu one (OPRM 1) binding capacity and catechol-O-methyltransferase (COMT) activity. A defective CYP 450 enzyme was any rating (poor, intermediate, or rapid) other than extensive or normal. A defective OPRM 1 rating was considered to be low or intermediate with high being normal. A low COMP rating was considered normal with intermediate or high being defective.

Results

Ninety-one (91) of 101 patients (91.1%) had one or more CYP450 enzymatic defects. A total of 132 defects were found in the 101 patients. Twenty-eight (28; 27.7%) patients had a defect in two and 8 (7.9%) had defects in all 3 CYP450 enzymes. The numbers of CYP450 defects for each enzyme were: 2C19 (52, 54.4%); 2D6 (43, 42.6%); and 2C9 (37, 36.6%). Thirteen (13; 28.9%) of 45 had intermediate or low OPRM 1 activity and 28 of 45 (62.2%) intermediate or high COMT activity levels. These defective activity levels require extra opioids for pain control.

Conclusions

The high percentage of defective CYP450 enzymatic, OPRM 1, and COMT activity ratings in this survey indicate that chronic pain patients who require over 100 MED a day have a very high prevalence of genetic metabolic defects that may mandate a higher than normal opioid dosage to control severe pain.

126 Underlying Causes of Chronic Pain Which Require High Dose Opioids

Forest Tennant

Veract Intractable Pain Clinic, West Covina, CA, USA

Purpose

A daily morphine equivalence dosage of no more than about 100 mg (MED) a day is sufficient for the majority of chronic pain patients. There is, however, a subgroup of chronic pain patients who require daily opioid dosages above this level. Little is known about this group. The purpose of this study was to identify and classify the underlying causes of pain in a group of chronic pain patients who required over 100 mg (MED) a day to achieve pain control.

Method

One hundred fifty-four (154) consecutive, severe chronic pain patients who were referred and in on-going medical management were taking over 100 mg (MED) a day. They were evaluated to determine their primary underlying cause of chronic pain. A chart review was done on each patient that included referring diagnosis, history, physical, viral titers, hormone profile, inflammatory markers, and magnetic resonance imaging (MRI) studies. One primary underlying cause out of eight was assigned to each patient. If the patient had more than one cause, the cause believed to be primary was assigned.

Results

Eight primary causes or categories of pain were identified in these patients who required over 100 mg (MED) a day for adequate pain control. The primary causes and percentage of the 154 cases were: (1) adhesive arachnoiditis: (69; 41.6%); (2) reflex sympathetic dystrophy/chronic regional pain syndrome: (35; 22.7%); (4) genetic connective tissue diseases: (15; 9.7%); (5) post viral encephalopathy/myelopathy: (14;9.1%); (6) peritoneal adhesions with neuropathies: (9; 5.8%); (6) traumatic brain injury: (9; 5.8%); (7) Lyme disease/neuropathy/arthropathy: (5; 3.2%) and (8) autoimmune disorder: (3;1.9%);. While many patients had multiple causes of pain, each patient was assigned in what was believed to be their primary, causation.

Conclusions

The underlying causes of severe chronic pain which required over 100 mg (MED) a day were relatively few in the patients studied here. It is essential to identify the primary underlying causes of pain in patients who require over 100 mg (MED) a day in order to justify opioid need and develop strategies to treat the underlying cause as opposed to providing symptomatic care.

127 Relative abuse of crush-resistant tablets of prescription opioids via alternative oral modes of administration

Steven Butler¹, Ryan Black¹, Ernest Kopecky², Christy Thompson², Alison Fleming²

¹Inflexxion, Inc, Newton, MA, USA, ²Collegium Pharmaceuticals, Inc, Canton, MA, USA

Purpose

Crush-resistant tablets (CRTs) formulated with gelling properties were one of the first marketed approaches to abuse-deterrent formulations (ADFs) for extended-release opioids. Such formulations have been shown to reduce abuse of opioids by non-oral routes of administration (insufflation, injection). However, an increase in the proportion of oral abuse has been observed among those who do abuse CRTs. We examined prevalence of alternate modes of oral abuse involving product manipulation (i.e., chewing, dissolving in mouth, or drinking after dissolving in liquid) versus swallowing the tablet whole. Such product manipulation is intended to defeat the extended-release mechanism of the tablets.

Method

Data from January 2009 through March 2015 were examined from the ASI-MV®, a computerized, clinical interview for adults in substance abuse treatment, which captures self-report of past 30-day abuse of prescription opioid products, including routes and modes of administration. Target drug categories included: crush-resistant ADF (reformulated OxyContin, reformulated Opana ER, and Nucynta ER), non-crush resistant versions of tablets, original/generic oxycodone ER, morphine ER, original/generic oxymorphone ER, and oxycodone IR SE (Single Entity).

Results

Among 364,329 unique patient assessments, 76,108 (20.9%) reported abuse of any Rx opioid, 28,107 (7.7%) reported abuse of the target drugs, and 18,135 (5.0%) reported use by the oral route. Among abusers of any product, the CRTs had a higher prevalence of alternate modes of oral abuse (26.3 per 100 abusers) than comparators (20.6 to 5.6; p < .001). When examined among oral abusers, the CRTs had a greater prevalence of alternate modes of oral abuse (41.5 per 100 abusers; p < .005). Conversely, CRTs were significantly less likely than comparators to be abused by swallowing whole (p < .0001). Crush-resistant tablets were significantly more likely to be chewed than all comparators (p < .005) and more likely to be dissolved in the mouth than the non-CRT versions of the products, original or generic oxycodone ER, and morphine ER.

Conclusions

Results suggest that CRTs are more likely than non-CRT versions and comparators to be abused by alternate modes of oral administration associated with product manipulation. Taken together, these results point to the need for a next generation of ADFs that include technology intended to preserve the extended-release characteristics of the formulation on manipulation, including by alternate oral modes of abuse such as chewing. This research was supported by Collegium Pharmaceutical, Inc., Canton, MA

128 The Prevalence of Nasal Obstruction as a Consideration in the Treatment of Opioid Overdose

Scott Weiner¹, Andrew Joyce², Heather Thomson³

¹Brigham and Women’s Hospital, Boston, MA, USA, ²Venebio Group, LLC, Richmond, VA, USA, ³kaléo, Inc., Richmond, VA, USA

Purpose

The intranasal route of administration for naloxone delivery is one treatment for opioid overdose, but treatment failures with this modality have been documented. One hypothesis is that nasal obstructive pathology may be a reason for failure, as it can lead to inadequate absorption of drug. The purpose of this exploratory study was to determine the incidence of obstructive nasal pathology in patients who suffered a serious opioid-related respiratory depression event (OIRD), the life-threatening aspect of overdose. The secondary objective was to determine if nasal pathology is independently associated with OIRD.

Method

This was a retrospective analysis of a large insurance database (IMS LifeLink), covering more than 150 million unique patients who are <65 years old and commercially insured. We included patients who had at least one opioid pharmacy claim and who experienced serious OIRD between 1/1/2009 and 12/31/2013. Serious OIRD was defined by prescription opioid poisoning plus respiratory or central nervous system adverse effect code or use of mechanical ventilation or critical care. OIRD events that involved poisoning codes exclusively related to heroin were excluded due to limitations of the dataset. We then determined which patients had concurrent diagnoses of nasal obstruction based on ICD-9 codes: 470 (deviated nasal septum), 471.0 (polyp of nasal cavity), 478.0 (hypertrophy of nasal turbinates), and 478.19 (other disease of nasal cavity and sinuses). A multivariable analysis determined the adjusted odds ratio of OIRD for patients with nasal obstructive pathology. Logistic model covariates included demographics, individual Charlson Comorbidity Index comorbidities, other pain- and non-pain-related health conditions, prescription opioid medication information, select concomitant medications known to potentiate opioid effects, and metrics of healthcare utilization.

Results

A total of 7,234 patients in the dataset were identified to have experienced a serious OIRD event. Of these, 840 (11.6%) had coded nasal obstruction pathology: 20 (2.4%) had deviated nasal septum, 246 (29.3%) had polyp of the nasal cavity, 130 (15.5%) had hypertrophy of nasal turbinates, and 659 (78.5%) had other disease of the nasal cavity and sinuses. For each case, there were four controls who did not experience a serious OIRD event; 6.7% of these had coded nasal obstruction pathology. In the multivariable analysis, the adjusted odds ratio for patients who experienced serious OIRD having concurrent nasal obstructive pathology was 1.28 (95% CI 1.13-1.46).

Conclusions

In this retrospective analysis of a large insurance database, nasal obstructive pathology appears to be relatively common in patients who experience serious OIRD, and in itself is associated with a higher risk of having OIRD. The results highlight the importance of knowledge of this pathology as a potential risk factor for OIRD that should caution practitioners prescribing opioids for these patients, and also may be an important consideration when choosing a route of administration of naloxone.

129 Virtual Reality For Chronic Pain Management: Pain Self-Modulation through Biofeedback and Cognitive Pain Distraction

Xin Tong, Diane Gromala

Simon Fraser University, BC, Canada

Purpose

Virtual Reality (VR) treatments for reducing acute pain have seen promising results in multiple studies. Hoffman et al. convincingly demonstrated that immersive VR is very effective to attract people’s attention into computer generated virtual places so that it can be used as the powerful pain control technique and tool for patients to manage and alleviate their pain. While evidence from numerous studies over fifteen years support VR’s effectiveness in addressing acute pain, little is known about the use of VR for chronic pain (CP) and/or for long-term pain management of functional rehabilitation. Only a few studies have investigated VR for CP management and the data are preliminary.

In this poster, we introduce two paradigms we have used to help Chronic Pain (CP) patients better self-manage their pain through VR technology: Pain Distraction and Pain Self-modulation. The attention of patients when managing their pain is driving to focus inward in VMW and outward in MF. Those two paradigms are the main design mechanisms used in most of the VR projects for both acute and CP management. Further, we demonstrate the findings from the user studies we conducted with both VR paradigms. Finally, we discuss the benefit of utilizing VR to mitigate pain and its challenges.

Method

For each paradigm, we designed a virtual environment based on theoretical research and practical experience with VR for patients. Then we validate two VR design through two studies. In the method section, we report how we designed the environment and the specific study procedures used in each scenario.

