PAINWeek Abstract Book 2018

1 Spinal Cord Stimulation at 10 kHz for the Treatment of Chronic Pain of the Upper Extremities: Results of a Prospective, Multicenter, Post-Market, Observational Study

Abram Burgher¹, Peter Kosek², Steven Surrett², Steven Rosen³, Todd Bromberg³, Ashish Gulve⁴, Anu Kansal⁴, Paul Wu⁵, Porter McRoberts⁵, Ashish Udeshi⁶, Michael Esposito⁶, Ami Shah⁷, Mona Maneshi⁷, Jeyakumar Subbaroyan⁷

¹Hope Research Institute, Pheonix, AZ, USA, ²Oregon Neurosurgery, Eugene, OR, USA, ³Delaware Valley Spine and Pain, Trevose, PA, USA, ⁴The James Cook University Hospital, Middlesbrough, UK, United Kingdom, ⁵Holy Cross Hospital Inc., Ft. Lauderdale, FL, USA, ⁶Florida Pain Institute, Merritt Island, FL, USA, ⁷Nevro Corp., Redwood City, CA, USA

Purpose

Chronic upper extremity pain (UEP) has several etiologies and can often be disabling to the patient. Current treatment options are either not supported by good evidence or offer only limited symptom relief. Traditional low-frequency spinal cord stimulation (SCS), although successful in treating UEP, is limited by variability in sensory paresthesia with movement of upper extremities. This can potentially limit the usage of therapy and/or compromise pain relief. High frequency SCS (HF-SCS) at 10 kHz, on the other hand, has been demonstrated to provide superior pain relief for back and leg pain without any paresthesia^1,2. Thus, the objective of this prospective, multi-center, post-market, observational study was to gain additional effectiveness data of HF-SCS at 10 kHz for the treatment of chronic, intractable pain of the upper extremities.

Methods

A total of 41 subjects, with significant upper extremity pain (Visual analog scale [VAS] ≥ 5 cm at baseline) underwent a trial phase of HF-SCS at 10 kHz at five centers in the United States and one center in the United Kingdom. The study was approved by the Institutional Review Board/Ethics Committee at each clinical site. Patient outcomes were assessed for a period of 12 months; and the primary outcome of the study was responder rate (percentage of patients experiencing ≥ 50% pain relief compared to baseline). Other assessments included Pain Disability Index (PDI), upper limb functioning (Disability of Arm, Shoulder and Hand; QuickDASH), Global Assessment of Functioning (GAF), 3-item pain and sleep questionnaire (PSQ3), and subject satisfaction. Interim 3-month data is reported as mean ± standard deviation.

Results

Thirty-seven subjects successfully completed the trial (90.2% trial success). Three subjects refused implant despite successful trial and thus 34 were permanently implanted with the Senza SCS system (Nevro Corp., Redwood City, CA). Three months after permanent device activation, the responder rates for upper limb, shoulder and neck pain were 82.8%, 76.0% and 68.2%, respectively, with mean VAS scores reducing from 7.9 ± 1.0 cm (n = 34) to 2.1 ± 2.4 cm (n = 29), 7.5 ± 2.5 cm (n = 34) to 2.4 ± 2.6 cm (n = 25) and 7.2 ± 2.8 cm (n = 34) to 2.8 ± 3.0 (n = 22), respectively.

Observed reduction in disability and improvement in functioning and sleep were also clinically meaningful; PDI reduced from 46.8 ± 12.2 (n = 34) to 21.7 ± 17.9 (n = 29), QuickDASH from 66.9 ± 15.3 (n = 34) to 36.29 ± 23.1 (n = 30), PSQ3 from 23.8 ± 5.3 (n = 34) to 11.4 ± 9.9 (n = 29) and GAF score increasing from 55.9 ± 11.9 (n = 34) to 73.2 ± 13.1 (n = 29). Moreover, 81% of the subjects were satisfied or very satisfied with the therapy at 3 months. None of the subjects reported experiencing stimulation-induced paresthesia. Six device/procedure related adverse events were reported (5 mild, 1 moderate).

Conclusions

HF-SCS at 10 kHz has previously demonstrated superior pain relief in the treatment of back and leg pain as compared to traditional low-frequency SCS. Preliminary results from this study suggest that this therapy can also provide sustained and substantial pain relief in subjects with UEP. Moreover, clinically meaningful improvement in functioning and sleep and decrease in disability were observed. These results thus validate that HF-SCS at 10 kHz is an effective and paresthesia-free treatment for chronic intractable pain of the upper extremities.

References

• Kapural L, Yu C, Doust MW, et al. Novel 10-kHz high-frequency therapy (HF10 Therapy) is superior to traditional low-frequency spinal cord stimulation for the treatment of chronic back and leg pain: the SENZA-RCT randomized controlled trial. Anesthesiology. 2015 Oct;123(4):851–860
   PubMed Web of Science ®Google Scholar
• Kapural L, Yu C, Doust MW, et al. Comparison of 10-kHz high-frequency and traditional low-frequency spinal cord stimulation for the treatment of chronic back and leg pain: 24-month results from a multicenter, randomized, controlled pivotal trial. Neurosurgery. 2016 Nov;79(5):667–677.
   PubMed Web of Science ®Google Scholar

2 Prescribing Trends for Hospice Patients with Amyotrophic Lateral Sclerosis

Adina Klingman, Leah Sera, Lynn McPherson

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

Purpose

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that commonly causes muscle weakness, muscle atrophy, dyspnea, dysphagia, and eventually respiratory failure. In 2014, approximately 6,500 people were admitted to hospice with a diagnosis of ALS.  The purpose of this study was to describe medication prescribing practices for hospice patients with a primary admitting diagnosis of ALS.

Methods

We conducted a retrospective review of a patient information database compiled by Seasons Hospice & Palliative Care. Patients were included if they were admitted to hospice care with a primary diagnosis of ALS, if they had at least one medication order, if they were admitted on or after 1 January 2016, and if they were discharged by death on or before 31 December 2016. The database included demographic and medication information, including medication name, dose, formulation, administration frequency, and dates of initiation and discontinuation. We used descriptive analysis to evaluate all information in this study. The investigational review board at the University of Maryland determined this study was not human subjects research.

Results

Of 18,040 patients admitted to hospice and discharged by death in 2018, fifty-nine patients had a primary admitting diagnosis of ALS and were included in the study. The 10 most commonly prescribed drugs were morphine sulfate (94.9% of patients), lorazepam (88.1%), acetaminophen (84.8%), hyoscyamine (69.5%), prochlorperazine (66.1%), bisacodyl (66.1%), haloperidol (64.4%), hydrocodone-acetaminophen (32.2%), riluzole (20.3%), and polyethylene glycol (18.6%). The most commonly prescribed pharmacological classes were opioid analgesics, non-opioid analgesics, benzodiazepines, laxatives, and antiemetics. Of note, riluzole, the only medication specifically approved to treat ALS at the time of this study, was prescribed to 20.3% of the patients. In addition, possibly due to the prevalence of dysphagia in ALS patients, approximately 50% of medication orders were for dosage forms other than solid oral formulations, including liquid oral formulations, topical, transdermal, rectal, injectable, sublingual, and inhaled medications.

Conclusions

Patients with advanced ALS have a high burden of symptoms requiring treatment with medications. Due to disease-related complications including dysphagia and muscle weakness a variety of formulations need to be used in order to safely and effectively treat patients. At the time of this study, riluzole was the only medication specifically approved to manage ALS. Riluzole is unlikely to provide therapeutic gain, and at this point in disease progression may actually be harmful. Continued use of riluzole also increases pill burden; however, both patients and prescribers may find discontinuing this medication difficult, even when the patient is hospice-appropriate. This study may be used to generate further research questions; develop education for hospice patients, caregivers, and clinicians; and inform formulary decisions and medication guidelines. 

3 Triptan Use and Discontinuation in a Representative Sample of Persons With Migraine: Results From Migraine in America Symptoms and Treatment (MAST) Study

Aftab Alam¹, Sagar Munjal¹, Michael Reed², Ryan Bostic², Dawn Buse³, Todd Schwedt⁴, David Dodick⁴, Richard Lipton^3,5,6

¹Promius Pharma, a subsidiary of Dr. Reddy’s Laboratories, Princeton, NJ, USA, ²Vedanta Research, Chapel Hill, NC, USA, ³Department of Neurology, Albert Einstein College of Medicine, Bronx, NY, USA, ⁴Department of Neurology, Mayo Clinic, Phoenix, AZ, USA, ⁵Montefiore Medical Center, Bronx, NY, USA, ⁶Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY, USA

Purpose

The MAST Study ascertained information about patterns of medication use in a sample of migraine patients. Triptans are indicated for the acute treatment of migraine and are available in oral, injectable, and nasal forms.  Patients try various forms of triptans in the course of their migraine journey. The objectives were to understand past and current triptan usage patterns and reasons for discontinuation for oral and non-oral triptans.

Methods

Respondents, ≥18 years, were recruited to the MAST Study from a nationwide online research panel, using stratified random sampling.  A validated screener used modified ICHD-3-beta criteria to identify individuals with migraine. Those included reported using prescription acute migraine medications, > 3 headache days in the previous 3 months, and > 1 headache day in the past 30 days. The survey questionnaire was designed to capture past and current triptan use and reasons for discontinuing triptan medications. For discontinuation due to side effect(s), respondents were asked to identify side effects from a pre-coded list. “Other” responses were allowed and coded. Descriptive results were provided for each route of triptan administration, but the groups are not mutually exclusive.

Results

Among respondents with migraine (15,133) the mean age was 43.1, 73% were women, 81% were Caucasian, and median monthly headache frequency was 3.3 days per month. 5,596 (37%) had ever used a triptan, 1,241 (8.2%) had used more than one route of administration, and 272 (1.8%) had used oral, nasal spray, and injectable forms. Among ever triptan users, 81.8% had used oral, 21.3% nasal spray and 19.0% injectable; 22.2% had used more than one route of triptan administration. 

Among current triptan users (2421, 15.9%) 84.7% use oral, 16.5% use nasal spray and 8.1% use injectable; 9.3% currently use more than one route of triptan administration. Discontinuation rates were highest for injectable (81.5%), then nasal sprays (66.5%), and then oral medications (55.2%). The most common reason for discontinuation was perceived lack of efficacy (“Did not work for me”; 38.4% oral, 39.8% nasal spray, 25.7% injectable) followed by “Side effects” (22.8% oral, 17% nasal spray, 20.6% injectable).  The most common side effect was “Dizziness” (37.4% oral, 29.4% nasal spray, 33.5% injectable) followed by nausea (30.7% oral, 32.4% nasal spray, 24.6% injectable) and fatigue (26.2% oral, 24.3% nasal spray, 21.2% injectable).

Conclusions

Although considered the gold-standard treatment for acute migraine, only 37% of survey respondents had used a triptan and 15.9% were current users. While oral treatment is most common, 11.5% (31.1% of ever triptan users, 40.4% of current triptan users) had ever used a non-oral formulation. Dizziness, nausea and fatigue were the most common reasons for discontinuation due to side effects. Among ever triptan users, 56.7% have discontinued use, indicating substantial unmet medical needs.

4 Assessment of Workplace Productivity Loss and Costs Associated with Opioid Abuse: A Retrospective Claims Analysis

Alan G White¹, Tim Spittle¹, Catherine Fernan¹, Elizabeth Marrett², Winghan Jacqueline Kwong², Louis F Rossiter³

¹Analysis Group, Inc., Boston, MA, USA, ²Daiichi Sankyo, Inc., Basking Ridge, NJ, USA, ³The College of William & Mary, Williamsburg, VA, USA

Purpose

Misuse and abuse of prescription opioids is a serious and costly public health concern affecting many sectors of society, but its effects also carry into the workplace. The objective of this analysis was to compare workplace productivity loss and indirect costs associated with opioid abuse from the perspective of employers.

Methods

A retrospective analysis of OptumHealth Care Solutions database was conducted. Continuously enrolled employer-based health plan members (12−64 years of age) with at least one medical claim for opioid abuse/dependence (ICD-9 codes 3040x, 3047x, 3055x, 96500, 96502, 96509) between Q1 2013 and Q3 2015 (index date) were matched with randomly selected but similar comparison health plan members having no medical claim for opioid abuse/dependence or heroin abuse (ICD-9 code 96501). Cohorts were propensity matched (1:1) on baseline demographic/clinical characteristics, availability of disability claims and absenteeism data, and baseline healthcare utilization/costs. Members were followed for 12 months after the index date to assess time missed from work while receiving disability benefits (disability claim absenteeism)  and time missed from work due to medical visits (medically-related absenteeism). Indirect cost associated with time lost from work was estimated using the average daily wage for plan members, adjusted to USD2016.

Results

A total of 101,752 members met study inclusion criteria of whom 8,561 had a medical claim associated with opioid abuse/dependence. Members with medical claims for opioid abuse/dependence (abusers) had significantly higher rates of non-opioid substance abuse (12% vs. 1.2%), psychiatric disorders (35.9% vs. 10.5%) and trauma (21.4% vs. 9.9%) compared to members with no medical claims for opioid abuse/dependence (non-abusers) (all p < 0.001) at baseline. Pain-related diagnoses (arthritis, back and neck pain, fibromyalgia, general and neuropathic pain) were also more frequent among members with diagnosed abuse (all p < 0.001).

Healthcare resource use and mean (standard deviation [SD]) total healthcare costs were higher among abusers versus non-abusers [$8,955 ($27,274) vs. $2,391 ($12,563), respectively]. After propensity matching (n = 2,311 per cohort), there were no statistically significant differences in baseline characteristics between groups, with the exception of the mean number of outpatient visits which was higher in the non-abuse cohort. The mean (SD) number of days missed due to disability claims (9.5 (40.9) vs. 5.6 (30.0); p < 0.001) and medically-related absenteeism (17.8 (18.5) vs. 10.0 (12.4); p < 0.001) was higher for abusers than non-abusers, resulting in higher mean (SD) indirect cost estimates of $7,777 ($13,948) per abuser compared with $5,162 ($12,988) per non-abusers (p < 0.001).

Conclusions

Results from this analysis suggest that opioid abuse and dependence was associated with significant work productivity loss and may pose a considerable cost to employers.

5 Implementation and Outcomes of a Pharmacist Led Pain E-Consult Service within the Veterans Affairs Population

Amanda Bellile¹, Michael Chandler¹, Lisa Dragic¹, Elizabeth Ryan Pritchard², Jacob Painter¹

¹Central Arkansas Veterans Healthcare System, Little Rock, AR, USA, ²University of Arkansas for Medical Sciences, Little Rock, AR, USA

Purpose

A pharmacist-led electronic consult (e-consult) service intended to assist providers with opioid tapering, opioid and non-opioid pharmacotherapy, and non-pharmacological recommendations at the Central Arkansas Veterans Healthcare System (CAVHS) is described.

Methods

A retrospective chart review was conducted on all pain e-consults completed from October 1, 2016 to September 30, 2017 by clinical pharmacy specialists in pain management. In this timeframe there were 347 total consults completed and reviewed. Metrics analyzed included the population baseline information as well as the type of recommendations given and the percentage of those accepted.

Results

There were 991 total recommendations made in the 347 e-consults reviewed. Of these, 585 (59%) were accepted and implemented by the requesting provider. There were 203 opioid taper recommendations and of those 171 were utilized (84.2%). Additionally, there were 19 requests for benzodiazepine taper recommendations with 18 being accepted (94.7%). Of the 315 recommendations for a non-opioid adjuvant to be added on to the patient’s current pain regimen, 95 were accepted by providers (30.2%).  Symptoms of depression increased from 4.9% of patients to 6.0% before and after the consult. Suicide ideation also increased from 0.6% to 2.6% before and after the consult.

Conclusions

An e-consult developed for chronic pain therapy recommendations in a Department of Veteran Affairs Healthcare System has been widely used and expanded with a variety of recommendations given and accepted by healthcare providers.

6 Identifying Opioid Use Disorder in Administrative Claims Data: Comparison of Medical Utilization by Diagnosis and Treatment Type

Amber Watson¹, David Simon¹, Meridith Blevins Peratikos^1,2, Elizabeth Ann Stringer¹

¹axialHealthcare, Nashville, TN, USA, ²Vanderbilt University Medical Center, Department of Biostatistics, Nashville, TN, USA

Purpose

Several methods may be utilized for identifying opioid use disorder (OUD) in administrative claims data. Multiple International Classification of Diseases, Tenth Revision (ICD-10) medical codes under the F11 heading for opioid related disorders may be documented. The Diagnostic and Statistical Manual of Mental Disorders (DSM-5) recommends practitioners utilize ICD-10 codes F11.10 (“opioid abuse, uncomplicated”) and F11.20 (“opioid dependence, uncomplicated”), with F11.20 indicating moderate to severe OUD. Additionally, patients may be identified as having OUD upon receipt of a prescription for buprenorphine for medication-assisted treatment (MAT). The method by which OUD is first recognized in administrative claims may be related to patient profiles and the nature of subsequent medical care that patients receive. The purpose of this analysis is to determine if differences exist in cost, receipt of buprenorphine for MAT, or continued receipt of non-MAT opioid prescriptions post-OUD diagnosis based on the method first utilized to document OUD in administrative claims data.

Methods

This is a retrospective study of administrative claims for commercial health coverage from Blue Health Intelligence™ in the United States.  Patients with at least 12 months of benefits eligibility before and after an initial OUD diagnosis were identified during October 2014 - March 2017. OUD was identified by one of two methods: 1) documentation of an initial prescription for buprenorphine for MAT with a duration of 3 or more days, or 2) documentation of an initial diagnosis of any F11 ICD-10 code (excluding F11.11 “opioid abuse, in remission” and F11.21 “opioid dependence, in remission”). Descriptive analyses included mean dollars spent per member per month (PMPM) and Kaplan-Meier estimates for receipt of buprenorphine for MAT one year following an OUD diagnosis. We further quantified the proportion of patients with prescription claims for a non-MAT opioid on a monthly basis.

Results

6,132 individuals were identified as having OUD. The majority (67.3%, N=4,128) received a diagnosis code of F11.20 (“opioid dependence, uncomplicated”). 6.4% (N=395) were identified as having OUD by receipt of an initial buprenorphine prescription for MAT with a duration of at least 3 days, while 26.2% (N=1,609) received an initial OUD diagnosis by any other applicable F11 ICD-10 code. On average, patients identified by the F11.20 code cost the health plan $4,636 PMPM during the month of diagnosis, while patients identified by any other F11 code cost $5,361 PMPM during the month of diagnosis. Patients identified by receipt of a buprenorphine prescription for MAT cost $1,430 PMPM during the month of diagnosis. PMPM cost 10 months post-OUD diagnosis decreased to $1,321 for the F11.20 group, $1,450 for the other F11 group, and $553 for patients identified by a buprenorphine MAT prescription.  Survival analysis revealed that the probability patients identified by the F11.20 diagnosis code would receive a prescription for buprenorphine for MAT within one year of diagnosis was 6.1% (95% CI: 5.4% - 6.9%), while the probability patients identified by other F11 ICD-10 codes would receive a buprenorphine MAT prescription was 7.5% (95% CI: 6.2% - 8.7%). A log-rank test indicated that the rate of subsequent buprenorphine MAT prescriptions were not significantly different between groups (p = 0.07). 59.7% of individuals diagnosed via the F11.20 code were prescribed non-MAT opioids in the diagnosis month, and 48% were prescribed non-MAT opioids after 10 months. For individuals diagnosed by any other F11 ICD-10 code, 44.7% were prescribed non-MAT opioids in the diagnosis month, and 34.5% were prescribed non-MAT opioids after 10 months. For individuals diagnosed via a buprenorphine MAT prescription, non-MAT opioids sharply decreased from 30.6% one month before diagnosis to 9.1%  in the diagnosis month, and 13.4% of patients were prescribed non-MAT opioids after 10 months.

Conclusions

Patients with OUD may have different member profiles based on the initial indicator of an OUD diagnosis in administrative claims data. This analysis supports that patients identified by the F11.20 ICD-10 diagnosis code represent a large portion of OUD diagnoses and are similar in healthcare utilization and treatment outcomes to patients identified by other applicable F11 ICD-10 codes. The proportion of these patients receiving non-MAT prescription opioids also does not markedly decrease after their diagnosis, while many individuals on buprenorphine for MAT discontinue non-MAT prescription opioids. Patients identified by any F11 code also have elevated healthcare costs compared to patients who immediately initiate a sustained buprenorphine MAT prescription, and comparative costs remain elevated at 10 months post-diagnosis. These sustained elevated costs are especially concerning given that only 6.5% of all patients identified by F11 ICD-10 diagnosis codes are prescribed buprenorphine for MAT within 12 months of diagnosis.

7 Human Factors Study of Subcutaneous Sumatriptan Delivery Devices: Performance, Comparative Ease of Use and Preference Among Migraine Patients Using Simulated Injections

Anthony Andre¹, Elimor Brand-Schieber², Margarita Ramirez¹, Sagar Munjal², Rajesh Kumar²

¹Interface Analysis Associates, Saratoga, CA, USA, ²Promius Pharma, a subsidiary of Dr. Reddy’s Laboratories, Princeton, NJ, USA

Purpose

A lower-dose sumatriptan (3 mg), 2-step, single-use autoinjector with a 29-gauge needle is available for the acute treatment of episodic migraine. Several other sumatriptan subcutaneous devices for the acute treatment of migraine patients are available that differ with respect to design and features. Ease of use is an important factor because functional impairment often characterizes migraine attacks for which patients use subcutaneous sumatriptan, such as migraines upon awakening, rapidly escalating migraine, and migraine with nausea and vomiting. Comparative device performance was assessed because patients experiencing a migraine attack may benefit from a simplified device design. Patient preference may impact adherence to optimal treatment. The objective of this human factors study using simulated injections was to compare migraine patient performance, ease of use, and preference for three sumatriptan subcutaneous autoinjectors: a 2-step, single-use autoinjector, a needle-free device, and a reloadable device.

Methods

Each subject performed 2 unaided, simulated injections with each of the 3 devices, which were presented in counterbalanced order. The first simulated injection occurred with no instruction or training. The second injection, occurred immediately after instruction and training. After the simulated injections were complete, participants were asked to rate the 3 devices on various subjective measures. Subject performance was assessed objectively on criteria of injection success/failure, time elapsed to start the injection, and performance errors. The primary endpoint was overall device preference using a 0 (lowest) to 100 (highest) visual analog scale. Secondary measures were obtained after each simulated injection on a 1 (not at all) to 7 (very) Likert-type scale.

Results

A total of 54 subjects participated and each subject performed two simulated injections with each of the three devices. Objective Measures: The 2 step, single-use autoinjector had a first injection, full-dose delivery success rate of 44.4%, higher than both the reloadable device (24.1%) and the needle-free device (3.7%). For the second injection, which occurred immediately after instruction and training, the differences in success rates for the 2 step, single-use autoinjector, (100%); the needle-free device, (90.7%); and the reloadable device, (74.1%) were not statistically significant. Mean time to start the first injection was significantly different among the 3 devices (P < 0.01). For the first injection, the number of errors overall with the 2 step, single-use autoinjector (3) was lower than the needle-free device (49) and the reloadable (44) device. For the second injection, there were no errors for the 2 step, single-use autoinjector, 3 errors for the needle-free device and 13 errors for the reloadable device. Subjective Measures: More subjects preferred the 2-step, single-use autoinjector (88.9%) than the needle-free (13.0%) or reloadable (1.9%) devices. Similarly higher subject ratings were found for the 2-step, single-use autoinjector on ease of use, intuitiveness, convenience, portability, control, and being least intimidating to use. Almost all subjects (96.3%) stated they would recommend the 2-step, single-use autoinjector to other migraine patients. The needle-free device would be recommended by 40.7% and the reloadable device by 24.1% of the subjects in this study. The 2 step, single-use autoinjector received the highest user acceptance rating of the three devices (2 step device 94.4%; needle-free device 70.4%; reloadable device 44.4%). No subject (0%) stated that they would not use the 2 step, single-use autoinjector, 25.6% said that they would not use the needle-free device and 44.4% said that they would not use the reloadable device.

Conclusions

In this human factors study, 54 migraineurs performed simulated injections to compare 3 sumatriptan subcutaneous delivery devices with and without training. In this study, migraine patients performing simulated injections were most successful, fastest, and had fewer errors in preparing and administering a full dose of medication with the 2 step, single-use autoinjector. The 2-step, single-use autoinjector was rated as easiest to use and most preferred compared with the needle-free and reloadable devices.

8 Pharmacokinetic Characterization and Dose Selection of a Novel Sumatriptan Nasal Spray Formulation, DFN-02

Arindam Pal¹, Anirudh Gautam², Sagar Munjal³

¹Dr. Reddy’s Laboratories Ltd., India, Bachupally, Telangana, India, ²Dr. Reddy’s Laboratories SA, Basel, Switzerland, ³Promius Pharma, a subsidiary of Dr. Reddy’s Laboratories, Princeton, NJ, USA

Purpose

A 3-way crossover study was conducted to evaluate the pharmacokinetics (PK) and dose-proportionality of 5 mg, 10 mg and 15 mg doses of intranasal sumatriptan (DFN-02) co-formulated with a permeation enhancer (Intravail® in 18 healthy adults. The objective was to determine which DFN-02 dose to develop for the acute treatment of migraine. The product development approach was based on bioequivalence to subcutaneous sumatriptan injection 6 mg.

Methods

This was an open label, 3-treatment, 3-sequence, randomized crossover study with 4 days washout separating each treatment. DFN-02 was supplied in opaque containers using Bespak monodose nasal spray devices (Consort Medical, UK). Devices delivered either 5 mg, 10 mg, or 15 mg of sumatriptan in 0.1 mL of an aqueous buffered solution with each spray. Subjects received single doses of DFN-02 treatments under fasting conditions. Blood sampling for estimating PK parameters was done for up to 24 hours after dosing. Dose proportionality between any two strengths was concluded if the 90% CI for log-transformed, dose-normalized C_max and AUC_0-∞was within 80% to 125%.

Results

With DFN-02, sumatriptan plasma levels peaked between 10 and 15 minutes post-dose, declining thereafter with a t_½ of about 2.5 hours. Mean C_max and AUC_0-∞ values increased linearly across doses. After DFN-02 doses of 5, 10, and 15 mg, mean C_max values were 40.7 ± 14.2, 71.2 ± 22.1, and 101.01 ± 49.5 ng/mL, and mean AUC_0-∞ values were was 49.89 ± 20.6, 87.06 ± 31.2 and 120.5 ± 53.3 ng*h/mL, respectively. The increase in sumatriptan bioavailability was less than dose-proportional between the DFN-02 doses studied.

Conclusions

Based on comparison of these results with the established PK of a 6 mg subcutaneous sumatriptan injection (median T_max of 12 minutes; mean C_max of  74 ± 15 ng/mL in the deltoid area of the arm, and 61 ± 15 ng/mL in the thigh),  the 10 mg dose of DFN-02 was selected as the does for further development. Overall, DFN-02 was well tolerated at dose levels of 5 mg to 15 mg, and no new safety concerns were identified. DFN-02 at a dose of 10 mg has been further developed for management of acute migraine.

9 Pharmacokinetics of Intranasal Sumatriptan With and Without the Effect of Intravail® (Dodecyl Maltoside or DDM)

Arindam Pal¹, Pradeep Singh Rawat¹, Anirudh Gautam², Sagar Munjal³

¹Dr. Reddy’s Laboratories Ltd., India, Bachupally, Telangana, India, ²Dr. Reddy’s Laboratories SA, Basel, Switzerland, ³Promius Pharma, a subsidiary of Dr. Reddy’s Laboratories, Princeton, NJ, USA

Purpose

The pharmacokinetics (PK) of intranasally dosed sumatriptan with and without Intravail® (dodecyl maltoside or DDM) was studied in rats to determine the effect on sumatriptan bioavailability. Clinical PK translation of the results of rat study was evaluated in a human PK study.   

Methods

A single-dose rat PK study compared a prototype DFN-02 (sumatriptan) nasal spray formulation containing 0.2% Intravail® and DFN-02-identical nasal spray formulation without Intravail® at a dose level of 5 mg/animal in 16 male and female rats divided in equal groups. Subsequently, a human PK study was conducted in 18 healthy adult males. This was a 3-way, randomized crossover study of  three treatments:  20 mg sumatriptan in a DFN-02 prototype formulation prepared with and without Intravail® and Imitrex® nasal spray. Blood sampling for the estimation of PK parameters was done prior to and up to 24 hours after dosing. A 4-day washout separated the dosing periods.

Results

In the rat study, compared to the nasal spray without Intravail®, DFN-02 nasal spray with Intravail® showed approximately 6-fold higher sumatriptan plasma peak concentration (C_max) and 1.5-fold higher total absorption (AUC). The time to peak sumatriptan concentration (t_max) was approximately 5 minutes for DFN-02 and approximately 15 minutes for the formulation without Intravail®. 

In the human study, mean±SD plasma sumatriptan C_max values for DFN-02 nasal spray, the formulation without Intravail®, and Imitrex were 60.5±31.9, 15.7±8.62 and 16.9±5.58 ng/mL, respectively and AUC_0-t values were 114±52.9, 77.4±39.2 and 81.1±26.1 ng.h/mL, respectively. Compared to the formulation without Intravail® and Imitrex nasal spray, the DFN-02 prototype formulation containing 0.2% Intravail® showed approximately 4-fold and 1.5-fold higher C_max and AUC values, respectively, which was analogous to the results of the rat study. Median t_max was much faster for the DFN-02 formulation (10 minutes) compared to the nasal spray without Intravail® (2 hours) and compared to Imitrex (1.25 hours).   

Conclusions

DFN-02, an intranasal sumatriptan plus permeation enhancer (Intravail^â), is being developed for the acute treatment of migraine. In these studies, median t_max was faster and both C_max and AUC were higher with the sumatriptan+permeation enhancer compared with sumatriptan alone and compared with Imitrex®. In both rats and healthy adult males, Intravail® increased both the rate and extent of systemic sumatriptan absorption following intranasal administration. 

10 Opioid Prescribing Practices in a Pediatric Hospital: Next Steps, Opioid Stewardship

Ashley Reid¹, Sarah Nickels¹, Ryan Mooney¹, Leigh Anne Bakel^1,2, Jennifer Reese^1,2, George Sam Wang^1,3, Patrick Fernandez¹, Sarah Hahn¹, Mark Erickson¹, Jan Grantham¹, Tod Bos¹, Alan Bielsky^1,2, Teresa Reyburn-Orne¹, Kristin Kalita¹

¹Children's Hospital Colorado, Aurora, CO, USA, ²University of Colorado School of Medicine, Aurora, CO, USA, ³University of ColoradoAnschutz Medical Campus, Aurora, CO, USA

Purpose

In 2017, Children’s Hospital Colorado finalized an opioid prescribing clinical pathway to reduce variation in discharge oral opioid prescribing for pediatric patients with acute pain. As part of the clinical pathway, the team launched an improvement project utilizing a pilot opioid stewardship team, reviewing opioid prescribing and consulting on inpatient acute pain therapy.  The objective was to evaluate the impact of this improvement project on the clinical pathway compliance and recommendation of a 7 day maximum for opioid prescribing among orthopedic surgery inpatients. 

Methods

A multi-disciplinary team conducted a retrospective review of prescribing data from January to December 2017. The team disseminated the clinical pathway to all care team members and orthopedic surgery providers, and implemented an EMR-based clinical decision support. The opioid prescribing team met with the orthopedic department in December 2017 and incorporated clinical decision support into discharge order sets in March 2018.  Post-implementation prescribing patterns were followed for 3 months.  Preliminary goal of 75% compliance with the recommended 7-day maximum for opioid prescriptions in post-op orthopedic patients with acute pain was determined. Balancing measures were reviewed through review of the prescription drug monitoring program (PDMP) to determine the need for additional prescriptions after discharge.

Results

From January to December 2017, 1375 orthopedic surgery patients were discharged with opioids. The median patient age was 10 years, 48% were female and 25% were Hispanic/Latino. Patients were discharged with an average of 7.35 days’ supply of opioids, with a range of 0.04 to 125 days prescribed. 56.2% (n = 772/1375) of discharge prescriptions followed the recommended 7-day maximum.   From March 2018 through June 2018, post-implementation and dissemination of the pathway, there was an increase in compliance of the 7 day maximum opioid prescription from 55.2% to 83.8%.  There was no statistically or clinically significant differences in the number of patients requiring additional prescriptions of opioids post intervention.

Conclusions

The opioid clinical pathway team reduced the average day supply of opioids at discharge for orthopedic surgery patients over a period of 3 months without compromising patient pain control.  The pathway incorporated innovative strategies for implementing and enforcing appropriate utilization of opioids for acute pain in pediatric patients. Future steps include (1) starting an opioid stewardship initiative to pilot interventions in the orthopedic population (2) expanding the pilot initiative to other areas of the hospital (3) building a Data Mart of opioid prescribing data; and (5) integrating Prescription Drug Monitoring Program data into the EHR.

11 Methylnaltrexone for the relief of constipation due to chronic opioid therapy in advanced illness patients with and without active cancer

Bruce Chamberlain¹, Michelle Rhiner², Neal E. Slatkin^3,4, Nancy Stambler⁵, Robert J. Israel⁴

¹Genesis Healthcare, Davenport, Iowa, USA, ²Loma Linda University Health, Loma Linda, California, USA, ³University of California Riverside, School of Medicine, Riverside, California, USA, ⁴Salix Pharmaceuticals, Bridgewater, New Jersey, USA, ⁵Progenics Pharmaceuticals, Inc, New York, New York, USA

Purpose

Opioid-induced constipation (OIC) occurs in up to 95% of advanced illness patients taking long-term opioids. Methylnaltrexone (MNTX) subcutaneous (SC) injection is approved for the treatment of OIC in adults with chronic noncancer pain and for the treatment of OIC in adults with advanced illness or with active cancer who require opioid dosage escalation for palliative care. This analysis describes data pooled by baseline characteristics and evaluates efficacy end points from 2 studies in which patients with advanced illness were stratified by those with and without active cancer.

Methods

This post hoc analysis included 2 multicenter, double-blind, randomized, placebo-controlled, phase 3 studies that included patients with advanced medical illness and OIC. In study 301, following IRB approval, patients were randomized to receive single SC injections of MNTX 0.15 mg/kg, MNTX 0.30 mg/kg (above the FDA approved dose of 0.15 mg/kg), or placebo. In study 302, following IRB approval, patients were randomized to receive SC injections of MNTX 0.15 mg/kg or placebo every other day for 2 weeks. Data from both studies were pooled and patients were stratified by those with active cancer and those without. Stratified populations were analyzed by baseline characteristics and the following efficacy end points: the proportion of patients with laxation within 4 hours after the first dose of study drug; time to rescue-free laxation (RFL); constipation distress scale; pain scores; opioid withdrawal; and Global Clinical Impression of Change (GCIC) ratings (by patient and clinician).

Results

The pooled population consisted of 123 patients in the placebo group (84 with cancer), 164 patients in the all MNTX group (119 with cancer), and 109 in the MNTX 0.15 mg/kg group (74 with cancer). Median baseline opioid use was higher in cancer patients versus noncancer patients (placebo: 192.5 mg/d vs 72.0 mg/d; all MNTX: 195.0 mg/d vs 90.0 mg/d; MNTX 0.15 mg/kg: 196.5 mg/d vs 90.0 mg/d). The mean number of laxatives used by patients in the placebo group was 2.5 (with cancer) vs 2.4 (without cancer), all MNTX: 2.1 vs 2.8, respectively, and in the MNTX 0.15 mg/kg: 2.2 vs 2.5, respectively. Baseline pain scores and percentages of patients with constipation distress of quite a bit or very much were similar among cancer patients (pain scores: placebo 3.1, all MNTX 3.2, MNTX 0.15 mg/kg 3.2; constipation distress: 57%, 61%, 61%, respectively) and noncancer patients (pain scores: 3.7, 3.7, 4.0; constipation distress: 59%, 53%, 57%, respectively). The median time to RFL for cancer patients was 1.8 hours for the MNTX 0.15 mg/kg group and 1.7 hours for the all MNTX group. The median time to RFL was 2.17 hours for the MNTX 0.15 mg/kg group and 1.5 hours for the all MNTX group in noncancer patients compared with a median time of >24 hours for the placebo group (P≤0.001 vs placebo). The MNTX groups had a higher percentage of patients with improvement in constipation distress (cancer: placebo 31%, all MNTX 60%, MNTX 0.15 mg/kg 57%; without cancer: 32%, 61%, 61%, respectively) and in GCIC ratings by clinicians (cancer: 27%, 59%, 61%; noncancer: 29%, 75%, 77%, respectively) and by patients (cancer: 28%, 61%, 64%; noncancer: 30%, 74%, 76%, respectively). There was no evidence of opioid withdrawal symptoms or worsening of pain in patients with or without cancer.

Conclusions

MNTX was effective at reducing time to rescue-free relaxation and other clinical signs of constipation in advanced illness patients with and without active cancer despite cancer patients being on higher opioid doses at baseline. MNTX treatment allowed patients to continue their opioid treatment while experiencing a reduction in constipation distress and without signs or symptoms of opioid withdrawal.

12 Comparison of effectgiveness of epidural analgesia and monitored anesthesia care for high-intensity focused ultrasound treatment of adenomyosis

Chang-Soon Lee, Jae Young Lee, Jee Youn Moon

Seoul National University Hospital, Seoul, Korea, Republic of

Purpose

High-intensity focused ultrasound (HIFU) treatment is a non-invasive, radiation-free, transcutaneous or transrectal thermodestructive procedure targeting internal tumors and lesions with concentrated ultrasound wave energy [1]. HIFU treatment has several advantages for indicative cancer patients, including being less invasive than surgical procedures, thereby permitting one-day intervention, and avoiding adverse reactions caused by chemotherapy or radiation therapy [2].

The HIFU treatment is usually painful because of localized tissue heating and is time-consuming. Therefore, an appropriate analgesic plan is imperative for patient tolerability and precise target ablation during the procedure, and for perioperative pain control [3]. Use of HIFU for treatment of intra-abdominal organs, such as the liver, pancreas, and kidney, requires general anesthesia or spinal anesthesia to control both visceral and somatic pain; ablation of uterine adenomyosis is less invasive, so monitored anesthesia care (MAC) or sedation have been utilized [3,4]. However, it is sometimes difficult to maintain a balance between pain control and spontaneous respiration during sedation. Moreover, patients under sedation may show disinhibited behavior or loss of coordination, which could result in serious complications during HIFU treatment [5]. Inability to self-report serious discomfort during deep sedation is another concern related to HIFU.

Epidural analgesia (EA) is one of the best analgesic modalities for several types of surgery [6,7]. It facilitates early recovery by reducing use of general anesthetics, stabilizes perioperative vital signs, and reduces postoperative complications [8]. Even though epidural spreading shows large individual differences [9], low thoracic EA using adequate volume of local anesthetics can provide consistent blockade of both somatic pain from abdominal wall and visceral pain from the uterus caused by HIFU ablation of adenomyosis without a concern of unintentional blockade to the area of sciatic nerve [10]. To the best of our knowledge, however, the safety and effectiveness of EA in HIFU treatment have not been examined.