1. Attention Outward – Mobius Floe (MF) is an immersive VR game designed as a tool to help chronic and acute pain patients lower their pain and sometimes attend anxiety. MF draws the attention away from patients’ embodied experience of pain and toward the virtual 3D environment and its current happenings. The game also includes many tasks designed to stimulate the patients’ working memory; because the tasks seek patients’ constant attention, it draws attention away from their physical pain.

2. Attention Inward – Virtual Meditative Walk (VMW) is not a form of pain distraction; rather, it is a paradigm we refer to as VR pain self-modulation. This VR system incorporates biofeedback sensors, an immersive VE and stereoscopic sound. It was designed to enable CP patients to learn mindfulness-based stress reduction (MBSR), a form of meditation that is known to be a useful adjuvant for CP patients. By providing real-time visual and sonic feedback, VMW enables patients to learn how to manage their pain with real-time feedback.

Results

1. Mobius Floe

Pain intensity during and after the interventions was measured. For pain intensity after the interventions, the two groups of the VR intervention and self-mediated control were not significantly different using repeated measures ANOVA (F(2, 38) = 1.377, p =.265). However, for pain intensity during the intervention, there was a significant difference between the VR intervention and control groups (F(2, 38) = 21.473, p <0.001, r = 0.505).

The user study result demonstrated that during the VR session, Mobius Floe could significantly reduce the perception of pain intensity for chronic pain suffers in comparison to the baseline. Compared with self-mediated interventions such as reading, listening to music, or playing mobile games. Mobius Floe gained more analgesic effect on chronic pain patients’ suffering. It also significantly distracted patients’ attention for their daily pain.

1. Virtual Meditative Walk

Compared to the control group, the VR group experienced a reduction of pain, on average, equaling 2.6 on the NRS scale. One must also consider that the patients themselves were only immersed in the VR for twelve minutes, which is a short amount of time for an MBSR session.

There was a significant Time x Condition interaction (as shown in Figure 4), F(1, 11) = 8.16, p < .05, r = .54, indicating that the changes in the pain level in the VR group were significantly different compared to the change in the control group. The findings indicate that the VMW (VR paired with biofeedback for MBSR training) was significantly more effective than MBSR alone at reducing reported pain levels among participants.

Conclusions

Our immersive VR research explores the design space for pain management of CP patients. Pain self-modulation and pain distraction approaches were utilized in designing the VEs, combining general non-pharmacological pain management approaches, such as MBSR meditation, biofeedback and games. Preliminary study results validated both pain management strategies could function effectively on reducing the pain and stress levels of CP patients.

130 Evaluation of Constipation in Opioid-Naïve and -Experienced Patients Receiving Buprenorphine Buccal Film for Chronic Pain Requiring Around-the-Clock Therapy

Vicente Tormo, Qinfang Xiang, Todd Kirby, Steven Passik, Stephen Camper

Endo Pharmaceuticals Inc., Malvern, PA, USA

Purpose

Constipation is a common and often distressing adverse event (AE) associated with the long-term use of opioids for chronic pain. Buprenorphine buccal film (BBF) is a long-acting formulation of the partial opioid agonist buprenorphine and is indicated for the management of pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate. The objective of this post hoc analysis was to evaluate the occurrence and severity of constipation associated with short- and long-term BBF use in both opioid-naïve and opioid-experienced patients.

Method

This post hoc analysis included data from 3 separate studies of BBF in adults with chronic lower back pain. Study 1 was a double-blind, placebo-controlled, randomized withdrawal study of opioid-experienced patients (N=810; 56.4% female; average age, 53.0 years) evaluated for 12 weeks. Study 2 was a double-blind, placebo-controlled, randomized withdrawal study of opioid-naïve patients (N=749; 56.6% female; average age, 50.7 years) evaluated for 12 weeks. Study 3 was a 48-week open-label safety study with a titration phase (N=506; 55.1% female; average age, 52.3 years) of 445 rollover patients (who originated from Study 1 or 2) and 61 de novo patients. In these studies, medication was permitted for constipation, but specific bowel regimens to reduce constipation were not stipulated by the protocols.

Results

In Study 1, the proportion of patients with ≥1 constipation AE was 8.3% in the open-label titration phase (n=810) and, in the double-blind treatment phase, was 2.8% in the BBF group (n=254) and 0.8% in the placebo group (n=256). There was 1 constipation AE rated as severe and 1 constipation AE leading to treatment discontinuation (both in the open-label titration phase). Use of medications for constipation was reported in 9.6% of patients at baseline, 14.7% during open-label titration, and 2.4% with BBF versus 0.8% with placebo during double-blind treatment. In Study 2, the proportion of patients with ≥1 constipation AE was 13.0% in the open-label titration phase (n=749) and, in the double-blind treatment phase, was 3.9% in the BBF group (n=229) and 2.6% in the placebo group (n=232). There were 4 constipation AEs rated as severe and 8 constipation AEs leading to treatment discontinuation (all in the open-label titration phase). Use of medications for constipation was reported in 2.8% of patients at baseline, 8.8% during open-label titration, and 3.1% with BBF versus 2.2% with placebo during double-blind treatment. In the long-term safety study (Study 3), the proportion of patients with ≥1 constipation AE was 5.9% overall (n=506) and 6.1% among rollover patients (n=445) in the titration phase, and 3.9% overall (n=435) and 4.0% among rollover patients (n=404) in the long-term treatment phase. There was 1 constipation AE rated as severe (in a rollover patient during the titration phase). Use of medications for constipation reported in the overall study population and rollover patients, respectively, was 10.5% and 5.8% at baseline, 13.0% and 13.3% during open-label titration, and 2.5% and 2.7% during long-term treatment. No serious adverse events of constipation were reported in any study.

Conclusions

The incidence of constipation AEs was low and similar to placebo during treatment with BBF for opioid-experienced patients with chronic pain. Similarly, low rates of constipation (<4%) were observed during the double-blind phase for opioid-naïve patients. Long-term use of BBF did not increase the occurrence of constipation AEs. In all patients, these studies demonstrated a low reported use of medications for constipation during double-blind or long-term treatment periods. These findings are consistent with previously published studies of BBF. Constipation was somewhat more common in opioid-naïve than opioid-experienced patients. Severe constipation and treatment discontinuation due to constipation were rare.

131 Efficacy and Tolerability of Buprenorphine Buccal Film in Older Adults With Chronic Pain Requiring Around-the-Clock Therapy

Vicente Tormo, Qinfang Xiang, Todd Kirby, Steven Passik, Stephen Camper

Endo Pharmaceuticals Inc., Malvern, PA, USA

Purpose

Opioid analgesics are used with caution in older patients due to the risk of adverse events such as delirium and falls. Buprenorphine buccal film (BBF) is a partial opioid agonist indicated for the management of pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate. The objective of this post hoc analysis was to evaluate the efficacy and safety of BBF in older patients with chronic pain.

Method

Patient-level data were pooled for patients ≥65 years of age enrolled in double-blind, placebo-controlled, randomized withdrawal studies of BBF conducted in opioid-naïve (Study 1) and opioid-experienced (Study 2) patients with moderate-to-severe chronic low back pain. Each study included an open-label BBF titration phase lasting up to 8 weeks, followed by a 12-week, double-blind, placebo-controlled, randomized withdrawal treatment phase. During the double-blind treatment period, BBF was dosed at 150-450 mcg every 12 hours in opioid-naïve patients and 150-900 mcg every 12 hours in opioid-experienced patients, based on the individualized optimal dose identified during the titration phase. The primary efficacy outcome was change in pain intensity (measured via a numeric rating scale (NRS)) from baseline to week 12 of the double-blind treatment phase. Other efficacy endpoints were the proportion of treatment responders, defined as ≥30% or ≥50% reduction in NRS pain score from the start of open-label titration to week 12 of double-blind treatment; patients who discontinued study participation prior to week 12 were counted as nonresponders.

Results

A total of 138 patients ≥65 years old (52.2% male, 84.8% white) completed open-label titration and were randomly assigned to double-blind treatment with BBF (n=65) or placebo (n=73); efficacy data were available for 61 and 67 patients, respectively. The least squares mean difference in NRS score change from double-blind baseline to week 12 (mixed-model repeated-measures analysis) was -0.70 for BBF versus placebo (P=0.0277). The proportion of treatment responders was 68.9% in the BBF group and 41.8% in the placebo group (P=0.0041) for response defined as ≥30% reduction in NRS pain score, and 49.2% and 28.4%, respectively (P=0.0372) for response defined as ≥50% reduction in NRS pain score. At least one adverse event was reported during the double-blind treatment phase for 50.8% of patients in the BBF group (n=65) and 50.7% of patients in the placebo group (n=73). Most adverse events were mild to moderate in intensity for both treatment groups; severe adverse events were experienced by 4.6% and 2.7% of patients receiving BBF and placebo, respectively. Adverse events led to treatment discontinuation for 3.1% of BBF-treated patients and 11.0% of patients in the placebo group. The most common adverse events were nausea (10.8% with BBF vs 8.2% with placebo), constipation (4.6% vs 1.4%), urinary tract infection (4.6% vs 1.4%), fall (3.1% vs 0%), rib fracture (3.1% vs 0%), and vomiting (3.1% vs 0%).

Conclusions

In this post hoc analysis of older patients (≥65 years) with moderate-to-severe chronic lower back pain, analgesic efficacy was significantly greater for patients with an optimized dose of BBF, ranging from 150-450 mcg every 12 hours in opioid-naïve patients and 150-900 mcg every 12 hours in opioid-experienced patients, compared with those randomized to placebo. BBF was generally well tolerated with a relatively low incidence of individual treatment-emergent adverse events. Due to the post hoc nature of this analysis, additional studies are required to fully evaluate the efficacy and safety of BFF in older patients with chronic pain.

132 The Burden of Opioid-Induced Constipation in Younger Patients With Chronic Pain

Anita Gupta¹, Karin S. Coyne², Catherine Datto³, Christine Venuti³

¹Division of Pain Medicine & Regional Anesthesiology, Department of Anesthesiology & Perioperative Medicine, Drexel University College of Medicine, Philadelphia, PA, USA, ²Evidera, Bethesda, MD, USA, ³AstraZeneca Pharmaceuticals LP, Wilmington, DE, USA

Purpose

Chronic pain exerts a considerable impact on patient functioning, productivity, and health-related quality of life (HRQL). Although opioid analgesics provide effective treatment for moderate to severe chronic pain, patients often experience the side effect of opioid-induced constipation (OIC), which could impact their overall treatment and progress. The prevalence of OIC in patients with chronic noncancer pain treated with opioid medications is reported to be 40%-80%; however, it is often not discussed with physicians. OIC has a high patient burden and may interfere with pain management because patients may stop or reduce the dose of their pain medication to avoid constipation. The incidence and burden of OIC are clinically recognized in older patients, and most studies examining the incidence and burden of OIC have focused on older patients. Therefore, data examining the burden of OIC in younger patients are limited and sparse, and prescribers may not be aware of the impact of OIC on younger patients. Previously, we conducted a prospective, longitudinal, observational cohort study to understand the burden of OIC in patients 18-85 years of age with chronic noncancer pain. The goal of the current post-hoc analysis of data from this study was to examine data from patients <65 years of age who participated in this study. We looked at 2 subgroups: participants <50 years of age and those 50-64 years of age to characterize the experience of OIC in younger patients and to identify potential age group differences on key study outcomes.

Method

This was a post-hoc analysis of data from a 24-week prospective, multinational, longitudinal observational cohort study of patients 18-85 years of age with chronic noncancer pain who had received at least 4 weeks of daily opioid therapy and who had experienced OIC in the past 2 weeks (NCT01928953). The study design has been described in detail and primary outcomes have been published previously (Coyne et al. Clinicoecon Outcomes Res 2014:6 269-281). Briefly, chronic pain patients on current opioid therapy were recruited from outpatient clinics in the United States, Canada, the United Kingdom, and Germany. At baseline and Weeks 2, 4, 6, 8, 12, 16, 20, and 24, patients answered questions regarding the number of spontaneous bowel movements (BMs), the frequency of their constipation symptoms, and the amount of bother associated with each symptom, as well as completed the Patient Assessment of Constipation-Symptoms (PAC-SYM), the Patient Assessment of Constipation-Quality of Life, the EuroQOL 5 Dimensions, and the Work Productivity and Activity Impairment Questionnaire-Specific Health Problem. The current analysis was limited to data from patients <50 years of age and patients 50-64 years of age. Descriptive statistics were used to describe the cohorts and impact of OIC.

Results

A total of 419 patients (age <50 years, n=184; age 50-64 years, n=235) were analyzed. No significant differences in sex, race, body mass index, and health rating existed between groups at baseline. Younger participants were more likely to be employed full time (29.9%) than older participants (14.5%). Overall 40.8% of younger participants were working full or part time, compared with 21.7% of older participants. A higher proportion of younger vs older participants reported chronic headache or migraine (22.3% vs 12.3%; P=0.0068) and a lower proportion reported osteoarthritis (12.0% vs 21.3%; P=0.0121). Older participants had a greater mean duration of chronic pain than younger participants (10.7±9.5 vs 7.7±7.1 years, respectively; P=0.0004) and opioid medication use (7.0±6.3 vs 5.0±4.8 vs years, respectively; P=0.0008). Constipation was experienced within the first week of opioid initiation by 32.8% and 35.9% of patients ages <50 and 50-64, respectively, and moderate interference with pain management was reported by 46.6% and 44.5%, respectively. In the PAC-SYM item and subscale analysis, the individual symptom severity ratings were similar between groups; the majority of participants generally reported moderate symptom severity on all items. OIC symptoms in general, such as abdominal/rectal symptoms and BM characteristics, appeared more bothersome for younger than for older participants. The younger patients were more likely than older patients to identify nausea, reflux, and headache as bothersome PAC-SYM symptoms they attribute to OIC. Across age groups, constipation affected the productivity of participants who worked to a similar extent, with an average of 5.0 (ages <50) and 4.3 hours (ages 50-64) of work missed in the past week due to constipation-associated problems. Percent overall work impairment was 30.9% and 25.1% for ages <50 and ages 50-64, respectively, and percent overall activity impairment was 39.9% and 37.7%, respectively, due to constipation.

Conclusions

The results of this post-hoc analysis confirm that younger patients (<50 years of age) experienced at least the same or more burden from OIC as older patients (50-64 years of age). The burden of OIC was consistent between age groups on a variety of patient outcomes, including frequency of constipation, time from opioid initiation to constipation, extent that constipation interfered with pain management, number of spontaneous BMs, symptom severity, and HRQL. In addition, younger patients were more likely to find symptoms, including abdominal and rectal symptoms, and BM characteristics more bothersome than older patients.

133 Assessing Outcomes of Educational Videos in Group Visits for Patients with Chronic Pain at an Academic Primary Care Clinic

Carrie Vogler^1,2, Stacy Sattovia², Laura Salazar², Tiffany Leung³, Albert Botchway²

¹Southern Illinois University Edwardsville School of Pharmacy, Edwardsville, IL, USA, ²Southern Illinois University School of Medicine, Springfield, IL, USA, ³Stanford University, Stanford, CA, USA

Purpose

Chronic pain is a major public health problem. The National Pain Strategy recognizes the need for pain self-management programs which provide patients with the opportunity to acquire knowledge about pain and to build skills and confidence to prevent, cope with, and reduce pain. When managing chronic pain, clinicians should use nonpharmacologic and nonopioid therapies when possible, establish realistic goals about pain and function with patients, and discuss with patients the benefits and risks of opioid therapy, according to The 2016 Reducing the Risks of Relief - The CDC Opioid-Prescribing Guideline. Multiple barriers may exist when implementing these potentially complex care recommendations, including low health literacy, multiple comorbid conditions, and additional social determinants of health.

A recent study demonstrated the effectiveness of group visits on behavior in patients with chronic pain. The primary goal of this intervention is to develop objective, evidence-based and patient-centered education materials, which included four patient-centered educational videos and facilitation guides to be used along with a group discussion led by a healthcare provider. Additionally, we performed an initial evaluation of this novel educational curriculum and format when implemented in structured group pain education classes targeted towards patients with chronic non-cancer pain. The primary aim of this project was to positively impact patients’ functional status. Secondary aims include improving patients’ knowledge about chronic pain and opioid therapy and opioid use.

Method

In this prospective cohort design, inclusion criteria were patients with a diagnosis of chronic non-cancer pain, age of at least 18 years old at the time of enrollment, and a primary care physician in Southern Illinois University’s General Internal Medicine or Family Medicine clinic between July 2014 to January 2016. Patients attended between one to four 90-minute unique educational classes about managing chronic pain. The free classes were offered twice monthly from July 2014 to January 2016 and were led by a healthcare provider.

The primary outcome, functional status, was measured by the Pain Intensity, Enjoyment of life, and General Activity (PEG) score and the Oswestry Disability Index. Evaluation of the appropriateness for using opioids was assessed using the Diagnosis, Intractability, Risk, Efficacy (DIRE) Score. To measure secondary outcomes, a five-question pre- and post-intervention knowledge assessment was administered and patterns of opioid use (in morphine equivalents) was assessed by patient chart review during the study period. This study was approved by the Institutional Review Board of Southern Illinois University School of Medicine.

Results

A total of 35 patient-classes were analyzed and 14 patients consented to chart review. Overall, the mean (± SD) age of the patients was 58 (± 11) years. Majority of the patients were female (77%), and the racial distribution was Caucasian (54%) and African-American (46%). A moderately positive correlation was observed between PEG and Oswestry Disability Index (r = 0.47, p<0.05), suggesting that patients with higher PEG scores also tended to have higher Oswestry scores.

Patients attended up to four classes. Knowledge improved after watching each of the four videos and participating in group discussion. A 14% point increase in knowledge before and after viewing the video was observed after viewing video 1 on “Talking to your doctor about Chronic Pain,” 32% increase for video 2 “Non-pharmacologic Treatment Options,” 17% increase for video 3 “Risks and Benefits of Opioid Therapy,” and 20% increase for video 4 “What is Pain?”

The amount of morphine equivalents used from the start of the study until the end of the study was analyzed. The median amount of morphine equivalents for patients (n=14) was 17.5mg (range 0-120mg) at the first study visit and it decreased to 12.5mg (range 0-110mg) at the last study visit. A Wilcoxon signed-rank test revealed that this difference was not statistically significant (z statistic=0.84, p=0.39). The most commonly used medication was a hydrocodone-acetaminophen combination product.

Conclusions

Our group designed a patient-centered educational intervention, including educational videos and group discussion, increased patient knowledge and was correlated with reduced opioid use, although without statistical significance. Study limitations included the short study period for chronic pain and a small study population. Further investigation is needed to determine the long term benefits of educational interventions and its impact on patient behavior.

134 Buprenorphine Transdermal System (Butrans) Utilization

Laura Wallace, Aditi Kadakia

Purdue Pharma L.P., Stamford, CT, USA

Purpose

In recent years, there has been a great deal of focus on safe opioid use and prescribing, including new state-based prescribing and training guidelines, FDA actions such as changes to safety information in immediate release (IR) opioid labeling, and introduction of the Centers for Disease Control and Prevention (CDC) opioid prescribing Guideline. In many of these materials, including the CDC Guideline, there is a stated preference for initial use of IR formulations, low morphine-equivalent doses (MED), and use of extended-release (ER) formulations only in opioid-tolerant patients. Buprenorphine is a partial opioid agonist with formulations approved for medication-assisted treatment and pain management; Butrans is an ER 7-day transdermal formulation of buprenorphine approved for the management of pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate.

With this in mind, this study was designed to fulfill two key objectives:

• To evaluate utilization patterns in patients initiating Butrans, a low-dose, ER 7-day transdermal formulation of buprenorphine, compared with patients prescribed other ER/LA opioids. Utilization variables of interest included the history of opioid use prior to the index prescription (to evaluate switching patterns and opioid tolerance); concomitant use of NSAIDS, immediate release (IR) opioids, and other pain treatments; and patient characteristics.

• To estimate the proportion and characteristics of patients prescribed Butrans who experienced decreases in their total opioid dose over time (expressed in MED to account for dose from both Butrans and other opioid treatments), perhaps as part of a dose step-down.