In this study, EA was introduced in the middle of the study period following the radiologist’s request for better pain management. The aim of our study was to investigate the effectiveness of fluoroscopy-guided, sciatic nerve-sparing EA, followed by patient-controlled EA (PCEA) for HIFU treatment of uterine adenomyosis.

Methods

Seventy patients who participated in a prospective clinical trial of an USgHIFU combined with MRI to treat adenomyosis were reviewed, and 68 patients were included in this study. [31 subjects in EA group (screening number 40–70) and 37 subjects in MAC group (screening number 1–39)].

Using a C-arm fluoroscope, an 18-gauge epidural catheter combined with a custom metal guidewire was advanced through the epidural needle and the tip placed in the sagittal midline and the upper endplate of the T10 vertebral body. Contrast media was administered to confirm appropriate placement. Afterward, the patient was moved to the HIFU intervention room.

During the HIFU, in the MAC group, intravenous remifentanil was administered with target-controlled infusion (TCI) to a target site concentration (Tc) of 3 ng mL⁻¹ in accordance with patient discomfort. In the EA group, 6 mL of 0.5% ropivacaine was administered epidurally prior to HIFU treatment to achieve sensory block at the level of T9–12 and to preserve sensory and motor function of the lower extremities. When the patient complained of insufficient analgesia despite epidural sensory block, intravenous remifentanil was administered with TCI up to a Tc of 3 ng mL⁻¹. After HIFU, in the EA group, a PCEA device was connected using 0.125% ropivacaine 4 mL h⁻¹ via the epidural catheter. They went home and re-visited the hospital to remove their epidural catheters at 3 days. OTC analgesics were allowed as rescue analgesics in both groups.

The primary outcome was the frequency of patients reporting severe or very severe intraoperative pain (4 or 5) as evaluated on a self-reported 6-point scale ranging from 0 (no pain) to 5 (very severe pain) at discharge on the day of the procedure. Secondary outcomes included differences in dosages of intraoperative remifentanil and postprocedural fentanyl between the groups. The nonperfused volume (NPV) ratio was evaluated to assess the effectiveness of the HIFU procedure. For the safety assessment, all adverse events were observed.

Results

The frequency of patients reporting severe or very severe intraoperative pain – the primary outcome – was significantly lower in the EA group than in the MAC group [41.9% (n = 13) vs. 75.7% (n = 28); p = 0.006]. In addition, the percentage of patients suffering from moderate pain or more severe pain was also significantly lower in the EA group than in the MAC group [71.0% (n = 22) vs. 94.6% (n = 35); p = 0.017].

In terms of secondary outcomes, the total dosages of intraoperative remifentanil and postoperative fentanyl administered were significantly lower in than EA group than in the MAC group. Consumption of remifentanil was significantly lower in the EA group than in the MAC group during treatment (173 ± 189 µg vs. 426 ± 380 µg; p = 0.001), and use of fentanyl in the recovery room was significantly lower in the EA group than in the MAC group (52 ± 38 µg vs. 75 ± 44 µg; p = 0.030). Moreover, the NPV ratio was significantly higher in the EA group than in the MAC group (0.87 ± 0.18 vs. 0.43 ± 0.32; p < 0.001). Multivariable linear regression analysis was used to assess the correlation between clinical variables and the NPV ratio. EA was found to contribute to an improvement in NPV ratio [B = 0.41; 95% confidence interval (CI) = 0.29–0.53; p < 0.001].

All adverse events related with epidural analgesia were mild and transient, and had disappeared at the 5-d follow-up phone call. Moreover, thermal injury associated with the HIFU treatment was more frequent in the MAC group (54.1%) than in the EA group (22.6%) (p = 0.008). One severe complication (proctitis that required hospitalization) and three moderate complications (one instance of coccygeal pain and two cases burning in the rectus abdominis muscle with moderate pain and redness) occurred in the MAC group. One severe complication (gluteal burning required local flap surgery) and a moderate complication (right sciatic nerve injury with calf pain required oral medication for 6 months) occurred in the EA group.

Conclusions

In this study, the EA group reported a significantly lower frequency of severe or very severe pain intensity in association with the HIFU treatment of uterine adenomyosis (41.9% in the EA group vs. 75.7% in the MAC group; p = 0.006). The total dosages of intraoperative remifentanil and postoperative fentanyl administered were significantly lower in than EA group than in the MAC group (p = 0.001 and 0.030, respectively). When we adjusted variables using multivariable analysis, EA was the largest contributing factor to increased ablation ratio. Although adverse events related to EA occurred in some patients, they were mild and transient. The frequency of thermal injury after HIFU treatment was higher in the MAC group than in the EA group.

In this study, EA reduced pain and reduced analgesics requirements during HIFU treatment of adenomyosis over those observed with MAC. Furthermore, PCEA effectively reduced postprocedural pain. EA also increased NVP and reduced the frequency of thermal injury after HIFU. EA caused minor adverse events, but they were mild and transient. Based on our investigation, EA may be considered an effective analgesic option in the HIFU treatment of adenomyosis.

13 High Frequency Spinal Cord Stimulation (HF-SCS) at 10 kHz for the Treatment of Neuropathic Limb Pain from Painful Diabetic Neuropathy

Charles Argoff¹, Nagy Mekhail², Christian Nasr², Rod Taylor³, David Caraway⁴, Brad Gliner⁴, Jeyakumar Subbaroyan⁴, Lisa Brooks⁴

¹Albany Medical Center, Albany, NY, USA, ²Cleveland Clinic Foundationi, Cleveland, OH, USA, ³University of Exeter, Exeter Medical Center, UK, United Kingdom, ⁴Nevro Corp., Redwood City, CA, USA

Purpose

Data from the Centers for Disease Control and Prevention estimate there are currently 29 million people in the United States living with diabetes, and another 86 million with prediabetes, resulting in $245 billion in healthcare costs and lost productivity.¹ Approximately 20% of patients with diabetes will develop painful diabetic neuropathy (PDN),² a debilitating, progressive chronic pain condition that significantly impacts the patient’s quality of life. Neither pharmacological treatments nor low frequency spinal cord stimulation (SCS) has provided significant, long-term pain relief for PDN patients.^3,4,5 This study aims to document the value of HF-SCS at 10 kHz in addition to conventional medical management (CMM) compared with CMM alone.

Methods

In a prospective, multicenter, randomized controlled trial (SENZA-PDN), 216 subjects with PDN will be assigned 1:1 to receive HF-SCS at 10 kHz combined with CMM or CMM alone after appropriate institutional review board (IRB) approvals. Key inclusion criteria include: 1) diagnosis of PDN for at least 12 months, 2) average pain intensity of ≥ 5 cm (on a 0−10 cm visual analog scale [VAS]) in the lower limbs, and 3) an appropriate candidate for SCS. Key exclusion criteria include: 1) large and/or gangrenous ulcers, and 2) average pain intensity of ≥ 3 cm on VAS in the upper limbs. Along with pain VAS, neurological assessments, health-related quality of life, sleep quality, and patient satisfaction will be captured. Subject follow-up will last for 24 months.

Results

Enrollment in the SENZA-PDN study commenced in 2017 and is expected to be complete in 2019.

Conclusions

The SENZA-PDN study will be the largest RCT conducted using SCS in subjects with PDN. This prospective, multicenter study will determine whether HF-SCS at 10 kHz improves clinical outcomes, health-related quality of life, and is a cost-effective treatment for PDN.

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14 Abstract Title: Sex & Pain: We need to talk. Subtitle: Pilot project for our Fibromyalgia Wellness Program

Christine Stamatos¹, Tara Larsen²

¹Northwell Health Division of Rheumatology, Great Neck, NY, USA, ²Northwell Health Division of Rheumatology, Great Neck, NY, USA

Purpose

Background/Purpose:

Fibromyalgia (FM) is one of the most common chronic musculoskeletal pain disorders. It is estimated that FM affects approximately 5 million adults in the United States (Jones et al., 2015). This condition is characterized by pain and tenderness along with other symptoms such as fatigue, depression, anxiety, and dyscognition. Together these symptoms can affect a person’s quality of life substantially. Individuals suffering from chronic pain can experience substantial barriers in their personal relationships. FM has been suggested to effect, “desire, pleasure, pain and intimate relationships,” (Kayhan et al., 2016). Sexual life is an important factor that contributes to one’s quality of life and should not be overlooked. There has been a lack of studies focusing on sexual dysfunction in the United States’ FM population. Understanding the association between sexual dysfunction and FM is of importance for the development of appropriate treatment strategies that focus on the overall person from a multidisciplinary perspective. Evaluating and treating sexual dysfunction in FM is often neglected and masked by other more pressing ailments that garner attention in the standard medical visit.  In the creation of our Fibromyalgia Wellness Center (FMWC), we seek to understand all aspects of a patient’s wellbeing and function through a complex intake that includes assessment of not only medical, but psychosocial wellbeing in an effort to provide individualized, comprehensive care for patients suffering from this complex condition. We present here results of our sexual function assessment.

Primary Aim: Evaluate sexual functioning in women with FM and to determine what domains (Desire Frequency & Interest, Pleasure, Arousal and Orgasm Completion) are most significantly impacted.

Methods

All participants of the FMWC at Northwell Health Division of Rheumatology were asked to complete the Changes in Sexual Functioning Questionnaire (CSFQ) as a part of their intake for our FMWC shared medical visit.  The shared medical visit is a 3 hour session which includes a history and physical by one of our FM expert providers, a comprehensive pharmacotherapeutic evaluation with a clinical pharmacist, a one hour didactic session on FM pathophysiology and treatment principles, followed by a one hour support group led by a clinical social worker.  The support group is open to all participants in the FMWC and is available twice monthly on an ongoing basis across the year. To date each session has had 4−6 patients with a goal of 6−8 patients per session in the future.  The CSFQ assesses sexual function across five domains: pleasure, desire/frequency, arousal/ excitement, desire/ interest and orgasm/ completion.  Additional assessments using the Polysymptomatic Distress Scale (PDS) and Patient Health Questionnaire-9 Depression (PHQ-9) were completed by all participants. 

Results

Sixteen FMWC shared medical visits were conducted from Oct 2017-May 2018 (N = 42).  All subjects had an existing diagnosis of FM and were referred to the program by their rheumatologist. A total of 20 FM females completed the CSFQ form.  Among the 20 women who answered the CSFQ, 100% of subjects were impaired across all measures with pleasure being the most frequently impaired domain. Fifty percent of subjects were significantly impaired across all the sexual domains. Ninety percent of all participants were also positive for depression based on the PHQ-9 and 97% reported fatigue as moderate to severe.   Overall 73% were Caucasian, 19.6% African American, remainder other. As with other studies of FM these patients were well educated with more than 60% having a college degree or higher.

Conclusions

This pilot study highlights the issue of sexual dysfunction in women with FM. Though the sample size is small and caution must be considered in generalizing these results, it does serve to inform the need for continued assessment of this important domain if we are to deliver a truly comprehensive wellness program for FM patients. Given the importance that a healthy sex life has on a patient’s quality of life, recognition of this type of dysfunction must be acknowledged and discussed. The discussion of sexual behavior and health is often a taboo subject and is too often overlooked as an essential part of FM care. These results provide evidence we need to continue to assess and discuss issues related to sexual function in order to achieve optimal wellness for patients suffering from FM syndrome.  As a result of this data, we will not only continue to assess sexual function in all of our patients but we will also be creating an educational program for patients in our monthly lecture series to discuss specific details and solutions for sexual health.  Additionally, this has been incorporated into routine discussions at our bimonthly support group offered to all participants in our FMWC.

15 Category 1 Assessment: Vaping of Abuse Deterrent Opioid Formulations Category 1 Assessment: Vaping of Abuse Deterrent Opioid Formulations

Christopher Altomare¹, Paul Fort¹, Anthony Costantino¹, August Buchalter², Edward Cone²

¹Drugscan, Horsham, PA, USA, ²Pinney Associates, Bethesda, MD, USA

Purpose

The use of e-cigarettes, also called vaping and more recently “JUULing”, is a well documented method used to administer nicotine and cannabis products.

In 2014, teenage use of vaping devices surpassed that of smoked cigarettes and its prevelance continues to increase across all age groups. Although ecigarettes are not designed with the intent to administer opioid drug products the success of newer e-cigarettes brands and technologies in administering alternative cannabis forms such as herbal, wax and concentrates, indicates other material forms, like ground opioid formulations, might be possible.

Some laboratory studies with rodents have reported success with other drug classes, e.g., methamphetamine, MDPV, alpha-PVP. Online drug tampering forums mention vaping marketed opioid formulations however, the success of such attemps is mostly undetermined. Questions have been posed by FDA Advisory Committee members regarding the potential for vaping opioids. To address the feasibility of e-cigarette devices to successfully deliver opioids, a laboratory model was developed and tested with pure oxycodone and a marketed abuse-deterrent formulation.

Methods

A laboratory model was assembled that consisted of a commercial vaping device connected to an air vacuum sampling bag and flow meter control. A preliminary optimization and verification procedure was conducted using pure oxycodone hydrochloride (HCl) diluted to a total volume of 2 mL with 50:50 propylene glycol/vegetable glycerin; for a final concetration of 10 mg/mL in the vaping concentrate. The vaping device was set to “VW” mode and 100 watts; causing the device to set the maximum watts and automatically apply voltage to avoid damage to the heating coil. The flow rate of air passing through the device was allowed to equilibrate to a range of 1800 – 2500 mL/min, typical of a human inhalation rate. Once the flow rate reached an acceptable range, the vaping device was turned on for 5 seconds, off for 2 seconds, and then back on for 5 more seconds. The vacuum flow was left on until the vapor ceased and then the tubing was immediately introduced into a collection solvent, thus rinsing the inside of the vapor tubing and collecting the oxycodone residue in the air sampling bag. The contents of the bag were analyzed by LC-MS/MS for total oxycodone recovery.

Experiments involving an abuse-deterrent tablet required a 3-5 minute thermal extraction process to yield a concentrated solution of oxycodone, without significant tablet excipient and gelling. The resulting tablet extract was diluted to a total volume of 2 mL with 50:50 propylene glycol/vegetable glycerin; for a final concetration of approximately 10 mg/mL. The vaping procedure optimized using pure oxycodone HCl was applied to the formulation derived vaping concentrate.

Results

Results from optimization and verification of the laboratory model showed vaporization of oxycodone HCl in the range of 1.6 – 2.2 mg. When the API measurement is taken in context of the total volume of vaping concentrate vaped, mass difference pre versus post vaping, approximately 57−63% (efficiency) of the oxycodone HCl was successfully transferred to the collection bag. The method was very consistent as shown by a CV < 6%. The same process with the abuse-deterrent formulation showed similar results in the range of 50−60% efficiency.

Conclusions

Based on this study, a laboratory model and process was developed that successfully utilized a commercial vaporizer to deliver oxycodone vapor (aerosol) derived from a marketed abuse-deterrent formulation in amounts likely to produce pharmacological effects. Given the trending popularity of vaping as a means of drug delivery (nicotine, cannabis), it is feasible that this laboratory method will be realized in the “real-world” to successfully administer and conceal opioid abuse.

16 Patient and Clinician Perspectives on the Unmet Needs and Stigma of Migraine

Daniel Kantor¹, Kayleen Hilyer², Merle L. Diamond³, Marissa Boruchow⁴, Srinivas Nalamachu⁵

¹Florida Atlantic University, Boca Raton, FL, USA, ²Erie, PA, USA, ³Diamond Headache Clinic, Chicago, IL, USA, ⁴New York, NY, USA, ⁵Mid America PolyClinic, Overland Park, KS, USA

Purpose

Migraine is a disabling illness impacting approximately 39 million Americans.¹ Episodic migraine (EM, defined as <15 headache days/month) is most common, and >4 million patients have chronic migraine (CM, defined as ≥15 headache days/month).¹ Migraine presents as a continuum over time and a number of patients with EM will develop CM.² Both migraine types impart a high burden to patients and often come with significant stigma affecting patients’ quality of life.³ Effective communication between patients and healthcare professionals is key to meeting the needs of patients with migraine. We therefore sought insights from patients with EM and CM, and clinicians to further elucidate unmet needs and stigma associated with migraine.

Methods

In-depth telephone interviews were conducted with two patient authors, KH and MB, regarding their experiences with CM and EM, respectively. The clinician’s perspective was provided by a headache specialist (MD), a pain specialist (SN), and a neurologist (DK). MEDLINE searches identified scientific journal articles that supported the patients’ and clinicians’ statements.

Results

CM Patient: KH described CM as an invisible disease, and said the public often uses the term “migraine” interchangeably with “headache”, which underestimates the impact of migraine on patients’ lives. KH felt it was difficult to convey CM symptom severity and disability, and spoke of the stigma and shame associated with it, because of inability to work. KH’s current healthcare team are involved in all aspects of her care and listen to her needs. She visits the ER when her medication does not control her migraines. KH considers herself both a migraine and a pain patient because she has multiple pain conditions. She does not use opioids for pain control and is concerned about medication overuse.

EM Patient: MB has also experienced misunderstanding by the public and healthcare professionals (HCPs) regarding severity and impact of her migraines and expressed frustration at disruption of daily life associated with the unpredictable nature of her migraines. She is currently receiving effective treatment in the care of a headache specialist neurologist, who is communicative and responsive to her needs (although she waited several months to be seen due to a long waiting list).

Both patients had tried many treatment types before settling on their current therapies. They spoke of trying to make plans, and the worry about possible disruption due to migraine. These experiences are supported by studies showing that many patients feel that HCPs do not always appreciate the true burden of migraine,^4,5 and dialogues between patients and HCPs may frequently fail to include elements necessary for diagnosis or therapy.⁶ Good medical communication between patients and their clinicians is crucial for an accurate diagnosis, developing an effective treatment plan, and improving patient satisfaction.⁷

Pain Specialist: SN expressed concern about the impact of headaches on the patient’s ability to work, their sleep quality and anxiety, as well as the effect on their family life. He is also worried about opioid usage in patients suffering from acute headache episodes.

Headache Specialist: MD has concerns regarding migraine control and the plan for treating acute attacks. A good plan for treating acute migraine attacks would allow the patient to continue to function.

Neurologist: DK said that stigma associated with “invisible” diseases like migraine is pervasive, and affects family members, public perception, and HCPs. There isn't an easily visualized objective measure to track patients, thus patients’ input, and trust between patients and HCPs, are paramount.

Conclusions

Patients with EM and CM face misunderstanding both in terms of the disability associated with migraines, and the impact of migraines on their ability to work and their social interactions. Migraine patients’ incapacity and needs can often be underestimated by HCPs, family members, co-workers and members of the public encountered in daily life, and can lead to migraine stigma for both EM and CM patients. Each patient has unique and valuable insights into the impact of migraine on their quality of life. Opportunities to improve communication between patients and HCPs, and to increase the patient’s perspective and participation in diagnosis and treatment of their disease, should ultimately improve outcomes.

Study sponsor: Novartis Pharmaceuticals Corporation

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17 Effect of eluxadoline on abdominal pain in adults with irritable bowel syndrome with diarrhea who report inadequate control of symptoms with previous use of loperamide

Darren M. Brenner¹, Catherine Gutman², Steven Elmes², Brooks D. Cash³

¹Northwestern University Feinberg School of Medicine, Chicago, IL, USA, ²Allergan plc, Madison, NJ, USA, ³University of Texas Health Science Center, Houston, TX, USA

Purpose

Irritable bowel syndrome with diarrhea (IBS-D) is a chronic gastrointestinal disorder characterized by recurrent abdominal pain and diarrhea.  Eluxadoline is a mixed µ- and κ-opioid receptor agonist and δ-opioid receptor antagonist approved for the treatment of IBS-D in adults.  The purpose of this analysis was to examine the efficacy of eluxadoline for treating abdominal pain in adults with IBS-D reporting inadequate symptom control with previous use of loperamide, an over-the-counter µ-opioid receptor agonist.

Methods

This Phase 4 multicenter, placebo-controlled, double-blind study enrolled adults with IBS-D who reported inadequate symptom control with loperamide in the previous 12 months.  Patients were randomized to oral eluxadoline (100 mg twice daily) or placebo for 12 weeks (RELIEF; NCT02959983).  Using a daily electronic diary, patients recorded their IBS-D symptoms over the previous 24 hours, including worst abdominal pain (WAP) [reported on a scale of 0 to 10, with 0 corresponding to no pain and 10 corresponding to the worst pain imaginable] and stool consistency.  The primary endpoint was a composite response based on simultaneous daily improvement from baseline in WAP and stool consistency for ≥50% of days over Weeks 1–12.  Baseline pain score was calculated as an average of the WAP score over the week before randomization.  Proportions of patients achieving ≥30%, ≥40%, and ≥50% improvements in WAP score from baseline for ≥50% of treatment days were calculated for the 12-week treatment period and for each 4-week interval (Weeks 1–4, Weeks 5–8, and Weeks 9–12).  Additional analyses included the change from baseline in WAP for each weekly interval of the 12-week treatment period.

Results

Overall, 346 patients were randomized, 174 to placebo and 172 to eluxadoline.  The proportion of pain responders at the ≥40% improvement level was significantly higher with eluxadoline (43.6%) than with placebo (31.0%) over the 12-week treatment period (p<0.02).  There was also a higher proportion of pain responders with eluxadoline compared to placebo for each of the 4-week intervals, although this difference was statistically significant only for Weeks 5–8 (45.9% vs. 31.6%; p=0.005).  Similarly, a significantly greater proportion of patients were pain responders in the eluxadoline treatment group at both the ≥30% (50.6% vs. 37.4%; p<0.05) and ≥50% responder levels (35.5% vs. 23.6%; p<0.05) over the 12-week treatment period.  When analyzed over the 4-week intervals, improvements compared to placebo were statistically significant at the Weeks 5–8 interval for the ≥30% responder level (54.7% vs. 37.9%; p<0.05) and were statistically significant at both the Weeks 5–8 and Weeks 9–12 intervals for the ≥50% responder level (Weeks 5–8: 37.8% vs. 25.9%, Weeks 9–12: 43.0% vs. 28.7%; p<0.05 for both).  The analysis of change from baseline in WAP score indicated a greater average improvement in the eluxadoline group compared to placebo at Week 12 (−3.09 vs. −2.51).

Conclusions

A significantly greater percentage of patients treated with eluxadoline experienced improvements in the pain component of their IBS-D over a 12-week treatment period, using ≥30%, ≥40%, and ≥50% improvement thresholds for responders.  This suggests that eluxadoline is effective for treating the abdominal pain component of IBS-D in patients who previously reported an inadequate response to loperamide.

18 Characterizing Chronic Pain Patients Using DSM-5 Emerging Measures to Improve Care

David Cosio

Jesse Brown VA Medical Center, Chicago, IL, USA

Purpose

The opioid epidemic reflects a serious unmet need for better recognition and treatment of common mental health problems in patients with chronic pain (Howe & Sullivan, 2014). In most cultures, the majority of mental health cases go unrecognized in primary care settings (Ballenger et al., 2001). About 60% of previously undetected depression cases could have been recognized if the patients had been evaluated for the mental health disorder (Katon, 1984). Patients attending pain specialty clinics have even more difficult-to-treat pain conditions and comorbid, psychiatric disorders, use more outpatient services, and receive a greater number of opioid prescriptions (Arout, Sofuoglu, & Rosenheck, 2017). Numerous studies have documented a strong association between chronic pain and psychopathology (Dersh et al., 2002). Previous research has shown that chronic pain is most often associated with depression, anxiety, somatoform, personality, and substance use disorders. Less is known about the relationship with other conditions, such as schizophrenia spectrum/psychotic, sleep-wake, bipolar, neurocognitive, obsessive-compulsive, and dissociative disorders. These data support the inclusion of mental health care in the specialized treatment of chronic pain. The purpose of the current pilot study was to statistically compare mixed, idiopathic, chronic pain patients for the types of DSM-5 disorders identified using emerging measures. These measures are being used as potentially useful tools to enhance clinical decision-making. In addition, the current study serves as a replication of previous studies using the most recent version of the APA’s Diagnostic and Statistical Manual of Mental Disorders (Fishbain et al., 1986).

Methods

A sample of 272 Veterans aged 18-89 years old with mixed, idiopathic (back, neck, extremity, head, and fibromyalgia), chronic pain conditions participated in the Pain Education School program at Jesse Brown VA Medical Center between November 1, 2013-October 31, 2014. JBVA is a 1B facility with the 5th highest population of severe mental illness, 4^th in addictions treatment, and 3^rd in homelessness in the nation (2012). Pain Education School is a comprehensive program that is open to all Veterans which introduces them to different disciplines that deal with pain. Veterans voluntarily participated in the program and were free to withdraw at any time. There was no exclusion criteria used for the study. As part of the introduction of the program, all participants completed a pre-education assessment. The assessment included the World Health Organization Disability Assessment Schedule (WHODAS 2.0) and the DSM-5 Self-Rated Level 1 Cross-Cutting Symptom Measure-Adult (CCSM-A). The WHODAS 2.0 is a 36 item, self-administered measure that assesses disability in adults across six domains. Each item asks the individual to rate how much difficulty they had in specific areas of functioning during the past 30 days. The DSM-5 Self-Rated Level 1 CCSM-A is a self-administered measure that consists of 23 questions assessing 12 psychiatric domains: depression, anger, mania, anxiety, somatic symptoms, psychosis, sleep problems, memory,  repetitive thoughts & behaviors, dissociation, personality functioning, and substance use. Each item inquires about how much (or how often) the individual has been bothered by the specific symptom during the past two weeks.

Results

The current sample was largely African American (57%) and male (89%) with the largest age grouping being between 55 to 64 years old (37%). Males and females did not differ significantly with regards to age or race. Significant differences between males and females were found for only three of the 12 domains (p < 0.05): mania, anxiety, and substance use. Only 1.5% of cases endorsed no domains; 18.5% had endorsed 1−6 domains; and 80% endorsed 7-12 domains. Latinos reported significantly more disability then all the other races (p < 0.01). Ethnic minority groups are disproportionately affected by chronic pain (Green et al., 2003), have a greater risk for pain-related disability (Institute of Medicine, 2011), and have higher rates of psychological comorbid conditions (Green et al., 2005).

Veterans reported mild to moderate difficulty in specific areas of functioning during the past 30 days, including understanding & communicating, getting around, self-care, getting along with people, life activities, participation in society, and general disability. In comparison to the original Fishbain study (1986), the current sample endorsed more mania, memory, and repetitive thoughts and behaviors. Providers should consider that the differential diagnosis of bipolar disorder includes other conditions that may have manic-like symptoms, including organic mood disorders, drug intoxications, and tumors. Providers may question whether these patients truly had memory loss or another cognitive problem which may be better explained due to aging, medications, and depression. Providers should also consider that the differential diagnosis of OCD includes depression, phobic disorders, anorexia nervosa, cluster c personality, and schizophrenia. These findings may be due to the dimensional vs. categorical approach of the DSM-5. It may also be due to a high rate of false positive answers on the measure. Providers may only want to consider those conditions that are endorsed in the lowest threshold (severe rating).

Conclusions

DSM-5 Self-Rated Level 1 CCSM-A may serve as a good measure to use to screen chronic pain patients for mental health concerns. However, it fails to measure PTSD, which is prevalent in the Veteran population. It also fails to measure polarizing, or “taboo” disorders, such as neurodevelopmental, feeding/eating, elimination, sexual dysfunction, gender dysphoria, paraphilic, and “process” addictive disorders. It may function better in helping to identify the negative prediction of symptoms. These emerging measures could help frontline providers document all of a chronic pain patient’s symptoms, aid in developing more precise treatment plans, and monitor treatment progress and improvements.

19 A Mixed Methods Exploration of Perceptions of the Effectiveness and Utilization of Electrical Stimulation in Veterans with Chronic Noncancer Pain

David Cosio¹, Jennifer Castellow¹, Rhesia-Maria Roumain-Ochoa²

¹Jesse Brown VA Medical Center, Chicago, IL, USA, ²The Chicago School, Chicago, IL, USA

Purpose

A study on Veterans' health by VA found that Gulf War deployment was associated with an increased risk for fibromyalgia. Because there is no cure for fibromyalgia and the cause is not understood, the quest to find the best treatment is ongoing. Past research has shown that electrical stimulation has modest beneficial effects on symptoms of fibromyalgia, or centralized sensitization, but the strength of the evidence is low. The VA/HSR&D QUERI Evidence-Based Synthesis Program released a review report in December 2016 about the effectiveness and risks of electrical stimulation. As a result, the VA temporarily halted the use of these devices due to the insufficient evidence to support conclusions. Despite the research evidence, the clinical experience with these units has provided enough anecdotal data to pursue support for the continued distribution and utilization of electrical stimulation. Sixty Veterans were identified using the Fibromyalgia Symptoms (Modified ACR 2010 Diagnostic Criteria) Questionnaire as potential candidates for an AlphaStim electrical stimulation unit trial during January 1, 2016-December 31, 2016 at the Jesse Brown VA Medical Center. Thirty-eight patients (63%) were distributed either an AID (cranial electrotherapy stimulation) or M unit (both micro-current & cranial electrotherapy stimulations) after completing a six-session trial where they reported at least a 30% reduction in pain (the standard used in research to determine whether a modality is effective) before the final treatment session. The purpose of the current study was to evaluate the effectiveness and utilization of these units at-home by Veterans who suffer from chronic, non-cancer pain.

Methods

As part of a quality assurance effort, each patient was called at follow-up to complete a brief, confidential semi-structured phone interview with an assigned research team member. Patient responses to “Where is pain from 0 (no pain) to 10 (worst pain ever experienced)?” and “Are you currently impacted by insomnia?… anxiety?… depression?” were transformed. Quantitative methods were used as the principal approach. ANOVA and chi-squares were used to determine differences between time points on different scores. Qualitative analyses were also employed to explore patient perceptions in response to open-ended inquiries, such as “How has the AlphaStim unit at-home been going? “ (Do you use it? How often?), “How has using the AlphaStim unit impacted your daily life, if at all?” and “Is there anything else that you think is important for me to know about you and your experience with AlphaStim?” Braun and Clarke’s thematic analysis, specifically the inductive semantic approach, was used to organize, summarize, and interpret the data. Two other investigators independently familiarized themselves with the data, searched for potential themes, and coded the data. Discrepancies in thematic codes were resolved in research team meetings. The themes and subcategories (i.e., subthemes) were finalized and thematic maps were generated to depict a visual representation of the data. Directed content analysis was utilized to ensure thematic codes addressed preconceived research questions while also reflecting emergent themes.

Results

Of the 60 participants initially evaluated for central sensitization, 73% were male, while 27% identified as being female. Sixty percent of the participants recognized being African American, while 27% identified as Caucasian and 13% as Hispanic/Latino. The average age of the participants was 50 years-old, and ranged from 29 to 75-years-old. Sixty percent of participants reported depression at the initial assessment, 65% reported anxiety, and 72% reported insomnia. Of the 38 patients distributed an Alphastim unit after completing a six-session trial (34% not given), 43% were given an AID and 23% were given a M unit. The average pain score at the initial assessment was a 6.5, which indicates participants were in “quite a lot of” or severe pain.

Quantitative findings from paired samples t-tests suggest that participants who were given an AID unit did not have a significant difference in pain level at follow-up (p = 0.064) when asked “Where is pain from 0 (no pain) to 10 (worst pain ever experienced)?,” but participants given the M unit did witness a significant difference in pain level (p = 0.007). When asked “Are you currently impacted by insomnia?… anxiety?… depression?,” participants who were given an AID unit reported a significant difference in anxiety symptoms at follow-up (p = 0.002) but no difference in depression (p = 0.180) and insomnia (p = 0.355); while participants given the M unit reported a significant difference in depressive symptoms (p = 0.040) but no difference in anxiety (p = 0.545) and insomnia (p = 0.779). Qualitative findings produced three thematic maps, including utilization (“How has the AlphaStim unit at-home been going?), effectiveness (“How has using the AlphaStim unit impacted your daily life, if at all?”), and satisfaction (“Is there anything else that you think is important for me to know about you and your experience with AlphaStim?”). Extracts corresponding with each theme and subtheme will be shared.

Conclusions

The current study is the first known investigation to examine the effectiveness and utilization of electrical stimulation units at-home by Veterans who suffer from chronic, non-cancer pain. It differs from previous studies in that it: (1) utilized a mixed-methods treatment outcome design; (2) combined utilization, effectiveness, and satisfaction components; and, (3) focused specifically on veteran patients with mixed idiopathic chronic pain conditions. The current study provides a novel way to contribute to the existing body of literature. This information is invaluable in helping patients who share the same or similar condition and for the providers aiding in their treatment.

20 Identifying Individuals at Risk for a Future Opioid Use Disorder Diagnosis with Machine Learning

David M. Simon¹, Meridith Blevins Peratikos^1,2, Amber R. Watson¹, Jianhong Shen¹, Elizabeth Ann Stringer¹

¹axialHealthcare, Nashville, TN, USA, ²Vanderbilt University, Nashville, TN, USA

Purpose

The growing prevalence of opioid use disorder (OUD) is recognized as a major public health crisis associated with substantially elevated health care costs and poor health outcomes. Previous research has identified numerous risk factors that contribute to whether a patient prescribed opioids will be diagnosed with OUD in the future. Manual review of healthcare records by pain practitioners for OUD risk factors is resource intensive due to the diversity of factors and the complexity of interactions found in healthcare data. Predictive models using machine learning offer a mechanism for distilling this high dimensional data into forms that are suitable for both risk stratification of patients and supporting healthcare decisions by practitioners. Such models offer a means to personalize treatment of pain patients in ways that mitigate patient risk and reduce the healthcare costs of opioid addiction. To address this opportunity we developed a predictive model using administrative healthcare claims. Our model primarily aimed to predict whether a patient who does not currently have OUD will receive a diagnosis of OUD in the next 12 months based on their administrative claims history.

Methods

Patients were selected from commercial and government healthcare claims databases on the basis of two years of continuous insurance eligibility between January 2015 and January 2018. Data for each patient were split into two one-year periods: predictive and outcome. A combination of ICD codes and prolonged prescriptions for medication-assisted treatment (MAT) were used to detect the onset of OUD. A total of 23,371 (0.00289%) of eligible individuals were diagnosed with new cases of OUD in the outcome year (positive cases), and we randomly selected a set of 1,051,695 individuals without an OUD outcome as negative cases. For each patient, we compiled 983 features describing medical diagnoses, healthcare utilization, and demographics. A machine learning algorithm known as extreme gradient boosting (xGBoost) was used to predict whether a patient would receive a diagnosis of OUD in the outcome period based on their administrative healthcare claims in the predictive period. Using approximately 80% of the available data, grid-search and cross-validation were used to identify the optimal model hyperparameters and a final model was trained. The model was then evaluated on a separate validation set consisting of approximately 20% of the available data. We evaluated model performance using area under the receiver operating characteristic curve (AUROC) and and area under the precision-recall curve (AUPRC).

Results

A high level of predictive accuracy was achieved for model predictions on the validation data (AUROC = 0.895; 95% CI: 0.890 − 0.900, chance = 0.5). AUPRC ranged from 0.071 to 0.123 depending patient subset (chance = 0.002 − 0.020). Automatic feature selection and automatic model complexity control retained 401 (41%) of the initial 983 model inputs, suggesting substantial diversity in the factors that contribute to and mitigate individual OUD risk. Notably, variable importance indicated that a patient’s opioid days supply served as the leading predictor of OUD outcomes. Numerous other factors such as the insurance provider, age, and specific medical diagnoses also contributed to predictions. Uncommon medical diagnoses such as unspecified amphetamine abuse (ICD-9 305.70; 0.063% of training data) and unspecified drug abuse (ICD-9 305.90; 0.087% of training data), which have previously been described in medical literature as major risk factors for OUD, were correctly retained by the model despite their low prevalence. Crucially, the model was able to predict future OUD outcomes with a surprising level of fidelity in individuals who did not have a prescription for opioids documented in administrative claims during the predictive period (AUROC = 0.837; 95% CI 0.829 − 0.845). This indicates that the model quantifies features which indicate susceptibility to future dependence, rather than solely through detecting currently undiagnosed cases of OUD. We additionally examined patient profiles from incorrect predictions. We determined that misclassification frequently occurred when patients either lacked a substantial medical history or their medical history strongly indicated they should be screened for OUD.

Conclusions

The machine learning predictive model we developed offers valuable insight for supporting healthcare decisions for pain management and patient screening in individuals who are currently prescribed opioids. Appropriate intervention with these patients before they are opioid dependent could serve to improve patient outcomes and reduce the sizable healthcare costs frequently associated with healthcare escalation prior to addiction treatment. Furthermore, the model achieved substantial sensitivity for patients who are not currently on opioids. This sensitivity to patient susceptibility supports the possibility of model deployment as a decision support tool when determining whether opioid treatment is appropriate for patients not currently on opioids.

21 A Longitudinal Study of the Impact of Opioid Use on Change in Pain Interference With Activities and Functional Limitations in a Nationally Representative Cohort of Adults with Osteoarthritis in the United States

Drishti Shah¹, Xiaohui Zhao¹, Kavita Gandhi², Wenhui Wei³, Nilanjana Dwibedi¹, Lynn Webster⁴, Usha Sambamoorthi¹

¹Department of Pharmaceutical Systems & Policy, West Virginia University School of Pharmacy, Morgantown, WV, USA, ²Teva Pharmaceutical Industries, Frazer, PA, USA, ³Regeneron Pharmaceuticals, Tarrytown, NY, USA, ⁴PRA Health Sciences, Salt Lake City, UT, USA

Purpose

Chronic pain is a primary symptom of osteoarthritis that may impair function and limit daily activities. Patients with osteoarthritis are prescribed opioids for osteoarthritis pain relief but require an evaluation of its risks and benefits by the prescribing physician. The primary objective of this retrospective longitudinal study was to characterize the association of opioid use patterns with pain interference with daily activities (PIA) and functional limitations among adults with osteoarthritis in the United States (US).

Methods

Data were from the 2010−2015 Medical Expenditure Panel Surveys (MEPS), which consist of 5 interview panels. Each panel had a total of 5 rounds of data collection during the 2-year survey period, enabling longitudinal assessment of outcomes in a nationally representative sample of non-institutionalized adults in the US. For study inclusion, adults (≥18 years during baseline) with osteoarthritis and without cancer were identified. Evaluated outcomes were longitudinal change in PIA and functional limitations. PIA, collected in rounds 2 (baseline) and 4 (follow-up), was categorized as no/mild, moderate, and severe based on a single pain interference item of the 12-item Short Form v2 scale. Limitations across functional categories (Yes/No) were collected in rounds 3 (baseline) and 5 (follow-up), and included activities of daily living (ADL), instrumental activities of daily living (IADL), social activities, work activities, and cognitive function. Opioid use patterns (rounds 1–3 for PIA analysis and rounds 2–4 for functional limitation analysis) were defined as persistent (opioid use in at least two consecutive rounds), intermittent (opioid use in any one of the rounds), and no opioid use (none of the rounds). Adjusting for baseline sociodemographic and clinical characteristics, and NSAID use, a multinomial logistic regression was conducted on follow-up PIA. Separate multivariable logistic regressions, stratified by baseline functional status, were conducted on follow-up functional status to explore the impact of persistent or intermittent versus no use of opioids. Regression results are expressed as adjusted odds ratios (AOR) and 95% confidence intervals (95% CI). All results were weighted to be nationally-representative.