Method

This study was a retrospective cohort study using data from the Truven MarketScan Commercial database from 2011-2014. This database contains demographic, prescription, in- and out-patient diagnoses, and procedure data on over 65 million commercially-insured patients in the United States. The study population included individuals age 18 and older with a new dispensing for Butrans or comparator who had at least 6 months of insurance coverage prior to this prescription (as a baseline period to allow evaluation of prescription history and medical comorbidities) and 6 months of follow up after the index prescription (to allow monitoring of utilization trends). It was assumed that prescriptions were used as dispensed. Episodes of continuous use were calculated for the primary drug/drug group of interest using a 30-day allowable gap between subsequent prescriptions. Exposure was classified based on person time. Baseline opioid use (for various periods prior to the index prescription to evaluate different time frames for opioid tolerance, with 6 months set as the standard) was defined and quantified in morphine equivalent dosing units (MED) for the sum of all concomitantly prescribed opioids; the same procedure was used for the combination of Butrans or comparators and other concomitant opioid prescriptions after the index prescription. For Butrans, a MED conversion factor of 1 mcg/hour of patch for a day to 2.4 mg morphine was used. Descriptive statistics (percentages, mean, median, distribution) were calculated for all patient characteristics and utilization variables of interest.

Results

This study included 38,565 patients prescribed Butrans and 590,469 prescribed other ER/LA opioids who met the study inclusion criteria. Overall, 26% of patients initiating ER/LA opioids and 12% of patients initiating Butrans did not have a prescription for an IR opioid during the 6-month baseline period. In patients prescribed ER/LA opioids, 52% had a history of IR opioid prescriptions between 6 and 12 months prior to their index prescription compared to 77% for Butrans, indicating long-term use of IR opioids prior to starting either other ER/LA opioids or Butrans. For those who initiated either Butrans or other ER/LA opioids without a pre-existing IR opioid prescription, the majority initiated the lowest patch or tablet strength available. A large proportion of Butrans users (50%) were co-prescribed NSAIDS or other opioids and 4% received other pain treatments; for other ER/LA opioids, the proportion of patients with concomitant prescriptions varied substantially by drug.

Analyses of MED were performed for Butrans; the median dose was 51.3 units ME mgs/day from Butrans and other opioids, with a broad range in total MED. During the study period, the median dose obtained from Butrans was 24.0 units, which did not change substantially over the first 6 months of use (median at month 1 was 24.0 units, compared to 25.6 units at month 6, for those patients who continued to receive prescriptions). A large proportion (80.5%) of patients prescribed Butrans had concomitant prescriptions for other opioids, most for IR formulations; in these drugs, there was only a small average change in dose over time. Examining change in dose at a patient level, however, the study found that 22% of patients prescribed Butrans had a reduction in total MED from baseline until the end of study; the median reduction in MED was 25.5 units (mean 66).

Conclusions

Most patients initiating treatment with Butrans and other ER/LA opioids had a history of treatment with IR opioids, in line with guidelines suggesting that IR opioids should be first line therapy in patients with pain severe enough to require opioids. The majority of patients had a long history of IR opioid use before receiving ER formulations. Though on average the change in opioid daily dose for patients prescribed Butrans was modest, Butrans was used by a substantial subpopulation who reduced their total MED after starting Butrans, suggesting Butrans may be an option to step patients down from higher opioid doses.

135 Are immediate-release (IR) opioids really safer than extended-release (ER) opioids?: a case study using data on ER and IR oxycodone

Laura Wallace, Paul Coplan, Angela DeVeaugh-Geiss, Aditi Kadakia

Purdue Pharma L.P., Stamford, CT, USA

Purpose

Safe opioid prescribing is an important concern that is being addressed through multiple channels, including FDA actions (such as changes to safety information on IR opioid labels and the May 2016 Advisory Committee on the ER/LA opioid REMS), introduction of CDC opioid guidelines, and others, though published evidence on safety differences between ER and IR opioids is relatively weak. A study using North Carolina State Medical Examiner data compared the rate of opioid overdose fatalities for specific types of ER and IR opioids, and showed that IR oxycodone prescriptions at a 30 mg tablet strength had a 2-fold greater risk of opioid overdose than 30 to 80 mgs of ER oxycodone; for ER oxymorphone the risk was greater for ER than IR, while for ER morphine, this varied by dose. This suggests that IR opioids are not clearly safer with respect to overdose than ER opioids. To assess this further, we extended this research to another data set and other endpoints, including addiction/dependence and abuse in addition to overdose/poisoning.

Method

The Truven MarketScan healthcare claims database (containing data on approximately 100 million commercially-insured people in the US, from November 2010 - October 2013) was used to assess patterns in rates of diagnosed abuse, addiction/dependence, and overdose/poisoning and whether these patterns were consistent with the observed elevation in fatalities seen in the North Carolina State study. This retrospective cohort study focused on single-entity IR vs. ER oxycodone using descriptive statistics as well as a person-time approach with Poisson regression. Patients who had prescriptions for IR or ER oxycodone (but not both concomitantly) were included and events were classified based on ICD-9 codes. Events were classified by prior opioid use within preceding 29 days.

This study also compared the frequency of prescribing for IR and ER oxycodone over time using IMS healthcare National Prescription Audit database to provide context for the safety findings. Patients 18 to 64 years of age with incident or prevalent use of ER oxycodone or single-entity (SE) IR oxycodone were included as separate cohorts for each opioid.

Results

IR oxycodone is the most commonly prescribed single-entity Schedule II opioid, accounting for 7.7% of all Schedule II opioid prescriptions in the US, compared to 2.9% for ER oxycodone. Data on oxycodone utilization over time indicate that use of IR oxycodone for analgesia is extensive, widespread, and growing, while use of ER oxycodone has decreased, particularly for higher-dose tablets (though the average prescribed daily dose of ER oxycodone remains higher than IR).

In terms of prescription duration, IR oxycodone is typically prescribed for shorter durations than ER oxycodone, though there is a small (but substantial in terms of absolute numbers) population of patients who are prescribed IR opioids over the longer term. The rate of diagnosed abuse among patients dispensed IR single-entity oxycodone was higher than that for ER oxycodone patients (0.79 per 100 person-years [PY] of opioid use vs 0.31 per 100 PY). Similarly, the rates of diagnosed addiction/dependence and poisoning/overdose were higher among individuals dispensed IR single-entity oxycodone without other opioids vs. ER formulations (5.58 and 0.40 per 100 PY for IR oxycodone and 3.00 and 0.28 for ER, respectively).

Conclusions

Consistent with the study on overdose fatalities using data from the North Carolina Medical Examiner, rates of diagnosed abuse, addiction/dependence, and overdose/poisoning diagnoses were higher for IR oxycodone than for ER oxycodone, despite the higher average ER oxycodone dose and shorter duration of use for IR oxycodone. Practitioners should be thoughtful about the risks of all opioids, regardless of IR or ER formulation.

136 Management of the failed long-term intrathecal morphine therapy in two patients

Kehua Zhou^1,5, Yong Zhang², Gary G. Wang^3,4

¹Daemen College Physical Therapy Wound Care Clinic, Daemen College, Amherst, NY, USA, ²School of Public Health and Health Management, Chongqing Medical University, Chongqing, China, ³Academic Buffalonias in Physical Medicine and Rehabilitation, Buffalo, NY, USA, ⁴Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY, USA, ⁵Department of Health Care Studies, Daemen College, Amherst, NY, USA

Purpose

Intrathecal morphine therapy is the most common intrathecal drug therapy for the treatment of chronic non-cancer pain. However, to date, the use of intrathecal morphine therapy has been based on weak evidence with unknown long-term benefits. As an opioid medication, morphine causes constipation, nausea or vomiting, sedation, tolerance, dependence, addiction, and overdose. Additionally, as a surgical intervention, intrathecal morphine therapy involves high complication rates, repeat invasive procedures, high costs, and strict requirements for a large amount of technical support. Here we reported two successfully managed patients with intractable pain and significant complications while on long-term intrathecal morphine therapy. The management of these two cases included the successful morphine tapering and finally pump explantation and the simultaneous multidisciplinary approaches for pain control.

Method

Both patients had morphine pump implantation due to chronic consistent pain and multiple failed surgical operations in the cervical and lumbar spine. Two years after morphine pump implantation, both patients developed significant uncontrolled pain and compromised function of activities of daily living while on large dose intrathecal morphine therapy. Both patients had also tried multiple high dose short acting opioids without success. Additionally, patient A also had four episodes of small bowel obstruction while patient B was diagnosed with “dementia” and became completely dependent on all activities of daily living.

Results

Both patients received morphine tapering and finally morphine pump explantation with low dose methadone and multidisciplinary interventions for pain control. These multidisciplinary interventions include patient education and counseling, therapeutic exercises, antidepressants, clonidine, therapeutic modalities, and alternative and complementary medicine. Methadone was then tapered off after morphine pump explantation. Upon last office visits, the patients were successfully weaned off from morphine and was no longer taking any opioid medication while their pain was well-controlled. Additionally, both patients reported better and more participation in social activities and were independent for activities of daily living.

Conclusions

Opioid tapering and discontinuation should be considered in patients with intractable pain and/or significant complications. The successful simultaneous morphine tapering and then pump explantation with pain management in the two patients indicate that management of these patients requires a multidisciplinary or interdisciplinary approach. We thus propose the use of the interdisciplinary or multidisciplinary interventions before the intrathecal drug delivery therapy for the management of intractable non-cancer pain. We believe the use of short-acting opioids in patients with intrathecal morphine therapy should be limited and methadone use for baseline pain control in these patients are necessary in opioid tapering.

137 Management of intractable neuropathic pain in patients with severe plexopathy, a case series report

Yong Zhang¹, Kehua Zhou^2,3, Gary G. Wang^4,5

¹School of Public Health and Health Management, Chongqing Medical University, Chongqing, China, ²Daemen College Physical Therapy Wound Care Clinic, Daemen College, Amherst, NY, USA, ³Department of Health Care Studies, Daemen College, Amherst, NY, USA, ⁴Academic Buffalonias in Physical Medicine and Rehabilitation, Buffalo, NY, USA, ⁵Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY, USA

Purpose

The current opioid epidemic in the United States is associated with the widespread use of prescription opioids. Correspondingly, patients with intractable neuropathic pain caused by plexopathy are commonly treated with long term opioids. However, the use of opioids for neuropathic pain is controversial. Besides lacking long term benefits, the use of opioids in these patients carries numerous side effects. The purpose of this study is to explore the effectiveness of a multidisciplinary approach for pain management in patients with intractable neuropathic pain caused by plexopathy.