Results

A total of 4,172 patients were included (66.2% female, 80.8% white, mean age 61.7 years). Opioid use patterns in rounds 1–3 and 2–4 were 15.9% and 14.7% persistent; 18.0% and 13.4% intermittent; 64.6% and 67.3% no use; NSAID use was 25.3% and 24.0%. Overall, 62.1% of patients at follow-up had no PIA change, 17.9% worsened, and 20.0% improved. While the majority of patients (51.0%−93.1%) reported no limitations across functional categories in the evaluated rounds, higher proportions worsened (3.8%−13.1%) than improved (1.1%−11.3%). Multivariable regression analyses showed that relative to non-opioid users, persistent opioid users had higher odds of reporting extreme/severe PIA (AOR 2.91, 95% CI 1.95−4.32; P < 0.001) and moderate PIA (AOR 2.04, 95% CI 1.31−3.20; P < 0.01) than mild/no PIA at follow-up; no significant difference was observed between intermittent and non-opioid users. For patients with baseline functional limitations, relative to non-opioid users, persistent opioid users had higher odds of reporting physical (AOR 1.63, 95% CI 1.07−2.49) and work (AOR 1.90, 95% CI 1.06−3.39) limitations at follow−up (both P < 0.05); intermittent opioid users had lower odds of social (AOR 0.35, 95% CI 0.17−0.72) and cognitive (AOR 0.28, 95% CI 0.13−0.62) limitations than non−opioid users (both P < 0.01). For patients without baseline functional limitations, relative to non−opioid users, persistent opioid users were more likely to report IADL (AOR 1.68, 95% CI 1.00−2.81; P < 0.05), physical (AOR 2.39, 95% CI 1.50−3.80; P < 0.001), social (AOR 1.51, 95% CI 1.05−2.17; P < 0.05) and cognitive (AOR 1.80, 95% CI 1.13−2.84; P < 0.05) limitations. Intermittent opioid users compared with non−opioid users had higher odds of reporting physical (AOR 1.52, 95% CI 1.02−2.26; P < 0.05) and social (AOR 1.44, 95% CI 1.00-2.07; P < 0.05) limitations.

Conclusions

Persistent opioid use in adults with osteoarthritis pain was associated with poorer outcomes with regard to both PIA and functional limitations, regardless of their baseline functional status. These findings suggest an unmet need for more effective pain control and alternative therapeutic strategies. Study limitations include PIA and functional limitations not measured at the same round, inability to link opioid prescriptions to osteoarthritis pain and no control for unobserved patient or disease characteristics that may potentially affect evaluated outcomes. Future prospective studies could validate study findings.

22 A Case Study of Treatment of Recalcitrant Nonpressure Chronic Ulcers Using Asteo Gel Topical Hydrogel With 4% Lidocaine for Autolytic Debridement and Pain Management

Elizabeth Hanley

Purpose

To highlight the significance of pain in the management of chronic wounds, share a case study that offers an option other than narcotics in and around the wound bed to manage debridement, a commonly painful procedure for the patient.In the United States of America 6.5 million patients will be treated for a chronic wound per year. The cost can be as high as 25 billion dollars per year treating the wounds and their myriad of complications. The significance of pain in the management of chronic wounds has been underestimated and undertreated. Historically, patients were forced to deal with this pain either with conventional OTC medications like acetaminophen or ibuprofen, or prescribed narcotics. Topical anesthetics are often ineffective due to the presence of a thick adherent slough requiring require the Physician to perform a field block using an anesthetic such as lidocaine or bupivacaine injected in and around the wound bed, a commonly painful procedure for the patient.

Methods

Most Wound Centers apply topical anesthetics to the wound bed prior to sharp debridement, however if a wound is covered with thick adherent slough, the anesthetic gel cannot penetrate this layer to give adequate pain management. This may require the physician to perform a field block using an anesthetic such as lidocaine or bupivacaine injected in and around the wound bed. This can be uncomfortable for the patient due to the fact several injections may be required and the amide anesthetics, due to their basic pH, can sting significantly when injected as the block sets up. Bupivacaine 0.5% may be useful because although the injection process is uncomfortable, the block can last up to 8 hours or longer, giving the patient no pain after debridement at the wound center. However, because it takes longer to set up than Lidocaine, the visit takes longer and slows the pace of the physician’s clinic.

Astero (Gensco Pharma, Miami, Florida USA) is the one of the few products currently available to solve many of these problems for Wound Care Clinicians. Astero combines a hydrogel and a topical anesthetic (Lidocaine 4%). Patients who present with thick, hard and adherent eschar on any type of wound who have significant pain with debridement, or wound pain all the time, are excellent candidates for this safe, easy-to-use product. The hydrogel softens the eschar so the lidocaine can penetrate and ease pain. The hydrogel also maintains a moist wound healing environment. Up to 12 pumps a day can be administered directly to the wound bed. In patients who are in compression wraps for venous leg ulcer who have pain with debridement, I recommend that they remove the wrap on the day of the wound care visit, shower, and then apply the Astero before coming to their wound care appointment. This way they are already “premedicated” with the topical anesthetic and they tend to tolerate sharp debridement much better.

Results

Both patients are elderly with large chronic complicated wounds requiring frequent therapy including sharp debridement. Both patients were exquisitely sensitive to pain which limited the extent of therapy and proper wound care. The inclusion of Astero, applied to the wound bed as part of the pre and post wound treatment regimen, permitted more aggressive debridement and more frequent dressing changes, encouraging faster wound healing. Both patients have subsequently gone on to heal these wounds completely.

Conclusions

Patiens benefited from consistent compression therapy as well as serial debridement and improved pain control through the use of Astero gel to the painful wound beds and negating the need for opioid based medications.

23 Budget Impact Analysis of MorphaBond™ ER (morphine sulfate extended-release) for the Treatment of Chronic Pain from a Managed Care Perspective

Elizabeth Marrett¹, Winghan Jacqueline Kwong¹, Louis F Rossiter²

¹Daiichi Sankyo, Inc., Basking Ridge, NJ, USA, ²College of William & Mary, Williamsburg, VA, USA

Purpose

The development of abuse-deterrent formulations (ADF) of prescription opioids (RxO) is an important step toward deterring inappropriate use of these medications. MorphaBond ER is an extended-release (ER) morphine sulfate tablet formulated with physiochemical properties to deter misuse/abuse via the intravenous (IV) and intranasal (IN) routes of administration. Previous studies have demonstrated that MorphaBond ER resists passage through a syringe, as well as reduced drug liking and willingness to take drug again relative to ER morphine following intranasal administration. However, abuse of MorphaBond ER by oral, intravenous and intranasal administration is still possible. The objective of this study was to estimate the potential financial impact to a hypothetical health plan of 10 million members 2 years after adding MorphaBond ER to the health plan drug formulary.

Methods

The model estimates incremental healthcare resource use (HCRU) associated with RxO misuse/abuse based on a health plan’s RxO formulary coverage and utilization.  RxO misuse/abuse rates, incremental HCRU and costs were informed by the 2015 National Survey on Drug Use and Health, an analysis of claims from Optum Health Care Solutions, Inc. (2013-15) and published literature. Proportions of RxO abuse cases attributable to morphine ER via IV and IN administration were obtained from 2016 ASI-MV data.  In the base case analysis, RxO formulary shares were based on 2016-17 Symphony Retail Prescription data.   MorphaBond ER was assumed to comprise a total of 0.14% market share in year 1 (taking 20% from branded and 0.3% from generic non-ADF morphine ER) and 0.26% market share in year 2 (30% from branded and 0.6% from generic non-ADF morphine ER) after formulary adoption.  Wholesale acquisition costs without discount were used for RxO prices. The proportion of misuse/abuse cases deterred by MorphaBond ER due to its physiochemical properties was assumed to be 90% via IV and 60% via IN administration.  Sensitivity analyses were performed to evaluate changes in model outcomes.

Results

In the base case analysis, adding MorphaBond ER to the drug formulary decreased abuse-related healthcare costs for a health plan of 10 million members by −$533,770 (−$0.00222 per-member-per month [PMPM]), offsetting the pharmacy cost increase of +$338,658 (+$0.00141 PMPM), resulting in a net cost-savings of -$195,111 (-$0.00081 PMPM) over 2 years.  In sensitivity analysis, increasing the generic morphine ER shares replaced by MorphaBond ER to 1% in year 1 and 2% in year 2 resulted in a net cost increase, however, the overall PMPM remained low (+$0.00002 PMPM).   In one-way sensitivity analyses on MorphaBond ER’s abuse deterrent properties, lowering IV abuse reduction to 75% resulted in a net cost increase of + $0.00011 PMPM. When IN abuse reduction was lowered to 20%, the total budget continued to show cost savings (-$0.00072 PMPM).

Conclusions

The budget impact model provides a framework to estimate the financial impact of including MorphaBond ER on a drug formulary.  Placing MorphaBond ER on a health plan’s drug formulary may result in overall cost savings or a marginal cost increase to health plans and those who pay their premiums, depending on MorphaBond ER’s market share and effectiveness in deterring opioid misuse/abuse.

24 The Effect of Food on the Pharmacokinetic Characteristics of Morphine ARER (MorphaBond^TM ER), an Abuse-Deterrent Formulation of Extended-Release Morphine

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

Inspirion Delivery Sciences LLC, Morristown, New Jersey, USA

Purpose

Extended-release (ER) opioid formulations are often misused and abused because they contain high amounts of opioid. Abuse-deterrent opioid formulations provide pain relief while deterring common methods of manipulation and extraction. Morphine ARER (MorphaBond™ ER, Daiichi Sankyo, Inc., Basking Ridge, NJ) is an abuse-deterrent ER opioid formulated with proprietary SentryBond™ technology that has abuse-deterrent physical and chemical properties. Morphine ARER is expected to deter abuse by the intranasal and intravenous routes of administration; however, abuse by the intranasal, intravenous, and oral routes is still possible. Food can alter the pharmacokinetics (PK) of certain abuse-deterrent formulations. High-fat meals may delay maximum plasma concentrations or increase bioavailability. Herein, we assess the effect of food on Morphine ARER PK.

Methods

This was a randomized, single-dose, 2-period, 2-treatment, 2-sequence crossover study under fasted and fed conditions. Morphine ARER 100-mg tablet was administered following an overnight fast of ≥10 hours (period I) or a standardized high-fat, high-calorie breakfast preceded by an overnight fast of ≥10 hours (period II), with a 7-day interval between treatment periods. Naltrexone 50 mg was administered before and after dosing to minimize opioid side effects. The plasma concentrations of morphine and its active metabolite morphine – 6 – glucuonide (M6G) were obtained at various times up to 48 hours postdose; area under the plasma concentration–time curve from 0 hour to the last measurable concentration (AUC_0-t); AUC from 0 hour extrapolated to infinity (AUC_0–∞) and various postdose timepoints; maximum observed plasma concentration (C_max); and time to C_max (T_max) were calculated. Analysis of variance was performed using the general linear model procedure of SAS and least-squares means for the treatments were calculated. The 90% confidence intervals (CIs) were constructed based on the geometric mean ratios. The geometric ratio of the means in fed and fasted states was calculated, and bioequivalence was established by the 90% CI falling within the 0.80–1.25 (80%–125%). Safety was evaluated by observation or report of adverse events (AEs), which were monitored and/or recorded during the treatment periods. Severity of each AE was determined by the clinic staff; relationship of the AE to the study treatments was judged by the investigator.

Results

Of 28 subjects enrolled in the study, 27 completed all treatments; 1 subject in the fasted group withdrew voluntarily. Mean C_max for morphine was 34% higher under fed compared with fasted conditions (44.8 vs 33.4 ng/mL, respectively) with median T_max for Morphine ARER fed 30 minutes longer than for Morphine ARER fasted (4.5 vs 4.0 hours, respectively). C_max was slightly outside the 80% – 125% equivalence range for fed vs fasted (ratio [90% CI]: 1.3324 [1.2090 – 1.4684]). Overall morphine exposure was similar for fed vs fasted conditions (AUC_0–∞, 440.6 vs 395.1 ng•hr/mL), with the geometric mean ratio and 90% CI falling within the equivalence range (1.1203 [1.0701 – 1.1729]). The C_max for M6G was similar (193.2 vs 196.8 ng/mL) and median T_max was 1 hour longer (4.5 vs 3.5 hours) under fed vs fasted conditions, respectively. C_max (ratio [90% CI]: 0.9746 [0.9200 – 1.0326]) and AUC_0–∞ (ratio [90% CI]: 0.9908 [0.9661 – 1.0162]) were within the equivalence range for M6G. A total of 11 AEs were reported by 10 of the 28 subjects who participated in this study. The most common AEs for both the fed and fasted states were somnolence (fed: n = 2; fasted: n = 3) and nausea (fasted: n = 2). All AEs were considered mild and resolved spontaneously before study completion.

Conclusions

In this single-dose bioavailability study, morphine C_max was 33% higher and T_max was 0.5 hours longer under fed vs fasted conditions. Morphine exposure (AUC_0–∞) was within the equivalence range for fed vs fasted conditions. C_max and AUC_0–∞ were within the equivalence range for M6G. Although morphine C_max was slightly outside the bioequivalence limit, overall exposure was similar for both morphine and M6G, suggesting that Morphine ARER can be administered without regard to food.

25 Abuse-Deterrent Morphine ARER (MorphaBond™ ER) Tablets Do Not Swell or Become Sticky to Complicate Oral Administration

Eric R Kinzler, Carmela Pantaleon, Stefan Aigner

Inspirion Delivery Sciences LLC, Morristown, New Jersey, USA

Purpose

Patients may have difficulty swallowing opioid tablets and may presoak or wet medications to facilitate ingestion; however, postmarketing reports suggest that some formulations, including some abuse-deterrent formulations, swell or become sticky when wet, further complicating oral administration in patients with dysphagia. Morphine ARER (MorphaBond™ ER, Daiichi Sankyo, Inc., Basking Ridge, NJ) is an abuse-deterrent, extended-release (ER) opioid formulated with proprietary SentryBond™ technology that has physical and chemical properties that contribute to abuse deterrence. The active ingredient is contained within a polymer matrix of inactive ingredients and is difficult to visually distinguish or physically separate from the polymer matrix. Manipulated Morphine ARER tablets form a viscous material when subjected to a liquid environment that resists passage through a needle. The purpose of this study was to evaluate the physical properties of Morphine ARER and ER oxycodone (Purdue Pharma LP, Stamford, CT) intact tablets when placed in aqueous solutions.

Methods

Morphologic changes to intact Morphine ARER and ER oxycodone tablets were assessed following immersion in a dissolution bath and Type II (basket) apparatus. Morphine ARER 100 mg tablets (n = 3) were individually immersed in 900 mL of tap water, pH 6.8 water, or simulated gastric fluid (SGF) at 37°C and agitated at 100 RPM. After 12 hours and 24 hours, Morphine ARER tablets were removed from the solvent, dried, weighed, and measured for thickness. One ER oxycodone 80 mg tablet was immersed in 900 mL tap water at 37°C and agitated at 100 RPM. After 15 and 30 minutes, 1, 2, 4, and 8 hours, the ER oxycodone tablet was removed from the solvent, weighed and measured for thickness. Percent change from initial measurement was calculated for tablet weight and thickness.

Results

Morphine ARER tablets changed minimally after 12 hours (0.7% to 2.1% lighter and 2.5% to 4.2% thicker) and were not sticky; after 24 hours, Morphine ARER tablets were 21% to 32% heavier, 6% to 8% thicker, and were not sticky. Results were similar for Morphine ARER among solvent groups, with no observed differences in weight, thickness, or stickiness. Conversely, at 15 minutes, ER oxycodone tablets began to stick to the basket and were 24% heavier and 30% thicker. ER oxycodone tablet weight and thickness continued to increase at each time point; after 8 hours, ER oxycodone tablets were 148% thicker and 263% heavier. As time progressed, the swelling/thickness progressively turned the tablet into a sticky gel.

Conclusions

Intact Morphine ARER tablets exhibited minimal morphological changes even after 12 hours. These results suggest that, when taken as intended, intact Morphine ARER tablets are not expected to swell or become sticky to hinder oral administration when wet. Conversely, ER oxycodone tablets swelled and became sticky within 15 minutes in aqueous solvent, supporting the recommendations in the ER oxycodone prescribing information instructing patients to not presoak, lick, or otherwise wet tablets prior to administration.

26 Multimodal Pain Management in Children: NSAID Use in the Perioperative and Emergency Department Settings

Francois Angoulvant¹, Sílvia Barbosa²

¹Hôpital Necker-Enfants Malades, Paris, France, ²HCFMUSP, Sao Paulo, Brazil

Purpose

Multimodal analgesia (MMA) is the practice of using different procedures, techniques, and/or medications with different mechanisms of action in order to achieve pain control. In terms of medication use, the advantages of MMA include its potential to improve upon the analgesic efficacy derived from a single effective agent, such as an opioid, while potentially minimizing opioid dose requirements and dose-dependent adverse effects that may complicate their use. MMA has gained popularity for the management of perioperative pain in adults in recent years, due at least in part to the ongoing opioid epidemic. In the pediatric population, MMA management options have become more common over time and are recommended for the management of pediatric perioperative pain, although fewer data are available to inform such use compared with the adult population. The addition of nonsteroidal anti-inflammatory drugs (NSAIDs) is a strategy commonly employed in MMA regimens. We conducted a literature search to determine the utility of NSAID use as part of an MMA treatment regimen, with particular attention to pain relief, reduction in daily opioid requirement, and reduction of adverse effects.

Methods

A literature search was conducted using the PubMed electronic database for randomized, controlled trials evaluating systemic NSAIDs (i.e., not topical, periarticular, or local infiltration) as a component of MMA for pain management in children (<18 years of age), focusing on use in the perioperative or emergency department setting. Key words relative to the subject matter included “multimodal pain management” and “opioid sparing.” Key words identified the “population” (children, pediatric), “treatment venue/timing” (emergency, emergency room, emergency department, perioperative, postoperative), and “intervention” (NSAIDs, ibuprofen, naproxen, ketoprofen, diclofenac, indomethacin, ketorolac, meloxicam, piroxicam, and coxibs). Various combinations of these search terms were used in order to find relevant trials. We added the specific terms “tonsillectomy,” “sickle cell,” “fracture,” and “musculoskeletal” to augment our search as conditions of special interest. Outcomes examined included the effect of MMA on opioid dose consumption, morbidity, pain scores, and adverse events. We limited our search to the published literature in English and in humans that was published after 1/1/2000. All abstracts from our literature search “hits” were reviewed for appropriateness. We obtained full text articles of all relevant publications determined by abstract review; if questions of appropriateness remained upon abstract review, full text articles were obtained and reviewed.

Results

Our search strategy yielded 70 potentially relevant articles. Upon abstract review, 39 articles were excluded. Upon full text review of the 31 remaining articles, 13 were excluded for reasons including not investigating a pediatric population, no NSAID comparator, or lack of assessments of interest. NSAIDs studied included ibuprofen (n = 9; ketoprofen (n = 4); diclofenac (n = 2); ketorolac (n = 2); and lornoxicam (n = 1). Two studies investigated different formulations of ketoprofen (intravenous vs intramuscular; intravenous vs per rectum). Eight studies involved orthopedic surgery/musculoskeletal injury, 5 involved tonsillectomy/adenoidectomy, 3 involved “other” types of surgeries, and 2 were in dental surgery. Assessment of pain score reductions was common; assessment of change in morphine equivalent consumption was rare. Ibuprofen significantly reduced meperidine use in the only study where this was assessed. Ibuprofen significantly reduced pain scores versus acetaminophen and placebo and versus acetaminophen and codeine (1 study each). Ibuprofen provided equivalent analgesia to oxycodone (1 study), to acetaminophen/codeine combination (2 studies), and to morphine sulfate (3 studies). Ketoprofen significantly decreased morphine equivalents in 3/3 studies where assessed (vs tramadol [n = 1] or placebo [n = 2]). Ketoprofen significantly reduced pain scores in 2/3 studies versus placebo and in 1 study versus tramadol. Morphine reduction was not assessed in diclofenac studies. Diclofenac combined with bupivacaine infiltration provided a longer duration of analgesia versus bupivacaine caudal block alone (n = 1) and significantly reduced pain scores versus placebo and acetaminophen in another study. Ketorolac significantly reduced morphine need over 48 hours in 1 study where assessed; pain score reduction was similar to tramadol in another study. Lornoxicam reduced pain at rest versus placebo; however, morphine use was not assessed. NSAIDs were well tolerated in children, with adverse event rates similar to placebo across most studies and lower than with opioids. Only 1 study reported a significantly increased operative blood loss with ketoprofen (vs placebo).

Conclusions

NSAIDs have become an important tool in multimodal pain management. In pediatric studies where NSAIDs are evaluated as part of a multimodal regimen, pain relief is consistent with their use, often in an equivalent fashion to pain relief from opioid analgesics such as morphine or oxycodone. Additionally, NSAIDS are better tolerated than opioids and do not appear to be associated with increased operative blood loss over placebo, with the possible exception of ketoprofen. Perioperative and emergency department use of NSAIDs as part of an MMA strategy may help optimize pain control while avoiding opioid adverse events.

27 Pain relief is greater with ibuprofen compared to acetaminophen with codeine: a systematic evaluation of studies using the dental extraction model

Hunter Watson, Kevin Rowland

SIU School of Dental Medicine, Alton, IL, USA

Purpose

The United States is in the midst of an opioid addiction epidemic.  Opioid prescribing habits for all medical professions have been heavily scrutinized recently, especially in light of recent studies indicating that the use of non-addictive alternatives may be more efficacious.  Although the field of dentistry makes up a relatively small proportion of opioid prescriptions in the United States, patients often experience their first narcotic under a dentist’s care, especially at a young age. Due to the urgency and importance of diminishing the current opioid epidemic, it is paramount that researchers and clinicians create and analyze existing data sets that will lead to informed decisions and the best patient care possible. Third molar extraction studies are often utilized to test the efficacy of putative analgesics because in such studies the procedure and response are predictable, and subjects are often young and healthy without other comorbid conditions.  Our goal was to identify all studies using the third molar surgical extraction model and screen for studies that measured post-operative pain relief differences among oral analgesics for at least six hours following the procedure.

Methods

We examined 1,456 articles from 1955 to 2018 that measured pain following third molar extraction.  Only studies that were randomized, double blinded and placebo controlled were included.  We analyzed articles that evaluated drug efficacy using the “Pain Relief Scale” where patients were asked to rate their relief of pain following third molar extraction on a five point scale where: 0 = “no relief”, 1 = “a little”, 2 = “some”, 3 = “a lot”, and 4 = “complete”.  Pain relief data were collected from published studies either from tables or graphs of the data. We compared group means of pain relief scores from patients treated with single doses of either ibuprofen (400 mg), acetaminophen with codeine (600 mg + 60 mg), or placebo immediately following surgery. Differences among groups were assessed with the Kruskal-Wallis rank sums test, and post-hoc assessments of differences between groups were performed with the nonparametric Steel-Dwass method, which is a nonparametric version of the all-pairs, and Tukey honestly significant difference test.

Results

Patients reported that both ibuprofen and acetaminophen with codeine resulted in higher pain relief when compared to placebo which was statistically significant (p < 0.05).  However, average pain relief scores were significantly higher for ibuprofen than for acetaminophen with codeine 6 hours following molar extraction (p < 0.0001). Verbal ratings of the efficacy of the drug in relieving the patient’s pain using the “Pain Relief Scale” resulted in average +/- SD pain relief scores of 0.72 +/- 0.25 for placebo, 1.2 +/- 0.35 for acetaminophen 600 mg + codeine 60 mg, and 2.3 +/- 0.58 for ibuprofen 400 mg. In other words, patients who took acetaminophen with codeine, on average, rated their pain relief between “a little” and “some”, whereas patients taking ibuprofen, on average, rated their pain relief between “some” and “a lot” six hours following the surgery.

Conclusions

Our results indicate that, on average, in studies that utilized the dental pain extraction model in healthy adults, a single dose of ibuprofen 400 mg was superior to acetaminophen 600 mg/codeine 60 mg at six hours following surgery. Our results support the findings demonstrating that management of acute pain with NSAIDs have added benefit over opioids when risks and benefits are both considered.

28 Poppy Seed Tea

Irving Haber¹, Joseph Pergolizzi, Jr.², Jo Ann LeQuang²

¹Private Practice, Terre Haute, Indiana, USA, ²NEMA Research, Inc., Naples, Florida, USA

Purpose

Poppy seeds, widely and legally available in the U.S. and other parts of the world in their “unwashed” state, can be used to make poppy seed tea. Opium is the dried extract of the exudate from the seedpods of unripe poppies and these unwashed seeds can be soaked or washed to remove the residual coating. Although poppy-seed beverages have a history dating back centuries, clinicians today may be largely unaware of the fact that some individuals may be making a tea concoction that allows them to ingest the alkaloid residue of poppies which have been found to contain high, even potentially life-threatening doses, of morphine.¹ The literature is sparse regarding poppy seed tea but does present several case studies from various countries. These case studies report individuals of different ages, social sittings, and countries who took poppy seed tea for pain control, for opioid management, or to supplement a heroin addiction.^2-4

While poppy plants are a Schedule II controlled substance in the United States, poppy seeds are considered an exception and may be purchased legally. Indeed, many large and small online sites sell “unwashed poppy seeds” in large quantities and these sites offer recipes for preparing poppy seed tea. In most cases, the unwashed poppy seeds are soaked in water, sometimes with lemon juice added, for up to 12 hours, but other recipes exist. The opioid concentration of poppy seed tea varies widely as it is based on the amount of alkaloid residue on the seeds, the amount of seeds used, how the tea is prepared, and how much tea the individual consumes. Regular users of poppy seed tea appear to develop dependence.

The purpose of this report is to present a case study of a man who had become addicted to poppy seed tea and the realization by those who cared for him that he had obtained the poppy seeds through reputable online sources and that they were legal. Clinicians must become aware of poppy seed tea as a potential source of opioids.

Methods

The patient presented at a clinic and saw Dr. Irving Haber, the lead author of this paper. Dr. Haber worked with him over time and recorded his original complaint, how he obtained poppy seeds, why he used them, how long he had used them, and how he was able to discontinue them.

Results

The 42-year-old man presented voluntarily at Dr. Haber’s clinic with a request for medication-assisted treatment (MAT) for opioid use disorder (OUD). He ran a family business, a professional design company, although he had a history of OUD. About a year before this initial visit, he learned that unwashed poppy seeds could be purchased online from places like Amazon, E-Bay, and Etsy, and he started to buy large quantities of these seeds to make poppy seed tea. At first, his consumption of poppy seed tea did not interfere with his ability to run the family business or manage his personal affairs. Over time, his consumption of poppy seed tea increased to the point that he was unable to manage things. He understood the importance of seeking medical help and self-referred to the clinic.

The patient was abstinent from poppy seed tea for over 24 hours when he entered detoxification at the clinic. At this time, his Clinical Opioid Withdrawal Scale (COWS) score was 23. In an effort to manage withdrawal symptoms, he was titrated to 16 mg of buprenorphine/naloxone, reducing his COWS score to 8. Over the next few days, he continued to be administered buprenorphine/naloxone and he reported that with each dose, he felt an unpleasant wave of nausea. His withdrawal symptoms were typical for opioids but were unusually tenacious and protracted.

The patient was titrated to 24 mg of buprenorphine monotherapy which was well tolerated and allowed him to discontinue antiemetic therapy (ondansetron 8 mg every six hours) or reduce it (promethazine 25 mg once a day instead of four times a day). At two weeks, a urine screen using mass spectrometry and liquid gas chromatography revealed no detectable levels of morphine. At six weeks, he was reduced to 20 mg of buprenorphine and has agreed to continue the taper.

The patient understood that unwashed poppy seeds could be used as a source of opioids. To him, the appeal was that poppy seeds were relatively inexpensive and completely legal. Despite the fact that preparing poppy seed tea was time consuming, he thought he had found a viable and relatively safe solution to OUD. His original presentation at the clinic occurred because he was alarmed at how his use of poppy seed tea had escalated quickly and was interfering with his business and personal life.

Conclusions

Unwashed poppy seeds are inexpensive, legal, and available on the internet from otherwise reputable websites (such as Amazon, eBay, Etsy) as well as smaller niche sites dedicated specifically to poppy seed tea.  There is not widespread appreciation of its dangers among the general public or even clinicians. Unwashed poppy seeds can be used to produce a tea with a substantial morphine content and prolonged use can result in opioid dependence. Regulators should be aware of the “legal loophole” that allows unwashed poppy seeds to be sold online; clinicians should be aware that this is a new way to use opioids; and the general public should appreciate that poppy seed tea is a sort of home-made morphine and not a benign, natural, completely safe pain reliever.

29 Crisaborole and Apremilast: PDE4 Inhibitors with Similar Mechanism of Action, but Different Indications for Management of Inflammatory Skin Conditions

Jan Kitzen¹, Robert Raffa^2,3,4, Joseph Pergolizzi^5,4, Robert Taylor⁵

¹Kitzen Pharmaceutical Consulting, Collegeville, PA, USA, ²Temple University School of Medicine, Philadelphia, PA, USA, ³University of Arizona College of Pharmacy, Tucson, AZ, USA, ⁴Neumentum inc, Palo ALTO, CA, USA, ⁵Nema research Inc, Naples, FL, USA

Purpose

Crisaborole (Eucrisa®, Pfizer) and apremilast (Otezla®, Celgene) are selective phosphodiesterase-4 (PDE4) inhibitors recently approved by the FDA for treatment of related but different dermatologic conditions (atopic dermatitis and plaque psoriasis, respectively). We summarize underlying biochemistry and pathophysiology associated with these conditions, review the chemistry, pharmacology and safety of both products, and present preclinical and clinical evidence that may help explain why these two PDE4 inhibitors offer treatment options for inflammatory skin conditions.

Methods

A search was conducted of the published literature (in English) using sources such as PubMed and MedLine. The identified material was reviewed and synthesized. Emphasis was placed on the two drugs, atopic dermatitis, and plaque psoriasis.

Results

Apremilast and crisaborole belong to different chemical classes. Apremilast is administered by the oral route, crisborole is administered via topical application directly to the affected area where it penetrates the epidermis and dermis to reach the site of inflammation.

Conclusions

Therapy with PDE4 inhibitors appears to offer effective management of atopic dermatitis, plaque psoriasis, and psoriatic arthritis at lower cost compared to monoclonal antibody targeted therapy. As more efficacy and safety data become avail-able, these products could become valuable alternatives or additions to the standard therapy of DMARDs, topical corticosteroids and topical calcineurin inhibitors for the management of these inflammatory skin conditions.

30 Meloxicam IV Dose Selection for the Management of Moderate to Severe Pain: An Evaluation Using a Population Pharmacokinetic and Exposure-Response Analysis

JF Marier¹, Elliot Offman¹, Nathalie Gosselin¹, Stewart McCallum², Randall Mack², Alex Freyer², Wei Du³

¹Certara Strategic Consulting, Princeton, NJ, USA, ²Recro Pharma, Inc., Malvern, PA, USA, ³Clinical Statistics Consulting, Blue Bell, PA, USA

Purpose

Intravenous (IV) meloxicam (Meloxicam IV) is a novel formulation of NanoCrystal Colloidal Dispersion® meloxicam, developed for the management of moderate to severe pain.  Meloxicam IV has been evaluated across a range of dose levels and patient populations during its development including four Phase 1, four Phase 2, and three Phase 3 clinical studies.  Population pharmacokinetic (PK) and exposure-response (ER) analyses were undertaken after completing Phase 2 studies to support dose selection for Phase 3 studies, and refined after completing Phase 3 studies to further validate the selected dose.  PK and ER models were refined to evaluate variability in drug exposure and to assess the effect of meloxicam IV on pain intensity and rescue analgesia use in patients undergoing bunionectomy or abdominoplasty surgeries.

Methods

The analysis was performed utilizing a pool of rich and sparse data collected across 7 clinical studies in patients and healthy subjects.  PK modeling was performed to describe the relationship between plasma concentration of meloxicam IV over time, and incorporated allometric functions relating size effect (body weight) on clearance and volume parameters.  Intrinsic and extrinsic covariates were explored to assess meloxicam IV sources of PK variability. The performance of the final population PK model was evaluated using diagnostic plots and predictive checks.  ER analyses were performed using the summed pain intensity difference over the first 24 hours (SPID₂₄) data with and without adjustments for rescue medication use.  ER models, relating pertinent PK exposure metrics of meloxicam IV (AUC₀₋₂₄, C_max, or C_min) to SPID₂₄, as well the number of rescue doses, were evaluated.  Model discrimination was evaluated using statistical estimator of goodness of fit graphical display of observed and predicted observations. Covariate analyses were performed using a stepwise approach.

Results

The population PK analysis included 316 subjects, primarily female (76.3%), mainly of White racial origin (66.1%) and considered non-elderly (< 65 years; 94.3%).  Body weight was observed to have an effect on the clearance of meloxicam IV.  While the clearance was moderately dependent on estimated glomerular filtration rate (eGFR), the findings suggested that there is no need for dose adjustments in subjects with mild or moderate renal impairment defined as an eGFR >30 mL/min at baseline. Other examined covariates (sex, race, markers of liver function) did not explain variability in the clearance or volume of distribution.  The ER analysis was performed based on response data from 479 subjects, primarily female (90.6%), mainly of White racial origin (61.6%), and considered non-elderly (< 65 years; 94.8%), who received either meloxicam IV 30 mg, 60 mg or placebo. A statistically significant inverse ER relationship (slope, β) was observed between AUC₀₋₂₄ and SPID indicating that higher meloxicam IV exposure was associated with lower SPID₂₄ scores.  A similar statistically significant ER relationship was observed where higher meloxicam IV AUC_0-24 meloxicam IV was associated with fewer uses of rescue doses over 24 and 48 hours.

Conclusions

The performed population PK and ER analyses provided an understanding of sources of variability and of the impacts of meloxicam IV exposure on pain reduction and total number of rescue doses required for pain control following hard and soft tissue surgeries. The 30 mg dose of meloxicam IV administered once daily is expected to result in optimal reductions in pain intensity and rescue medication use in patients undergoing bunionectomy or abdominoplasty surgeries.

31 ‘Multigesics’

Joseph Pergolizzi^1,2, Jo Ann Lequang¹, Robert Taylor¹, Michael Ossipov³, Daniel Colucci⁴, Robert Raffa^2,5,6

¹NEMA Research Inc, Naples, FL, USA, ²Neumentum Inc, Palo Alto, CA, USA, ³University of Arizona College of Medicine, Tucson, AZ, USA, ⁴Northeastern University, Boston, MA, USA, ⁵University of Arizona College of Pharmacy, Tucson, AZ, USA, ⁶Temple university School of Pharmacy, Philadelphia, PA, USA

Purpose

The dramatic increase in intentional and unintentional deaths attributed to opioids refocused attention on the risk-benefit ratio of opioid analgesics. Almost all of the traditional opioid analgesics produce their effects (therapeutic and adverse) via the activation of m-opioid receptor (MOR) pathways. We examine the question of whether this natural endogenous pathway can still be activated, but with greater safety.

Methods

The basic science and clinical literature on multi-mechanistic analgesics was summarized and synthesized. The authors’ extensive familiarity with the topics allowed for formulation of the concepts, conclusions, and perspective.

Results

Tramadol and tapentadol, plus buprenorphine and the newest in development, cebranopadol, activate MOR, but exhibit characteristics atypical of conventional opioids. They are often called ‘atypical opioids’. They combine at least one additional non-opioid mechanism of analgesic action, usually synergistically. They thus can reduce the equiva-lent amount of opioid administered without loss of analgesic efficacy. These examples provide a template for one approach for designing safer analgesics that work through m-opioid receptor pathways.

Conclusions

Four ‘atypical opioid’ analgesics act as MOR agonists, but have at least one non-opioid mechanism of action that significantly contributes to the effect. The multi-mechanistic action of these products confers clinical utility in that they provide effective analgesia with relatively lower opioid load, and they are generally associated with fewer or less severe opioid-related adverse effects and less abuse compared to the traditional opioid analgesics.

32 New-look Opioids: ‘Biased’ Ligands

Joseph Pergolizzi^1,2, Michael Ossipov³, Robert Taylor², Robert Raffa^1,4,5

¹Neumentum Inc, Palo Alto, CA, USA, ²NEMA Research Inc, Naples, FL, USA, ³University of Arizona College of Medicine, Tucson, AZ, USA, ⁴Temple University School of Pharmacy, Philadelphia, PA, USA, ⁵University of Arizona College of Pharmacy, Tucson, AZ, USA

Purpose

Between the illicit use of opioids and the attendant overdoses, and accidental overdoses with prescribed drugs, overuse of opioids has become a serious problem. At the same time, finding a fine balance between minimizing the risk of opioid misuse and abuse while at the same time providing access to treatment for patients who need pain control presents an ongoing challenge. Efforts to discover/develop better agents have led to what we term ‘new-look’ opioids. We summarize one such approach: biased ligands.    

Methods

A search was conducted of the published literature (in English) using sources such as PubMed and MedLine. The identified material was reviewed and synthesized. Emphasis was placed on the concept of biased ligands.

Results

The discovery that genetically altered mice that do not express β-arrestin still respond to opioids with antinociception – but with less respiratory depression – led to the concept that activating the m-opioid receptor without engaging β-arrestin regulation may be key to the development of safer opioid analgesics. Compounds with a greater bias towards β-arrestin, are more likely to produce respiratory depression even at low doses, whereas those with G protein signaling bias have broader therapeutic windows. It is hoped that this guides the development of safer alternatives to the current opioid therapeutics.

Conclusions

Opioid analgesics mimic the body’s own pain attenuation physiology, and can be effective pain relievers. But the traditional opioids suffer from a questionable safety profile. In the search for ‘new-look’ – safer – opioid analgesics, biased-ligands is one such promising approach.

33 Study CGAL: A Placebo-Controlled Study of Galcanezumab in Patients with Episodic Cluster Headache: Results from the 8-Week Double-Blind Treatment Phase

James M. Martinez¹, Peter J. Goadsby^2,3, David W. Dodick⁴, Jennifer N. Bardos¹, Tina M. Oakes¹, Brian A. Millen¹, Chunmei Zhou¹, Sherie A. Dowsett¹, Sheena K. Aurora¹, Jyun Yan Yang¹, Robert R. Conley¹, Marissa I. Daniele¹

¹Eli Lilly and Company, Indianapolis, IN, USA, ²NIHR-Wellcome Trust King’s Clinical Research Facility, King’s College London, London, United Kingdom, ³University of California, San Francisco, CA, USA, ⁴Mayo Clinic, Phoenix, AZ, USA

Purpose

To determine if galcanezumab (LY2951742), a humanized monoclonal antibody that selectively binds to calcitonin gene-related peptide (CGRP), is efficacious as a preventive treatment of episodic cluster headache.