Method

We performed a retrospective chart review of patients with chronic intractable neuropathic pain in our outpatient office Academic Buffalonias in Physical Medicine and Rehabilitation in Buffalo, New York. Inclusion criteria includes: 1) diagnosis of plexopathy via electromyography (EMG), 2) pain caused by plexopathy with a duration of longer than 10 years, 3) consistent pain while on long term opioids (>3 months).

Results

From the year of 2010 to July 13, 2016, four out of 2452 patients met the inclusion criteria. They include 2 males and 2 females, were 42 to 77 years old, and had pain for 15, 17, 19 and 20 years with pain intensity of 9-10/10 upon initial examination. Two cases were diagnosed with brachial plexopathy and the other two were diagnosed as lumbosacral plexopathy. Upon initial visit at our clinic, the two brachial plexopathy patients had significant functional limitations at their affected hand, and the two lumbosacral plexopathy patients were wheel chair bound. Among the etiologies of plexopathy, one was caused by motor vehicle accidents, the other three were insidious onset or work injury related. All received multiple cervical or lumbosacral surgical operations for pain together with years of opioid use without success. All patients received multidisciplinary pain management approaches at our clinic. This comprehensive pain control regime includes: 1) discontinuation of all short acting narcotics; 2) physical treatments for pain, such as acupuncture, massage, and temperature modality; 3) nonsteroidal anti-inflammatory drugs (NSAIDs), acetaminophen, antidepressants, anesthetics and anticonvulsants as needed; 4) mood control and insomnia treatments with medication, diet therapy, nutrition, and physical exercises; 5) education of patients and their caregivers about pain and how to manage pain in at home. After treatments for several months to 2.5 years, all four patients were successfully weaned off all opioids, had pain well-controlled to 1-4/10, had better function and quality of life as indicated by better participation in daily activities. One patient with brachial plexopathy case returned to full time work and the other restarted the hobby of gardening; the two patient with lumbosacral plexopathy restarted community ambulation with a walker.

Conclusions

The multidisciplinary approach seems effective for the management of neuropathic pain caused by plexopathy. It is also an effective method for opioid tapering and discontinuation. The patients had less pain, better mood, and improved quality of life as indicated by better participation in activities after opioid tapering and discontinuation. Thus, we challenge the role of prolonged opioid use for patients with neuropathic pain caused by plexopathy.

138 A Literature Review and Perspectives in the Management of Chronic Non-Cancer Pain

Kehua Zhou^1,2, Yong Zhang³, Gary G. Wang^4,5

¹Daemen College Physical Therapy Wound Care Clinic, Daemen College, Amherst, NY, USA, ²Department of Health Care Studies, Daemen College, Amherst, NY, USA, ³School of Public Health and Health Management, Chongqing Medical University, Chongqing, China, ⁴Academic Buffalonias in Physical Medicine and Rehabilitation, Buffalo, NY, USA, ⁵Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY, USA

Purpose

Chronic non-cancer pain (CNCP) is defined as all chronic pain disorders outside of cancer pain or pain at the end of life. Besides depression or anxiety, patients with chronic pain also experience impaired sleep, diminished ability to perform normal activities of daily living, and severe impairment in the health-related quality of life (QOL). The current management of chronic pain requires an interdisciplinary approach with multiple pharmacological and nonpharmacological options. Although nonsteroidal anti-inflammatory drugs (NSAIDs), acetaminophen, antidepressants, anesthetics, anticonvulsants are commonly used, pain management of these patients usually inevitably involves the use of opioids. Nonetheless, besides death, the addiction and abuse of these opioids cause significant burden on the health, social, and economic welfare of the society, and the controversy regarding the use of opioid analgesics in CNCP continues. The purposes of this study was to review the understandings of pain, history of pain management, critical issues related to opioid use and various interventions in CNCP

Method

After the review, we proposed an algorithm for the management of CNCP. This algorithm underscores the logic sequence of CNCP interventions beginning with patient education, psychological, physical, and complementary and alternative interventions, followed by non-opioid pharmaceuticals including antidepressants and lastly surgery, device implantation and long-term opioids.

Results

CNCP is defined as the non-cancer pain that extends beyond the expected period of healing. Common types of CNCP include nociceptive and neuropathic pain. Symptoms of chronic pain include allodynia (pain to innocuous stimuli), hyperalgesia (abnormally increased pain response) and accessory nonsensory neurological and musculoskeletal symptoms, like weakness, fatigability, dystonia, and others. Chronic pain is a result of a complex and dynamic interaction among psychological, social, and physiological factors. Chronic pain results from the complex interaction between biopsychosocial factors and the nervous system which mainly involves ascending nociceptive pathways and descending modulatory pathways. Various pain management methods existed in the history; however, opioids seem to remain the mainstay treatment for CNCP during the past decades. Opioids may improve function and relieve pain in a short-term basis, but their role for long term pain management remains unclear. Besides the common side effects of constipation, nausea or vomiting, and sedation, additional adverse events of opioids include tolerance, dependence, addiction, and overdose which become more apparent and prevalent with long term opioid use. Although some evidence exists for short term pain control and quality of life, high complication rates, repeat procedures, and possible symptom worsening years after surgery remain concerns for surgical interventions. Side effects of non-opioid pharmaceutical interventions seems less than those of opioids. Pain management using physical therapy interventions, psychotherapy, and some alternative and complementary medicine has strong evidence support with minimal to no side effects.

Conclusions

The logical algorithm in the management of CNCP should underscore long-term benefits while meeting patients’ needs and decreasing side effects. Patient education, psychological intervention, physical methods, and NSAIDs should be recommended as the first line treatments; whereas surgery, device implantation and long-term opioids should be considered as the last resorts. Additionally, opioids may be temporarily used in acute pain exacerbations or other conditions that warrant temporary pain relief, and CAM methods may be advised for complicated and/or refractory CNCP.

139 Management of intractable pain in patients on prolonged methadone use: a study of two cases

Kehua Zhou^1,2, Yong Zhang³, Gary G. Wang^4,5

¹Daemen College Physical Therapy Wound Care Clinic, Daemen College, Amherst, NY, USA, ²Department of Health Care Studies, Daemen College, Amherst, NY, USA, ³School of Public Health and Health Management, Chongqing Medical University, Chongqing, China, ⁴Academic Buffalonias in Physical Medicine and Rehabilitation, Buffalo, NY, USA, ⁵Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY, USA

Purpose

Although an interdisciplinary approach with multiple pharmacological and nonpharmacological options are recommended, the management of chronic pain usually inevitably involves the use of opioids. However, opioids also cause hyperalgesia (abnormally increased pain response) and/or allodynia (pain to innocuous stimuli). As a result, in clinical practices, patients with intractable pain while on prolonged opioids are not uncommon. Methadone is also one of the commonly used opioid medications for chronic pain. Methadone maintenance treatment (MMT) is the traditional method and remains the mainstay treatment for opioid dependence, and methadone is also recommended for opioid tapering. Nevertheless, as an opioid medication, methadone carries similar side effects as other opioid medications, and pain is prevalent in patients on prolonged methadone use. Here we reported two successfully managed patients with intractable pain while on prolonged methadone use. The management of these two cases included the successful methadone weaning and the simultaneous multidisciplinary approaches for pain control.

Method

Patient A was a 62-year-old obese female who developed insidious onset lower back pain for longer than 10 years. Through the years, her pain over different body parts including the left lower back, leg, and foot had been treated with various interventions including oxycodone and fentanyl patch with minimal improvements. More than six years ago before visiting our office, the patient was put on methadone. Due to unsatisfactory pain control, the dosage of methadone gradually increased to 120mg/d while patient had become wheelchair bound and was unable to perform basic house hold chores because of pain (9/10). Other major symptoms included depression, day time sleepiness (was taking modafinil), insomnia, constipation. Patient B was a 42-year-old male heating and cooling mechanic with prolonged severe sharp pain (9/10) over the neck, shoulder, middle and lower back, and lower extremities. The pain started after motor vehicle accidents (MVAs) in 1991 (whiplash injury) and 1996 (cervical spine injury). Patient recovered well with conservative treatment after the first MVA; however, the patient was paralyzed for 10 days after the 2nd MVA and received cervical decompression and fusion at C5-7. After surgery, the patient was treated with multiple pain medications including oxycodone, hydrocodone, and morphine. With unsatisfactory pain control, the patient had been taking methadone for longer than 10 years. The dose of methadone slowly increased to 140mg/d. The patient eventually developed left side hand weakness and atrophy long QT syndrome and had been struggled with his full time work because of the intractable pain.

Results

Using multidisciplinary interventions of patient education and counseling, physical interventions, and non-opioid medications (mainly antidepressants and clonidine) by the same physician, pain in the two patients were well controlled with methadone discontinuation after longer than one year tapering. These multidisciplinary interventions target pain etiology, withdrawn symptoms, anxiety and depression, mood instability, and involves holistic therapeutic interventions.

Conclusions

Opioid tapering and discontinuation should be considered in patients with intractable pain. The successful simultaneous methadone weaning and pain management in the two patients required multidisciplinary interventions of patient education and counseling, physical exercises, alpha-2 adrenergics and antidepressants. Additional interventions include other physical methods. We thus propose the establishment of pain management centers incorporating interdisciplinary or multidisciplinary approaches for the management of intractable pain while upon prolonged opioid use. Although further research is needed, we hope our case study will provide some directions for clinicians in the management of similar cases.

140 Oral methylnaltrexone does not negatively impact analgesia in patients with opioid-induced constipation and chronic noncancer pain

Lynn Webster¹, Joseph Harper², Robert Israel²

¹PRA Health Sciences, Salt Lake City, UT, USA, ²Salix Pharmaceuticals, Raleigh, NC, USA

Purpose

An oral formulation of methylnaltrexone has been developed and has been reported to be efficacious and well tolerated for treatment of opioid-induced constipation (OIC). Because methylnaltrexone is a peripherally acting mu-opioid receptor antagonist, we determined the impact of oral methylnaltrexone on opioid analgesia.

Method

In a phase 3, randomized, double-blind, placebo-controlled trial, changes in pain intensity scores (rated from 0 = “no pain” to 10 = “worst possible pain”) and opioid use in adults with chronic pain of noncancer origin were evaluated. Patients taking ≥50 mg oral morphine equivalent dose (MED) daily (for ≥14 days before screening visit) with <3 rescue-free bowel movements per week received oral methylnaltrexone 150 mg/d (n=201), 300 mg/d (n=201), 450 mg/d (n=200), or placebo (n=201) once daily for 4 weeks followed by 8 weeks of oral methylnaltrexone as needed.

Results

The primary pain condition requiring opioid use was back pain reported by 68.2% of the 803 patients. Baseline pain intensity scores were similar among treatment groups (mean range, 6.2-6.4) and remained stable throughout the 4-week double-blind (mean range, 6.1-6.5) and 8-week “as needed” (mean range, 6.3-6.5) periods. Baseline mean MED was comparable between oral methylnaltrexone 150 mg (200.0 mg/d), methylnaltrexone 450 mg (218.0 mg/d), and placebo (209.7 mg/d), but was slightly higher in the oral methylnaltrexone 300-mg group (252.6 mg/d). Nonsignificant, minimal changes in mean MED were observed after 4 weeks of daily treatment (range, 214.5-235.6 mg/d) and at the end of the “as needed” phase (range, 202.4-234.9 mg/d). The percentage of patients who initiated new opioid medications during the 4-week, once-daily dosing period was generally similar among the oral methylnaltrexone 150-mg, 300-mg, and 450-mg groups (44.8%, 43.3%, and 35.0%, respectively), the oral methylnaltrexone combined group (41.0%), and the placebo group (39.8%). The most common newly initiated opioid medications during this once-daily period were oxycodone (oral methylnaltrexone groups combined, 14.6%; placebo, 12.4%) and morphine (oral methylnaltrexone combined, 10.1%; placebo, 7.0%).

Conclusions

In conclusion, oral methylnaltrexone does not elicit opioid withdrawal or interfere with opioid analgesia.

Supported by Salix Pharmaceuticals, Raleigh, NC, USA.

141 Oral methylnaltrexone is efficacious and well tolerated for the treatment of opioid-induced constipation in patients with chronic noncancer pain taking concomitant methadone

Lynn Webster¹, Joseph Harper², Robert Israel²

¹PRA Health Sciences, Salt Lake City, UT, USA, ²Salix Pharmaceuticals, Raleigh, NC, USA

Purpose

An oral formulation of methylnaltrexone has been developed and has been shown to be efficacious and well tolerated for the treatment of opioid-induced constipation (OIC) in patients with chronic noncancer pain. In this post hoc analysis of a randomized, double-blind, placebo-controlled, phase 3 trial, the safety and efficacy of oral methylnaltrexone for OIC were evaluated in a subgroup of patients with chronic noncancer pain receiving methadone.

Method

Adults with chronic noncancer pain for ≥2 months and OIC (confirmed during 14-day screening and defined as <3 rescue-free bowel movements [RFBMs] per week associated with ≥1 of the following: ≥25% of RFBMs categorized as type 1 or type 2 on the Bristol Stool Form Sale; straining during ≥25% of RFBMs; or ≥25% of RFBMs with a sensation of incomplete evacuation), who had been receiving opioid doses ≥50 mg/d of oral morphine equivalents for ≥14 days, were randomly assigned to receive oral methylnaltrexone (150 mg, 300 mg, or 450 mg) or placebo once daily (QD) for 4 weeks followed by 8 weeks of oral methylnaltrexone as needed. Double-blinding was maintained throughout the study. The primary endpoint was the mean percentage of dosing days that resulted in an RFBM within 4 hours of dosing during the 4-week QD dosing period. Key secondary endpoints included percentage of responders (ie, had ≥3 RFBMs/week, with an increase of ≥1 RFBM/week from baseline for at least 3 of the 4 weeks) during the QD period and the change in weekly number of RFBMs from baseline during the QD period.

Results

Overall, 120 patients reported concomitant use of methadone (oral methylnaltrexone: 150 mg [n=33], 300 mg [n=30], and 450 mg [n=31]; placebo [n=26]). Compared with placebo, a significantly greater mean percentage of dosing days resulted in an RFBM within 4 hours of dosing during the QD period with oral methylnaltrexone 300 mg (15.1% vs 33.6%; P < 0.01) and oral methylnaltrexone 450 mg (15.1% vs 38.2%; P < 0.001), but not oral methylnaltrexone 150 mg (15.1% vs 20.0%; P = 0.4). The percentage of responders was greater versus placebo for the 2 higher oral methylnaltrexone doses during the QD period (150 mg [39.4%]; 300 mg [60.0%]; 450 mg [67.7%]; placebo [38.5%]); however, differences were not statistically significant. Change from baseline in mean number of weekly RFBMs during weeks 1 to 4 (QD period) was significantly greater with oral methylnaltrexone 450 mg versus placebo (least-square mean [LSM] difference versus placebo, 1.2; P = 0.04); no significant differences were noted for oral methylnaltrexone 300 mg: LSM versus placebo 1.0 (P = 0.06) or for oral methylnaltrexone 150 mg: LSM vs placebo -0.2 (P = 0.7). In this methadone-treated population during the study (QD and as-needed periods), the most common adverse events (≥5% for all oral methylnaltrexone groups combined) were abdominal pain (19.1% for all oral methylnaltrexone groups combined vs 0% for placebo), nausea (12.8% vs 0%), diarrhea (8.5% vs 0%), hyperhidrosis (7.4% vs 0%), flatulence (6.4% vs 7.7%), and vomiting (5.3% vs 0%). Only 2 patients discontinued from the study because of adverse events: 1 patient treated with oral methylnaltrexone 300 mg discontinued because of upper abdominal pain, and 1 patient treated with oral methylnaltrexone 450 mg discontinued because of vertigo.

Conclusions

Although the numbers of patients in each treatment group were small (≤33 patients for each group), oral methylnaltrexone, particularly the 450-mg dose, was efficacious and well tolerated for treating OIC in patients with chronic noncancer pain receiving concomitant methadone.

Supported by Salix Pharmaceuticals, Raleigh, NC, USA.

142 Pharmacodynamic Effects From a Category 3 Intranasal Human Abuse Potential Study of an Abuse-Deterrent, Extended-Release Morphine Product Candidate in Nondependent, Recreational Opioid Users

Lynn R. Webster¹, Michael D. Smith¹, John Lawler², Karsten Lindhardt², Jeffrey M. Dayno²

¹PRA Health Sciences, Salt Lake City, UT, USA, ²Egalet Corporation, Wayne, PA, USA

Purpose

Extended-release (ER) opioids without abuse-deterrent (AD) properties have significant abuse potential because of vulnerability to manipulation that enables administration via alternative routes, including nasal insufflation. In a single-center, double-blind, double-dummy, 5-period crossover study, the abuse potential of a novel morphine AD, ER injection-molded tablet product candidate developed using proprietary Guardian^TM Technology (Egalet Corporation, Wayne, PA) was compared with a currently marketed, non-AD morphine ER product and placebo.

Method

Volunteers aged 18-55 years who were nondependent, recreational opioid users (experienced in nasal insufflation) received 60 mg doses of manipulated intranasal high-volume morphine-ADER injection-molded tablets (ADER-IMT), manipulated intranasal low-volume morphine- ADER-IMT, manipulated intranasal low-volume morphine ER, oral intact morphine- ADER-IMT, or placebo. Pharmacodynamic outcomes included peak effect (E_max) on the Overall Drug Liking Visual Analog Scale (VAS), Take Drug Again Assessment (TDAA) VAS, and Drug Effects Questionnaire (DEQ).

Results

46 subjects completed the study. Median E_max scores for Overall Drug Liking were lower (all P<0.0001) for intranasal high-volume (51.0), intranasal low-volume (50.5), and oral intact (59.0) morphine-ADER-IMT vs intranasal low-volume morphine ER (71.0). Median E_max scores for TDAA were lower (all treatment values P≤0.0003) for intranasal high-volume (50.0), intranasal low-volume (50.0), and oral intact (56.0) morphine-ADER-IMT vs intranasal low-volume morphine ER (73.0). Median E_max scores on the DEQ for “I can feel good drug effects” were lower (all P<0.0001) for intranasal high-volume (17.0), intranasal low-volume (4.5), and oral intact (32.5) morphine-ADER-IMT vs intranasal low-volume morphine ER (62.0). Adverse event profiles of morphine-ADER-IMT and morphine ER were similar and typical of morphine; no serious adverse events occurred.

Conclusions

These results demonstrated significantly reduced drug liking for morphine- ADER-IMT after manipulation and snorting, suggesting that this product candidate may have lower intranasal abuse potential compared with currently available non-AD formulations of ER morphine.

143 Pharmacologic Treatment Utilization among Patients with Trigeminal Neuralgia

Ying Liu, Brian Werneburg, Ning Wu, Deborah Hoffman

Biogen, Inc., Cambridge, MA, USA

Purpose

This study examined the real world utilization of select pharmacologic treatments for trigeminal neuralgia (TN) using a large US insurance claims database. TN is a syndrome of unilateral, paroxysmal, stabbing facial pain, originating from the trigeminal nerve. Anti-epileptic drug (AED) carbamazepine (CBZ) is the only approved treatment for TN. Clinical guidelines also recommend AED oxcarbazepine (OXC) as a first line treatment based on limited clinical trial evidence. In addition, a newer AED Gabapentin (GAB) is often used in clinical practice given its documented efficacy in epilepsy despite a lack of clinical trial evidence in TN. Opioids are not recommended for TN due to insufficient evidence and abuse risk. Pharmacologic treatment utilization pattern among patients with TN is not well understood because of its relatively low incidence.