Methods

This study was designed to assess the efficacy and safety of galcanezumab in individuals with episodic cluster headache (International Classification of Headache Disorders-3 beta). This study comprised a screening period; a prospective baseline period; an 8-week, double-blind, placebo-controlled treatment period; and a 4-month post-treatment (washout) period. We present findings from the double-blind treatment period. In this period, participants were randomized 1:1 to galcanezumab 300 mg (N = 49) or placebo (N = 57) subcutaneously (SC) once monthly for 2 months. The primary endpoint was the overall mean change from baseline in weekly cluster headache attack frequency across Weeks 1 to 3. The key (gated) secondary endpoint was the proportion of participants achieving a response, defined as a reduction from baseline of ≥50% in the weekly cluster headache attack frequency at Week 3. Other secondary endpoints included proportion of participants reporting very much/much better based on Patient Global Impression of Improvement (PGI-I) at Weeks 4 and 8.

Results

Baseline demographics of the galcanezumab and the placebo groups were similar. Mean age was 47 years and 45 years, respectively; 84% and 82%, respectively, were male. The mean number of weekly cluster headache attacks in the baseline period was 17.8 for galcanezumab and 17.3 for placebo. Overall, 4 participants (8%) in the galcanezumab treatment group discontinued during the double−blind period versus 12 (21%) in placebo. In the placebo group, 8 participants (14%) discontinued due to lack of efficacy versus 1 (2%) in the galcanezumab group (p = 0.036 for treatment group difference). The mean change in weekly cluster headache attack frequency across Weeks 1 to 3 was −8.7 for galcanezumab versus −5.2 for placebo (difference between treatment groups in mean change, −3.5 [95% CI −6.7, −0.2]; p = 0.036). The proportion of participants achieving a ≥50% reduction in weekly cluster headache attack frequency was 76% for galcanezumab versus 57% for placebo (p = 0.04). The proportion of participants very much/much better based on PGI−I was significantly greater with galcanezumab versus placebo at Week 4 (73% vs 46%; p = 0.016) but not at Week 8 (72% vs 66%; p = 0.58). There were no clinically meaningful differences between treatment groups on tolerability or safety parameters except for a statistically significantly greater incidence of injection site pain with galcanezumab versus placebo (8.2% vs 0%, p = 0.043).

Conclusions

In individuals with episodic cluster headache, galcanezumab 300 mg SC significantly reduced the weekly cluster headache attack frequency across Weeks 1 to 3 (primary endpoint) and resulted in a significantly greater percentage achieving a ≥50% reduction in the weekly cluster headache attack frequency at Week 3. The safety profile of galcanezumab in this population was similar to that seen previously in patients with episodic or chronic migraine.

34 Effect of Naldemedine on Frequency of Spontaneous Bowel Movements and Associated Symptoms

James Wild¹, Tadaaki Yamada², Juan Camilo Arjona Ferreira², Martin Hale³

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

Purpose

Opioid-induced constipation (OIC) is a well-known side effect of opioid therapy.  OIC is defined by a decrease in the frequency of bowel movements, reduction in complete evacuation, an increase in straining and hard stools after initiation of opioid therapy.  Naldemedine (NAL) is a peripherally-acting µ-opioid receptor antagonist approved for the treatment of OIC in patients with chronic non-cancer pain in the United States.  This exploratory analysis evaluated the effect of NAL on these defining criteria of OIC.

Methods

Two randomized, double-blind placebo (PBO) controlled 12-week studies (NCT01965158 and NCT01993940), assessed the effect over time of NAL 0.2 mg once daily vs PBO in the frequency of spontaneous bowel movements (SBMs), complete SBMs (CSBMs, defined as SBMs with a perception of complete evacuation), SBMs without straining, and SBMs with a Bristol Stool Scale (BSS) Score of 3 or 4 in adult (age 18–80 years) subjects with chronic non-cancer pain and OIC. Subjects were required to not be on laxatives at screening or to agree to discontinue laxatives upon signing informed consent. The mean changes in the frequency per week from baseline to each week was compared between NAL and PBO, with a mixed-effects model repeated measures with opioid dose strata and study as a covariate and treatment group, time, time-by-treatment group interaction as fixed effects. Safety was assessed based on the incidence of adverse events (AEs).

Results

In the two studies pooled, 1095 subjects were randomized 1:1 to NAL (N = 549) or PBO (N = 546) for 12 weeks. In all four endpoints, NAL was associated with a significantly (P≤0.0001) greater improvement from baseline at each week relative to PBO.  The improvement in all in the symptoms started at Week 1 and persisted to Week 12. The overall incidence of AEs was generally similar between groups. Treatment with NAL was associated with a greater incidence of gastrointestinal AEs (abdominal pain, diarrhea, nausea) compared with PBO.

Conclusions

Treatment with NAL over 12 weeks compared with placebo improved the four key defining components of OIC (frequency, incomplete evacuation, straining, and hard stools).  This is demonstrated by the increase in the frequency of SBMs, increase in the number of CSBMs (reduction in the perception of incomplete evacuation), increase in the frequency of SBMs without straining (reduced need for straining), increase in the number of SBMs with a Bristol Stool Scale of 3 or 4 (reduction in hard stools), and was well tolerated.  These data illustrate the efficacy and safety of NAL in treating OIC  in chronic non-cancer pain patients.

35 Long-Term Impact of Fremanezumab on Response Rates, Acute Headache Medication Use, and Disability in Patients with Episodic Migraine: Interim Results of A One-Year Study

Jan Brandes¹, Paul Yeung², Joshua Cohen², Sanjay Gandhi², Ronghua Yang², Ernesto Aycardi²

¹Nashville Neuroscience Group, Nashville, TN, USA, ²Teva Pharmaceuticals, Frazer, PA, USA

Purpose

Fremanezumab, a fully humanized monoclonal antibody(IgG2∆a) targeting the calcitonin gene-related peptide (CGRP) ligand, has demonstrated  to be an efficacious and safe preventive therapy in 3-month episodic migraine (EM) studies.  This analysis assesses the long-term effect of fremanezumab in the prevention of episodic migraine.

The purpose was to investigate the long-term effect of fremanezumab on response, acute headache medication and disability in adults with EM.  

Methods

This is a 52-week, multicenter, randomized, double-blind, parallel-group study to evaluate the long-term safety, tolerability and efficacy of fremanezumab in adults with migraine that also assessed disability using the Migraine Disability Assessment (MIDAS).  Most patients rolled over from a pivotal EM study, but some patients enrolled directly into this long-term study.  Patients were assigned to one of two subcutaneous dose groups: (1) monthly dosing: 225 mg doses of fremanezumab every month, or (2) quarterly dosing: 675 mg doses of fremanezumab every 3 months.  Percentage of patients achieving at least a 50% reduction in monthly average number of migraine days, the mean change from baseline in the monthly number of days of use of any acute headache medications, and the mean change from baseline in MIDAS score were assessed for both doses.

Results

This study enrolled 780 EM patients.  In this interim analysis, the mean change in monthly number of migraine days from baseline to month 1 was −4.6 days for the 225 mg monthly treatment group and −4.9 days for the 675−mg quarterly treatment. The proportion of patients achieving at least a 50% reduction in monthly average number of migraine days at month 6 was 61% with monthly dosing, and 65% with quarterly dosing. The mean change in monthly number of days of use of any acute headache medications from baseline to month 6 in patients with EM was −4.1 days in the 225−mg monthly treatment group and −4.3 days in the 675−mg quarterly treatment group.  The change from baseline in the MIDAS disability score in patients with EM was similar in both the fremanezumab 225 mg monthly and fremanezumab 675 mg quarterly treatment groups at month 6; disability scores decreased by 27.1 and 27.3 at month 6 for patients who received both 225 mg monthly and 675 mg quarterly, respectively. For a subset of patients who had completed the entire 12 month treatment period, data available at the cutoff date indicated that the response achieved at month 6 was maintained throughout the treatment period to month 12.

Conclusions

Efficacy and disability data from this interim analysis indicated that the level of efficacy observed at month 1 of this study was maintained during the remainder of the study.

36 Early Onset of Action with Fremanezumab Versus Placebo for the Preventive Treatment of Chronic Migraine

Jan Brandes¹, Paul Yeung², Ronghua Yang², Melissa Grozinski-Wolff², Yuju Ma², Ernesto Aycardi², Tricia Blankenbiller², Marcelo Bigal²

¹Nashville Neuroscience Group, Nashville, TN, USA, ²Teva Pharmaceuticals, Frazer, PA, USA

Purpose

Migraine prevention, with earlier onset of action, could increase benefit to migraine patients.  Fremanezumab is a fully-humanized monoclonal antibody (IgG2∆a) that selectively targets calcitonin gene-related peptide (CGRP).

The purpose of this analysis is to assess the early onset of action of fremanezumab in the prevention of chronic migraine.

Methods

A 16-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group study comparing the efficacy, safety, and tolerability of 2 subcutaneous dose regimens of fremanezumab and placebo in adults with chronic migraine (CM).  Patients  were randomly assigned to 1 of 3 treatment groups: (1)monthly dosing: 675 mg fremanezumab followed by 225 mg fremanezumab at months 2 and 3, (2)quarterly dosing: 675 mg fremanezumab at month 1, followed by placebo injections at months 2 and 3, and (3)monthly administration of matching placebo.  The primary efficacy endpoint, mean change from baseline to the 12-week treatment period in monthly average number of migraine days, was analyzed using an ANCOVA or the Wilcoxon rank sum test. Mean change from baseline to weeks 1−4, after 1^st dose was analyzed using a mixed-effect model for repeated measures.

Results

Statistically significant reduction in number of monthly headache days of at least moderate severity was experienced during the 12-week period after 1st dose for both fremanezumab dosing regimens [monthly(−4.6 days);quarterly(−4.3 days); p< 0.0001] vs. placebo(−2.5 days), and during the 4-week period after 1st dose, for both dosing regimens (p < 0.0001).  Fremanezumab resulted in significant reduction in the weekly number of headache days of at least moderate severity:

Week 1, (−1.1 days; p < 0.0001) versus placebo (−0.5 days) 

Week 4, (−1.1 days; p = 0.0006) versus placebo (−0.7 days)

Posthoc analysis indicated more patients reported no headache of at least moderate severity [fremanezumab(69%; p=0.0036) versus placebo(61%)] by the next day following first injection.

Conclusions

Onset of action with fremanezumab occurred rapidly for preventive treatment of migraine and significant improvement was maintained for both dosing regimens.

37 Early Onset of Action with Fremanezumab Versus Placebo for the Preventive Treatment of Episodic Migraine

Jan Brandes¹, Paul Yeung², Ronghua Yang², Yuju Ma², Melissa Grozinski-Wolff², Ernesto Aycardi², Marcelo Bigal²

¹Nashville Neuroscience Group, Nashville, TN, USA, ²Teva Pharmaceuticals, Frazer, PA, USA

Purpose

Migraine prevention is intended to reduce the frequency, severity, and disability associated with migraine attacks, and faster onset of action could increase benefit to patients with migraine.  Fremanezumab is a fully-humanized monoclonal antibody (IgG2∆a) that selectively targets calcitonin gene-related peptide. 

The purpose of the analysis was to assess the early onset of action of fremanezumab in the prevention of episodic migraine (EM).

Methods

A 16-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group study comparing the efficacy, safety, and tolerability of 2 subcutaneous fremanezumab dose regimens and placebo in adults with EM.  Patients randomly assigned to 1 of 3 treatment groups: (1)monthly dosing: 225 mg fremanezumab at months 1, 2 and 3, (2)quarterly dosing: 675 mg fremanezumab at month 1, followed by placebo injections at months 2 and 3, and (3)monthly administration of matching placebo.  The mean change from baseline in the monthly average number of migraine days assessed using a mixed-effect model for repeated measures.

Results

Statistically significant reduction in the monthly average number of migraine days experienced during the 12−week period after 1st dose for both fremanezumab dosing regimens [monthly (−3.7 days);quarterly (−3.4 days); p< 0.0001] vs. placebo (−2.2 days), and during the 4 week period after 1st dose, for both dosing regimens (p < 0.0001).  Fremanezumab dosing resulted in significant reduction in the weekly number of migraine days,

Monthly:

At Week 1, (−0.9 days; p < 0.0001) versus placebo (−0.3 days) 

At Week 4, (−0.9 days; p = 0.0123) versus placebo (−0.6 days)

Quarterly:

At Week 1, (−0.8 days; p < 0.0001) versus placebo (−0.3 days) 

At Week 4, (−0.8 days; p = 0.0403) versus placebo (−0.6 days)

Posthoc analysis indicated more fremanezumab patients reported no migraine days [monthly (79.4%; p = 0.0002); quarterly (79.2%; p = 0.0004) versus placebo (66.6%)] by the next day following first injection.

Conclusions

Onset of action with fremanezumab occurred rapidly for preventive treatment of EM. Significant improvement was maintained for monthly and quarterly dosing regimens.

38 Content Validity of a Survey to Evaluate the Benefits and Risks Associated with Treatments for Pain

Janetta Iwanicki, Ruth Magtanong, Joshua Black, Richard Dart

Rocky Mountain Poison and Drug Center, Denver, CO, USA

Purpose

Treatment of pain is a major reason that patients seek medical care, and is a major cause of loss of productivity in the workforce. Prescription drug abuse, misuse, and diversion have been studied by the RADARS System in the United States since 2001. However, no current systems collect data specifically on patients self-reporting pain or describe the benefits and risks associated with treatments for pain. As such, a pilot survey utilizing a combination of questions from well-established instruments to evaluate pain, treatments for pain, and risks and benefits associated with these treatments was developed. The objective of this study is evaluate the ease of use, feasibility, and content validity of a self-administered survey evaluating the overall benefits and risks associated with the treatment of pain.

Methods

A single center, prospective, observational study was conducted at a large urban safety-net hospital emergency department from June 2017 through November 2017. Eligible adult patients were recruited and completed a self-administered web-based survey evaluating the overall benefits and risks associated with the treatment of chronic pain. Following survey completion, a standardized semi-structured interview for content validity was performed with survey respondents who reported a history of chronic pain to assess survey readability, question comprehension and interpretation. Descriptive statistics for demographics and qualitative responses are from the content validation interview are reported.

Results

From June 2017 through November 2017, 41 patients were enrolled in the survey pilot study. 36.6% completed the content validation interview. 51.2% of study participants were female. Mean age of participants was 41.8 years, with a range from 18 to 66 years. 55% had total household income of less than $20,000 per year. During the content validation interviews, subjects confirmed that they understood the overall content and intent of questions, and were able to provide meaningful interpretations. However, 46.7% of subjects reported confusion on 12 questions, and recommended changes in wording on 18 questions. Feedback from participants included confusion with use of symbols such as less than (<), use of abbreviations and parentheses, and use of medical terminology.

Conclusions

Overall, the content of this pilot survey to evaluate the risks and benefits of treatment for pain was well understood in this population of emergency department patients in an urban safety-net hospital with low socioeconomic status and low literacy. However, structural elements including the use of symbols and abbreviations caused some confusion. Future versions of this survey will incorporate changes to improve readability in this population.

39 Assessment of Tapentadol API Abuse Liability with the Researched Abuse, Diversion, and Addiction-Related Surveillance (RADARS) System Poison Center Program

Janetta Iwanicki¹, Suzanne Vosburg¹, S. Geoffrey Severtson¹, Richard Dart¹, Theodore Cicero², Steven Kurtz³, Mark Parrino⁴, Jody Green¹

¹Rocky Mountain Poison and Drug Center, Denver, CO, USA, ²Washington University, St Louis, St Louis, MO, USA, ³Nova Southeastern University, Fort Lauderdale, FL, USA, ⁴American Association for the Treatment of Opioid Dependence, New York, NY, USA

Purpose

Tapentadol, a Schedule II opioid with a combination of µ-opioid activity and norepinephrine reuptake inhibition, is used for the management of moderate to severe acute and chronic pain. Its dual-mechanism of action is thought to reduce opioid-related side effects that can complicate pain management. Since approval, tapentadol has been tracked across multiple outcomes and a pattern of relatively low, although not absent, abuse liability has been found. This study compared the rate of intentional abuse of tapentadol active pharmaceutical ingredient (API) to other opioids in the RADARS Poison Center program.

Methods

The number of intentional abuse case mentions reported to the Poison Center program from fourth quarter 2011 through second quarter 2016 were analyzed and compared to 7 APIs (tapentadol, oxycodone, hydrocodone, oxymorphone, hydromorphone, morphine, tramadol). Rates were calculated per quarter using 3 denominators: population, total number of prescriptions dispensed, and total number of dosage units dispensed. Confidence intervals (CI) were calculated using the exact Poisson method, and rate ratios comparing the cumulative rates of abuse for each opioid to tapentadol were calcuated using a saturated Poisson regression.

Results

From fourth quarter 2011 through second quarter 2016, there were 87 mentions of tapentadol product intentional abuse exposure cases reported to participating poison centers. When adjusted per population, rates of tapentadol intentional abuse were the lowest among all products (0.007−0.036/1,000,000 population).The average quarterly rate was 0.015 (95% CI 0.012−0.019) per 1,000,000 population. The rate ratio between tapentadol and comparators showed other APIs were intentionally abused at rates of 7.414 (oxymorphone) to 84.322 (oxycodone) times the rate of tapentadol per 1,000,000 population. When adjusted for drug availability, tapentadol had neither the largest nor the smallest rate of intentional abuse. Average quarterly rate of intentional abuse of tapentadol per 100,000 dosing units dispensed was 0.028 (95% CI 0.023−0.035), while rates were greatest for oxymorphone (0.166, 95% CI 0.153-0.179), and lowest for hydrocodone (0.020, 95% CI 0.019 to 0.020).

Conclusions

The rate of intentional abuse of tapentadol is the lowest of all APIs evaluated when adjusted per population. When adjusted for drug availability, rates were neither the highest nor the lowest. It is important to note that in some instances, utilization rates may be largely driven by the volume of drug dispensed (i.e., small vs. large denominator) rather than by actual abuse cases (i.e., the numerator).  This phenomenon becomes particularly important when comparing products with low vs. high utilization volumes (e.g., tapentadol vs. hydrocodone or oxycodone).  Therefore, it is critical to assess utilization rates in the context of population rates and raw abuse endorsements in order to obtain a clear understanding of the overall abuse of a product. RADARS Poison Center program data suggest that tapentadol intentional abuse presents a low but present public health burden.

40 Nucynta ER abuse profile: an evaluation of abuse and route of administration among individuals receiving substance abuse treatment

Jared Beaumont, Jody L. Green, Taryn Dailey Govoni, Stephen F. Butler

Inflexxion, Inc, Waltham, MA, USA

Purpose

The current opioid crisis in the United States is well documented, including the role of prescription opioids and the rise of heroin and illicitly manufactured fentanyl. Despite risks, prescription opioids have an important role in analgesia therapy as demonstrated by the July 2018 statement by FDA Commissioner Dr. Gottlieb to “enable appropriate access to those patients who have legitimate medical need for these medicines”. Safety measures intended to reduce risk of abuse/misuse include development of prescription opioids with abuse-deterrent properties as well as the use of atypical opioids that have different mechanisms of action such as tapentadol. Tapentadol is a centrally acting analgesic that differs from other opioids in that it has two mechanisms of action: µ-opioid receptor agonism and noradrenaline reuptake inhibition. Tapentadol has a lower affinity to the μ-opioid receptor compared to morphine and its noradrenaline reuptake inhibition may be less rewarding compared to other opioids. Previous reports suggest lower rates of abuse for tapentadol-containing products compared to other schedule II opioid analgesics as reported to poison centers and substance abuse treatment centers as well as lower rates of diversion as reported through a law enforcement network. Nucynta extended-release (ER) is the sole ER tapentadol-based product approved in the United States. In light of the unique properties of tapentadol, this analysis aims to examine the abuse profile of Nucynta ER compared to ER opioids with FDA abuse-deterrent labeling and non abuse-deterrent ER opioids.

Methods

Data were collected over a four-year period (January 2014 through December 2017) from the National Addictions Vigilance Intervention and Prevention Program (NAVIPPRO®) Addiction Severity Index–Multimedia Version (ASI-MV®). NAVIPPRO ASI-MV consists of a network of substance abuse treatment centers throughout the United States. A standard clinical interview collects self-reported data on past 30-day abuse of product-specific prescription medications as well as alcohol and illicit substances. Based upon the patient’s responses, the ASI-MV provides a validated score indicative of the severity of addiction (the higher the score the more severe the addiction). Data are also collected on the route of administration. Distribution of demographics is presented for each study group. Abuse prevalence estimates were calculated yearly and for the aggregate time period for Nucynta ER and two comparators: 1) ER opioids with FDA abuse-deterrent labeling (abuse-deterrent formulation, or “ADF opioids”) and 2) non abuse-deterrent ER (“non-ADF opioids”). Rates were first calculated using number of abuse cases per 100 ASI-MV assessments and were then adjusted for drug utilization (number of abuse cases per 100 ASI-MV assessments per 1,000,000 tablets dispensed). Drug utilization data was obtained from IQVIA. Distribution of routes of administration are also described for each study group.

Results

A total of 205,189 adults were assessed at 776 centers in the United States. The majority of Nucynta ER abusers were between 18 and 34 years old (58.7%), male (65.2%), and white (67.4%). Abusers of ADF ER opioids and non-ADF ER opioids were mostly between 18 and 34 years old (68.0% and 67.4%, respectively), were evenly split by gender (51.6% and 47.5%, male respectively), and white (80.1% and 86.2%, respectively). Abusers of Nucynta ER had lower drug severity ratings than abusers of ADF ER opioids and non-ADF ER opioids (67.4%, 83.8%, and 85.1% respectively).

During the study period, abuse rate per 100 ASI−MV assessments was greatest for non−ADF ER opioids (3.55; 95% Confidence Interval (CI) 3.47−3.63), followed by ADF ER opioids (2.61; CI 2.54−2.68), then Nucynta ER (0.023; CI 0.017−0.03). Annual abuse rates of Nucynta ER were relatively stable (ranging from 0.22 to 0.24 cases/100 assessments annually). Annual abuse rates of ADF ER opioids ranged between 1.96 and 3.41 cases/100 assessments annually and non−ADF ER opioids ranged between 3.05 and 3.84 cases/100 assessments.  When adjusted for drug utilization (number of tablets dispensed), abuse of Nucynta ER (0.009 cases/100 assessments/1,000,000 tablets; CI 0.006−0.011) was statistically significantly lower than ADF ER opioids (0.064; CI 0.062−0.066) and non−ADF ER opioids (0.045; CI 0.044−0.046). Annual tablet−adjusted abuse rates were stable throughout the study period with the exception of one significant decrease in ADF ER opioid rates from 2014 to 2015.

Of Nucynta ER abusers, 58.7% reported swallowing the product whole, while a smaller proportion reported using other oral routes (i.e., chewing, dissolving in mouth, or drinking after dissolved in liquid; 17.4%), snorting (2.2%), or injecting (10.9%). Abusers of ADF ER opioids reported swallowing whole (53.8%), other oral routes (23.5%), snorting (29.3%), and injecting (26.1%). Abusers of non-ADF ER opioids reported swallowing whole (35.0%), other oral routes (11.3%), snorting (39.0%), and injecting (42.9%). These patterns were consistent during the study period for Nucynta ER and ADF ER opioids.

Conclusions

This analysis of adults entering substance abuse treatment centers across the United States suggests that Nucynta ER is associated with lower rates of abuse than that of other schedule II opioid analgesics, including those with ADF labeling.  Of the three groups studied, Nucynta ER had the lowest reported abuse rate even when adjusted for drug utilization. As suggested by previous publications, the lower abuse rate may be related to the dual mechanism of action unique to tapentadol as an active pharmaceutical ingredient. When abuse was reported it was most often via swallowing the product whole. Non-ADF opioid products were more frequently abused via routes that require manipulation of the product (snorting and injecting) which more than doubles the risk of a life-threatening event. In summary, the abuse profile of Nucynta ER indicates less risk of abuse and less use via alternate routes than other schedule II opioid analgesics.

41 Nursing Knowledge and Attitudes Regarding Pain in a Tertiary Hospital in the Southeastern United States

Jeanne Dockery, Rebecca Langner, Connie White-Williams

The University of Alabama at Birmingham Hospitals, Birmingham, Alabama, USA

Purpose

Pain is a common patient experience during hospitalizations with intensity varying according to underlying etiology. Ineffective pain management may cause physiological and emotional consequences for patients. Hospitals may experience prolonged length of stays, poor clinical outcomes, patient readmissions, and decreased patient satisfaction. Inadequate nursing knowledge regarding pain assessments and management as well as misperceptions regarding pain are cited in the literature as barriers to effective pain management.

Despite a hospital educational pain symposium and various hospital pain committee initiatives, this tertiary Hospital’s “pain domain” on HCAHPS is consistently lower than the desired benchmark with only 72.3% of patients marking “always.”

The purpose of this study was to examine frontline nurses’ knowledge of pain management and to identify pain control biases that may serve as barriers to effective pain management. 

Methods

As part of a quality improvement project, the Knowledge and Attitudes Regarding Pain Survey which consists of 38 questions (20 true/false, 14 multiple choice, and 4 case study), was sent electronically to an “all RN” (N=3627) group at a tertiary hospital in the Southeastern United States on April 11, 2018 with a follow-up email sent May 31, 2018. Demographic information collected was age, years of nursing experience, education level, gender, work area, religious affiliation, ethnicity, work shift, and personal experience with acute and chronic pain. Descriptive statistics were used to analyze the data.

Results

A total of 425 nurses responded to the survey. Not all nurses answered every question. Nurses were between the ages of 21 and 68, 90% female, 85% Caucasian, 11% African American, 2.5% Asian, 9% Native American/Pacific Islander, 1% American Indian/Alaskan. Educational level of respondents was  ADN (19.48%), BSN (64.37%), MSN (12.59%), DNP (2.61%) and PhD (0.95%). Years of nursing experience were 0-2 years (31.82%,), 3-5 years (16.75%), 6-10 years (11.72%,) and over 10 years (39.71%). Nurses reported their religious affiliation as Christian (78.97%), Catholic (5.38%), Muslim (0.49%), Atheist (2.44%), and non-religious (10.51%). Nurses worked day shift (64.4%) or night shift (35.5%) in the following areas critical care (27.78%), acute medical-surgical (34.30%), obstetrics (5.07%), neonatal (3.62%), psychiatric (1.21%), emergency room (4.35%), operative services (5.56%), special procedures (2.42%), oncology (10.87%), and ambulatory clinic (4.83%). Most nurses had a personal experience with acute pain (81.7%), but did not have a personal experience with chronic pain (53.7%).

On The Knowledge and Attitudes Regarding Pain Survey, nurses incorrectly answered the following:

- Aspirin and other nonsteroidal anti-inflammatory agent are NOT effective analgesics for painful bone metastases – 48.96%

- Respiratory depression rarely occurs in patients who have been receiving stable doses of opioids over a period of months – 51.20%

- The usual duration of analgesia of 1-2mg morphine IV is 4-5 hours – 26.64%

- Research shows that promethazine (Phenergan) and hydroxyzine (Vistaril) are reliable potentiators of opioid analgesics – 66.90%

- Opioids should not be used in patients with a history of substance abuse – 23.45%

- Norco (Hydrocodone 5mg + Acetaminophen 325mg) po is approximately equal to 5−10mg of morphine po – 74.48%

− If the source of the patient’s pain is unknown, opioids should not be used during the pain evaluation period, as this could mask the ability to correctly diagnose the cause of pain – 49.47%

- Benzodiazepines are not effective pain relievers unless the pain is due to muscle spasms – 50.70%

- A patient with persistent cancer pain has been receiving daily opioid analgesics for 2 months. Yesterday the patient was receiving morphine 200mg/hour intravenously. Today he has been receiving 250mg/hour intravenously. The likelihood of the patient developing clinically significant respiratory depression in the absence of new comorbidity – 89.59%

- The time to peak effect for morphine given orally – 37.92%

- Following abrupt discontinuation of an opioids, physical dependence is manifested by – 79.10%

Conclusions

Inadequate nursing knowledge or misperceptions regarding pain management are barriers to effective pain management. This, in turn, can lead to adverse consequences for the patient. Examining knowledge and attitudes of frontline staff assists nursing leadership to design educational strategies for overcoming ineffective pain management, and ultimately improving HCAHPS pain scores.

42 False-Positive 6-mono acetyl morphine (6-MAM) Saliva Test Result In a Patient Taking Morphine and Aspirin: A Case Report

Jeffrey Fudin¹, Jeffrey Bettinger¹, Erica Wegrzyn¹, Jacqueline Cleary²

¹Stratton Veteran Affairs Medical Center, Albany, New York, USA, ²Albany College of Pharmacy and Health Sciences, Albany, New York, USA

Purpose

The purpose of this case report is to outline how a reported 6-MAM saliva test by liquid chromatography mass spectrometry (LCMS) result could have occurred in a patient taking regularly scheduled morphine and as needed oxycodone, in the absence of illicit heroin use.

Methods

Patient medical records were used to present a patient case report for poster presentation. The patient signed a consent and all researchers have signed agreements consistent with and abiding by all HIPPA regulations. No patient specific identifiers were used in the creation of this case report.

Results

This is a case of a 48 -year old female with lumbar spinal, hip, and lower extremity pain who took an oral fluid (saliva) drug test in September, 2016 as part of initial evaluation by a private pain management clinic. At the time, pertinent medications she was taking included oxycodone/acetaminophen 10/325mg by mouth every 6 hours, MS Contin (morphine) 15mg by mouth every 12 hours, gabapentin 400mg by mouth every 6 hours, methocarbamol 750mg by mouth every 8 hours, aspirin 81mg by mouth once daily, and Excedrine brand aspirin almost daily as needed.  The patient also reported eating at Olive Garden frequently, often eating soup and salad with house dressing (containing oil and vinegar), as well as regularly ingesting honey, vinegar, and cinnamon for health benefits. The saliva test was confirmed by LCMS showing unexpected positive results for buprenorphine, 6-MAM, and codeine, as well as expected positive results of morphine, noroxycodone, oxycodone, and oxymorphone. The patient’s opioids were tapered to discontinuation due to the abnormal results indicating use of heroin (6-MAM) and unprescribed buprenorphine and codeine.

Heroin chemically is diacetyl morphine, which is two morphine molecules connected by a 2-carbon (acetyl) chain. Heroin is metabolized into two morphine molecules, where one of the molecules retains the acetyl group at the “6” position (6-MAM metabolite). This same acetyl chain is seen in molecules including vinegar (acetic acid) and aspirin (acetyl salicylic acid).

While there are reports of false positive 6-MAM in patients on morphine when tested by gas chromatography/mass spectrometry (GCMS), generally, LCMS is more accurate and those same results were found to be negative. However, there have been in-vitro studies that showed 6-MAM formation by co-administration of morphine and aspirin, whereby aspirin donates the acetyl group to morphine to form 6-MAM. We believe that it is possible, and in fact plausible (after interviewing the patient and reviewing her history prior to and following the test results) that her use of aspirin, ingesting vinegar on her salad in close proximity to the test, and/or use of vinegar products in her tea (which all contain acetyl groups) could have interacted with morphine and donated their acetyl groups to the morphine molecules to form 6-MAM in the saliva. While this is a true 6-MAM rather than a false positive, the source of the 6-MAM we believe was not from heroin.

Conclusions

This case report showed that a positive 6-MAM result by oral fluid drug testing could have been caused by co-administration of morphine and aspirin, as well as ingestion of vinegar (from salad in close proximity of the test and from supplements), whereby aspirin and/or vinegar could have donated their acetyl group to morphine to form the 6-MAM compound. This knowledge may help guide future providers in the appropriate analysis of oral fluid drug testing, including utilizing confirmatory testing methods (by urine and/or blood) to help determine absolute presence of certain medications/compounds in a patient.

43 Development of a VA Protocol for Buprenorphine Use Perioperatively for Elective and Emergency Procedures

Jeffrey Fudin¹, Nayma Moya Romero², Jeffrey Bettinger¹, Abigail Brooks², Sandra DiScala², Christine Vartan²

¹Stratton Veteran Affairs Medical Center, Albany, New York, USA, ²West Palm Beach Veteran Affairs Medical Center, West Palm Beach, Florida, USA

Purpose

Buprenorphine is a mu-opioid receptor partial agonist and kappa receptor antagonist that has Food and Drug Administration approval for the treatment of opioid use disorder, acute pain, or chronic pain, depending on the formulation. Buprenorphine has unique pharmacologic and pharmacokinetic characteristics that make treating acute pain in patients on long term buprenorphine therapy a challenge. Because it binds very tightly to the mu-opioid receptor, opioid agonists at safe/low doses cannot displace the molecule from the receptor when these medications are used to treat acute pain in those patients on chronic or long-standing buprenorphine treatment. There are several buprenorphine formulations approved in our country. Buprenorphine for opioid use disorder can be prescribed as buprenorphine alone (Subutex®, Sublocade®) or in combination with naloxone (Suboxone^TM, Zubzolv®, Bunavail^TM), for acute pain there is a parenteral formulation (Buprenex®), and for the treatment of chronic pain there is a buccal film (Belbuca^TM) and a transdermal patch (Butrans®).  

In the perioperative setting, either as an elective or emergency procedure, managing the expected post-surgical pain becomes very challenging, and procedures on how to approach this clearly is an unmet need. This is still an area that requires a multidisciplinary approach to tackle several challenging dilemmas. The need for a comprehensive protocol is essential especially when considering the number of patients currently receiving buprenorphine. The purpose of this literature review is to obtain information that will allow the development of a protocol for perioperative management of patients on chronic buprenorphine therapy.

Methods

In consideration of developing an open access perioperative protocol for how to treat patients receiving buprenorphine when faced with elective versus emergent surgery, we started by querying PubMed for published articles related to procedures or studies of buprenorphine use perioperatively for any type of surgical procedure. The search was limited to studies within the past 5 years, in humans subjects, written in English, and studied in adults at least 19 years of age. Search terms included buprenorphine, acute pain, acute pain management, perioperative pain, elective and emergency procedures, opioid maintenance, and opioid addiction. In addition, another search was performed including community resources such as paindr.com and professional organization websites (American Pain Society and American Society of Addiction Medicine) to obtain a more comprehensive list of articles related to this topic.

Background knowledge of the pharmacokinetic and pharmacodynamic properties of buprenorphine, opioids used in the treatment of acute pain, and principles of receptor saturation were also considered, and used to help guide authors in the creation of the protocol, which will be designed to include all the currently approved buprenorphine formulations with consideration to pipeline products as well. The policy is to be divided by procedures for management of elective versus emergency surgeries, as different factors must be considered respectively.

Results

Extensive literature search was performed to obtain information that would aid in the creation of this protocol for buprenorphine use in perioperative setting. Upon examination of the literature, with the limitations stated in the methods section for PubMed and the articles listed in the community resources and organization websites reviewed, it was found that as of July 12, 2018, there are no controlled prospective human trials outlining such procedures for treating acute pain in patients on buprenorphine therapy perioperatively. There are two case studies, five case series, two retrospective cohorts, two in-vitro studies, two safety studies, six pharmacokinetic studies, one observational study, and thirty-one review articles that have been published and will be utilized to create the proposed protocol.

Conclusions

No current guidelines, policies, or protocols exist to guide clinicians in the treatment of pain from elective or emergent procedures in patients receiving buprenorphine therapy outpatient. With the limited evidence available in this subject, protocol recommendations should reasonably be developed to guide clinicians on how to manage this complex patient population. Our team will therefore outline important considerations for developing such a protocol and embark on the development of a reasonable approach to help providers appropriately, safely, and effectively manage surgical and post-surgical (elective or emergency) pain in patients on buprenorphine. We will also use this information to encourage a professional organization to embark on developing consensus guidelines.

44 Concurrent Use of Opioid and Benzodiazepine:What the Prescription Drug Monitoring Database Does Not Tell You

Jeffrey Gudin¹, Fred Leland McClure², Justin Niles², Harvey Kaufman²

¹Englewood Hospital and Medical Center, Englewood, NJ, USA, ²Quest Diagnostics, Secaucus, NJ, USA

Purpose

Opioid-related morbidity and mortality are well recognized issues in the United States, but unlike opioid prescribing, which has stabilized or decreased, benzodiazepine prescribing continues to rise. For 2015, more than 30% of the estimated 33,000 opioid-related deaths also involved benzodiazepines. From 2002 to 2015 there was a 4.3-fold increase in the total number of benzodiazepine-related deaths. Our previous studies demonstrated that the use of prescription data alone may underestimate the extent of concurrent opioid and benzodiazepine use. To gain further insights into the extent of concurrent opioid and benzodiazepine drug use, we analyzed prescription patterns in the context of laboratory drug testing results reported during 2017.

Methods

All specimens from patients who were prescribed at least 1 drug and were tested for both opioids and benzodiazepines by a national reference laboratory were included. The analytical data set included more than 456,675 test results from 276,953 patients who had diverse demographic factors and were tested in a variety of health care settings. When describing demographics at the patient level results were limited to each patient’s first test result. 

Results

Concurrent use of opioids and benzodiazepines was indicated in over 20% (95,648) of laboratory test results. For patients whose test results indicated concurrent use, 36% (34,059) had been prescribed both drug classes and 64% (61,589) had at least one non-prescribed. Nearly 1 in 6 specimens (16%) that tested positive for prescribed opioids also tested positive for non-prescribed benzodiazepines. Similarly, 13% of specimens that tested positive for prescribed benzodiazepines also tested positive for non-prescribed opioids.

Conclusions

Clinicians should be aware of potentially dangerous drug interactions including those of non-prescribed agents. The extent of concurrent use of benzodiazepines and opioids, particularly non-prescribed use, cannot be determined by prescription drug database monitoring programs, suggesting the need for more effective clinician assessment and intervention. Our results support the Centers for Disease Control and Prevention (CDC) opioid prescribing guidelines, which indicate that drug testing should occur before and periodically throughout opioid use and that testing should be extended to patients prescribed benzodiazepines as well.

45 Treatment Patterns and Medication Use in Patients with Postherpetic Neuralgia

Jeffrey Gudin¹, Jennifer Gilbert², Thomas Goss², Kalpana Patel³

¹Englewood Hospital and Medical Center, Englewood, NJ, USA. ²Boston Healthcare Associates, Inc., Boston, MA, USA. ³Scilex Pharmaceuticals Inc, Mission Viejo, CA, USA

Purpose

Background: Postherpetic neuralgia (PHN) is a frequent complication of herpes zoster (HZ) infection characterized by chronic neuropathic pain. Evidence-based guidelines for 1st line PHN treatment (tx) – including American Academy of Neurology, European Federation of Neurological Societies, & Special Interest Group on Neuropathic Pain – recommend lidocaine patches (LIDO), gabapentin (GBP), pregabalin (PGB), or tricyclic antidepressants (TCA). Opioids & capsaicin are sometimes recommended as 2nd or 3^rd line tx. Nonsteroidal anti-inflammatory drugs (NSAIDs) are not recommended.Objective: Explore treatment patterns & healthcare utilization associated with PHN diagnosis (dx) & treatment (tx).