Method

This study drew data from the TruvenHealth MarketScan® research database, which consists of insurance claims from more than 100 payers and health plans for over 50 million individuals who were enrolled in commercial or Medicare Managed Care plans from all 50 states in the United States. The study population included patients aged 18 years or older who were diagnosed with TN and were continuously enrolled during Jul 2014 to Jun 2015. Key utilization outcomes included the percentage of patients with use of the treatments of interest (i.e., CBZ, OXC, GAB, and Opioids), mean and distribution of the number of prescriptions and days of supply received in 12 months. Analyses were stratified by insurance type (commercial vs. Medicare) and whether the patients had a concurrent diagnosis of osteoarthritis [OA] or lower back pain [LBP] because these may often be treated with opioids. ​

Results

7008 (5028 commercial and 1980 Medicare) patients met the study criteria. Among the commercial population, the mean age was 50.6 years with 76.0% being female; 63.0% (3168) did not have an OA or LBP diagnosis. Patients were from all four US geographic regions (Northeast, North Central, South, and West) with the South having the greatest representation (45.5%), followed by Northeast (21.0%). During the 12 months study period, 86.8% of the commercial patients received at least one treatment of interest and 49.8% received two or more treatments of interest. The percentage that received at least one prescription of CBZ, OXC, GAB, and Opioids was 38.4%, 16.2%, 39.4%, and 58.8%, respectively, with those receiving 4 or more prescriptions of each treatment being 20.8%, 9.5%, 21.1%, and 26.3%, respectively. The annual mean number of prescriptions filled was 1.9 for CBZ, 0.8for OXC, 1.9 for GAB, and 3.6 for Opioids. 30.6%, 13.2%, 30.8%, and 27.6% of the patients, respectively, received more than 30 days of supply of CBZ, OXC, GAB, and opioids. Utilization pattern was similar among the 3168 commercial patients without an OA or LBP diagnosis except a lower proportion of patients receiving opioids (51.9%), a smaller annual mean number of opioid prescriptions (2.8), and a lower proportion of patients with more than 30 days of supply of opioids (20.5%). Utilization pattern was also similar among the 1980 Medicare patients who met the study criteria except relatively lower opioid utilization and higher CBZ utilization: 46.6% patients received opioids with an annual mean number of opioid prescriptions of 2.0; 45.7% patients received CBZ with an annual mean number of CBZ prescriptions of 2.4.

Conclusions

In clinical practice the majority of patients with TN received pharmacologic treatments. While CBZ is the only indicated treatment for TN, more than half of the patients received OXC or GAB despite limited (OXC) or no (GAB) evidence supporting their efficacy, safety, and tolerability. The prevalence and frequency of opioid use were high, even among patients who did not have concomitant diagnoses of pain conditions commonly treated with opioids. This finding warrants further investigation because opioids are not recommended for TN and are associated with abuse liability.

144 Local Administration of HTX-011, a Long-Acting Biochronomer-Based Bupivacaine/Meloxicam Combination, in Hernia Repair: Initial Results

Peter Winkle¹, Harold Minkowitz², Erol Onel³, Guy Boccia³, Alice Chu³, Neil Clendeninn³, Mary Rose Keller³, Tom Ottoboni³, Sanjay Patel³, Barry Quart³

¹Anaheim Clinical Research, Anaheim, CA, USA, ²Memorial Hermann Memorial City Medical Center, Houston, TX, USA, ³Heron Therapeutics, Inc., San Diego, CA, USA

Purpose

Although local anesthetics have been used for decades in the management of post-operative pain, a major limitation is that their duration of action is short (6 to 12 hours) compared to the pain from surgery (usually several days). This leads to the increased use of opioid analgesics for additional pain relief in the days following surgery, which has been linked to an increased risk of abuse and may directly contribute to the current opioid public health crisis. To address the unmet need of extended non-opioid post-operative pain control, Heron Therapeutics, Inc. is developing HTX-011: an extended release, fixed-dose combination product that contains both bupivacaine, a local anesthetic, and low-dose meloxicam, a nonsteroidal anti-inflammatory drug (NSAID), in a biochronomer-based delivery system. Initial data on the efficacy, safety and pharmacokinetics (PK) of two formulations of HTX-011 (400 mg HTX-011 and 400 mg HTX-011B) in hernia repair is presented.

Method

This is an ongoing Phase 2 randomized, controlled, multicenter study evaluating the efficacy and safety of HTX-011 in adult patients undergoing elective open inguinal hernia repair. The primary objective is to evaluate efficacy and duration of analgesia following administration of two doses of HTX-011, 200 mg and 400 mg, in two formulations, HTX-011 and HTX-011B, via 2 administration techniques, injection or instillation. This interim analysis is focused on the comparison of the 400 mg dose of the 2 formulations of HTX-011 to the saline placebo control. Institutional Review Board approval was obtained at all sites then patients provided written informed consent. Following administration of HTX-011 at the end of surgery, pain scores and opioid usage were recorded via patient diaries at pre-specified time points through the first 72 hours after study drug administration; safety data and PK were also studied.

Results

This analysis includes 29 subjects who received 400 mg HTX-011, 13 subjects who received 400 mg HTX-011B and 39 subjects who received normal saline placebo. The study achieved its primary endpoint; HTX-011 had a mean area under the curve of the numeric rating scale score for pain through 24 hours (AUC_0-24) of 87 compared to 114 for normal saline placebo (p=0.016) and HTX-011B had an AUC_0-24 of 82 compared to 114 for normal saline placebo (p=0.04). Regarding HTX-011A, mean bupivacaine plasma Cmax was 311 ng/mL, with a mean Tmax of 21 hours. Regarding HTX-011B compared to normal saline placebo: the AUC_0-72 was 205 vs 294, demonstrating a trend towards statistical significance (p=0.068). Opioid use through 72 hours decreased by 63% from 36.8 mg to 13.5 mg, while time to first opioid use increased from 1.6 hours to 10.2 hours. Mean bupivacaine plasma Cmax was 560 ng/mL (range 362-949 ng/mL), with a mean Tmax of 15 hours. No deaths, treatment-related serious adverse events, or adverse events leading to early termination were reported; the most common adverse events were constipation (18.0% of all HTX-011 subjects vs 18.4% of normal saline placebo subjects) and nausea (5.6% vs 14.3%, respectively).

Conclusions

Early results in this hernia study showed that HTX-011 provided pain relief with decreased opioid use over several days compared to placebo. No safety signals were noted, and the maximum PK showed a bupivacaine concentration level well below that suggested in the literature for central nervous system or cardiac toxicity (2000 ng/mL and 4000 ng/mL, respectively). HTX-011 is currently in phase 2 testing in humans in several surgical/anesthetic models. While further testing is necessary, this study suggests HTX-011 may be an exciting new therapeutic option in the fight against pain and opioid abuse.

145 Gaps in Consumer Awareness of NSAID Risks: Results of a Nationwide Survey

Bill McCarberg¹, Brett Snodgrass², Jeff Craw³, Claire Sheridan⁴, Melanie Lauterio⁴, Daniel Solorio⁴, Clarence Young⁴

¹School of Medicine, University of California San Diego, San Diego, CA, USA, ²LifeLinc Pain Center, Memphis, TN, USA, ³Kelton Global, New York, NY, USA, ⁴Iroko Pharmaceuticals, LLC, Philadelphia, PA, USA

Purpose

Non-steroidal anti-inflammatory drugs (NSAIDs) are effective treatment options for pain that are available over-the-counter (OTC) and by prescription. NSAIDs are associated with serious dose-related cardiovascular and gastrointestinal adverse events, leading the US FDA to issue a Public Health Advisory in 2005, recommending their use at the lowest effective dosage for the shortest duration. In 2015, the FDA strengthened the warning regarding the increased risk of cardiovascular thrombotic events. The purpose of this study was to understand US consumer perspectives on pain and the medications, including NSAIDs, that they typically use for their pain management and their awareness of NSAID risks.

Method

An online survey consisted of a sample of 1,056 demographically representative adults from the general US population, including 515 adults that reported experiencing pain at least twice a week or pain due to surgery.

Results

Seventy-seven percent (810/1056) of respondents had experienced pain at any time. Commonly reported types of pain included: general (acute; 467/1056; 44%), recurrent (240/1056; 23%) and chronic (171/1056; 16%) pain. Among respondents who had experienced pain, OTC pain medications (497/810; 61%) were used most frequently, while 34% (277/810) used a prescription pain medication. Nearly half of respondents (495/1056; 47%), including 40% (282/700) of respondents from the representative US sample who took any pain medication in the last 12 months, did not know what NSAIDs were. Many respondents who indicated some knowledge of NSAIDs failed to correctly identify common NSAIDs/NSAID-containing products such as: Excedrin (436/561; 78%), Advil (310/561; 55%), Aleve (301/561; 54%), naproxen (303/561; 54%), and ibuprofen (237/561; 42%).

Many prescription NSAID or OTC pain medicine users (351/608; 58%) acknowledged that there are risks associated with NSAIDs, but only 27% (166/608) were aware of FDA recommendations to use the lowest effective NSAID dose for the shortest duration. Over half (316/608; 52%) of respondents who had used NSAIDs or acetaminophen were not familiar with low-dose options. Among users of NSAID or OTC pain medicines, 33% (198/608) believed a high-dose treatment option was needed to treat their pain. After learning about FDA recommendations, 58% (351/608) of NSAID or OTC pain medicine users indicated they would talk to their doctor about pain medications.

Conclusions

Despite the widespread presence of pain and pain medication use, many consumers lack a basic understanding of prescription NSAIDs and OTC pain medications and their associated safety risks. This underscores the need for patient education regarding the safe use of NSAIDs.

146 A Novel Application of the Medication Event Monitoring System to Track Rescue Medication Use in a Phase 3 Efficacy Study of Low-dose SoluMatrix Meloxicam in Patients with Osteoarthritis Pain

Roy Altman¹, Allan Gibofsky², Alan Kivitz³, Daniel Solorio⁴, Claire Sheridan⁴, Clarence Young⁴

¹David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA, ²Hospital for Special Surgery, New York, NY, USA, ³Altoona Center for Clinical Research, Duncansville, PA, USA, ⁴Iroko Pharmaceuticals, LLC, Philadelphia, PA, USA

Purpose

Recording rescue medication use is a common challenge in arthritis studies. FDA guidance regarding osteoarthritis (OA) efficacy studies advises standardization of rescue medication usage and analysis. Pill counts provide data on total rescue medication use; self-reported diary cards provide information on timing of rescue medication events but are limited by issues such as missing data, back-filling, and forward-filling. Medication Event Monitoring Systems (MEMS^TM), which electronically record the date and time of each medication bottle opening, are generally considered the gold standard for measuring medication adherence (such as in patients with HIV, asthma, and hypertension) and represent a promising new approach for the collection of rescue medication data. To achieve a potentially more accurate measure of rescue medication events over time, we used MEMS to track the timing and patterns of rescue medication use in a 12-week, randomized, double-blind, placebo-controlled study of once-daily low-dose SoluMatrix® meloxicam 5 mg and 10 mg.