Methods

Methods: We examined medical & pharmacy claims from 2010–2014 in Truven Health Analytics MarketScan Commercial & Medicare Supplemental databases (n = 232 million) to compare tx patterns & healthcare utilization in adults with PHN. Patients (pts) were identified by a dx of HZ & met PHN dx criteria reported by Klompas (2011) or received newly prescribed LIDO tx within 60 days of HZ dx. Tx patterns are reported for pts < 65 (n = 42,465) & ≥ 65 years (n = 20,806) based on tx newly initiated after dx.

Results

Results: Of the 0.4% of pts < 65 & 1.3% ≥65 years diagnosed with HZ, 14% & 34% of pts, respectively, were subsequently diagnosed with PHN & patterns of initial analgesic use were observed. 29% of pts were started on a tx recommended as 1st line tx in PHN tx guidelines (LIDO 8% of pts, GBP 15%, PGB 3%, or TCA 2%). 22% of pts were started on opioids & 9% started on NSAIDS, which are not recommended in guidelines. Opioids (22% of pts) & GBP (15% of pts) were the most common initial tx in both age groups. In younger pts, NSAIDs were used prior to 1st or 2nd line tx more frequently (11% of pts < 65 versus 6% of pts ≥65; p < 0.001).

Conclusions

Conclusions: Recommended 1st line txs are underutilized in PHN pts. Despite evidence of inefficacy for neuropathic pain, NSAIDs are frequently prescribed for PHN pts & likely to be even more frequently used in these pts when overthecounter use is considered. These analyses indicate substantial opportunity for provider & payer education related to benefits of improved adherence to guidelines for 1st line PHN tx. The elderly population more commonly affected by PHN are at increased risk for tx AEs. Our data indicate that more than 1 in 5 pts with PHN is started on opioids as 1st line tx. Choosing the right analgesic for an older adult can be challenging for a number of reasons, including comorbidities, polypharmacy, physiological changes, and cognitive challenges.

46 Adhesion Performance of 3 Lidocaine Patch Formulations

Jeffrey Gudin¹, Sri Nalamachu², Charles Argoff^3,4, Emileigh Greuber⁵, Kalpana Patel⁶, Kip Vought⁶

¹Englewood Hospital and Medical Center, Englewood, NJ, USA, ²Mid America PolyClinic, Overland Park, KS, USA, ³Albany Medical College, Albany, NY, USA, ⁴Albany Medical Center, Albany, NY, USA, ⁵Clinipace Worldwide, Morrisville, NC, USA, ⁶Scilex Pharmaceutcals, Inc., Mission Viejo, CA, USA

Purpose

BACKGROUND: In general, skin adhesion is one of the most important properties of topical systems/patches as it contributes directly to the optimal efficacy, safety, and patient compliance.¹ Furthermore, lack of proper adhesion can result in heightened need for more frequent patch replacement which can in turn increase the treatment cost for the patient.¹  This is especially the case for drug-in-adhesive systems such as ZTlido™ (lidocaine topical system) 1.8% (ZTlido), and Lidoderm® Patch 5% (Lidoderm) and the currently marketed generics of Lidoderm® 5%.  Because the drug is contained in the adhesive of these products, any area of the adhesive not maintaining contact with the skin compromises adequate delivery of the drug. ZTlido 1.8%, a thin, single-layer, anhydrous drug-in-adhesive delivery system, is a recent FDA approved system that demonstrated bioequivalence to Lidoderm 5% in a pivotal clinical study.     

OBJECTIVES: To describe and compare the adhesion characteristics of two branded lidocaine topical system/patch products (ZTlido and Lidoderm).  Note that this study included Versatis® Medicated Plaster 5% (Versatis), which is the same product as Lidoderm 5% but marketed under a separate tradename overseas.  Because Lidoderm and Versatis are the same product, only data for ZTlido 1.8% and Lidoderm 5% is presented.

Methods

METHODS: An open label, three-period, single-application, study in 47 healthy, adult, human subjects evaluated adhesion performance of ZTlido, Lidoderm and Versatis.  Three topical systems/patches of each study product were placed on the back of each subject for a 12-hour dosing period. Trained study personnel recorded percent adhesion of each patch at 0, 3, 6, 9, and 12 hours after application.  The percent adhesion was also converted to a 5-point FDA recognized scoring system. Skin irritation was evaluated at 30 minutes and 2 hours post-patch removal.

Results

RESULTS: Forty-four (44) subjects completed the study; (three subjects were unable to return for evaluation due to inclement weather).  Mean percent [90% CI] adhesion is as follows for ZTlido vs. Lidoderm respectively, at each time point: 0hr 99.9% [99.2,100] vs. 97.1% [96.4,97.8]; 3 hrs. 95.6% [92.4,98.8] vs. 82.5% [79.2,85.7]; 6 hrs. 93.1% [89.2,97.0] vs. 78.2% [74.3,82.1]; 9 hrs. 92.3% [87.6,96.9] vs. 72.4% [67.8,77.1]; 12hrs. 91.3% [85.7,96.8] vs. 64.3% [58.7, 69.8].  ZTlido demonstrated statistically significant superior percent adhesion for all time points compared to Lidoderm.  A significantly larger number of ZTlido subjects were able to maintain ≥90% adhesion (FDA score 0: essentially no lift off the skin) at 12 hours post-application time point (33/44 subjects, 75.0%) compared to Lidoderm (6/44 subjects, 13.6%).  The dermal response score was either 0 (no irritation) or 1 (mild erythema, barely perceptible) for all assessments at each time point for both ZTlido and Lidoderm. There was no significant difference in the mean irritation scores between the two products at 30 minutes and 2 hours post-topical system/patch removal. There were no AEs during the study.

Conclusions

CONCLUSIONS:  ZTlido was well-tolerated and demonstrated a statistically superior adhesion profile with 75% of subjects maintaining ≥90% adhesion compared to Lidoderm with 13.6% of subjects at 12-hours. This adherence profile should contribute to consistent drug delivery, minimize inappropriate patch replacements, and may have potential patient compliance and pharmacoeconomic benefits.

References

• Wokovich AM, Prodduturi S, Doub W, et al. Transdermal drug delivery system (TDDS) adhesion as a critical safety, efficacy and quality attribute. Eur J Pharmaceutics Biopharmaceutics. 2006;64:(1):1–8.
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47 What are Your Patients Using (and How Do You Know): Using Clinical Laboratory Results to Understand Drug Use Patterns In A State-Wide Model

Jill Warrington^1,2, Gregory Warrington²

¹Aspenti Health, Burlington, VT, USA, ²University of Vermont, Burlington, VT, USA

Purpose

Identified Substance Use Disorders (SUDs) and/or patterns of aberrant drug use have reached epidemic proportions throughout the United States (1). Pain and SUDs are frequently co-occurring clinical conditions with the potential for misuse of prescribed medications or use of alternative, nonprescribed drugs to manage pain (2).  Treatment for patients with or at risk for SUDs can be very challenging, in part, because providers may not know which drugs a patient is consuming.  For example, patients may not fully disclose their substance use or lack of adherence to treatment (3). Further, clandestine drug manufacturing and substitutions can further complicate the landscape, as the patients themselves may not be fully aware of what drugs they are using. Heroin laced with illicit fentanyl remains a critical example of this phenomenon (4).

With these gaps in knowledge, a keen understanding of drug use patterns within a region is critical to providing adequate patient care. There is a wealth of information on drug use patterns using survey and overdose data (5, 6). Unfortunately, reliance on these sources can provide a skewed perspective for physicians and counselors by relying on outdated information or extreme toxic levels of use rather than day-to-day shifts in use.

We examined the feasibility of using current laboratory data to provide insight into drug use patterns across one state. This clinical data, including geospatial mapping and drug trends over time, provides insight into regional variation and can provide a model of decision support for providers hoping to identify what drugs are accessible to their patients.

Methods

Laboratory data, representing an estimated 1.8 million tests results over one year (March 2016-2017), was obtained from a private diagnostic laboratory located in Burlington VT. A total of over 9,000 unique patients were included, representing approximately 80% of the zip codes across the state. The data spans rural (population <5000 people), suburban (population: 5,000 to 10,000 people) and urban (population >10,000 people). By estimates by Medicare/Medicaid claims data, this is estimated to represent approximately 75% of urine drug testing across the state. Analysis of data was performed using Excel, Anaconda python and Pandas software. Graphics and geospatial mapping were generated using Geopandas, matplotlib and Excel software. The research is characterized as Not Human Subjects Research by the Institutional Review Board at the University of Vermont. The primary objective of this descriptive study was to understand whether or not patterns in use of different substances could be seen across the state and across time. Immunoassay technology has been used to generate the laboratory results.

Results

Through evaluation by geospatial mapping, geographic variation in drug use is observed across the state with eastern regions demonstrating higher rates of positive tests for heroin and fentanyl than western regions. In contrast, opioid and oxycodone use demonstrated little variability across the state. Benzodiazepines and an alcohol metabolite (EtG) demonstrate strikingly similar geographic patterns to one another, supporting the validity of the model. Some drugs of lower abuse potential, such as tapentadol, tramadol, and carisoprodol, did not display enough positive values to warrant conclusions using this model.

Evaluating trends in use over time demonstrated that positive results for general opioids (including morphine, codeine, hydromorphone, hydrocodone) and oxycodone decreased over the year, corresponding to anticipated changing legislation in the state at that time.  Non-opioid analytes evaluated did not change over the same time course.

Conclusions

Use of laboratory data can provide another avenue into understanding drug prevalence across a region. This information can supplement current analysis of existent and emerging drug trends already acquired by other methods including drug seizure data, emergency department overdose rates, forensic findings and patient-provider surveys. Further work beyond this descriptive analysis is necessary to validate this model in comparison to other data sources.

References

• Lipari RN, van Horn SL Trends in substance use disorders among adults aged 18 or older. The CBHSQ Report. National Survey on Drug Use and Health. Substance Abuse and Mental Health Services Administration; 2017 Jun 29. [cited 2018 Jul 26]. Available from: https://www.samhsa.gov/data/sites/default/files/report_2790/ShortReport-2790.html
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48 Using the Pain Self-Efficacy Questionnaire (PSEQ) as a service outcome measure for a community-based chronic pain service

Johanna Theron

Kent Community Health NHS Foundation Trust, Broadstairs, Kent, United Kingdom

Purpose

The NHS in East Kent serves a population of 750 000, managed by five different Clinical Commissioning Groups (CCGs). Pain services consist of a comprehensive multidisciplinary service within primary care (offered by the Community Trust) and an interventional service within secondary care (East Kent  Hospitals  University Foundation Trust). They work collaboratively to support patients to develop self-management strategies. There is a single point of access for referral letters, where triage is managed by senior clinicians.

The MusculoskeletaI Services Framework document published in 2006, led to the remodelling of the pain services previously based solely in secondary care. The biopsychosocial component with medicines management, non-pharmacological therapies and pain management programmes takes place in the community across several regional sites.

Annual audits were being performed on the different treatment modalities and patient satisfaction. Key Performance Indices were published monthly  but there was no measure in place to demonstrate the global improvement of a patient in their journey through the community service.

Guidelines, like the IMMPACT recommendations, exist for measuring changes in individual patients. It was less clear how global changes relating to a service should be measured. The chosen method also had to be fast, user-friendly and computer compatible. Local commissioners indicated that they wanted to see that patients became more self-sufficient when attending the service. It was thus decided to trial the Pain Self-efficacy Questionnaire (PSEQ) as a service outcome measure. This tool measures the confidence patients have to manage different areas of their lives, despite being in pain. The higher the score (out of a potential 60), the better a patient is coping. It was anticipated that patients would score lower on entry into the service and would demonstrate higher scores on exit.

Methods

From Monday, 2 July 2014, all new patients referred to the service were posted the questionnaire and asked to provide their scores within a two week time frame by phone, otherwise they were not offered an appointment. Exceptions were those patients unable to fill in a form, for instance due to dementia or language difficulties.

Entry scores were recorded on computer within the Trust clinical informatics system by administrative triage staff and exit scores were captured by the discharging clinician.

After one year, all scores were extracted from the system by the Trust IT department.

Results

1602 entry scores and 115 exit scores were captured. On entry into the service, 87 per cent of patients score 30/60 or less, 64 per cent score 20/60 or less, 30 per cent scored 10/60 or less, three per cent scored zero. On exit from the service, none scored zero and 75 per cent scored more than 30/60.

These scores can be regarded as a ‘snapshot’ of entry and exit scores, as most were not from the same patients. There were 39 patients who had both an entry and exit score, with an average increase of 17 points (range minus three to +41). Only one patient scored less on exit. Records revealed that he developed a large disc prolapse and was discharged to undergo spinal surgery.

There were no scores captured for those who were discharged because of non-attendance, those who discharged themselves by phone or those discharged in the first appointment. This still left a gap between the number of patients with a planned discharge and those with a recorded exit score. Clinicians had to be reminded to always do the questionnaire.

Conclusions

First year data revealed a clear trend in increased levels of confidence and self-efficacy in patients after receiving treatment from the community-based chronic pain service and thereby potentially a higher likelihood to self-manage. Although numbers were still low, both commissioners and clinicians were satisfied that the PSEQ was a suitable way of measuring the outcome of the service itself.

References

• Dworkin RH, Turk DC, Peirce-Sandner S, et al. (2010). Research design considerations for confirmatory chronic pain clinical trials: IMMPACT recommendations. Pain; 149(2):177–193.
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49 Connecting Patients to Providers: Application of Wearable Health Technology to a Multidisciplinary Pain Program

John Han¹, Kelly Baylor¹, Dawn Snyder¹, Jove Graham¹, Christopher Bond², Steven Wang², Stacy Baldridge², Brian Sullivan², Thomas Alfieri²

¹Geisinger, Danville, PA, USA, ²Purdue Pharma LP, Stamford, CT, USA

Purpose

Effectively managing and engaging patients with chronic pain can be challenging due to the episodic nature of traditional care. Geisinger’s Multidisciplinary Pain Program (MPP) utilizes a biopsychosocial-spiritual approach to improve function and quality of life for individuals with chronic pain, through empowering patients to take responsibility for pain management, while setting and tracking personalized goals. The 12-month MPP consists of a 3-day multidisciplinary educational class covering topics of self-maintenance, nutrition, sleep, alternative therapies, and traditional pain management.  Patients are followed closely, with monthly phone and clinic follow-up with providers specializing in chronic pain management.

When integrated with expert intervention such as the MPP, wearable health technology (WHT) may support behavior change, allowing for comprehensive management and proactive care. Current smartphone pain applications have limitations for integrated tracking of symptoms and interventions, and use tends to decrease over time. WHT has been shown to be effective in improving outcomes for patients with osteoarthritis, diabetes, and other chronic diseases, but data is limited in chronic pain. With WHT, patients have access to health and wellness data, which may help promote awareness of activities associated with pain improvement or exacerbation, supporting appropriate behavior change.

An ongoing proof-of-concept study was designed to show how integration of WHT and provider dashboards (which organizes WHT data for review) in a group of chronic pain patients treated at a specialty clinic improves outcomes. Over one year, patients enrolling in the MPP will be offered study participation and followed for 12 months. The WHT intervention (Apple Watch, iPhone, and Pain application), collects data on patients’ self-reported pain, sleep, and activity on a regular basis.  Dashboard data will be reviewed by the MPP staff to augment information collected during office visits.  With chronic pain known to impact sleep, function, and quality of life, study outcomes include analysis of pain scores, depression, sleep, function, and medication use. This interim analysis was designed to highlight WHT usage patterns for all patients, as well as a detailed analysis of a subgroup of patients with 4 months of data to evaluate how the various outcomes are being captured.

Methods

This prospective, non-randomized, non-blinded trial with historic and concurrent controls assesses the effect of WHT on patient and health-system outcomes. This interim analysis provides descriptive statistics for use of the WHT and patient characteristics. 

WHT are the Apple Watch and iPhone, a pain application (Pain App) and the customizable provider dashboard. The Pain App and dashboard were designed specifically for this study. Patients are instructed to use the WHT 20 hours/day, daily for 12 months. Study visits occur at baseline and months 2, 4, 6, 8, 10 and 12.  The WHT tracks patient-reported pain (daily and breakthrough), medication usage, and passively collected activity and sleep. With the Pain App, patients document pain intensity (0−10), location and description, breakthrough medications, and alternative therapies (stretching, mindfulness, or hot/cold therapy).  The Apple Watch allows patients to enter breakthrough pain scores and to view daily summaries, while reminding patients to integrate alternative therapies, consistent with MPP training. Activity is monitored passively with the watch.  Sleep data is collected by the Pillow application (Neybox Digital Ltd, Nicosia, Cyprus). The provider dashboard offers a customizable, patient-specific, comprehensive view of data, including data from the WHT and electronic health record (EHR), such as interventional procedures and medications.

Results

Successful uptake of WHT was observed. Most patients used the devices consistently.   Data are presented for 55 patients enrolled in this ongoing study (75% female, mean age 50.8 years, SD 13.7).    Patients access the pain application regularly, with a median frequency of use on 67.2% of days (Interquartile Range [IQR]:37.6%-92.3%). For sleep data, the median usage was 54% of days (IQR: 27.4 – 79.1%).

The number of pain scores logged per day varies, with many patients documenting multiple locations of pain in a single day. At least 50% of days with pain score entry have up to 4 end-of-day pain scores and 5 breakthrough pain scores.  The majority of patients (n = 53, 96%) recorded use of alternative therapies, including stretching, mindfulness, and hot/cold therapy to augment their pain management, with many applying various modalities multiple times per day.

Usage data was analyzed for the subset of 28 patients with at least 4 months of data.  In the first 133 days (3724 total patient days), the watch was worn by patients on 64% of days (defined as days when any data were captured).  All patients in the subgroup (n = 28) recorded activity, steps, pain scores, and use of alternative therapies.  Most patients entered sleep data (22/28, 79%) and medication data (23/28, 82%).  The pain application was accessed on 55.3% of enrolled days (85.4% of days with watch use), with a per-patient median of 53.4% (interquartile range [IQR]: 23.7% - 85.7%).

Average pain scores were calculated for each patient in the subgroup.  The average end-of-day pain score was 4.7 (SD 1.1, range 2.8 to 7.0, median 4.9).  The average breakthrough pain score was 5.4 (SD 1.3, range 3.1 to 8.0, median 5.3).  On days when breakthrough pain was recorded, patients typically recorded multiple breakthrough pain scores for various painful areas on the body with 67% of days having multiple entries.   Alternative therapies were recorded on 42.9% of enrolled days (66.2% of days with watch use), with a per-patient median of 28.2% (IQR: 23.3% - 66.2%).  Breakthrough medication was logged on 28.7% of enrolled days, with a per-patient median of 21.8% (IQR:3% -41.7%).

Sleep was recorded on 38.5% of enrolled days (59.4% of days with watch use), with a per-patient median of 23.7% (IQR: 11.3%- 78.2%).  Among those patients with any sleep data, it was recorded on 48.4% of enrolled days, with a per-patient median of 38% (IQR:19.5% - 84.2%).

Conclusions

Interim analyses show promising uptake of WHT, with patients using WHT to document pain scores, medications, alternative therapies, sleep, and activity.  Adding WHT to the MPP increased communication between providers and patients.  Patients are using the technology, with many using it frequently and consistently with little indication of fatigue or decreased use over time. 

Ongoing WHT use in the subgroup is encouraging, with patients continuing to use the technology and maintaining communication with providers.  The availability of sleep data has proven valuable, leading to identification of potential sleep disorders and formal evaluation.   WHT integration supports comprehensive care by augmenting the assessments conducted in clinic with additional data. Patients have access to WHT health data, which may promote awareness of activities associated with pain, supporting behavior change.  Patients report increased engagement with providers, increased attention to activity, sleep, and alternative therapies, and an overall benefit.   With the potential for WHT to be used by patients with chronic pain and other chronic conditions, this study provides important information on the use, benefits, and possible challenges of WHT.  Once the study is completed, an analysis of the effect of the addition of WHT on patient and health care system outcomes will be conducted.

50 What Red Wine Triggers Tell Us About Migraine and Cluster Headaches

Joseph Pergolizzi, Jr.¹, Flaminia Coluzzi², Giustino Varrasi³, Dean Mariano⁴, Peter Magnusson⁵, Robert Colucci¹, Jo Ann LeQuang¹

¹NEMA Research, Inc., Naples, Florida, USA, ²Sapienza University of Rome, Rome, Italy, ³Paolo Procacci Foundation, L'Aquila, Italy, ⁴Mariano Medical, LLC, West Hartford, Conn., USA, ⁵Karolinska Institute, Solna, Sweden

Purpose

Red wine is a frequently reported trigger for migraines and cluster headaches, but it is not clear why red wine is more associated with headaches than white wine, sparkling wines, or spirits. Biogenic amines (histamines, phenylethylamines, tyramines, and others), phenols, polyphenols, and sulfites have been implicated in headache. Enzymatic activity associated with the metabolism of certain phenols and polyphenols may cause fluctuations in dopamine and serotonin levels, which, in turn, could trigger a headache. A promising new explanation of the red wine headache involves the sulfotransferase (SULT) enzyme.

Considering the burden that migraines and cluster headaches place on the healthcare system, it is surprising that so little is known about their etiology. Migraine headaches cost about $8,924 per year per patient more than patients without migraines (in 2014 dollars)¹ and migraine patients are 1.94 times as likely than non-migraineurs to have short-term disability.²  Headaches of various types are the fifth most-frequently named reason for emergency department visits³ and persistent headaches have been associated with lifetime suicide attempts.⁴ About 18% of American women and 6% of men are migraineurs¹  while cluster headaches have a much lower prevalence at 0.1% in the U.S. and affect disproportionately more men than women at a ratio of 4.3 to 1.⁵

Migraine and cluster headache patients often report headache triggers and red wine is named more frequently than any other alcoholic beverage.⁶ A better understanding of the red wine trigger may help further elucidate the pathophysiology of migraine and cluster headache. It was the objective of this review to evaluate recent research on red wine headaches and, in particular, to describe previous and current understanding of why red wine is such a prominent headache trigger.

Methods

This was a narrative review. The authors reviewed literature on “red wine triggers” and “red wine headaches” with an emphasis on more recent literature. A search of PubMed for “red wine headache” yielded 26 results; “red wine trigger” yielded 36 with some duplication. The bibliographies of these articles were searched.

In the research, it was found that there are often important differences in migraineurs with and without aura; about one-third of migraine suffers experience aura.⁷ Certain foods (beer, citrus, certain vegetables) have been found to trigger a headache in migraineurs with aura but not in those without aura.⁸ Wine appears to trigger headaches significantly more often in migraineurs without aura.⁹ This is an intriguing area for future study but there is only sparse research on this to date.

The literature discussed important constituents of red wine: sulfites, phenols, histamine, and alcohol, which can have a vasodilatory effect. Many substances have been examined as headache triggers but refuted. For instance, histamine can induce headache in susceptible individuals, histamines in other foods (such as vinegar, fish, pickles, raisins, tomatoes, and so on) are not reported as headache triggers and are unlikely to cause red wine headache. Tannins, present in red wines, have been suggested as the culprit in red wine headaches but other high-tannin beverages like black tea are not associated with headache.¹⁰ Sulfites are unlikely to be the culprit as white wine contains a higher sulfite content and is less associated with headache.¹¹ And while alcohol may cause a “hangover headache,” it does not explain why red wine is more associated with headache than other alcoholic beverages, including spirits.¹²

Recent research has also proposed that migraine may be a symptom of serotonin dysregulation and low levels of serotonin may activate the nociceptive pathways in the trigeminovascular system.¹³ Dopamine is known to contribute to severe forms of headache although the exact mechanisms are not elucidated.¹⁴  Indeed, some of the premonitory symptoms of migraine appear to be related to dopamine.¹⁵  It was our objective to review the literature in light of these findings.

Results

About 97% of circulating dopamine in humans is sulfonated (inactivated) by the SULT1A3 enzyme, with the result that unsulfonated free dopamine may be used to form norepinephrine and epinephrine.¹⁶ Sulfonation is a metabolic process catalyzed by the SULT enzymes which reside primarily in the liver and intestines.¹⁷ In broad terms, sulfonation makes certain xenobiotics more water soluble and thus easier to excrete in the urine. One of the substances SULT enzymes metabolize is dopamine.¹⁸ An in vitro study showed that SULT enzymes could be inhibited by red wine¹⁶ and a human study found red wine (but not water or ethanol) significantly lowered plasma levels of free dopamine.¹⁹  Thus, it may be that certain phenols and polyphenols found in red wine inhibit SULT1A1 and SULT1A3 enzymes, which, in turn allows for a rapid build-up of dopamine in the body.²⁰  Stress—another known headache trigger—also inhibits SULT enzymatic action.²⁰ This cascade of events is subject to an interplay of specific factors—the type of red wine, the inhibitory capacity of the trigger, the amount of catecholamines released in the body, the patient’s individual sensitivity to dopamine, and specific patient factors such as overall health, stress level, and even hormonal influences.

Many SULT inhibitors have been identified including coffee, cherries, curcumin, grapes, grapefruit juice, lemons, olives, orange juice, peppermint, red wine, white wine, and certain teas.^17,19 Red wine contains phenols and polyphenols which can inhibit the SULT enzyme. It is theorized that migraines and cluster headaches resolve once dopamine levels are brought back within normal range. It remains unclear if migraineurs are hypersensitive to dopamine and thus respond more profoundly to dysregulation of dopamine levels; droperidol, a dopamine antagonist, has been shown effective in the emergency treatment of migraine, suggesting that dopamine regulation may help relieve migraines,^21,22 but the relationship of dopamine to headache pathophysiology remains to be further studied.

Conclusions

Migraines, cluster, and other severe forms of headache are sometimes triggered by external stimuli and red wine is frequently mentioned as a headache trigger. A better understanding of the constituents of red wine may help elucidate the pathophysiology behind these severe headaches. An emerging theory is that red wine may inhibit SULT enzymes which, in turn, leads to increases in circulating dopamine levels which may cause a headache. Certainly, high levels of dopamine have been implicated in headache already. It is not clear whether migraineurs and others with cluster or severe forms of headache might be hypersensitive to dopamine. The role of dopamine antagonism in the emergency treatment of migraine further supports this concept. As migraines and cluster headaches are a prevalent and costly condition for the healthcare system, better understanding of the pathophysiology of these headaches is urgently needed.

51 Cannabinoid Hyperemesis Syndrome: A Paradoxical Property of Marijuana

Joseph Pergolizzi, Jr., Jo Ann LeQuang, John Bisney

NEMA Research, Inc., Naples, Florida, USA

Purpose

With the liberalization of marijuana laws and increasingly favorable public opinion about the positive medical properties of cannabinoids, clinicians in emergency medicine are increasingly dealing with cannabinoid hyperemesis syndrome (CHS). CHS involves episodes of intractable vomiting with nausea and sometimes abdominal pain separated by longer asymptomatic periods of weeks or months in patients with long-term cannabis use. Since cannabinoids are known for their antiemetic properties and may even be recommended to ease chemotherapy-induced nausea and vomiting, CHS seems paradoxical. Some patients who develop CHS unintentionally exacerbate it by taking more cannabinoids to ease the vomiting. CHS can be puzzling to diagnose but, unlike other cyclic vomiting syndromes, CHS is relieved with hot showers or topical capsaicin. Abstinence from cannabinoids will cause complete resolution of CHS, sometimes in a matter of days or hours.

About 22.2 million Americans have used some form of cannabinoid product in the past month.¹ Since 2009 when marijuana restrictions were loosened, the rate of persistent vomiting increased 17.9% of pre-legalization rates and continues to increase about 8% year over year.² Although once considered a “rare” or perplexing syndrome, CHS cases are increasingly being reported and occur all over the world. CHS is not trivial; the literature reports fatal cases of CHS.[SD1] 

The purpose of our research was to evaluate the literature for reports of CHS and to distill this information in a meaningful way that could better explain this seemingly paradoxical condition. The authors wanted to establish a clinically meaningful and actionable description of CHS and describe appropriate diagnostic and therapeutic options.

 [SD1]I don’t remember this from all those papers I looked at.

Methods

The authors searched the PubMed databases for clinical studies, trials, and case reports using the keywords “cannabinoid hyperemesis,” “cannabis hyperemesis,” and “marijuana hyperemesis.” In May 2018, the search resulted in 105 unique articles, many of which were case studies or case series. Articles that were not in English were excluded. Case studies or series that did not report the age, sex, presentation, diagnosis, and treatment of the patient(s) were excluded. In some cases, bibliographies of articles were searched.

CHS was first described in the literature in 2004 when Allen and colleagues presented a case report of 19 marijuana users who presented with cyclic vomiting.³  Since then, cases have been published from France, the Netherlands, Canada, the United States, Germany, Spain, New Zealand, and others. Many case studies were reported allowing for a distillation of common themes. No clinical studies were reported and relatively few reviews are available.

It has been speculated that the reason CHS is emerging as a condition now and not previously is that marijuana products today have a much higher tetrahydrocannabinol (THC) content than marijuana available decades ago. Advances in marijuana cultivation have resulted in unprecedented potency with the result that THC concentrations in cannabis products have roughly doubled from 2000 to 2015.⁴

Results

From the case reports, it appears that CHS is an episodic syndrome with intractable vomiting, nausea, and stomach cramps that last for 24 to 48 hours separated by relatively long asymptomatic periods (weeks or months). Conventional antiemetics (ondansetron, promethazine, etc.) are not effective. Patients may become dehydrated, disorientated, and require emergency care due to vomiting up to 20 times a day. CHS occurs in patients with a history of relatively prolonged and heavy use of marijuana. Its incidence and prevalence are not known, and it is likely that many cases are not correctly diagnosed. In a study of outpatients at a marijuana rehabilitation clinic, 18.2% of respondents reported symptoms suggestive of CHS.⁵ A two-year epidemiological study found 494 patients aged 18 to 55 years who presented at a Canadian hospital with vomiting or cyclic vomiting; of these patients, 19.4% had chart notations indicating they used marijuana and 10.4% reported using marijuana >3 times a week.⁶  In Colorado, cyclic vomiting episodes nearly doubled in the first year after marijuana laws were liberalized.⁷

Simonetto presented diagnostic criteria for CHS in 2012 based on a case series of 98 patients at a single tertiary center.⁸ A prerequisite for CHS is long-term use of cannabinoids (botanical, synthetic, prescription-grade), cyclic vomiting episodes separated by longer asymptomatic periods, and relief obtained by hot showers or topical capsaicin. CHS resolves when marijuana is discontinued. There is no laboratory test or radiographic examination that can diagnose CHS.

Diagnostic challenges involve differentiating CHS from cyclic vomiting, psychogenic vomiting, or hyperemesis gravidarum, but only CHS can be relieved with hot showers or topical capsaicin. Furthermore, antiemetic therapy is ineffective for CHS. Case reports from the literature cannot be used to draw definitive information about the condition but it appears to occur in younger rather than older patients, some of whom have used marijuana regularly for decades. Many patients present at emergency departments and/or are hospitalized repeatedly before a diagnosis is made. In some cases, patients do not believe that marijuana causes their vomiting episodes, although symptoms resolve in days once marijuana is stopped. While most patients are over the age of 20 and have used marijuana for years, the literature reports cases of CHS that have occurred in patients as young as 15.⁹

Conclusions

CHS may be a much more prevalent syndrome than is currently recognized and is likely to increase as marijuana use increases and cannabinoid products increase in potency. CHS is characterized by long-term marijuana use, episodes of intractable vomiting, relief from hot showers or topical capsaicin, and longer asymptomatic periods between vomiting episodes. CHS can be very severe; fatalities have been reported and many patients require emergency care or hospitalization. CHS resolves completely, sometimes in a matter of days, with cannabinoid abstinence. To avoid unnecessary tests and procedures as well as protracted delays in diagnosis, clinicians should consider CHS in cyclic vomiting patients who find relief in hot showers and who have a history of cannabinoid use.

52 Tapering Opioids: Clinical Strategies in Light of CDC Guidelines

Joseph Pergolizzi, Jr.¹, Melanie Rosenblatt², Dean Mariano³, Jo Ann LeQuang¹

¹NEMA Research, Inc., Naples, Florida, USA, ²Pain Management Strategies, Naples, Florida, USA, ³Mariano Medical, LLC, Windsor, Connecticut, USA

Purpose

The Centers for Disease Control and Prevention (CDC) in Atlanta published guidelines for general practitioners about opioid prescribing in 2016 and recommend tapering opioids when they are to be discontinuing rather than risking withdrawal symptoms that may occur when long-term opioids are stopped abruptly.¹ Long-term opioid therapy may need to be discontinued for any number of reasons: resolution or improvement of the condition causing pain, ineffective pain control, intolerable side effects, tolerance requiring dangerously high doses to treat pain, opioid use disorder, nonadherence to treatment plan, overdose, comorbid conditions where opioids are contraindicated, polypharmacy involving drugs that could potentially interact with opioids, drug-seeking behaviors, and mental health disorders which might be exacerbated by opioids.^2,3 Opioid prescribers should never initiate opioid therapy without an exit plan, which may involve tapering strategies.

Tapering strategies are not clearly described in the literature and must be individualized to adapt to the needs of each patient. Tapering opioid therapy and discontinuation is optimally a shared decision between patient and prescriber and may include the patient’s family or support systems. Patients often require supportive care in this vulnerable time and may need help with pain control, tactics to manage withdrawal symptoms, and psychological or emotional comfort.⁴ While many sorts of patients may require tapering and discontinuation of opioid therapy, the more successful patients tend to be younger, highly motivated, with a dissatisfaction for opioid therapy, and whose underlying painful condition has resolved or is improving.

The purpose of this article was to review the literature and provide guidance and broad outlines of how tapering might be carried out, with the understanding that tactics may have to be individualized for each patient.

Methods

This paper is a review of tapering literature and concepts from clinical practice. In evaluating the literature, it was discovered that there are many prevailing “myths” about opioid tapering that still find resonance among clinicians. For instance, many clinicians believe that people taking opioids for a protracted period of time will not want to discontinue them. A study of 110 chronic noncancer pain patients at a single center on long-term opioid treatment found that 75% agreed to taper their dose, providing the clinic could help them.⁵ This suggests that patients may be hopeful to decrease or discontinue opioid therapy providing there was a validated plan in place and they had extensive support as they moved forward. It has also been thought that individuals with opioid use disorder (OUD) would not be amenable to tapering and discontinuation of an opioid prescription. While there is some truth to that, a study of 140 chronic pain patients with OUD (pain for 9.6 ± 8.4 years) found that 27.9% could be successfully tapered to the point that they discontinued opioids and remained abstinent at one year.⁶  This points to the fact that clinicians should not prejudge who might—or might not—be a good candidate for tapering and opioid cessation.

Tapering is not the same as detoxification, which requires a specific licensure and is usually carried out prior to entering a rehabilitation program. Tapering is a stepwise process of weaning the patient off opioids in an incremental fashion. The authors reviewed the limited literature and shared their insights on tapering and discontinuation.

Results

As a rule of thumb, the daily dose of opioids needed to prevent acute withdrawal symptoms is roughly 25% of the previous day’s dose.⁷ A good tapering plan will avoid decreasing the dose by more than 75% in a single step. The CDC recommends that patients not be administered opioid daily doses in excess of 90 morphine milligram equivalents (MME) per day. Patients on long-term opioid therapy sometimes build up tolerance and take doses far in excess of 90 mg. Tapering may be further complicated if the patient is taking multiple opioid products or is using product(s) with different routes of administration, such as an oral product plus a transdermal system. In such cases, it may be preferable to rotate the patient from these opioids to a single product or to a new opioid, ideally an extended-release oral opioid. To rotate the opioid, doses must be converted to the MME value to achieve analgesic equivalency; the morphine equivalent dose (MED) is the sum of the MMEs of all of the opioids that the patient is likely to ingest in 24 hours. Once an equianalgesic dose is established, it should be halved to account for potential cross-tolerance. For example, a patient rotated from 65 mg of oral oxycodone per day to the equivalent of 100 mg of oral morphine per day should be started with a dose of 50 mg of oral morphine daily (50% of 100 mg) and, if need be, supplement this dose with short-acting opioids at first to control analgesic gaps until the patient can be titrated to the appropriate dose.

The MED value established by the CDC as the highest dose appropriate for opioid patients is 90 MED, although many patients take higher doses owing to tolerance.⁸ It must be noted that both high dose and extended duration of opioid therapy are risk factors for OUD.⁹

Short-acting opioids may be helpful both at the outset of a tapering effort or at the end of the process once the patient has reached the lowest dose of long-acting opioids but cannot quit entirely without withdrawal symptoms.¹⁰ For example, a patient who has tapered down to one 15-mg long-acting morphine tablet per day may be switched at the end to a half-tablet of 15 mg short-acting morphine twice daily (7.5 mg each dose), then tapered to one half-tablet daily, and finally discontinued altogether.

Conclusions

Those who prescribe opioid therapy for long-term use should be familiar with how and when to discontinue opioids. Abrupt cessation of opioids can result in distressing withdrawal symptoms and intense cravings for opioids, which can be counterproductive. Tapering can minimize or prevent withdrawal symptoms and aid the patient in stopping opioid therapy but requires close clinical supervision. Tapering strategies require a good knowledge of opioid conversion, the appropriate dose decrements, and supportive care for the patient. Ideally, the decision to discontinue opioid therapy should be one reached by patient and provider together. The stepwise diminution of opioid dose may take time; if the patient is cooperative and things are going well, the taper may be slowed at the end. Withdrawal symptoms may break through even when the tapering process is carefully managed and can be addressed with supportive care but should not be treated with opioids or benzodiazepines.² Many things can complicate tapering and opioid cessation: OUD, reticent patients, the use of multiple opioid products, withdrawal symptoms, increasing pain levels, and tapering strategies that are not individualized for the patient. In general, gradual tapering appears to produce more durable positive results than rapid tapers.

53 Clinical Tips for Managing Withdrawal in Opioid Patients

Joseph Pergolizzi, Jr.¹, Melanie Rosenblatt², Dean Mariano³, Robert Colucci¹

¹NEMA Research, Inc., Naples, Florida, USA, ²Pain Management Strategies, Pompano Beach, Florida, USA, ³Mariano Medical, LLC, West Hartford, Connecticut, USA

Purpose

Many prescribers are reducing opioid doses or discontinuing opioid therapy for certain patients in light of the 2016 guidelines for opioid prescribing by primary care physicians issued by the Centers for Disease Control and Prevention (CDC).¹ Even when opioids are carefully tapered under medical supervision, patients may experience opioid withdrawal symptoms (OWS) that include nausea, vomiting, stomach cramps, restless muscles, insomnia, depression, excessive yawning, runny nose, lachrymation, hyperhidrosis, fever, anxiety, agitation, drug cravings and so on. While there is interpatient variability, OWS typically begin within 24 hours or 48 hours of discontinuation of short-acting or long-acting opioids, respectively, and OWS may last several days to a week. Late withdrawal symptoms may differ from early symptoms and include intense cravings for more drugs. The Clinical Opiate Withdrawal Scale (COWS) is a validated metric to assess these symptoms.²

Much is known about the physiology of OWS which mainly involves the locus coeruleus (LC) of the brain, which produces and regulates noradrenaline. When opioids are use, the receptor-dense area of the LC inhibits the production of cyclic adenosine monophosphate (cAMP), decreasing the neurons’ ability to produce noradrenaline which, in turn, induces symptoms of sleepiness, confusion, and decreased respiration. When opioids are used continuously, compensatory mechanisms ramp up noradrenaline production but if the opioids are discontinued suddenly, cAMP is not inhibited and large amounts of noradrenaline flood the body, fueling symptoms of anxiety, nervousness, agitation, and physiological symptoms such as nausea, vomiting, and stomach cramps.^3-6

Opioid withdrawal is likely to be encountered with increasing frequency as prescriptions for opioids decrease, opioids are discontinued for many patients (with or without appropriate tapering strategies), and those using illicit opioids may find it harder to obtain opioids. The CDC guidelines do not offer guidance in how to manage opioid withdrawal. The purpose of this project was to offer clinical perspectives on addressing OWS.