Method

Patients (N=403) ≥40 years with hip or knee OA pain were chronic users of non-steroidal anti-inflammatory drugs and/or acetaminophen. Patients were randomized to once-daily treatment with SoluMatrix meloxicam 5 mg, SoluMatrix meloxicam 10 mg, or placebo for 12 weeks. Rescue medication, acetaminophen 500 mg (4-6 h as needed), was permitted. All doses of rescue medication were provided in a bottle equipped with MEMS cap to collect data on the timing of rescue medication use. The MEMS caps electronically recorded the date and time of each bottle opening. Data were supplemented by clinic-based rescue medication accountability (ie, pill counts) performed at each study visit.

Results

Patients in the 10 mg (LS mean doses ± SE; 48.4 ± 7.13; P = 0.0013) and 5 mg (52.4 ± 6.61; P = 0.006) SoluMatrix meloxicam groups received less rescue medication over 12-weeks compared with placebo (73.2 ± 7.03). The mean daily rescue medication dosage was lowest in the 10 mg SoluMatrix meloxicam group (313.6 mg ± 45.50; P = 0.0024) followed by SoluMatrix meloxicam 5 mg (326.2 mg ± 41.36; P = 0.0046) and placebo (464.1 mg ± 43.73). The mean number of days with a rescue event was lowest in the 10 mg SoluMatrix meloxicam group (23.5 ± 2.34, P < 0.0001) followed by SoluMatrix meloxicam 5 mg (25.3 ± 2.16, P = 0.0007) and placebo (33.9 ± 2.36). A dose-related trend was observed in the average number of rescue events per patient over 12-weeks by time of day. The average number of rescue events per patient over 12-weeks by time of day was as follows (10 mg, 5 mg, and placebo, respectively): >24:00-6:00: 1.9, 2.1 and 3.9; >6:00-12:00: 7.6, 7.6 and 13.5; >12:00-18:00: 6.5, 7.2 and 12.0; and >18:00-24:00: 8.0, 10.1 and 15.3.

Conclusions

MEMS caps allowed for real-time capture of rescue events and provided important insight into rescue events relative to time of day over this 12-week study.

147 Efficacy and Safety of LY2951742 in a Randomized, Double-blind, Placebo-controlled, Dose-ranging Study in Patients with Migraine

Tina Oakes¹, Qi Zhang¹, Margaret Ferguson¹, Vladimir Skljarevski¹, James Martinez¹, Kirk Johnson¹, Aaron Schacht¹, Michael Due¹, Peter Goadsby^2,3, David Dodick⁴, Colin Zappone¹

¹Eli Lilly and Company, Indianapolis, IN, USA, ²King’s College of London, London, UK, ³University of California San Francisco, San Francisco, CA, USA, ⁴Mayo Clinic, Phoenix, AZ, USA

Purpose

The aim of Study I5Q-MC-CGAB was to evaluate the efficacy and safety of LY2951742, a monoclonal antibody to calcitonin gene-related peptide, in the prevention of migraine headache.

Method

We conducted a randomized, double-blind, placebo-controlled study at 40 centers in the USA. Patients 18-65 years of age with 4 to 14 migraine headache days (MHD) and at least 2 migraine attacks per month were randomized (2:1:1:1:1) to placebo or 1 of 4 LY2951742 dose groups (5, 50, 120, and 300 mg) given subcutaneously once monthly for 3 months. The primary objective was to assess whether at least one dose of LY2951742 was superior to placebo in the prevention of migraine headache. Superiority was defined as a ≥95% posterior probability of greater improvement for any LY2951742 dose compared with placebo, as measured by the mean change from baseline in the number of MHD in the last month of the treatment phase. Analyses were conducted on an intent-to-treat population (ClinicalTrials.gov, NCT02163993).

Results

Between July 24, 2014 and February 23, 2015, 410 patients were randomized to LY2951742 (n=273) or placebo (n=137). Compared with placebo, LY2951742 groups showed greater mean reduction in the number of MHD from baseline in the last month of the treatment phase, where the 120 mg dose of LY2951742 met the primary objective (-4.9 versus -3.6 days for the LY2951742 and the placebo groups, respectively, p=0.004). Two other LY2951742 doses were associated with statistically significantly greater improvement than placebo in the number of migraine headache days at Month 1 (for the 50-mg and 300-mg doses) and Month 2 (for the 300-mg dose). The overall change from baseline over 3 months in number of MHD was significant for both the 120 mg and the 300 mg dose groups (p=0.018 for both). Treatment- emergent adverse events (TEAE) that occurred more frequently with LY2951742 than with placebo during the 3-month treatment phase (those with an incidence of ≥5% of LY2951742 treated patients and greater than that for placebo) included injection site pain, upper respiratory tract infections, nasopharyngitis, dysmenorrhea, and nausea. Additional TEAEs that occurred during the 3-month post-treatment phase (those with an incidence of ≥2% of LY2951742 treated patients and greater than that for placebo), were back pain, sinusitis, bronchitis, urinary tract infection, influenza, neck pain, and pain in extremity.

Conclusions

These results provide evidence that monthly subcutaneous injection of LY2951742 is safe, well tolerated and efficacious in the prevention of migraine.

148 Efficacy of LY2951742 in Subgroups of Patients with Migraine of Different Frequency

Vladimir Skljarevski, James Martinez, Tina Oakes, Margaret Ferguson, Yoko Tanaka, Michael Due, Aaron Schacht, Colin Zappone

Eli Lilly and Company, Indianapolis, IN, USA

Purpose

In a recently reported study, LY2951742 significantly reduced the number of migraine headache days (MHD). The baseline frequency of MHD was 4 to 14 MDH per month. The objective of this study was to examine mean change in MHD from baseline in subgroups of patients based on their baseline monthly frequency of MHD.

Method

The post-hoc analyses were conducted using data from a double-blind, phase 2a study in adult patients randomly assigned to LY2951742 or placebo for 12 weeks (NCT01625988). The primary endpoint was the mean change in the number of MHD during the last 28-day period. Subgroups were examined based on the number of MHD during the baseline period from 5 (i.e. ≥ 5 vs. < 5 MHD) to 10. 50% response rates were also examined for the same subgroups.

Results

A total of 217 patients were randomized and received LY2951742 (n=107) or placebo (n=110). A difference from placebo was observed at month 3 from 1.5 days reduction from baseline in MHD for the ≥5 MHD subgroup and continued to increase to 2.4 days reduction from baseline in MHD for the ≥8 MHD subgroup. The increase in reduction of MHD failed to continue past the ≥8 MHD subgroup. Similarly, this trend was also observed when 50% response rates were examined for the same subgroups.

Conclusions

LY2951742 effect appeared maximized for the high-frequency subgroup (≥8 MHD).

149 Use of the Qualities of Pain Index (QPI) to demonstrate beneficial effects on affective and sensory qualities of pain

Bernard Schachtel¹, Elliot Hersh², John Zuniga³, Stephen Daniels⁴, Derek Muse⁵, Kyle Patrick⁴, Daniel Oreadi⁶, Jeffrey Bennett⁷, Emily Schachtel¹, Athena Papas⁶

¹Charleston Laboratories, Inc., Jupiter, FL, USA, ²University of Pennsylvania School of Dental Medicine, Philadelphia, PA, USA, ³UT Southwestern Medical Center, Dallas, TX, USA, ⁴Formerly with Premier Research Group, LLC, Durham, NC, USA, ⁵Jean Brown Research, Inc., Salt Lake City, UT, USA, ⁶Tufts School of Dental Medicine, Boston, MA, USA, ⁷Indiana University School of Dentistry, Indianapolis, IN, USA

Purpose

Evaluative endpoints are customarily the only endpoints measured in clinical trials to demonstrate analgesia; affective and sensory qualities (as described by Melzack and Torgerson)¹ are often overlooked by clinical investigators even though patients commonly describe their pain in these terms. To test the utility of these different types of pain measurement, we interviewed patients who had experienced oral surgery pain and other types of acute postoperative pain and developed the QPI, consisting of 2 affective descriptors (annoying, agonizing), 11 sensory descriptors (eg, throbbing, swollen, hot, stinging), and 2 evaluative terms (aching, hurting). Here we report the first use of this measurement instrument, testing the effects of an approved analgesic, hydrocodone 7.5 mg/acetaminophen 325 mg (HC/APAP) in a randomized, double-blind, placebo-controlled clinical trial.

Method

After surgical removal of at least 2 impacted molar teeth, patients rated pain intensity on a standard categorical pain intensity scale (PI-CAT) and on 0-10 Likert scales for the 15 sensory, affective, and evaluative qualities in the QPI. Patients with at least moderate pain intensity on the PI-CAT were randomized under double-blind conditions to 1 dose of HC/APAP or placebo. They rated their pain using the PI-CAT every 30 minutes over 6 hours and repeated the QPI scales at 6 hours.

Results

Two-hundred and five patients were randomized to HC/APAP and 50 patients were randomized to placebo. Analgesia was demonstrated on the PI-CAT for summed pain intensity differences (SPID₆) comparing HC/APAP to placebo (3.7 vs 0.7; p <0.001). Patients treated with HC/APAP reported significantly greater reductions in the QPI than placebo-treated patients (21.4 vs 5.6; p <0.001). Changes in the sensory and affective qualities of pain clearly identified analgesic efficacy by HC/APAP compared to placebo (both p <0.001), too.

Conclusions

We conclude that affective and sensory qualities of pain are sensitive indicators of analgesia which complement standard tools utilized to measure pain intensity. Because changes on the QPI scales were analyzed for all patients in this trial regardless of baseline severity, future research will examine the sensitivity of the QPI (in particular, its sensory and affective components) in patients with at least moderate severity of these qualitative expressions of pain.

¹Anesthes 1971;34:50-9.