Methods

The authors all have professional expertise and clinical experience in managing OWS in a variety of patients. The literature was reviewed for “opioid withdrawal” and articles offering practical clinical advice were evaluated for inclusion, balanced by the perspectives of the authors. This is a short commentary rather than a review.

Results

Symptomatic relief of OWS may be provided with clonidine, lofexidine (the first nonopioid treatment for OWS approved in the US in May 2018⁷), or even nonpharmacological treatments such as transcutaneous electrical stimulation.^8,9 Combination therapy may be used, adding benzodiazepines for anxiety, loperamide or bismuth salicylate for diarrhea, nonsteroidal anti-inflammatory drugs (NSAIDs) for muscle pain, ondansetron for nausea, and possibly sleep aids for insomnia.¹⁰

Withdrawal symptoms may also be managed by opioids, typically buprenorphine or methadone. It is thought that OWS can be suppressed if no more than half of all mu-opioid receptors are available (which corresponds roughly to buprenorphine trough plasma concentrations of 1 ng/ml or higher, that is, one daily dose of 4 mg buprenorphine). To block the reinforcing effects of opioids, less than 20% of mu-opioid receptors should be available (≥ 3 ng/ml buprenorphine, single daily dose >16 mg). However, there can be variability among patients and some patients will try to thwart this blockade with higher-than-normal doses of abused opioids, so fixed dose limitations of buprenorphine for maintenance as set forth by reimbursement policies or guidelines is not medically advisable.¹¹

Opioid maintenance programs do not necessarily prevent OWS. Opioid maintenance may require the patient to rotate to a specific opioid(s) which can be better tapered and discontinued. Opioid maintenance therapy is most effective when it can be individualized for each patient and may be continued long-term as the patient and prescriber work out the opioid exit strategy.

Supportive care may play an important role in managing OWS. Counseling, group therapy, or psychological support may be utilized during the detoxification and rehabilitation program. Tapering strategies can help mitigate or even eliminate OWS but optimal tapering requires careful clinical supervision, a cooperative patient, and patience as the taper may take months.

Conclusions

OWS are distressing symptoms that accompany the abrupt cessation of opioids in a dependent patient. OWS can sometimes be prevented, or at least greatly reduced, by tapering opioids gradually until the patient can quit without symptoms, but in many cases symptoms occur. OWS can be measured using the COWS tool. Symptoms typically last several days to a week and may vary in severity, with late symptoms differing from early symptoms. Most patients experiencing OWS will have intense cravings for the drug. Pharmacological support may be helpful in many patients; in May 2018, the FDA approved the use of lofexidine for OWS. In addition to drug therapy, patients in opioid withdrawal benefit from supportive care. An opioid agent may be used at a low dose in maintenance therapy to stave off OWS and help patients “feel normal” while avoiding the psychoactive effects of opioids. Opioid maintenance programs typically involve buprenorphine or methadone and do not necessarily prevent OWS.

54 Opioids and Driving: Prescribers, Patients, and the Police

Joseph Pergolizzi, Jr.¹, Robert Taylor, Jr.¹, Jo Ann LeQuang¹, John Bisney¹, Robert Raffa², Fabianna Pergolizzi³, Daniel Colucci¹, Lisa Batastini⁴

¹NEMA Research, Inc., Naples, Florida, USA, ²NEMA Research Group, Naples, Florida, USA, ³Spear, Greenfield, Richman & Weitz, Philadelphia, Pennsylvania, USA, ⁴Opioid Consulting Educatiobal Solutions, Medford, New Jersey, USA

Purpose

Vehicular accidents are a major cause of morbidity and mortality in the U.S.¹ and in 2009, 28% of all fatally injured drivers in this country tested positive for one or more legal or illegal substances aside from alcohol.²  Testing on fatally injured drivers show that the prevalence of those under the influence of alcohol remained relatively consistent from 1999 to 2010 (around 39%), drugged driving increased significantly from 16.6% in 1999 to 28.3% in 2010.³ A study of traffic accidents in Switzerland (n = 2,291) found 10% of drivers tested positive for opioids.⁴ In most parts of the world, the legal system does not differentiate between legal (prescribed) opioids taken under medical supervision and illicit opioids. Thus, a driver taking prescribed opioids as directed may be charged with driving under the influence (DUI) or drugged driving (different areas have different terms). Few if any DUI laws specify the exact substances, allowing broad police enforcement and prosecutorial discretion.

There are three main categories of DUI laws: zero tolerance, impairment laws, and per se laws. Zero tolerance laws allow drivers to be charged with a DUI if any amount of a substance is detected, regardless of how small or clinically important. Impairment laws, on the other hand, do not allow drivers to operate a vehicle if they are taking a substance that impairs their driving ability. This is a much more challenging law to enforce in that impairment must be objectively measured and proven. Finally, per se laws set forth a certain concentration of a substance and make it illegal to operate a vehicle if the concentration exceeds that amount; many states have per se laws for alcohol. Per se laws are much easier to enforce as there is a clear objective measure.

The purpose of this study was to search the literature to better understanding the potential legal consequences for driving while taking opioids, including prescribed opioids as directed and under medical supervision. Such information would help clinicians better advise and counsel their patients.

Methods

This was a narrative review relying on a literature search of the PubMed database for “driving under the influence opioids.” With no delimiters applied, about 72 relevant articles were found. All articles were reviewed and several were discarded as being superseded with newer information. The bibliographies of relevant articles were examined as well.

Every nation has its own DUI laws and the situation is complicated in the U.S. where each state has its own regulations and, in some cases, terminology. Furthermore, these laws are subject to revision and interpretation. As such, the authors could not provide specific information on laws by state or country. In some regions, multiple DUI laws may be in force. For example, in Spain, if a patient is driving under the influence of prescribed opioids, then impairment laws apply but if the opioids are illicit, then zero tolerance laws apply.⁵

The authors also considered that many package inserts for medications advise patients not to drive or operate machinery until they see how the particular medication affects them. However, there are no laws the authors could find in which the patient’s self-determination of intoxication was legally relevant if the patient was charged with a DUI. While it is good counsel to refrain from driving when taking a new medication, patients are not always informed that even if they feel a drug does not impair their ability to drive that it may still be possible for them to be charged with a DUI. Furthermore, it may be possible for certain central nervous system drugs to alter the patient’s self-perception to the point that they may not be able to fairly evaluate their own driving skills.

Our goal was to offer a narrative review of broad trends and observations rather than specific legal advice for individual states. Clinicians are advised to learn the laws in the region where they practice.

Results

About 20 US states do not permit a “legal entitlement” defense even when the patient is taking only prescribed drug(s) as directed. In other states, the laws can get complex.  In Maryland, for example, a defendant may claim innocence providing the driver was not aware that the drug might affect driving skills. In North Carolina, prescribed drugs may be evaluated based on per se laws. Utah permits prescription medications to be an affirmative defense in DUI cases.⁶

It is also not clear-cut if opioids impair driving ability since many factors come into play: the dose, the patient’s level of tolerance, whether the opioid is a prescribed or illicit substance, and whether other drugs were used concomitantly.⁷ Some studies found opioid use did not adversely affect driving performance.^8,9 However, in many drugged driving cases, driver impairment is not legally relevant.

Roadside drug testing may be governed by local laws and test kits available to law enforcement officers. A number of saliva tests can be used to detect opioids but because of variations in cutoff values, a positive roadside test may require a second drug test at a lab. Since heroin (diamorphine) and prescription codeine (methylmorphine) both metabolize in the body to morphine, it is not always possible to determine in a toxicology test whether the driver has taken legal or illegal drugs.¹⁰  The metabolite 6-acetylmorphine (6-AM) is specific to heroin but its short half-life means it is only found in a blood test for approximately one to two hours after heroin ingestion¹¹ although it can be detected for a longer period of time in the urine.¹² Of course, urine tests pose challenges for roadside traffic stops. Moreover, concentrations of drug cannot always be adequately measured by saliva tests and any positive test for drugs does not necessarily mean the drug intake was pharmacologically meaningful.¹³ 

Both clinicians and patients may not be aware that taking prescription opioids (or other prescription drugs) may expose them to legal risk of DUI even if the drug is taken as directed and under a physician’s guidance. This may be particularly important for patients on chronic opioid therapy or those on opioid maintenance programs. Healthcare providers are in an excellent position to better inform patients about drugged driving risks as DUI charges can be serious and carry with them high fines, suspension of driving privileges, and possible imprisonment.

Conclusions

Laws regarding drugged driving in the U.S. are written broadly and may be interpreted to include many substances, including prescribed drugs (including but not limited to opioids) as well as illicit drugs. Three main types of drug laws are in place: zero tolerance (any detectable amount of drug is illegal), pro se laws (which establish specific cutoff values for DUI charges), and impairment laws. These laws can differ from region to region. Impairment is the most difficult to prove legally. Many patients incorrectly assume that impairment is the governing principle for drugged driving or that only illegal substances count toward drugged driving. But depending on the type of laws in place, people taking appropriately prescribed opioids as directed may be charged with a DUI even if they are not impaired or have not been warned of this by their physician or pharmacist. Clinicians in the U.S. should learn about the local laws and inform and counsel patients about their potential risks. In many cases, the law does not differentiate between legal and illicit opioids.

55 Gabapentinoid Use Disorder

Joseph Pergolizzi¹, Robert Taylor, Jr.¹, Jo Ann LeQuang¹, John Bisney¹, Christopher Gharibo²

¹NEMA Research, Inc., Naples, Florida, USA, ²NYU, New York, NY, USA

Purpose

Gabapentinoids (gabapentin and pregabalin) are versatile drugs often prescribed as anticonvulsants or for the treatment of neuropathic pain along with numerous off-label uses. These familiar drugs are emerging as drugs of abuse. Among those with opioid use disorder, 15% to 22% may also abuse gabapentinoids (gabapentinoid use disorder occurs in about 2% of the general population).¹ There are perhaps many explanations for gabapentinoid use disorder: the drugs are relatively inexpensive, few clinicians are aware of their potential for misuse, are associated with withdrawal and therefore craving and they remain fairly easy to obtain. Gabapentinoids may have psychoactive effects that include euphoria and they may enhance the psychoactive effects of opioids. The first reports of gabapentinoid misuse were published in Europe in 2012.

There is not widespread clinical appreciation of gabapentinoid use disorder. It was our objective to offer an introduction to this topic and to offer clinically relevant insights to those on the front lines of pain therapy and those who deal with individuals suffering from other types of substance use disorder.

Methods

Gabapentin and pregabalin are both structural analogs of the γ-aminobutyric acid (GABA) mammalian neurotransmitter and may be considered alpha-to-delta (α2δ) ligands.² Their exact mechanism of action remains to be elucidated but it is thought they inhibit neuronal excitability which reduces ectopic neuronal activation of hyperexcited neurons while not interfering with normal activation. Gabapentin was approved for use in the USA in 1993 (recommended daily dose 900 to 3600 mg/day) with pregabalin released to market in 2004 (recommended daily dose 160 to 600 mg/day). Of the two agents, pregabalin is the more potent, has a more rapid onset of action, and is absorbed faster with >90% bioavailability even at high doses (gabapentin’s bioavailability decreases as dose increases).

The authors conducted a literature search in 2017 using the PubMed databases for “pregabalin abuse” and “gabapentin abuse” and retrieved 146 and 263 results, respectively, including many duplicates. Papers not in English were excluded and emphasis was given to the more recent publications. In addition, bibliographies were used to find further literature. This provided materials to produce a narrative review that would be descriptive of the topic, gabapentinoid use disorder.

Results

Several important themes emerged from the literature search.

Gabapentinoids are being prescribed in increasingly large numbers and some patients are prescribed supratherapeutic doses. These consumption patterns suggest abuse.

³ In a large UK study of 13,480  patients prescribed pregabalin, 136 were prescribed supratherapeutic doses; of this group, 18.4% had a history of substance use disorder compared to a 14.0% incidence among the entire patient cohort.

⁴ The GABAergic properties of gabapentinoids are thought to play a role in substance use disorder and GABA-modulating properties are present in many substances such as alcohol, benzodiazepines, and the hypnotic Z-drugs.

^5,6 About a third of those with pregabalin use disorder experience withdrawal symptoms when the drug is discontinued suddenly.

⁷ Withdrawal is associated with numerous symptoms including disorientation, anxiety, insomnia, heart palpitations, diaphoresis, and stomach cramps. Gabapentinoid use disorder is associated with polydrug abuse. In a systematic review, it was observed that about 1.6% of the general population has gabapentinoid (monotherapy) use disorder while gabapentinoid use disorder was reported from 3% to 68% of those with opioid use disorder.

⁸ Risk factors for gabapentinoid use disorder have started to emerge from studies and include: history of substance use disorder, especially opioid use disorder, mental health disorder, supratherapeutic doses of prescribed gabapentinoids. Age is a more nebulous risk factor; in a study of 440 patients in substance abuse rehabilitation, the median age of pregabalin abuser was 38 years,

⁹ but other studies have been less conclusive. Male sex is an independent predictor of high dose use of pregabalin,

¹⁰ but results are equivocal in terms of whether one sex is more likely to be addicted than the other and high-dose use is not the same as use disorder. Many individuals taking gabapentinoids inappropriately get their drugs by prescription from healthcare providers but may supplement that with drugs from friends, dealers, or online sources.

¹¹ A Google search conducted in July 2018 for “buy gabapentin without a prescription” and “buy pregabalin without a prescription” yielded 4,480,000 and 622,000 results, respectively. A similar search conducted about a year earlier, in September 2017, yielded 1,190,000 and 352,000 results, respectively. The line between “recreational user” and “prescribed patient” is not sharply defined.Few urine assays screen for gabapentinoids making them easy drugs to conceal in random testing.

Conclusions

Gabapentinoids are widely prescribed, inexpensive, fairly easy to obtain, and may be drugs of abuse particularly in patients with opioid use disorder. Although not typically considered to be drugs of abuse, gabapentinoid prescribing and their recreational use is increasing. Clinicians should be aware of the potential for gabapentinoid abuse and be cautious in prescribing them (a) to patients with opioid use disorder, (b) for off-label indications, or at (c) supratherapeutic doses.

56 Efficacy of Lofexidine for Opioid Withdrawal Syndrome: Focus on Pain Symptoms

Joseph V. Pergolizzi, Jr¹, Mark Pirner², Thomas Clinch²

¹Naples Anesthesia and Pain Associates and NEMA Research Inc., Naples, Florida, USA, ²US WorldMeds, LLC, Louisville, Kentucky, USA

Purpose

Chronic pain patients undergoing abrupt discontinuation of opioids may experience a highly distressing constellation of symptoms known as opioid withdrawal syndrome. Symptom severity and type varies from patient to patient but often includes flu-like symptoms, nausea, diarrhea, palpitations, anxiety, insomnia, aches and pains, muscle spasms/tension and stomach cramps. Patients may wish to continue opioid analgesics beyond a medical need to avoid this syndrome. Additionally, because pain and pain-associated symptoms are components of opioid withdrawal syndrome, patients may confuse these symptoms with primary pain and incorrectly assume that continuation of opioid analgesics is necessary for pain control. Treatment of opioid withdrawal syndrome in patients discontinuing opioid analgesics may allow for a more comfortable transition to non-opioid analgesics or other pain management strategies. 

Lofexidine is an alpha-2 adrenergic agonist recently FDA-approved for mitigation of opioid withdrawal symptoms to facilitate abrupt opioid discontinuation in adults. The mechanism of action of lofexidine opposes the increase in neural norepinephrine release that occurs after discontinuation of chronic opioids and results in opioid withdrawal syndrome. Two pivotal trials were conducted to evaluate the efficacy and safety of lofexidine. The purpose of this analysis was to evaluate the effect of lofexidine on individual symptoms of opioid withdrawal syndrome in a pooled database including both pivotal trials. The importance of pain-associated symptoms within opioid withdrawal is assessed.

Methods

This analysis included pooled data from 2 phase 3 placebo-controlled, double-blind studies that evaluated withdrawal symptoms during the first 7 days after abrupt discontinuation of short-acting opioids (heroin or opioid analgesics). Subjects were opioid-dependent men or women ≥18 years old. In the first study, subjects were randomized 1:1 to lofexidine 2.88 mg/day (0.72 mg QID) or placebo for 5 days. In the second study, subjects were randomized 3:3:2 to lofexidine 2.16 mg/day (0.54 mg QID), lofexidine 2.88 mg/day (0.72 mg QID) or placebo, for 7 days. The Short Opiate Withdrawal Scale of Gossop (SOWS-G) was a primary outcome measure in both trials. It is a validated, subject-rated, 10-item assessment with each symptom rated from 0 (none) to 3 (severe) for a possible total score of 30. The 10 symptoms included in the SOWS-G are: ‘feeling sick’, ‘stomach cramps’, ‘muscle spasms/twitching’, ‘feeling of coldness’, ‘heart pounding’, ‘muscular tension’, ‘aches and pains’, ‘yawning’, ‘runny eyes’, and ‘insomnia/problems sleeping’.

Results

In the pooled database, 865 subjects were randomized and received at least 1 dose of study drug. Most of the subjects were male (72% of lofexidine subjects and 73% of placebo subjects) with ages ranging from 18 to 74 years. Two thirds of the population was white and heroin was the primary misused opioid for most; ~25% primarily misused prescription opioids.  The proportion completing the 7-day, double-blind treatment period was significantly higher in both lofexidine groups: 41.9% for the lofexidine 2.16 mg group (p < 0.002), 40.7% for the lofexidine 2.88 mg group (p = 0.001), and 28.2% for the placebo group.

Mean total SOWS-G scores over the 7-day period were significantly reduced in both lofexidine groups versus placebo (p < 0.05 for lofexidine 2.16 mg; p < 0.0001 for lofexidine 2.88 mg) based on pattern mixture model analysis. Mean scores for SOWS-G individual items were calculated on the day of peak SOWS-G score. For each of the 10 items, mean score was higher in the placebo group than in either of the lofexidine dose groups. The 4 items related to pain (‘stomach cramps’, ‘muscle spasms’, ‘muscular tension’ and ‘aches and pains’) accounted for 40% of the peak total SOWS-G score and ‘aches and pains’ accounted for the highest proportion (12.42%) of the peak total SOWS-G score compared to other items. Insomnia was the second-highest, accounting for 12.35% of the peak total SOWS-G score.

Hypotension, orthostatic hypotension, and bradycardia were the most common lofexidine-associated adverse events but rarely required study discontinuation.

Conclusions

In this large pooled database, subjects treated with lofexidine were more likely to complete the 7-day study and overall severity of opioid withdrawal symptoms over 7 days was significantly reduced versus placebo. Pain-associated symptoms comprised a substantial proportion of the total symptom burden as assessed with the SOWS-G and ‘aches and pains’ was the most prominent of the 10 individual SOWS-G items. Pain and hyperalgesia can be a key symptom during opioid withdrawal whether or not opioids were originally used for pain relief and may interfere with opioid discontinuation. Lofexidine provides a non-opioid treatment option for opioid withdrawal symptoms. Patients with moderate or severe opioid use disorder will require long-term management with opioid agonists (methadone or buprenorphine), naltrexone or other long-term treatment strategies after discontinuation of the problematic opioid.

57 Reversion of Patients with Chronic Migraine to an Episodic Migraine Classification with Fremanezumab Treatment

Joshua Cohen¹, Kristen Bibeau¹, Maja Galic¹, Michael Seminerio¹, Verena Ramirez-Campos¹, Rakshmi Halker Singh², Jessica Ailani³

¹Teva Pharmaceuticals, Frazer, PA, USA, ²Mayo Clinic, Phoenix, Arizona, USA, ³Medstar Georgetown University Hospital, Washington, District of Columbia, USA

Purpose

Chronic migraine (CM) and episodic migraine (EM) are clinically, functionally, and anatomically differentiated, with evidence suggesting that they may be separate conditions. Furthermore, patients with CM usually have more comorbid conditions and more-frequent medication overuse, which complicates their clinical management. Fremanezumab, a fully-humanized monoclonal antibody (IgG2∆a) that selectively targets calcitonin gene-related peptide (CGRP), is a preventive treatment designed to specifically target a pathophysiologic mechanism of migraine and has proven efficacy in the treatment of migraine.

The purpose of this analysis was to evaluate the effect of fremanezumab on reversion from chronic migraine to episodic migraine. Recent data from imaging studies suggest that chronic migraine may be a distinct entity, different from episodic migraine (Schwedt T et al, Headache 2015;55(6):762−777).

Methods

In this Phase III, multicenter, randomized, double-blind, placebo-controlled, parallel-group study, adults with prospectively confirmed CM (≥15 headache days and ≥8 migraine days per month) were randomized 1:1:1 to subcutaneous injections of fremanezumab quarterly (675 mg at baseline; placebo at Weeks 4 and 8), fremanezumab monthly (675 mg at baseline; 225 mg at Weeks 4 and 8), or matching placebo over a 12-week treatment period. Post hoc analyses evaluated the proportion of patients who reverted from CM to EM, defined as patients who had ≥ 15 headache days per month at baseline (28-day pre-treatment period) and then had <15 headache days per month in all 3 months of the treatment period.

Results

In post-hoc analysis of the 1130 CM patients randomized in this trial (quarterly, N = 376; monthly, N = 379; placebo, N = 375), significantly more fremanezumab-treated patients reverted from having ≥15 headache days per month at baseline to < 15 headache days per month in Months 1, 2, and 3 (quarterly: 121 patients [32%]; monthly: 133 patients [35%]) than those who received placebo (86 patients [23%]; both, P ≤ 0.002). On average, these fremanezumab-treated patients had 18–19 headache days per month at baseline and showed reductions to 6–9 headache days during any month in the treatment period, representing up to an approximately 70% reduction in headache days.

Conclusions

Along with its efficacy as a migraine preventive treatment, fremanezumab demonstrated the potential benefit for reversion from chronic migraine to episodic migraine.

58 Efficacy of Fremanezumab in Patients With Chronic Migraine and Comorbid Moderate to Moderately Severe Depression

Joshua Cohen¹, Paul Yeung¹, Ronghua Yang¹, Kristen Bibeau¹, Maja Galic¹, Michael Seminerio¹, Ernesto Aycardi¹, Richard Lipton², Dawn Buse², Marcelo Bigal¹

¹Teva Pharmaceuticals, Frazer, PA, USA, ²Albert Einstein College of Medicine, Bronx, NY, USA

Purpose

Depression is common in CM and contributes to the already substantial burden of disease. Fremanezumab, a fully-humanized monoclonal antibody(IgG2∆a) targeting calcitonin gene-related peptide (CGRP), has demonstrated efficacy in migraine prevention. 

The purpose of this analysis was to evaluate the efficacy of fremanezumab on migraine symptoms and depression in patients with chronic migraine (CM) and comorbid moderate to moderately severe depression.

Methods

In this Phase III, multicenter, randomized, double-blind, placebo-controlled, parallel-group study, eligible patients aged 18–70, with prospectively confirmed CM (≥15 headache days and ≥8 migraine days per month) were randomized 1:1:1 to receive subcutaneous injections of fremanezumab quarterly (675 mg at baseline; placebo at Weeks 4 and 8), fremanezumab monthly (675 mg at baseline; 225 mg at Weeks 4 and 8), or matching placebo over a 12-week treatment period. Post hoc analyses evaluated changes in headache and migraine frequency and depression in patients with moderate to moderately severe depression (score of 10–19 on the 9-item Patient Health Questionnaire [PHQ-9]) at baseline.

Results

Almost 20% (219/1130) of randomized patients had moderate to moderately severe depression at baseline (quarterly, n = 74; monthly, n = 88; placebo, n = 57). As in the overall study population, fremanezumab-treated patients in this subgroup had significant reductions from baseline in the mean number of monthly headache days of at least moderate severity (quarterly: –5.4 ± 0.79; monthly: –5.6 ± 0.75) versus those who received placebo (–2.2 ± 0.84) during the 12-week treatment period (both, P < 0.001), with effects observed as early as Week 4 (P < 0.0001). Similar treatment differences were observed for change in the mean number of migraine days (P < 0.001). Fremanezumab also reduced the mean PHQ-9 score from baseline to Week 12 (quarterly: –10.5 ± 0.68; monthly: –9.5 ± 0.63) versus placebo (–8.7 ± 0.71); the quarterly group reached significance (P<0.05).

Conclusions

Fremanezumab demonstrated efficacy in preventive treatment of CM in patients with comorbid moderate to moderately severe depression, reducing migraine and headache frequency and improving depression.

59 Topical delivery of NSAIDs: Influence of drug choice, formulation, and dose on in vitro skin permeation

Julie Pradal, Coralie Vallet, Guillaume Frappin, Maria Stella Lombardi, Clotilde Cheignon

GSK Consumer Healthcare S.A., Route de l'Etraz 2, 1260 Nyon 1, Switzerland

Purpose

Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used for treatment of acute and chronic pain. However, long-term use of systemic NSAIDs may be limited by side effects (eg, gastrointestinal events, including dyspepsia, abdominal pain, ulcers, and bleeding) and other potential safety risks (eg, certain cardiovascular events). Topical administration of NSAIDs is a useful alternative as demonstrated in clinical studies showing fewer systemic adverse events and similar efficacy compared with oral administration. However, NSAIDs must be appropriately selected and formulated for topical use in order to have a therapeutic effect. Three key factors that influence the clinical efficacy of topical NSAIDs are: (1) the extent to which the formulation allows the NSAID to penetrate the skin and permeate deeper tissues, (2) how potently the active pharmaceutical ingredient (API) inhibits cyclo-oxygenase-2 (COX-2) activity, and (3) the reversibility or duration of COX-2 inhibition.

These 2 in vitro studies were conducted to evaluate the first 2 of those factors. These studies were designed to characterize the influence of the API and formulation of 2 currently marketed NSAIDs (diclofenac and ibuprofen) on permeation into human skin in vitro, and to rank the products based on a combination of their absorption and their potency in inhibiting COX-2 activity.

Methods

We performed 2 in vitro studies using Franz diffusion cells to evaluate permeation of the API from currently marketed topical NSAIDs through ex vivo abdominal human skin. In the first study, 6 diclofenac products (1% or 2% strength) and 6 ibuprofen products (5% or 10% strength) were selected from commercially available gel or cream topical NSAIDs in European countries. The second study was similarly designed but used only 2 formulations consisting of diclofenac at strengths of 1.16% and 5%.

In both studies, a fixed 10 mg/cm² dose of each product, corresponding to the single-application dose for topical products recommended in most of the Patient Information leaflets, was applied to a 0.64 cm² area of the stratum corneum surface. Receptor fluid samples were collected at 0, 2, 4, 8, 16, and 24 hours after application, and analyzed by liquid chromatography/tandem mass spectrometry to quantify API permeation. Log-transformed mean cumulative absorption of each API at 24 hours was compared between formulations post hoc using a restricted maximum likelihood estimation-based mixed-effects model with formulation as a fixed effect and donor as a random effect. A qualitative analysis comparing products was conducted to highlight the potential influence of the excipients on the API skin permeation.

To rank the products based on a combination of their skin permeation and potency relating to inhibition of COX-2 activity, we performed a post hoc analysis using a modified Index of Topical Anti-inflammatory Activity equation as follows: ranking index (RI) = median cumulative absorption at 24h/IC_50. Here, IC₅₀ (ie, the concentration of API needed to inhibit 50% of COX-2 activity) was based on previously published values for diclofenac (0.013 μM) and ibuprofen (9 μM) measured in human whole blood using production of prostaglandin E2 as a surrogate of COX-2 activity (Esser R, et al. Br J Pharmacol. 2005;144:538-550).

Results

Study 1: In vitro, cumulative permeation of human skin was at least 7-fold greater with topical ibuprofen than diclofenac under conditions mimicking recommended topical application. However, the calculated ranking index that took into account both cumulative absorption and potency was higher for diclofenac (RI = 4 to 32) than for ibuprofen products (RI = 0.37 to 2.04).

Absorption did not necessarily correspond directly to formulation strength. Cumulative absorption of API from products containing the same strength of the same API varied widely, and formulations containing twice as much API (eg, 2% vs 1% diclofenac or 10% vs 5% ibuprofen) typically resulted in more than double the cumulative absorption. For instance, geometric mean cumulative absorption at 24 hours for 4 formulations all containing 1.16% diclofenac ranged from 119 to 334 ng/cm², whereas absorption for the only formulation containing 2.32% diclofenac was 849 ng/cm²—a 2.5- to 7.1-fold difference. Similarly, for ibuprofen-containing formulations, absorption ranged from 5944 to 9293 ng/cm² for 4 formulations containing 5% ibuprofen vs 15,421 and 25,282 ng/cm² for the 2 formulations containing 10% ibuprofen—a 2.7- to 4.3-fold difference for the 10% ibuprofen formulation with the highest value.

Study 2: The formulation containing 5% diclofenac exhibited less permeation of human skin than the product with only 1.16% diclofenac (361 vs 554 ng/cm²; ratio of adjusted geometric means: 0.65, 95% confidence interval: 0.48–0.88). The percentage of the applied dose that permeated human skin was 7-fold greater with the 1.16% diclofenac formulation (0.54%) than the 5% formulation (0.077%). Thus, contrary to what might be expected, a higher strength does not always increase skin permeation.

Results from these 2 studies suggest that factors other than formulation strength may strongly influence absorption of topical NSAIDs. Although not directly assessed in these 2 studies, the excipients in topical formulations likely influence skin permeation as well as drug solubility, thereby affecting release of the API within the skin. For instance, organic solvents, such as ethanol and isopropanol, are known to increase drug solubility, allowing a better release of the drug from the formulation. The presence of excipients considered skin irritants (eg, methanol) in the formulation disrupts the stratum corneum, thereby facilitating penetration of the drug. Dosage forms (gels, emulsions, creams) may also influence skin permeation.

Conclusions

Ranking indexes that take into account cumulative absorption into the skin and potency in inhibiting COX-2 were higher for topical diclofenac products than ibuprofen products, despite diclofenac having a lower skin permeation. Both choice and dose of API influence absorption of the API from topical NSAIDs, but wide variation was seen among formulations of comparable strength, and dose did not directly relate to degree of permeation. Other characteristics/ingredients of the formulation likely also affect permeation.

60 Intradermal Botulinum toxin A Injection Effectively Reduced Residual Limb Hyperhidrosis and Improving Vigorous Exercise Tolerance inA Veteran Patient with Below Knee Amputation A Case Report.

Junlong Ren

VA Northern California Healthcare System, Martinez, CA, USA

Purpose

Botulinum toxin A injection is a common treatment of axillary hyperhidrosis and it is also a treatment choice on residual limb patients with excessive sweeting, since it inhibits the action of sweat gland by release of acetylcholine. Hyperhidrosis or excessive sweeting of the residual limb is reported in up to 50−70% of patients with amputation and impact prosthetic fitting and function and reduced their vigorous exercise tolerance and their quality of life. 

The patient is a 39 years old male veteran with history of low back injury and left leg injury, s/p left 5th toe amputation due to osteomyelitis in 2009, causing his left foot deformity with difficulty walking. He underwent elective below knee amputation in 2014. Post BKA he recovered so smoothly.  He was an active K 4 level prosthetic user who participates in running, hiking, cycling and other outdoor activities. He wears a cycling socket, with a silicone liner and suction suspension sleeve and cycling foot. He denied residual stump pain or phantom pain, skin rash, or breakdown. He denied generalized hyperhidrosis.  He complaints of excessive sweating of the residual limb during or after exercise  causing excess water in the liner-prosthetic interface of his BK prosthesis which in turn lead slippage of the prosthesis, decreased stamina in the prosthesis, and even fall. After discussion the botulinum toxin A injection effective and possible side effect, he requested to have trial of Botulinum toxin A injection on his BK stump. Examination of his residual stump confirmed skin intact, scars, without rash of evidence of breakdown. His Hyperhidrosis Disease Severity Scale is 3.

Methods

Informed consent was obtained after risks and benefits of the procedure were discussed. The patient is in supine/prone position on the examiner table. The 100 units Botulinum toxin A was diluted to 4 ml with preservative free NS. The 30 gauge 1/2 needle was used. Mapping the hyperhidrotic area (distal stump and posterior distal stump area)with Minor's Starch-Iodine Test. Use a surgical marker to identify locations with the sweating area that are 1.5 cm apart from one another. Ethyl chloride freezing spray was used on injection area prior to perform injection.  Injection the Botulinum toxin A via an intradermal slowly injected at sites 1.5 cm apart. Total 40 sites were injected with 100 Units Botox (each site 2.5 Units Botox). Patient tolerated the procedure well and without any complications. The patient avoid strenuous activity for at least 24 hours.

　

Results

Three months later, the patient returned to the clinic for re-evaluation.  He was doing fine. He reported no side effect of Botulinum toxin A injection, and much reduced sweating at least 50% during cycling or other outdoor activities. He could ride his bicycle continuously for many miles without stopping his cycling exercise. He is very happy. He feels the Botulinum toxin A injection still effective, he does not need another injection after 3 months and 6 months. He continues to report a sustained benefit from the initial Botulinum toxin A injection.

Conclusions

Intradermal Botulinum toxin A injection is an effective treatment for residual stump hyperhidrosis, resulting in amputee patient improvement of vigorous exercise tolerance and prosthetic fitting and function, improving quality of life.

61 CT-guided percutaneous removal of lumbar intraspinal cysts

Junmo Park

Kyungpook National University Chilgok Hospital, Daegu, Korea, Republic of

Purpose

Lumbar radiculopathy is commonly caused by degenerative conditions, such as a herniated nucleus pulposus or lumbar spinal stenosis. Less common etiologies include intraspinal extradural masses, such as synovial cysts, gas-containing ganglion cysts, pseudocysts, hematoma, metastatic tumor and chondroma. Intraspinal extradural cysts that communicate with the intervertebral disc are a rare entity. Generally, surgical treatments, such as laminectomy or partial hemilaminectomy and medial facetectomy, are done in these cases. However, laminectomy has the potential risk of destabilizing the lumbar spine, which might increase the number of patients who require spinal fusion. To avoid the risk, the aim of this research was to treat patients with radiculopathy caused by lumbar intraspinal cysts by CT-guided percutaneous technique.

Methods

Five patients were scanned to determine a suitable approach and target points for the 18G spinal needle. The needles were inserted into the target points under CT guidance. I performed multiple punctures to the cysts after confirming the needles located within the cysts using radiolucent contrast. I completed all the procedures after performing selective root blocks at corresponding nerve roots.

Results

The symptoms improved in all patients immediately after the procedure. But among them, one patient with lumbar synovial cyst recurred after 3 days. He required endoscopic cyst removal. However, symptoms recurred again. Finally, he underwent surgical removal. The other patients did not require any further surgical treatment.

Conclusions

I think that if I performed steroid injections into the corresponding facet joints in synovial cyst cases, I probably could get the better outcomes. However, CT-guided percutaneous removal technique of lumbar intraspinal cysts is a safe and effective first-line procedure for treating radiculopathy caused by lumbar intraspinal cysts, especially in lumbar discal cysts.

62 Analysis of relapse in gabapentin and pregabalin use in the Substance Abuse Treatment Program at the Chillicothe Veterans Affairs Medical Center

Justine Zick, Suzanne Rettey, Christopher Thomas

Chillicothe VA Medical Center, Chillicothe, Ohio, USA

Purpose

The primary purpose of this study was to investigate whether patients prescribed gabapentin or pregabalin and concurrently enrolled in the Substance Abuse Treatment Program (SATP) were more likely to relapse than those patients who were not prescribed either medication while enrolled in the SATP.

Methods

The Veterans Affairs database was queried for all patients admitted to the SATP at the Chillicothe Veterans Affairs Medical Center (VAMC) from November 1^st, 2014 to November 1^st, 2017. The patient population was separated into three groups: patients prescribed gabapentin, patients prescribed pregabalin, and patients not prescribed either gabapentin or pregabalin (control group) during the SATP. An electronic, retrospective chart review was conducted in order to collect all necessary data pertaining to the primary and secondary outcomes. The primary outcome was number of patients relapsed during the six-month period following Day-1 of the SATP. Relapse was defined as a positive urine drug screen (UDS), positive breathalyzer, loss to follow-up, readmission to the SATP, or documentation of patient relapse. The secondary outcomes were to investigate the difference in number of patients relapsed with alcohol use disorder versus opioid use disorder, to determine each patient’s substance of choice and compare patients’ substance of choice versus substance abused at relapse, and lastly, to investigate the difference between the number of patients relapsed in the subset of patients who graduated from the SATP versus those who failed to complete the program.

Results

Among the 965 patients assessed for eligibility, 832 were included in the study. Following a review of medication history, patients were separated to gabapentin (n = 290), pregabalin (n = 11), and control (n = 531). The number of patients relapsed during the six-month period following Day-1 of programming was 208 (71.7%) in the gabapentin group, 7 (63.6%) in the pregabalin group, and 388 (73.1%) in the control group. There was no significant difference in number of patients relapsed between the control group versus the gabapentin group (p = 0.6831). The pregabalin group did not meet the predetermined sample size needed to assess a significant difference from the control group in terms of the primary or secondary outcome. The number of patients relapsed on their drug of choice in the gabapentin group was not statistically different from the number of patients relapsed on their drug of choice in the control group (p = 0.80). There was no statistically significant difference between number of patients relapsed in the gabapentin group with a diagnosis of alcohol use disorder compared to the number of patients relapsed with a diagnosis of opioid use disorder (p = 0.61). However, there was a significant difference found in the number of patients relapsed between those who completed the SATP compared to those who did not (p = 0.0000015).

Conclusions

The data from this retrospective chart review failed to show that gabapentin or pregabalin use during the SATP had a significant impact on the number of patients relapsed compared to patients who did not receive either medication during programming. Patients prescribed gabapentin were no more likely to than patients not prescribed gabapentin. Conclusions regarding relapse in the pregabalin group could not be drawn due failure to meet sample size. Further research may be warranted to assess if patients receiving gabapentin or pregabalin at moderate to high daily doses are more likely to relapse.

63 A randomized, comparative pharmacokinetic (PK) study of ZTlido™ lidocaine topical system 1.8% (36 mg) versus Lidoderm® lidocaine patch 5% (700 mg).

Kalpana Patel¹, Jeffrey Gudin², Kip Vought¹, Monil Shah³, Derek Grimes⁴, Philip LaStella⁴, Emileigh Gruber⁵

¹Scilex Pharmaceuticals Inc, Mission Viejo, CA, USA, ²Englewood Hospital Pain Mangement, Englewood, NJ, USA, ³JamaPharma Consulting, Skillman, NJ, USA, ⁴TKL Research, Fair Lawn, NJ, USA, ⁵Clinipace Worldwide, Morrisville, NC, USA

Purpose

Background: A lidocaine topical system 1.8% (36 mg) formulated as a thin, single-layer, anhydrous drug-in-adhesive delivery system was recently approved by FDA for the treatment of pain associated with post herpetic neuralgia (PHN). Objective: To demonstrate bioequivalence(BE) of the lidocaine topical system 1.8%(ZTLido) vs. lidocaine patch 5% (Lidoderm).

Methods

A randomized, comparative pharmacokinetic (PK) study was conducted in 54 healthy adult subjects. Serial blood samples were collected to determine lidocaine plasma concentrations at pre-dose and at scheduled time for up to 48 hours following a single dose of 3 patches over 12-hour administration period. PK parameters (C_max, AUC_0-t, and AUC_0-∞) were tested to demonstrate BE between ZTlido and Lidoderm. Safety, skin irritation and adhesion were determined during the study.

Results

The 90% confidence interval (CI) of the geometric mean ratios of C_max, AUC were within the regulatory range of 80%-125% establishing BE between ZTlido and Lidoderm.  Mean adhesion at the 12-hour time point was superior for ZTlido (mean score 0.22 on 0-4 FDA scale with 0 being ≥ 90% adhesion and 4 being complete detachment) compared to Lidoderm (mean score 0.86) (p < 0.001). None of the ZTlido subjects had a score >2 (i.e., < 75% adhesion) vs. 13 Lidoderm subjects had a score >2 (5 subjects with complete detachments). There were 2 nontreatment related AEs, 1 in each group tested. Both treatment groups reported similar irritation scores.

Conclusions

ZTlido™(lidocaine topical system) 1.8% was well tolerated, showed superior adhesion, and demonstrated bioequivalence to lidocaine patch 5%(Lidoderm®). 

64 A Multi-Center, Prospective, Clinical Trial of the High Frequency Spinal Cord Stimulation (HF-SCS) at 10 kHz in the Treatment of Chronic Upper Limb and Neck Pain

Kasra Amirdelfan¹, Ricardo Vallejo², Ramsin Benyamin², Cong Yu³, Thomas Yang³, Richard Bundschu⁴, Thomas Yearwood⁵, Todd Sitzman⁶

¹IPM Medical Group Inc, Walnut Creek, CA, USA, ²Millennium Pain Center, Bloomington, IL, USA, ³Swedish Pain Center, Seattle, WA, USA, ⁴Coastal Orthopedics and Pain Medicine, Bradenton, FL, USA, ⁵Comprehensive Pain and Rehabilitation, Pascagoula, MS, USA, ⁶Advanced Pain Therapy PLLC, Hattiesburg, MS, USA

Purpose

Disorders of the cervical spine are frequently disabling to the patient and costly to treat.^1,2 When patients do not improve with conservative care, surgical procedures, including anterior cervical discectomy with or without fusion, are often employed. In a randomized comparison trial of various surgical techniques in patients with cervical radiculopathy secondary to single level pathology, the incidence of arm pain and neck pain was 0−8% and 17−27%, respectively, at 24 months.³

Axial neck pain and associated (radicular) upper limb pain remain difficult-to-treat conditions. Traditional spinal cord stimulation (SCS) has been successfully used to treat upper limb and neck pain but is limited by variability in the distribution and intensity of the induced paresthesias as well as obtaining effective coverage of axial neck pain dermatomes.^4-6 High frequency SCS (HF-SCS) at 10 kHz is a paresthesia-independent therapy that has demonstrated long-term safety and effectiveness in the treatment of chronic, intractable back and leg pain.^7,8 The lack of paresthesia may reduce the positional variation that can compromise neck and upper limb pain relief. The goal of this study is to assess the safety and effectiveness of the HF-SCS at 10 kHz system in treatment of upper limb and neck pain.

Methods

Subjects with chronic, intractable neck and/or upper limb pain of  ≥ 5cm (on a 0-10 cm visual analog scale) were enrolled in a prospective, multi-center study (NCT02385201). Mechanical instability of the spine, cervical stenosis, significant epidural scarring or symptoms of myelopathy were causes for exclusion. An investigative device exemption (IDE) was obtained from the US Food and Drug Administration (FDA), and enrollment occurred following institutional review board (IRB) approval. Each subject was implanted with two epidural leads spanning C2-C6 vertebral bodies. Subjects with successful trial stimulation (≥ 40% pain relief) were implanted with a Senza system (Nevro Corp., Redwood City, CA) and included in the evaluation of the safety and effectiveness endpoints (≥ 50% pain relief) at 12 months post-implant. Results are presented as mean ± SD.

Results

A total of 51 subjects were trialed; 45/50 subjects with neck pain and 26/29 subjects with upper limb pain had successful trial (90% trial success rate in both groups). Forty-six subjects received a permanent implant. Majority of subjects (n = 28) presented both upper limb and neck pain whereas 18 subjects had only neck pain. Upper limb pain presented bilaterally in most of subjects (n = 21). Common diagnoses included radiculopathy (n = 34), degenerative disc disease (n = 32), and failed cervical spine surgery syndrome (n = 25). At 3-month primary endpoint analysis, response was reported in 33/42 subjects with pain in neck or upper limb (79% response rate), in 32/42 subjects with neck pain (79% response rate) and in 20/24 subjects with upper limb pain (83% response rate). At 12-month interim analysis, response rate increased to 87% (13/15) in subjects with pain in neck or upper limb, to 87% (13/15) in subjects with neck pain and to 100% (9/9) in subjects with upper limb pain. Baseline neck pain scores of 7.6 ± 1.3 cm improved to 2.6 ± 2.4 cm at 3-month and to 1.7 ± 1.8 cm at 12-month. Baseline upper limb pain scores of 7.1 ± 1.4 cm improved to 2.2 ± 2.1 cm at 3-month and to 1.0 ± 1.1 cm at 12-month.

Two device-related AEs were reported. No neurological deficits or paresthesias from HF-SCS at 10 kHz were reported.

Disability, as measured by Pain Disability Index score, decreased from 43.2 ± 11.7 at baseline to 21.6 ± 15.9 at 3 months post-implant, and to 17.1 ± 13.4 at 12 months post-implant.

Conclusions

Preliminary results from a multicenter, prospective study using high frequency spinal cord stimulation at 10 kHz to treat upper limb and neck pain are promising with outcomes similar to SENZA-EU and SENZA-RCT results for back and leg pain.

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65 Response to Lasmiditan for Acute Treatment of Migraine Based on Prior Response to Triptan Therapy

Kerry Knievel¹, Louise Lombard², Andrew Buchanan², Simin K. Baygani², Joel Raskin², Joshua Tobin³, Marissa I. Daniele²

¹Barrow Neurological Institute, Phoenix, AZ, USA, ²Eli Lilly and Company, Indianapolis, IN, USA, ³21st Century Neurology, Xenoscience, Phoenix, AZ, USA

Purpose

In the American Migraine Prevalence and Prevention Study, >40% of patients with episodic migraine had unmet acute treatment needs with current therapies, including lack of efficacy and intolerance; those with ≥1 unmet need were more likely to have used triptans in the past 3 months [1]. Lasmiditan, a novel, central nervous system penetrant, highly selective 5-hydroxytryptamine_1F receptor agonist, has demonstrated superiority to placebo in the acute treatment of migraine in adults. In two Phase 3 studies, SAMURAI (NCT02439320) and SPARTAN (NCT02605174), the percentage of patients who were migraine pain-free 2 hours post-first dose was significantly greater with lasmiditan 200mg and 100mg (all comparisons p < 0.001 vs placebo) taken within 4 hours of a single migraine attack. This post-hoc analysis determined whether response to lasmiditan differed according to prior triptan therapy response in participants in SAMURAI and SPARTAN.

Methods

Both studies included patients with moderate/severe migraine disability (MIDAS score ≥11). Current analyses considered combined data from participants reporting triptan use within 3 months prior to screening randomized to receive lasmiditan 100mg or 200mg, or placebo, as first dose. At baseline, patients rated themselves as good, poor or nonresponders prior to triptan therapy. To determine whether therapeutic benefit varied according to prior triptan response, treatment-by-subgroup analyses of 2-hour outcomes used a logistic regression model, including study, treatment, rescue medication use and triptan responder subgroup (good vs poor/nonresponder). Significance for interaction was defined as p < 0.1.

Results

In combined analyses, there was no evidence that the benefit (on headache pain freedom, most bothersome symptom [MBS] freedom, headache pain relief) of lasmiditan 200mg versus placebo varied significantly between triptan responder subgroups. A significant differential benefit of lasmiditan 100mg over placebo favouring poor/nonresponders vs good responders was seen for headache pain freedom (odds ratio 4.5 vs 1.8, p = 0.056) and MBS freedom (odds ratio 3.2 vs 1.5, p = 0.042). Risk relative to placebo of experiencing a treatment-emergent adverse event was significantly lower for poor/nonresponders vs good responders for each lasmiditan dose. Significant differences between subgroups were not consistently seen in individual studies.

Conclusions

Therapeutic benefit of lasmiditan in patients with moderate/severe migraine disability was generally unaffected by prior triptan therapy response. Lasmiditan offers a possible alternative migraine therapy option for patients regardless of prior response to triptans.

66 Using DNA Authenticated Drug Testing to Reduce Illicit Drug Consumption among Patients Treated for Chronic Pain in Richmond and Booneville Kentucky

Kim Cox^1,2, Tina Holbrook¹, Heather McClure¹, Nicholas Laude³

¹Family Health Care Clinic, Richmond, Kentucky, USA, ²Family Practice Clinic of Booneville, Booneville, Kentucky, USA, ³Genotox Laboratories, Austin, Texas, USA

Purpose

Patients being treated for chronic pain and other conditions are at a high risk for use of illicit drugs.  In certain parts of Kentucky methamphetamine use has become a problem among patients dealing with chronic pain.  Over a 1-year period the illicit drug positivity rates for these patients were studied after beginning the use of DNA-Authenticated Urine Drug Testing.

Methods

DNA-Authenticated drugs testing was performed on selected patients from the population being treated at two locations in Booneville and Richmond Kentucky.  Urine specimens were collected and stored under refrigerated conditions and shipped overnight to the testing laboratory.  DNA Analysis was performed using magnetic bead separation followed by end-point PCR and MALD-TOF mass spectrometry analysis of the amplicons.  Toxicology measurements were made using high performance liquid chromatography triple quadrupole mass spectrometers which analyzed over 100 drugs and metabolites.  DNA Authentication was able to identify patients attempting to substitute urine for other human or synthetic urine.  Urine substitution and drug positivity rates were evaluated quarterly at each clinic and declines in aberrant behavior were determined as compared with the initial rates in the fourth quarter of 2017.

Results

Aberrant behavior in the form of overall illicit drug positivity, non-compliance with prescribed medications, and specific drug use including methamphetamine, cocaine, THC, and heroin were observed to decline in the patient population after beginning to use DNA-Authenticated drug confirmation testing.  Declines were measured over four quarter from October 2017 to July 2018.  THC Positivity rates declined from 12.1% to 4.6% overall between the two clinics.  Heroin positivity declined from 0.5% to 0%.  Cocaine positivity declined from 6.8% to 3.6%.  Methamphetamine use dropped from 19.4% to 4.6% in the same period.  No PCP positives were reported during the entire study.

Conclusions

DNA Authenticated urine drug confirmation testing is useful both as a deterrent from drug seeking behavior but also to build trust between the patient and health care provider.  In areas of the country stricken with illegal drug use, it is important for doctors treating chronic pain to establish a baseline for illicit drug positivity and use different tools to attempt to decrease the rates of drug use in their patient population.  DNA Authentication technology such as ToxProtect^TM is one such tool that has been involved in the positive trends in decreasing drug use at the Family Health Care Clinic in Richmond Kentucky and Family Practice Clinic of Booneville in Booneville Kentucky.

67 Topical lavender for pain in hospice

Laura Meyer-Junco, PharmD, BCPS, CPE¹, Kasia Wielgosz, PharmD Candidate¹, Liz Fiorenza, RN and aromatherapist²

¹University of Illinois at Chicago College of Pharmacy at Rockford, Rockford, IL, USA, ²Mercyhealth at Home--Hospice, Rockford, Illinois, USA

Purpose

Pain is a common and distressing symptom for both hospice patients and their families.  In addition to the physical dimension of pain, end-of-life pain may also be comprised of psychological, spiritual, and existential pain.  Traditional analgesics, however, may not effectively treat the multidimensional “total pain” experienced by hospice patients.  Complicating this further, patients may be more comfortable expressing their “total pain” using physical terminology. Therefore, an ideal adjuvant modality for such “total pain” would not only be therapeutic for the body, but also for the mind.  This ideal modality would also allow family members to take an active role in the patient’s pain care, which may help with family coping.  Considerable literature exists on the benefits of inhaled lavender aromatherapy for the management of psychological symptoms and pain in varied patient populations, including the hospice population.  The two main components of lavender–linalyl acetate and linalool–are believed to give this essential oil its therapeutic effect.  By inhaling the volatile oils through the olfactory system, lavender aromatherapy is capable of stimulating the limbic system and producing relaxation, a sense of well-being, and ultimately influencing the perception of pain. Topical (or perhaps, even “transdermal”) application of lavender oil may provide a second mechanism of pain relief beyond inhalation of evaporated oils.  Lavender essential oils are believed to penetrate the skin and gain access to the blood stream and tissues, particularly with massage.  From animal models, topical lavender application may produce an analgesic effect via blocking sodium channels in afferent nociceptive neurons or as a result of anti-muscarinic activities.  The objective of this literature review was to evaluate studies exploring the effect of topical application of lavender oil on patients' self-reported pain.

Methods

A literature review was performed to identify randomized, controlled clinical trials on the use of topically applied lavender oil for the treatment of pain. Due to limited studies in hospice patients, trials examining topical lavender oil in other pain populations were included. Studies examining the use of inhaled lavender oil, oral ingestion of lavender oil, or use of lavender baths were excluded.  A comprehensive search of PubMed, CINAHL Plus and EMBASE databases was conducted to identify pertinent trials.  Additional articles were obtained by manual review of references contained within the studies identified in the database search.

Results

A total of 9 randomized trials were identified.  Most studies were conducted in patients with non-malignant pain and used topical lavender oil in conjunction with massage. Only two studies were performed in hospice patients, and one study was conducted in patients with cancer attending a palliative day center.  In the first hospice study of 42 cancer patients with mostly metastatic disease, a 30 minute back massage using a 1% lavender oil was given weekly for four weeks.  After four weeks, there was no additional benefit of using lavender oil during the massage over massage alone.  In the second hospice study, 28 hospitalized patients with terminal cancer received a five minute hand massage on each hand for seven days using a blended mixture of 1.5% lavender oil, bergamot, and frankincense in a 1:1:1 ratio.  The intervention group experienced significantly lower pain intensity compared to the 30 patients receiving placebo massage.  The palliative care study utilized a blend of 1% lavender and chamomile in conjunction with the patient’s choice of back, neck, shoulders, or hand massage for four weeks.  No significant difference in physical symptom severity (including pain) was seen between the intervention group and the control group (no intervention given).  Completion rates in this study were low due to poor attendance to the day center. Studies in non-cancer populations produced more favorable results. In two studies of acupressure massage using 3% lavender oil for neck pain or lower back pain, respectively, there was statistically significant reduction in pain in the intervention group versus the control group in which acupressure was not provided. One study conducted in patients aged 50 to 60 years old with knee osteoarthritis examined the effect of 3% lavender oil knee massage to massage alone. In this study patients were taught to perform effleurage massage themselves and instructed to perform 20 minutes self-massage nine times in three weeks.  Significant improvement in pain intensity was evident between aroma massage and control massage group.  Lavender massage for dysmenorrhea was also found to be beneficial over massage alone in a study of younger, female patients. Topical application of lavender oil without massage was examined in two studies—one in a dialysis population prior to painful arterial needle insertion and one conducted in patients with herpes simplex lesions.  Both studies demonstrated a significant benefit in decreasing pain intensity over the control group, in which topical placebo was applied.

Conclusions

The evidence for topical lavender oil for pain in hospice patients is limited, and the benefit of lavender massage in end-of-life pain populations is mixed. However, several limitations exist, including small sample sizes in both the hospice and palliative studies in this review and low completion rate in the palliative study. From this review, lavender oil with or without massage had a positive impact on self-reported pain for patients without active cancer.  While two of the three end-of-life studies did not demonstrate benefits of topically applied lavender oil for pain, it is important to note the severity of illness and potentially higher baseline pain in these populations (metastatic cancer) and the lower concentration of lavender used (less than 3%). More studies using topically applied lavender are needed in hospice patients with non-malignant pain and using higher lavender concentrations to explore the full utility of this treatment modality in hospice.  From the knee osteoarthritis study, it is evident that aroma massage can be taught, and therefore, such massage could be taught to family members.  This could result in increased patient and caregiver satisfaction not only through relaxation and human closeness but by greater attention to the “total pain” experience at end-of-life.

68 Are Pediatric Patients Just Short Adults? Most Commonly Prescribed Drugs For Pediatric Hospice Patients

Leah Sera, PharmD, MA, BCPS, Jill Morgan, PharmD, BCPS, BCPPS, Mary Lynn McPherson, PharmD, MA, MDE, BCPS

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

Purpose

According to the most recently published data from National Hospice and Palliative Care Organization, approximately 78% of hospice providers in the United States serve pediatric patients, and the majority of these serve 1-10 patients per year. As with adult patients, palliative care for children focuses on holistic care, including the alleviation of physical, psychosocial, and spiritual suffering. Medications are used in hospice patients to palliate physical symptoms of terminal illness, including pain, dyspnea, nausea, and fatigue. The purpose of this study was to characterize the most commonly prescribed medications and medication classes in a population of pediatric hospice patients.

Methods

We conducted a retrospective review of a patient information database compiled by a national hospice organization. The database contained demographic information, as well as information on drug name, dosage, formulation, and strength. Medications were also characterized by pharmacological class. We compared proportions of the most commonly prescribed pharmacological classes among the three most common admitting diagnoses: cancer, central nervous system disorders, and genetic disorders. We used chi-square test or Fisher’s exact test to detect any associations between admitting diagnosis and drug class. The institutional review board at the University of Maryland determined that this study was not human subjects research.

Results

Of 177 patients in the database, 116 patients were included in the study; these patients were admitted to hospice on or after January 1, 2011 and discharged by death on or before December 31, 2016. Sixty-one patients who were discharged prior to death were excluded. The average age of patients at admission was 6 years old (SD = 6.1) and 63% of patients were female. The median length of stay was 14.5 days (range: 0-411 days). A total of 3 017 medication orders were evaluated. Medication classes used for symptom management were most commonly prescribed. Six of the 10 most commonly prescribed drugs (morphine, lorazepam, acetaminophen, hyoscyamine, prochlorperazine, and haloperidol) were all included in the symptom management medication kits provided to most patients at admission. Other drugs prescribed for over 20% of patients included metoclopramide, diphenhydramine, albuterol, altropine, ondansetron, diazepam, polyethylene glycol, levetiracetam. Opioid analgesics, anxiolytics, anticholinergics, and antiemetics were prescribed to over 50% of patients at some point during admission. Other frequently prescribed medication classes non-opioid anageiscs, anticonvulsants, antiinfectives, laxatives, corticosteroids, acid reducers, antipsychotics, and vitamins/supplements. Of the 20 most commonly prescribed drug classes, patients with cancer were significantly more likely than those with CNS disorders or genetic disorders to be prescribed anticholinergics (p = 0.03), antiemetics (p < 0.0001), non-opioid analgesics (p = 0.003), laxatives (p = 0.003), corticosteroids (p = 0.0004), antihistamines (p = 0.01), acid reducers (p = 0.03), and antipsychotics (p < 0.0001).

Conclusions

Medications commonly prescribed for children receiving hospice care include those intended to treat symptoms including pain, dyspnea, nausea, seizures, and constipation. A general understanding of medications used in hospice care may be helpful in the development of educational materials, medications guidelines and protocols, and questions for future research.

69 Battling the Opioid Epidemic: Use of Multi-modal Analgesia in Women Post-Cesarean Section

Lelas Shamaileh^1,2, Serene Abuzir^1,2, Noha Mohamed^1,2, Ashleigh Swearingen¹, Zahra Khudeira¹

¹Mount Sinai Hospital, Chicago, IL, USA, ²University of Illinois College of Pharmacy, Chicago, IL, USA

Purpose

Pain management has received extra attention over the past few years as the opioid epidemic was declared a major healthcare issue in the United States. The Centers for Disease Control reported that over 42,000 Americans died due to opioid overdose in 2016, an average of 115 people per day, with about 40% of these deaths resulting from prescription opioids.  In the midst of this opioid epidemic, the Obstetrics Department at Mount Sinai Hospital in Chicago implemented multimodal therapy for post-cesarean patients in efforts to decrease opioids prescribed immediately postpartum and at discharge, while maximizing pain management. Controlling pain in the post-cesarean patient population is particularly important because the immobility caused by the pain further increases these women’s risk for thromboembolic events beyond their already increased baseline risk. Additionally, uncontrolled pain may negatively affect mother-baby bonding and can increase risk for postpartum depression and anxiety. The purpose of this study was to analyze the effectiveness of multimodal therapy in comparison to traditional management with opioids. The management of post-cesarean medication order-set was revised to reflect multimodal analgesia management. Our objectives were to standardize analgesia with the multimodal approach while adequately controlling pain, decrease hospital length of stay, and reduce the amount of opioids prescribed at discharge.

Methods

This was a retrospective chart review comparing post-cesarean patients who underwent traditional analgesia with opioids from September-November 2016 (pre-implementation) versus post-cesarean patients receiving multimodal analgesia from January-March 2018 (post-implementation). The multimodal approach utilizes analgesics with different mechanisms of action for an additive or synergistic effect in order to minimize opioid use. The non-opioid medications used were: nonsteroidal anti-inflammatory drugs, acetaminophen, and gabapentin. Hydromorphone was incorporated into a patient’s pain management for pain score of 7 and above on a 10-point scale. Unpaired t-test with heteroscedasticity for each variable was used to assess associations between the two groups.

Results

Records were reviewed for a total of 155 patients pre-implementation and 166 patients post-implementation of the multimodal analgesic approach for post-cesarean pain management. The average morphine equivalents prescribed inpatient were 44.9 mg pre-implementation versus 23.5 mg post-implementation (p < 0.001).  Upon discharge, 89% of pre-implementation patients were discharged with opioids verses 32.5% of patients post-implementation (p < 0.0001), effectively decreasing the number of opioid tablets prescribed upon discharge by 52% (p < 0.0001).  Multimodal analgesia was associated with a decreased length of hospital stay by 0.5 days (p = 0.008).

Conclusions

Multimodal analgesia reduced the amount of opioids prescribed after cesarean section.  Inpatients received less morphine equivalents and opioid discharge prescriptions were significantly less.  The positive results can possibly impact the war against opioid addiction and has substantial economic benefits. The reduction in length of stay translates to a projected annual savings of $4.8 million for our institution.

70 Phase 3 Studies (SAMURAI, SPARTAN) of Lasmiditan Compared to Placebo for Acute Treatment of Migraine

Linda A. Wietecha¹, Bernice Kuca², Josephine Asafu-Adjei¹, Sheen K. Aurora¹, Marissa I. Daniele¹

¹Eli Lilly and Company, Indianapolis, IN, USA, ²CoLucid Pharmaceuticals, Inc., a wholly owned subsidiary of Eli Lilly and Company, Indianapolis, IN, USA

Purpose

Lasmiditan is a novel centrally acting serotonin (5-HT_1F) agonist that lacks vasoconstrictive activity.  Efficacy and safety findings from two pivotal Phase 3 studies of lasmiditan for acute treatment of migraine are reported here.

Methods

SAMURAI (NCT02439320) and SPARTAN (NCT02605174) were Phase 3, randomized, double-blind, placebo-controlled studies. Inclusion criteria included Migraine Disability Assessment Score ≥11 (moderate disability) and 3–8 migraine attacks per month. Patients were randomized to a first dose of treatment (SAMURAI, 1:1:1 ratio of lasmiditan 200/100 mg or placebo, SPARTAN, 1:1:1:1 ratio of lasmiditan 200/100/50 mg or placebo) which was taken within 4 hours of migraine onset (moderate severity or worse and not improving). For rescue or recurrence, patients took a randomly assigned second dose of the previously assigned lasmiditan dose or placebo. The primary and key secondary analyses compared the proportions of patients in the lasmiditan 200-mg group with the placebo group who were headache pain-free and who were most bothersome symptom (MBS)-free at 2 hours post-first dose, respectively. Treatment-emergent adverse events (TEAEs) were used to assess safety. Logistic regression was used for comparisons.

Results

At 2 hours post-first dose, significantly greater proportions of patients (p < 0.001) were headache pain-free (lasmiditan 200 mg: SAMURAI 32.2%, SPARTAN 38.8%; placebo: SAMURAI 15.3%, SPARTAN 21.3%) and MBS-free (lasmiditan 200 mg: SAMURAI 40.7%, SPARTAN 48.7%; placebo: SAMURAI 29.5%, SPARTAN 33.5%) with lasmiditan 200 mg compared with placebo. For both endpoints, significance was also noted for other lasmiditan dose groups (100 mg, 50 mg) compared to placebo. The most frequently reported TEAEs with lasmiditan (≥ 2% and greater than placebo) after the first dose were dizziness, paresthesia, somnolence, fatigue, nausea, and lethargy, and most events were mild-to-moderate in severity.

Conclusions

The primary and key secondary endpoints were met and safety outcomes were consistent across the two Phase 3 studies.

71 In-House Urine Drug Screening (Immunoassay): The First Step for Identification and Rehabiliation of At-Risk Patients Recieving Treatment for Chronic Pain and Substance Abuse

Luc Frenette¹, David Hardin^1,2, J. Michael Hardin³

¹Preferred Pain Associates, Birmingham, AL, USA, ²Brookwood Baptist Health System, Birmingham, AL, USA, ³Samford University, Birmingham, AL, USA

Purpose

Public health officials have called the current opioid epidemic the worst drug crisis in American history, killing approximately 55,000 people in 2016.[1]

This study is a retrospective analysis of patients in a single pain management clinic providing opioid management, interventional pain procedures, and opioid dependence treatment. The clinic accepts most commercial and public insurance providers. To solve the opiate crisis, a first step is to gather basic information describing the characteristics of our patients, particularly those who may be at risk for illicit drug use or other activities which would impede the treatment of chronic pain or addiction management.

The purpose of this study is to determine the characteristics of the chronic pain and opiate dependent patient population, investigating predictors of at-risk behavior that may correlate with the need for dismissal from a practice. These at-risk patients can be targeted for additional counseling, medication changes, or other interventions to prevent misuse and abuse of narcotics or other substances.

Methods

For this study a random sample of 168 patients was taken from a population of 4700 different patients involved with Preferred Pain Associates between August 2014 and August 2017. An individual chart review was performed on each patient in the sample to gather data on sex, age, diagnosis requiring pain management, reason for dismissal, and number of months patient is established with practice. Descriptive statistics were computed and censored Cox regression was performed to establish patient characteristics correlated with fewer months until patient is dismissed from practice.

All patients wihin the sample had been managed per a standard clinic policy that outlines consistent use of short-acting and long-acting narcotics for chronic pain patients, and buprenorphine-containing drugs to manage patient being treated for opiate dependence.

The Prescription Drug Monitoring Program (PDMP) database was queried and a urine drug screen (UDS) measured by in-office immunoassay was performed prior to every provider visit. Ambiguous results were confirmed by outside, third-party labs. Discrepancies in medication reconcillation were discussed with the patient and behavior leading to dismissal was recorded in the patient sample.

Results

For this sample, 96 (57.1%) of patients were female and 72 (42.9%) male. Of patients in the sample who were dismissed from the clinic, 74 (52.86%) were female and 66 (47.14%) were male. The mean ages for patient dismissed and those still active are 48.7 years and 56.8 years respectively. Patient were seen in clinic for a mean of 5.4 months before being dismissed. 72 of 140 (51.43%) dismissed patients were dismissed at 3 months or fewer, with 127 (90.7%) dismissed at 12 months. Active patients have been established for a mean of 14.6 months. The most common reason for dismissal was UDS inconsistent with prescribed medications and/or including illicit substances with 70 (50.0%) patients dismissed for this reason. PDMP review accounted for only 8 (5.71%) dismissals The most common treatment diagnosis across both categories of patient was chronic back pain (90% of patients). Cox regression analysis showed a statistically significant correlation with younger age, male sex, and diagnosis of chronic back pain predictive of a shorter time until dismissal.

Conclusions

Characteristics such as young age, male sex, and chronic back pain are associated with patients at high risk of dismissal from a pain medicine practice. Urine drug screening also appears to be one of the most valuable tools in detecting at-risk behavior and potential need for dismissal, disrupting ongoing chronic pain and addiction management care, With screening tools such as the PDMP having much lower rates of dismissal for patients in this sample, other measures such as UDS may be more effective in the behavior screening of patients with chronic pain and substance abuse. Further investigation into characteristics of these patient population will help to target high risk patients, improve patient retention, and ensure continuity of care for this vulnerable population.

72 Perioperative Opioid Sparing: The Utility of Conventional NSAIDs in Adults

Luc Martinez¹, Evan Ekman², Nardine Nakhla³

¹Formerly of University Paris VI, Paris, France, ²Aiken Regional Medical Center, Aiken, South Carolina, USA, ³University of Waterloo, Ontario, Canada

Purpose

Opioids have long been used to treat acute postsurgical and postprocedural pain, but opioid-related adverse events (AEs) contribute to poor patient outcomes. A retrospective review of over 135,000 patients treated with opioids after in-hospital surgical or endoscopic procedures found that 10.6% had opioid-related AEs associated with poor patient outcomes, including increased inpatient mortality, prolonged length of stay, and higher 30-day readmission rates. Unfortunately, perisurgical exposure to opioids may also be an inciting event for the development of opioid use disorder. In 2015, nearly 6% of the US population aged 15–64 years reported abusing opioids, and in 2016 opioid use disorder was found to represent the 7th leading cause of disability-adjusted life-years, compared with 1990, when it was the 11th leading cause. The incidence of addiction in opioid-treated chronic pain patients in the United States ranges from 20% to 33%.

 The opioid epidemic in North America has been well publicized and is at least partially responsible for efforts to reduce the use of opioids perioperatively through the use of multimodal therapy. This involves a process by which different procedures or techniques, and/or medications with different mechanisms of action, are used in order to achieve pain control and minimize potential complications of opioid use. Nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit cyclooxygenase, thus blocking formation of prostaglandins, which mediate pain and inflammation. This review assessed the effects of adjunctive conventional NSAIDs given systemically for opioid-sparing abilities. Differences in pain control, AE rates, and morbidities were also assessed.

Methods

A literature search was conducted, using the PubMed electronic database for clinical trials, that evaluated the use of systemic conventional NSAIDs as part of a perioperative multimodal pain management strategy in adults undergoing various surgical procedures. Search terms were identified for the population of interest (adults), timing of the intervention (surgical; perioperative; postoperative), and the treatment of interest (NSAIDs; ibuprofen; naproxen; ketoprofen; dexketoprofen; diclofenac; indomethacin; ketorolac; oxaprozin; meloxicam; and piroxicam). The search was limited to clinical trials, research in humans, English language, and publication on 1/1/2000 or later. Abstracts from search “hits” were reviewed for relevancy. For abstracts that reported 1 or more of the outcomes of interest (including effects on opioid dose requirement, pain scores, morbidity, and/or AEs) based on the use of NSAIDs, full text articles were obtained and reviewed. Trials in which NSAIDs were used to decrease pain via periarticular injections, local infiltration, or regional blocks were excluded.

Results

Our search yielded 55 potentially relevant trials. Thirty trials were excluded on abstract review. Upon full text review of the remaining 25 trials, 3 were excluded, leaving 22 articles in our review. NSAIDs investigated included diclofenac (n = 9); ibuprofen (n = 6); dexketoprofen (n = 3); ketoprofen (n = 2); lornoxicam (n = 2); ketorolac (n = 1); piroxicam (n = 1); and dipyrone (n = 1). Comparators varied; some trials evaluated 2 or more NSAIDs ± placebo; not all outcomes were reported in each trial. Diclofenac significantly reduced morphine requirements in 5/6 trials (inferior to dexketoprofen in 1 trial) and pain scores in 3/7 trials where these outcomes were reported. Ibuprofen provided a significant morphine-sparing effect in 3/4 trials and significant pain score reductions in 5/6 trials where assessed. Dexketoprofen significantly reduced morphine consumption in 2/2 trials and pain scores in 1/3 trials; pain scores were reduced similarly with ketoprofen and diclofenac in the remaining trials. Lornoxicam significantly reduced morphine requirements in 2/2 trials and pain scores in 1 trial. Ketoprofen reduced pain scores significantly in 2/2 trials, but changes in morphine requirements were not measured in either trial. Ketorolac significantly reduced both morphine consumption and pain scores, but the latter effect was short-lived. Piroxicam and dipyrone significantly reduced pain scores in 1 trial each; morphine consumption was not affected by piroxicam and not assessed in the dipyrone trial. Overall, NSAIDs were well tolerated. In an analysis looking at renal AEs, no differences were found between diclofenac, ketorolac, and placebo. Ibuprofen was associated with no differences in gastrointestinal AEs in the 3 trials that reported them (vs placebo) and significantly less nausea (vs morphine) and constipation (vs placebo control) in 1 trial each. Dexketoprofen appeared to be better tolerated than ketoprofen. No trial reported increased postoperative bleeding.

Conclusions

NSAIDs can help spare the use of opioids in the management of postoperative pain, generally without compromised pain control and most likely via treatment of the inflammatory component of pain. NSAIDs were well tolerated, had similar rates of gastrointestinal AEs as placebo, caused fewer AEs compared with traditional morphine analgesia, and generally were not associated with increases in postoperative bleeding. NSAIDs have the potential to play an important role in reducing opioid need postoperatively, and as such, may have a role in helping to reverse the opioid epidemic.

73 Improving Pain Management knowledge Among Nurses

Lucia Amendano

Montefiore Nyack Hospital/EMA, Nyack, NY, USA, James. Peters VA Medical Center, Bronx, NY, USA

Purpose

The purpose of the quality improvement project was to increase emergency department nurses knowledge of pain management and utilization of pain assessment guidelines, resources and policies. By nurses having adequate education, they can provide timely and efficient care to support optimal patient outcomes, improve patient comfort, and improve overall patient satisfaction.

Methods

A pre and post-test method was used to evaluate nurses knowledge and attitudes regarding pain management. The Knowledge and Attitudes Survey Regarding Pain (KASRP) tool was used to assess nurses’ knowledge and attitudes regarding pain management which included aspects of pain assessment, pharmacological, and non-pharmacological intervention.  There were 30 questions where the answers were either scored as 1 = correct or 0 = incorrect. The answers were added up, and the total percent of correct answers were calculated for each of the 23 participants at both pre-intervention and post-intervention.

Results

The results of the data analysis showed statistically significant mean difference increase of 23.91% from pre-intervention (65.65%) to post-intervention (89.56%) percent scores correct regarding patient pain management guidelines and assessment, t (22) = −5.715, p < 0.001. This means that the quality improvement project intervention had a significant impact on raising pain knowledge scores on management guidelines and assessment.

Conclusions

Appropriate pain management is a vital component to quality patient care. Emergency department nurses play an essential role in implementing pain management. The lack of knowledge and attitudes regarding pain management and ineffective pain assessment, reassessment, and documentation are barriers to effective pain management. Thus, having guidelines, along with providing education, having resources such as pain scales, visual reminders, and binders with pain managment policy and pain assessment guidelines proved to be useful as evidenced by post-test score improvement. This quality improvement project will provide a basis for future studies in improving nurses’ pain management knowledge.

74 Burden of illness among treated migraine patients with ≥4 headache days in the past month

Lulu Lee¹, Jvawnna Bell², Timothy Fitzgerald², Joshua Cohen²

¹Kantar Health, San Mateo, CA, USA, ²Teva Pharmaceuticals, Frazer, PA, USA

Purpose

Migraine is a chronic condition that disrupts health-related quality of life.  It is the seventh global cause of years of life lost to disability (YLD), accounting for 3.79% of total YLDs.  Additionally, it is the most burdensome disease among neurological causes evaluated in the Global Burden of Disease study.

The purpose of the survey was to determine the burden of illness among patients treated for migraine with ≥4 headache days in the past month.

Methods

Data from the nationally representative 2016 US National Health and Wellness Survey (N = 97,503) was used. Respondents were included in this analysis if they self-reported a migraine diagnosis, experienced ≥ 4 headache days in the past month, and were currently using a prescription migraine treatment. Using propensity score matching to reduce bias, respondents meeting the above criteria were matched with people without migraine on demographics and health characteristics.  Outcomes included mental health comorbidities, metrics from the Work Productivity and Activity Impairment Questionnaire, healthcare utilization in the past 6 months (i.e., healthcare provider (HCP) visits, emergency room visits, and hospitalizations), and estimated annual indirect and direct costs. Post-match, groups were compared using One-Way ANOVAs and chi-square tests on outcomes.

Results

A statistically significantly greater proportion of treated migraine patients reported the following  compared to non-migraine controls: (1) being diagnosed with depression, (2) being on long-term disability, (3) greater losses in work productivity and increases in activity impairment, (4) greater absenteeism (5) presenteeism  (6) overall work impairment and (7) activity impairment, all p < 0.05.  Treated migraine patients had greater work productivity loss which resulted in higher estimated annual indirect costs and utilized more healthcare services.

Conclusions

The overall burden associated with migraine is substantial despite the availability of treatment options. As a result, patients treated for migraine incurred substantially greater direct and indirect costs compared to non-migraine controls.

75 SAFETY OF NALDEMEDINE FOR THE TREATMENT OF OPIOID-INDUCED CONSTIPATION IN SUBJECTS WITH CHRONIC NON-CANCER PAIN RECEIVING OPIOID THERAPY: RESULTS OF THREE GLOBAL PHASE 3 CLINICAL TRIALS

Lynn R Webster¹, Harold I Magazine², Tadaaki Yamada³

¹1. PRA Health Sciences, Salt Lake City, UT, USA, ²Shionogi Inc., Florham Park, NJ, USA, ³Shionogi Inc., Salt Lake City, Utah, USA

Purpose

Opioid-induced constipation (OIC) is a common side effect of opioids in the treatment of chronic non-cancer pain. Effective treatment of OIC can be impacted by how particular treatments are tolerated. Naldemedine (NAL), an oral, peripherally acting µ-opioid receptor antagonist (PAMORA), is approved for the treatment of OIC in adult patients with chronic non-cancer pain in the US. In this analysis, we evaluated the safety and tolerability of NAL from integrated analysis across three global phase 3 trials up to 12 weeks.

Methods

Results from three phase 3, double-blind, randomized, placebo (PBO)-controlled trials were integrated to evaluate the safety and tolerability of NAL up to 12 weeks. Subjects 18 to 80 years old, with chronic non-cancer pain and OIC, taking opioids for ≥3 months, received either NAL 0.2 mg (N = 1163) or PBO (N = 1165) taken orally once daily with or without food. Tolerability and adverse events, including potential opioid withdrawal (OW) were analyzed.

Results

The majority of subjects completed the trial (NAL, 88.7%, PBO, 88.4%) and the proportion that discontinued was similar across treatment groups. The duration of treatment was similar across treatment groups with a mean exposure of 76.6 and 77.2 days in the NAL and PBO groups respectively, approaching the maximal possible exposure of 84 days for the 12-weeks of study. Adverse Drug Reactions were reported more frequently in the NAL group compared with PBO across the studies and in the pooled population (NAL, 20.1%, PBO, 13.6%, 95% CI of difference: 3.4, 9.5). The assessment of summary measures of Treatment Emergent Adverse Events (TEAEs) demonstrated that the overall incidence was similar between groups in all studies and associated primarily with the gastrointestinal system. TEAEs with ≥ 1% difference between the NAL and PBO groups were limited to abdominal pain, diarrhea, and nausea. In general, TEAEs were mild to moderate in severity and short in duration. The majority of reports of diarrhea occurred early in the study, reports of abdominal pain occurred early and only once, and nausea generally occurred early but with reports throughout the study. The incidence of OW was low in the NAL and PBO groups (NAL, 1.0%, PBO, 0.6%).

Conclusions

An integrated analysis across three Phase 3 trials demonstrated that treatment of OIC with NAL in subjects with chronic non-cancer pain was well tolerated with the majority of TEAEs occurring early, of short duration, mild to moderate in nature and generally limited to the gastrointestinal system. Furthermore, the incidence of OW was low and similar between NAL and PBO.

76 The Relative Bioavailability of Oxycodone ARIR (RoxyBond™), a Novel Abuse-deterrent Formulation of Immediate-Release Oxycodone, Compared with Immediate-Release Oxycodone

Lynn Webster¹, Eric R Kinzler², Carmela Pantaleon², Matthew Iverson², Stefan Aigner²

¹PRA Health Sciences, Salt Lake City, Utah, USA, ²Inspirion Delivery Sciences LLC, Morristown, New Jersey, USA

Purpose

In 2016, 11.5 million individuals aged 12 years or older reported the misuse or abuse of prescription opioids. The US Food and Drug Administration (FDA) encourages the development of abuse-deterrent formulations (ADFs) and initially developed guidance for industry in 2013. Since then, 7 extended-release (ER) formulations have been approved with labeling consistent with the FDA’s guidance. However, only 1 immediate-release (IR) formulation is approved with ADF labeling. The population-adjusted rates of intentional abuse and diversion are 4.6 times and 6.1 times greater, respectively, for IR opioids than for ER opioids (Iwanicki JL, et al. PLoSOne. 2016;11:pe0167499). IR opioids are preferred by 66% of advanced opioid users, compared with only 4% preferring ER opioids (Cicero TJ, et al. Pharmacoepidemiol Drug Saf. 2017;26:56-62). Epidemiologic evidence suggests that a decrease in the misuse and abuse of an ADF ER oxycodone may be accompanied by an increase in the misuse and abuse of non-ADF IR oxycodone, highlighting the need to develop and commercialize IR ADFs (Cassidy TA, et al. Pain Med. 2014;15:440-451). Oxycodone ARIR (RoxyBond™, Daiichi Sankyo, Inc., Basking Ridge, NJ) is the first FDA-approved IR opioid with ADF labeling. Oxycodone ARIR is formulated with proprietary SentryBond™ technology to deter abuse by the intranasal and intravenous routes of administration; however, abuse by oral, intranasal and intravenous routes is still possible. Herein, we compare the relative bioavailability of Oxycodone ARIR to IR oxycodone under fasted conditions.

Methods

In an open-label, single-dose, randomized, 3-period, 3-treatment, 6-sequence crossover study, 30 mg oral Oxycodone ARIR or 30 mg IR oxycodone was administered to healthy subjects. Only results under fasted conditions are presented herein. Each treatment period consisted of study check-in, 2 days of participation, and study completion or early termination, separated by a minimum 4-day washout between doses. Study treatment was administered after an overnight fast of ≥10 hours. Naltrexone 50 mg was administered before and after dosing to minimize opioid side effects. The plasma concentrations of oxycodone were obtained at pre-dose and at various times up to 24 hours post-dose. The following pharmacokinetic (PK) parameters were calculated: the area under the plasma concentration-time curve from 0 hour to the last measurable concentration (AUC_0-t), extrapolated to infinity (AUC_0–∞), and various post-dose timepoints; the maximum observed plasma concentration (C_max); and time associated with C_max (T_max). Oxycodone PK parameters were summarized using descriptive statistics. The SAS mixed-effect linear model procedure (PROC MIXED) was used to construct the analysis of variance (ANOVA) models of log_e-transformed values for each parameter. The 90% confidence intervals (CIs) were based on the least square means estimation using the mean square error. The ratio (and 90% CIs) of geometric means for Oxycodone ARIR and IR oxycodone were calculated for AUC parameters and C_max. Treatments were considered equivalent if the 90% CIs were within the equivalence range of 80% – 125%. Safety assessments included reports of adverse events (AEs), clinical laboratory tests, electrocardiograms, and physical examinations.

Results

Of 75 enrolled subjects, 58 completed all treatments. Of the 17 subjects who prematurely discontinued from the study, 10 withdrew because of AEs before study drug administration, 6 withdrew at their own choice, and 1 was lost to follow up. The mean C_max was 14% lower for Oxycodone ARIR (57.8 ng/mL) compared with IR oxycodone (67.7 ng/mL). AUC_0 − t and AUC_0-∞ were each slightly lower (4%) for Oxycodone ARIR than for IR oxycodone. Oxycodone ARIR and IR oxycodone were within the equivalence range of 80% – 125% for total exposure (AUC_0−t, 92.5% – 98.7% and AUC_0-∞,92.8% – 98.9%). The 90% CI for C_max was slightly outside the 80% – 125% bioequivalence range (78.8% – 94.3%). The median T_max for Oxycodone ARIR was 29 minutes longer than for IR oxycodone. AEs occurred more frequently with Oxycodone ARIR (20%) than with IR oxycodone (11%). The most common AEs were gastrointestinal disorders (ie, nausea, vomiting, and dyspepsia) followed by nervous system disorders (dizziness, headache, and somnolence). All AEs were mild or moderate in severity and typical of opioid-related AEs. One subject withdrew prematurely during IR oxycodone treatment due to vomiting.

Conclusions

Oxycodone ARIR and IR oxycodone are within the accepted bioequivalence range for AUC. Although the 90% CI for C_max for Oxycodone ARIR was slightly below bioequivalence range, this finding is not expected to be clinically meaningful. Oxycodone ARIR is expected to have the same efficacy and safety profile as IR oxycodone.

77 The Effect of Food on the Pharmacokinetic Characteristics of Oxycodone ARIR (RoxyBond™), a Novel Abuse-Deterrent Formulation of Immediate-Release Oxycodone

Lynn Webster¹, Eric R Kinzler², Carmela Pantaleon², Matthew Iverson², Stefan Aigner²

¹PRA Health Sciences, Salt Lake City, Utah, USA, ²Inspirion Delivery Sciences LLC, Morristown, New Jersey, USA

Purpose

Prescription opioids are often targeted for misuse and abuse, with misuse and abuse reported by 11.5 million individuals aged 12 years or older in 2016. The development of abuse-deterrent formulations (ADFs) is encouraged by the FDA, which initially developed guidance for industry in 2013. Currently, 7 extended-release (ER) and 1 immediate-release (IR) ADFs have been approved with labeling consistent with the guidance. Oxycodone ARIR (RoxyBond™, Daiichi Sankyo, Inc., Basking Ridge, NJ) is the first FDA-approved IR oxycodone tablet with ADF labeling. It is formulated with proprietary SentryBond™ technology and has physical and chemical properties to deter abuse. Food can alter the pharmacokinetics (PK) of some ADFs. High-fat meals may delay maximum plasma concentration or increase bioavailability. Herein, we assess the effect of food on the PK of Oxycodone ARIR.

Methods

In an open-label, single-dose, randomized, 3-period, 3-treatment, 6-sequence crossover study, 30 mg oral Oxycodone ARIR (fed and fasted conditions) or IR oxycodone (fasted conditions only) was administered. Results herein are presented for Oxycodone ARIR under fasted and fed conditions. Each treatment period was separated by a minimum 4-day washout between doses. All subjects fasted for at least 10 hours prior to dosing. For the fed condition, a high-fat meal was consumed 30 minutes prior to dosing. Naltrexone 50 mg was administered before and after dosing to minimize opioid side effects. The plasma concentrations of oxycodone were obtained at various times up to 24 hours postdose. The following PK parameters were calculated and summarized using descriptive statistics: area under the plasma concentration time curve from 0 hour to the last measurable concentration (AUC_0-t); AUC from 0 hour extrapolated to infinity (AUC_0–∞) and various postdose timepoints; maximum observed plasma concentration (C_max); and time to C_max (T_max). The SAS mixed-effect linear model procedure (PROC MIXED) was used to construct the analysis of variance models of log_e-transformed values for each parameter. The 90% confidence intervals (CIs) were based on the least-squares means (LSM) estimation using the mean square error. Relative bioavailability was compared for AUC parameters and C_max using the ratio (and 90% CIs) of geometric means in fed and fasted states. Treatments were considered equivalent if the 90% CIs were within the equivalence range of 80% – 125%. Safety assessments included adverse events (AEs), clinical laboratory tests, electrocardiograms, and physical examinations.

Results

Of 75 subjects enrolled in the study, 58 completed all treatments. Mean oxycodone C_max was 18% higher (68.0 vs 57.8 ng/mL) under fed compared with fasted conditions. AUC_0-t and AUC_0-∞ were 23% higher when Oxycodone ARIR was administered in the fed vs fasted state. The 90% CIs were slightly outside the equivalence range of 80% – 125%; C_max (108.6% – 129.4%) and for oxycodone exposure (AUC_0-t: 119.1% – 127.0%; AUC_0-∞: 119.7% – 127.4%). The median T_max for Oxycodone ARIR was 30 minutes longer in the fed vs fasted state (2.0 vs 1.8 hours, respectively; LSM difference, 0.5). AEs occurred somewhat more frequently with Oxycodone ARIR fasted treatment (20%) than with fed treatment (17%). One subject withdrew prematurely during Oxycodone ARIR fed treatment due to headache (considered unrelated to study treatment). The most common AEs were gastrointestinal disorders (ie, nausea, vomiting, dyspepsia) followed by nervous system disorders (dizziness, headache, somnolence). Nausea occurred more frequently with Oxycodone ARIR fasted treatment (15%) than with fed treatment (5%). All were mild or moderate in severity and typical of opioid-related AEs.

Conclusions

In this single-dose bioavailability study, oxycodone C_max was 18% higher and T_max was 30 minutes longer under fed conditions compared with fasted conditions. Overall oxycodone exposure (AUC_0-∞) and C_max were slightly outside the 80% – 125% equivalence range for fed vs fasted treatments. Although there were differences due to administration with and without food, these differences were considered moderate, indicating that Oxycodone ARIR can be administered without regard to food.

78 Nerve Growth Factor (NGF) as a Target for Treatment of Neuropathic Pain

Michael Ossipov¹, Joseph Pergolizzi^2,3, Robert Taylor², Robert Raffa^4,5,3

¹University of Arizona College of Medicine, Tucson, AZ, USA, ²Nema research Inc, Naples, FL, USA, ³Neumentum Inc, Palo Alto, CA, USA, ⁴University of Arizona College of Pharmacy, Tucson, AZ, USA, ⁵Temple University School of Pharmacy, Philadelphia, PA, USA

Purpose

A potential target that has recently gained the attention of the analgesic drug development community is nerve growth factor (NGF). We summarize the rationale and current status of some NGF-related approaches to analgesia.

Methods

A search was conducted of published literature (English) using sources such as PubMed and MedLine, plus gene and protein database registries. The information was reviewed, assessed, and synthesized. Emphasis was placed on the efficacy and safety of NGF-related agents.

Results

Since the discovery of NGF and subsequent studies designed to determine its functions, several investigations revealed that NGF occurs in anatomical sites where it can affect the transmission or modulation of pain signals. Other studies have shown that NGF increases the sensitivity of nociceptors to noxious stimuli. Converging evidence also indicates that NGF can mediate pain both acutely and chronically. It can directly activate nociceptors to trigger pain signals, and sensitize the same nociceptive nerves to further stimuli, enhancing further pain transmission of pain signals.

Conclusions

The development of anti-NGF pain therapeutics was interrupted because of unexpected adverse effects. However, clinical studies are continuing, with additional cautionary measures in place to mitigate against unforeseen adverse effects related to NGF function.

79 Urine drug test results track the co-occurrence of non-prescribed fentanyl in national and regional populations of heroin-positive patients: A 2018 update

Maria Guevara, Eric Dawson, Angela Huskey, Maria Chianta, Kelly Olson, Joseph Stanton, Leah LaRue

Millennium Health, San Diego, CA, USA

Purpose

The United States continues to experience unabated proliferation of illicit fentanyl and its analogues.¹  In 2016, both the Centers for Disease Control (CDC) and the Drug Enforcement Administration (DEA) issued nationwide warnings on the increased prevalence of fentanyl in the illicit market.^2,3  Up to 50 times more potent than heroin and up to 100 times more potent than morphine, fentanyl is often spiked into heroin or sold as heroin, frequently without the knowledge of the consumer.⁴  To date, the epidemiology of fentanyl-spiked heroin has relied largely on reports of seizures by law enforcement agencies and accounts of fatal and non-fatal overdoses by emergency healthcare professionals, first responders, medical examiners and coroners.⁴  In an effort to provide additional insights into the increasing use of fentanyl-spiked heroin, the current study examines urine drug test results (UDTs) acquired by a national drug testing laboratory to track the co-occurrence of non-prescribed fentanyl in national, regional and statewide populations of heroin-positive healthcare patients.  This is an update to data presented in September 2017.

Methods

A retrospective review was conducted for urine drug test results from January 1, 2013 through May 31, 2018 for patient samples submitted for testing by healthcare providers as part of therapeutic treatment. The analysis was completed on tests ordered for definitive drug testing by LC-MS/MS for 6-MAM (metabolite of heroin) and fentanyl (which includes testing of parent drug fentanyl and metabolite norfentanyl). Patients that were reported to have been prescribed fentanyl were removed from the analysis. Heroin-only positives were examined, and within those heroin positives, fentanyl positives without a reported prescription were measured.

Results

As previously observed, heroin-only positive rates in a population of patients in healthcare remain approximately the same. However, positivity rates for non-prescribed fentanyl in the heroin-positive population have risen remarkably since 2013.  Nationally, in 2013 we found that 2.04% of samples with heroin positives were concomitantly positive for non-prescribed fentanyl. In 2018, 38.72% of heroin positive samples were concomitantly positive for non-prescribed fentanyl, a 1500% rise.  The national average has stayed fairly steady in the last year and a half (40.93% in 2017, 38.72% in 2018).  However, this varies substantially by region of the United States. The percent of heroin with non-prescribed fentanyl ranged in 2018 from 4.82% in the Pacific region up to 83.93% in the East South Central region.  There was an increase in the correlation between heroin and non-prescribed fentanyl from 2017 to five months into 2018 in the following regions: East North Central (58.09 % to 72.96%), East South Central (77.45% to 83.93%), Mid-Atlantic (55.11% to 61.24%), New England (66.28% to 76.09%), South Atlantic (62.16% to 67.87%), West North Central (46.61% to 68.04%), and West South Central (12.30% to 22.06%).

Conclusions

Though the source of non-prescribed fentanyl cannot be verified as definitively fentanyl-spiked heroin, the data suggests that the national average has remained about the same in the last year and a half. However, regionally, there continues to be increases in the prevalence of fentanyl-spiked heroin. These results may help inform and focus clinicians, first responders, and those responsible for public health to better leverage various modalities at their disposal, (ex. medication assisted addiction treatment, naloxone, and fentanyl specific messaging) in their ongoing efforts to halt the devastating toll of fentanyl-spiked heroin.  Secondarily, the current study demonstrates the potential utility of UDTs from healthcare patients as an epidemiological tool to track emerging patterns of drug-use.

80 Efficacy and Safety of Lofexidine for Opioid Withdrawal Syndrome: Pooled Analysis of Phase 3 Studies

Mark Pirner¹, Carlos Tirado², Thomas Clinch¹

¹US WorldMeds, Louisville, Kentucky, USA, ²CARMAhealth, LLC, Austin, Texas, USA

Purpose

Chronic opioid use changes noradrenergic pathways in the brain and leads to physiologic dependence. Abrupt discontinuation of opioids in dependent patients results in noradrenergic hyperactivity and a highly distressing constellation of symptoms known as opioid withdrawal syndrome. Patients may decide to continue with opioid analgesics beyond a medical need to avoid this syndrome which includes flu-like symptoms, nausea, diarrhea, anxiety, insomnia, aches and pains, muscle spasms and stomach cramps. Lofexidine is an alpha-2 adrenergic agonist recently approved by the FDA for mitigation of opioid withdrawal symptoms to facilitate abrupt opioid discontinuation in adults. Two pivotal trials were conducted to evaluate the efficacy and safety of lofexidine for treatment of opioid withdrawal syndrome.

Methods

This analysis included pooled data from two phase 3 placebo-controlled, double-blind studies that evaluated withdrawal symptoms during the first 7 days after abrupt discontinuation of short-acting opioids (heroin or opioid analgesics). Subjects were opioid-dependent men or women ≥18 years old. In the first study, subjects were randomized to placebo or lofexidine 2.88 mg/day (0.72 mg QID) for 5 days. In the second study, subjects were randomized to placebo, lofexidine 2.88 mg/day (0.72 mg QID) or lofexidine 2.16 mg/day (0.54 mg QID) for 7 days. In the pooled database, 586 subjects were randomized to lofexidine and 281 subjects were randomized to placebo. Mean score on Short Opiate Withdrawal Scale of Gossop (SOWS-G) was a primary endpoint in both trials. The SOWS-G is a validated, subject-rated, 10-item assessment with each symptom rated from 0 (none) to 3 (severe). Other outcomes included proportion of subjects completing the study and study retention time.

Results

The majority of the study population was white, male, and used heroin. Ages ranged from 18 to 74 years. In the intent-to-treat population, 40.7% the lofexidine 2.88 mg group, 41.9% of the lofexidine 2.16 mg group and 28.2% of the placebo group completed the double-blind treatment period. Subjects in the lofexidine groups stayed longer in the trials than those on placebo. The most frequently reported reasons for premature discontinuation were consent withdrawn (lofexidine, 29.0%; placebo, 32.4%) and lack of efficacy (lofexidine, 15.7%; placebo, 31.7%). The LS means for SOWS-G score over Days 1-7 was lower in both lofexidine dose groups compared with placebo (P <0.05), indicating greater reduction in withdrawal symptoms with lofexidine. The peak SOWS-G score over Days 1-5 was also significantly lower in the lofexidine groups than in the placebo group, both when actual data were analyzed and when actual or imputed data were analyzed (P ≤0.001). Differences between the lofexidine and placebo groups for SOWS-G mean scores were clinically important. Most adverse events (AEs) were mild or moderate in severity. Treatment-related AEs that were reported at a higher rate (by at least 5% of subjects) in the total lofexidine group compared with placebo were hypotension, orthostatic hypotension, bradycardia, dizziness, somnolence, dry mouth and sedation. Serious AEs (SAEs) were low in these studies: 2.2% in the total lofexidine group and 3.6% in the placebo group. Most SAEs were related to hypotension, bradycardia or brief prolonged hospitalization to stabilize withdrawal symptoms in subjects who prematurely withdrew from the trial.

Conclusions

These data suggest that lofexidine can be safely administered at 2.88 and 2.16 mg/day, lofexidine reduces opioid withdrawal symptoms to a clinically meaningful extent, and lofexidine facilitates opioid discontinuation treatment. Lofexidine, as a non-opioid option, may provide additional access to treatment of opioid withdrawal syndrome in a variety of healthcare settings.

81 Pilot Study of Fixed-Site High-Frequency Transcutaneous Electrical Nerve Stimulationin Fibromyalgia

Mauro Zappaterra¹, Frank McGillin², Shai Gozani²

¹Synovation Medical Group, Pasadena, CA, USA, ²NeuroMetrix, Inc., Waltham, MA, USA

Purpose

Fibromyalgia is a condition of unknown etiology that is characterized by chronic widespread pain, poor sleep quality, fatigue, and neurological complaints. The disorder affects an estimated 10 million people in the U.S. and 3-6% of the world population. The primary therapeutic focus is pain management. Common treatments include anticonvulsants, antidepressants and benzodiazepines. However, most patients do not obtain adequate pain relief and may suffer from dose limiting side effects. There is a need for non-pharmacological treatments with limited adverse effects.

Transcutaneous electrical nerve stimulation (TENS) is a non-invasive treatment for chronic pain that has no major side effects. Conventional TENS is delivered through surface electrodes to generate a strong, nonpainful sensation. The resulting stimulation of large diameter, deep tissue afferents produces widespread pain relief by decreasing central excitability and increasing central inhibition. TENS has not been extensively evaluated in fibromyalgia, however several studies have suggested benefit. It is likely that the efficacy of TENS has been adversely impacted by sub-optimal dosing. One contributing factor may be barriers to frequent use. In traditional practice, TENS electrodes are applied to the painful area. This is not practical in fibromyalgia due to the widespread distribution of pain. Fixed-site high-frequency TENS (FS-TENS) is an emerging form of TENS in which the device stimulates a predetermined area rather than to overlap the pain. FS-TENS has been shown to produce widespread analgesia and to be effective in chronic multi-site pain.

The objective of this pilot study was to evaluate FS-TENS efficacy in diagnosed fibromyalgia.

Methods

This was a prospective, open-label, single-site, interventional study of FS-TENS in fibromyalgia.  Consecutive patients presenting to a multispecialty pain clinic were considered. The inclusion criteria were age ≥ 18 and a diagnosis of fibromyalgia according to the 2010 American College of Rheumatology criteria. Exclusion criteria were a physical or psychological impediment to use of FS-TENS. Patients meeting the inclusion and exclusion criteria were offered the opportunity to participate. Enrolled subjects provided informed consent and filled out a baseline Fibromyalgia Impact Questionnaire (FIQR). The FIQR has 3 domains representing function, overall disease impact and symptoms (including pain level). Subjects were given a FS-TENS device (Quell®, NeuroMetrix, Waltham, MA) and basic instructional training. The subjects were directed to self-administer therapy as much as possible for 30 days, including during sleep. Subjects returned to the study site for a 30-day follow-up at which time they filled out a follow-up FIQR and indicated patient global impression of change (PGIC) on a 7-point scale (0 – “no change” to 7 – “a great deal better”).

The primary outcome measure was the baseline to 30-day change in the FIQR. Statistical significance was assessed by the non-parametric Wilcoxon Signed-Rank test, with a one-sided hypothesis that FS-TENS improves FIQR over 30 days. FIQR responders were defined as ≥14% improvement. A PGIC responder was defined as ≥4 on the 7-point scale. Post-hoc analyses included evaluation of FIQR domains, the FIQR pain level (over past 7 days) item, the FS-TENS dose-response relationship and interactions between FS-TENS and concurrent prescription opioids.

Results

A total of 12 subjects were enrolled and completed the study. Subject age was 56 ± 9 years (range 33-68), 100% were female and the BMI was 27.7 ± 5.7 kg/m². The median time since symptoms was 9.5 years and the median time since diagnosis was 6.5 years. Fibromyalgia severity was mild (1), moderate (0) and severe (11) according to the baseline FIQR.

The FIQR improved for 8 out of 12 subjects, with 5 (42%) classified as FIQR responders. The baseline FIQR was 69.0 ± 15.9 and the 30-day FIQR was 58.2 ± 24.7. The baseline to 30-day change approached statistical significance (p=0.068). A total of 7 (58%) subjects reported possible or definite improvement on PGIC. Fibromyalgia severity at 30-days was mild (3), moderate (3) and severe (6). Two subjects reported that FS-TENS aggravated their fibromyalgia symptoms. There were no serious adverse events.

Pain level decreased from 7.2 ± 2.0 at baseline to 5.9 ± 2.5 at 30-days which was a statistically significant change (p = 0.007). 25% of subjects were responders at the 30% pain reduction level (moderate clinical improvement) and 50% of subjects were responders at the 15% pain reduction level (minimal clinically significant improvement). The relative change in FIQR was correlated (r = 0.40, p<0.05) to the amount of FS-TENS therapy suggesting a dose-response relationship. Subjects not taking prescription opioids showed a trend towards greater improvement in FIQR, however the sample size was too small for statistical testing.

Conclusions

In this study, FS-TENS use for 30-days decreased the severity of fibromyalgia in about half of subjects as assessed by changes in FIQR and PGIC. The efficacy of FS-TENS was dose-dependent. Strengths of this study include use of validated FIQR and PGIC outcome instruments and objective assessment of therapy adherence. Limitations include a small samples size, non-compliance by several subjects, lack of a control group and a short study duration. The results of this study suggest that FS-TENS may be useful as a non-pharmacological treatment option for fibromyalgia and should be further evaluated.

82 EP-104IAR − A Potential New Treatment for Knee Osteoarthritis: Prolonged Local Exposure of Fluticasone Propionate with No Impact on Cartilage Health.

Murray Webb, James Price, Nicola Price, Sarah Luettgen, Amanda Malone

Eupraxia Pharmaceuticals Inc., Victoria, British Columbia, Canada

Purpose

Intra-articular (IA) injections of corticosteroids are frequently used to manage pain in knee osteoarthritis (OA); however, their duration of effect is limited, requiring repeated treatments to provide ongoing pain relief.  To date, only one extended-release corticosteroid has been approved in the US.

Eupraxia Pharmaceuticals Inc. (Eupraxia) is currently developing EP-104IAR (a long-acting corticosteroid for IA injection) to treat OA symptoms. EP-104IAR employs a novel controlled-release technology to optimize the pharmacokinetics (PK) of fluticasone propionate (FP), a corticosteroid with a well-established systemic safety record. Controlled-release of FP is achieved by coating well-defined crystals of FP with a thin membrane of cured polyvinyl alcohol (PVA). The combination of FP crystal characteristics and the PVA membrane provides fine control of FP release rate via diffusion. Consequently, the aim of EP-104IAR is to maximize IA residence time while simultaneously limiting systemic exposure. EP-104IAR is currently in Phase 2 clinical development.

Recently, McAlindon et al., (2017) suggested repeat IA injections of triamcinolone (commonly used in knee OA) over 2 years may lead to cartilage volume loss. When examining the local toxicity of a new IA formulation, an important measure is cartilage health as cartilage does not regenerate.  Key secondary measures of local toxicity include inflammation of the synovium and synovium degeneration/necrosis. Eupraxia have performed non-clinical studies to evaluate PK and local safety, including cartilage health, after IA administration of EP-104IAR in dogs.  When evaluating cartilage health, we have examined both the comprehensive Mankin Score and chondrocyte vacuolation.

Methods

A preliminary study determined the toxicity and toxicokinetic (TK) profile after a single epidural injection in beagle dogs. Doses were: 0 mg (vehicle), 9.2 mg EP-104IAR, 10 mg uncoated FP or 10 mg micronized FP powder. Three animals per group were euthanized 7 days post-dose to determine toxicities. Four animals per group (except vehicle) were followed until Day 180.

A GLP study evaluated the safety and pharmacokinetics of a single IA injection of EP-104IAR (at 1.9, 5.5 and 55 mg doses of FP) compared to its constituents, 60 mg of uncoated FP or 11 mg of PVA in beagle dogs for 10 months. The low (1.9 mg) and mid (5.5 mg) doses were selected to elucidate safety and PK at anticipated clinically relevant doses. The 55 mg dose was selected to identify possible adverse effects at a dose significantly higher than anticipated for clinical use.  Plasma and synovial fluid samples were analyzed for FP concentrations using a validated LC/MS-MS bioanalytical method. In addition to clinical and histopathology assessments, Mankin scores were evaluated at all follow-up timepoints. Mankin scores are a validated way to measure chondrocyte and cartilage health that encompass the cartilage structure, Safranin O staining, cellular health, and tidemark integrity (Pritzker et al., 2006). Cartilage is scored from 0-14, where a lower score indicates healthier tissue.

A clinical study in patients with knee OA was recently completed. Subjects received a single injection of 15mg EP-104IAR or placebo and were followed for up to 42 weeks.

Results

After a single epidural administration, the highest C_max was observed with the micronized FP powder, followed by the highest plasma concentrations over the first month post-dose; the drug cleared fastest when delivered as a micronized powder. The uncoated FP crystals gave the second highest C_max and exposure over the first month. In comparison, the PVA coating in the EP-104IAR formulation resulted in the lowest C_max value, lowest exposure over the first month, and a controlled rate of dissolution/drug release over the follow-up period.  These results showed a clear increase in FP retention time and decrease in peak exposures with controlled crystal size and coating. Although local concentrations were not measured in this study, the systemic levels are indicative of prolongation of exposures in the local space. 

In the IA study, administration of EP-104IAR provided local residence times beyond 10 months, with plasma levels being approximately 2-3 orders of magnitude lower than those in the synovial fluid. Compared to an equivalent dose of uncoated FP, administration of EP-104IAR resulted in reduced peak exposures (C_max) and prolonged residence time. In spite of the extended exposure of the knee to FP, the Mankin scores consistently scored at 0 (no effect) across all doses and sample times out to 10 months.  Chondrocyte vacuolation was graded as normal or minimal at all doses and all time points out to 10 months.

In the clinical study, 24 patients with knee OA were administered a single injection of EP-14IAR and 8 patients were administered placebo and followed for up to 42 weeks. PK data generated in this study support the non-clinical findings. There were no local or systemic safety findings of concern.

Conclusions

Non-clinical data demonstrate that EP-104IAR provides long term local exposure to FP with corresponding low systemic exposure. These results indicate that control of particle size distribution and the addition of a coating to limit solubilization of the FP crystals via diffusion allows for maintenance of local drug effects without systemic burden.

Evaluation of Mankin scores indicates that prolonged local residence time of EP-104IAR had no impact on cartilage health.

Nonclinical data appear to be validated in the initial clinical study. A dose-ranging study is planned to further explore efficacy and safety.

83 Botulinum Toxin Type A for Neuropathic Pain in Patients with Spinal Cord Injury

Myungeun Chung

The Catholic University of Korea, Seoul, Korea, Republic of

Purpose

Botulinum toxin is commonly used to treat spasticity or dystonia. Recent studies have suggested that botulinum toxin type A (BTX-A) is effective for the treatment of chronic pain conditions such as chronic migraine, post-herpetic neuralgia, post-traumatic neuralgia, or diabetic neuropathy. It has been suggested that BTX-A may inhibit neurogenic inflammation and the peripheral sensitization of nociceptive fibers by inhibiting the release of local neuropeptides such as substance P, calcitonin gene-related peptide, or glutamate, thereby reducing pain. In addition, a retrograde effect of BTX-A on the spinal cord by axonal transport is proposed as the central mechanism of the antinociceptive effect of BTX-A. We propose that BTX-A may be effective for the treatment of intractable neuropathic pain in patients with SCI due to these mechanisms. To the best of our knowledge, the efficacy of BTX-A on neuropathic pain in patients with spinal cord lesions has been suggested in only a few case reports.

This study is the first to evaluate the potential effects of BTX-A on neuropathic pain in patients with SCI using a double-blind, placebo-controlled, parallel group design.

Methods

The effect of BTX-A on 40 patients with spinal cord injury-associated neuropathic pain was investigated using a randomized, double-blind, placebo-controlled design. A one-time subcutaneous BTX-A (200 units) injection was administered to the painful area. Visual analogue scale scores (0-100 mm), the Korean-version of the short-form McGill Pain Questionnaire, and the World Health Organization WHOQOL-BREF quality of life assessment were evaluated prior to treatment and at 4 and 8 weeks after the injection.

Results

At 4 and 8 weeks after injection, the VAS score for pain was significantly reduced by 18.6 ± 16.8 and 21.3 ± 26.8, respectively, in the BTX-A group, whereas it was reduced by 2.6 ± 14.6 and 0.3 ± 19.5, respectively, in the placebo group. The pain relief was associated with preservation of motor or sensory function below the neurological level of injury. Among the responders in the BTX-A group, 55% and 45% reported pain relief of 20% or greater at 4 and 8 weeks, respectively, after the injection, whereas only 15% and 10% of the responders in the placebo group reported a similar level of pain relief. Improvements in the score for the physical health domain of the WHOQOL-BREF in the BTX-A group showed a marginal trend toward significance (p = 0.0521) at 4 weeks after the injection.

Conclusions

We conclude that subcutaneous BTX-A injections are an effective and safe method of reducing severe neuropathic pain in patients with SCI. Our data shows that subcutaneous BTX-A injections might be considered as a treatment regimen for intractable neuropathic pain in patients with SCI. Further studies should be performed to evaluate the underlying mechanisms, onset time, duration, optimal dosage, and optimal route of administration for BTX-A therapy for the treatment of neuropathic pain in patients with SCI.

84 A Randomized Study of Meloxicam IV following Laparoscopic Abdominal Surgery

Neil Singla¹, Stewart McCallum², Randall Mack², Sue Hobson², Alex Freyer², Wei Du³

¹Lotus Clinical Research, Pasadena, CA, USA, ²Recro Pharma, Inc., Malvern, PA, USA, ³Clinical Statistics Consulting, Blue Bell, PA, USA

Purpose

Intravenous (IV) meloxicam (Meloxicam IV) is a novel formulation of NanoCrystal Colloidal Dispersion® meloxicam, being developed for the management of moderate to severe pain.  Postoperative pain after laparoscopic surgery is a major concern of patients, and improper pain management can be associated with varied respiratory, cardiovascular, gastrointestinal, and psychological complications.  Pain after laparoscopic surgery may be transient or persistent and opioids have traditionally been the mainstay treatment for postoperative pain.  Increasing evidence exists to support use of multimodal treatment approachs for postoperative pain that may reduce opioid side effects and improve pain intensity scores.  The reported randomized controlled Phase 2 study was undertaken to evaluate meloxicam IV for the management of pain following laparoscopic abdominal surgeries.

Methods

This was a Phase 2, randomized, double-blind, placebo and active controlled study in subjects undergoing laparoscopic abdominal surgery.  Allowed procedures included biliary tree surgery, common bile duct exploration/surgery, cholecystectomy, and inguinal hernia surgery.  This study was conducted under an FDA IND, IRB approval was obtained prior to study conduct and all subjects provided written informed consent.  Subjects were randomized 1:1:1:1:1 to IV doses of placebo, ketorolac IV 30 mg every 6 hours (Q6H), meloxicam IV 7.5 mg every 12 hours (Q12H), meloxicam IV 15 mg Q12H, or meloxicam IV 30 mg once daily (QD) for up to 48 hours; placebo doses were administered Q6H as appropriate to maintain blinding.  Following surgery, subjects who experienced moderate to severe pain were treated with study drug, and underwent safety and efficacy assessments throughout a 48-hour inpatient period.  Efficacy was evaluated using pre- and post-dose pain intensity assessments (100 mm visual analog scale) and rescue analgesia use.  Safety was monitored through the reporting of adverse events, clinical laboratory testing, vital sign assessments, 12-lead electrocardiograms (ECGs), and wound site assessments.  The study was planned to enroll 200 evaluable subjects; however, the study was terminated for business reasons after 50 subjects were enrolled.  Due to the early termination of the study, efficacy data were not formally analyzed for the study report, but ad-hoc analysis of efficacy data were subsequently performed.

Results

A total of 50 subjects were randomized and received at least one dose of study drug.  Mean pain intensity differences from baseline over the 48-hour assessment period were similar between the meloxicam IV 15 mg Q12H and 30 mg QD groups, and demonstrated reductions in pain comparable to those seen in the ketorolac IV 30 mg Q6H group.  The most common treatment-emergent adverse events (TEAEs) reported across the meloxicam groups included headache, dry mouth, dysuria, and nausea; these events were reported at rates similar to placebo.  Most TEAEs were mild in intensity and unrelated to treatment.   No deaths were reported.  One ketorolac-treated subject who underwent hernia repair had a serious adverse event of post procedural hemorrhage.  One meloxicam IV 7.5 mg Q12H treated subject had a TEAE of mild truncal maculopapular rash that lead to discontinuation; this subject had no signs of anaphylaxis.  The mean changes from baseline in laboratory parameters were small and similar across treatment groups.  Mean blood pressure tended to decrease in all groups following treatment, while heart rate and ECG parameters were virtually unchanged.  Wound examinations showed normal healing in the meloxicam and ketorolac groups. 

Conclusions

Meloxicam IV was generally well tolerated in this study with a safety profile comparable to placebo.  Pain intensity differences over time suggest meloxicam IV 15 mg Q12H, meloxicam IV 30 mg QD, and ketorolac 30 mg IV Q6H provided pain relief after laparoscopic abdominal surgery. 

85 Evaluation of the impact of pre-operative multimodal analgesia on oral morphine equivalent requirements 24 hours post-operatively in patients undergoing elective spinal surgery

Paige Broccio, Brittany Johnson, Lyndsey Livermore, Joseph Cammilleri, Benton Stamper

UF Health Jacksonville, Jacksonville, FL, USA

Purpose

The American Pain Society recommends using pre-operative multimodal analgesia (PMMA) in an effort to reduce post-operative pain. Multimodal analgesia is the use of medications with various mechanisms of action to target different pain pathways in the nervous system. Medications recommended for PMMA include acetaminophen, nonsteroidal anti-inflammatories (NSAIDs), cycloxygenase-2 (COX-2) inhibitors, and gabapentinoids. In November 2015, University of Florida- Health Jacksonville implemented a PMMA order set which included acetaminophen, celecoxib, and gabapentin to be administered in the pre-operative holding area prior to surgery. The purpose of this study is to evaluate the effect of pre-operative multimodal analgesia (PMMA) medications on opioid consumption in the first 24 hours following surgery.

Methods

This is a single center, retrospective, observational chart review of patients who underwent an elective spinal surgery between August 4, 2016 and February 4, 2018. Adult patients were included if they underwent an elective spinal surgery including: anterior or posterior spinal fusion, laminoplasty, laminectomy, and fixation kyphoplasty. Patients were excluded if they received spinal surgery associated with trauma, prescribed a patient controlled analgesia (PCA) pump following surgery, currently enrolled in another research study, pregnant, or incarcerated. The primary outcome was to determine if compliance vs non-compliance of the PMMA order set resulted in reduced oral morphine (OME) consumption in the first 24 hours following surgery. Compliance with the order set indicates that the patient received at least one medication from the order set prior to surgery. Non-compliance with the order set means that the patient did not receive any of the medications prior to surgery. Secondary outcomes included: OME consumption at 48 hours, median pain score during the first 24 post-operative hours, time to first opioid dose administered, and length of stay in the post-anesthesia care unit (PACU). Continuous variables were compared using ANOVA and Kruskal-Wallis tests and categorical variables were compared using the chi-square or Fisher’s exact tests. Based off of a previous study conducted, it was calculated that each group needed 59 patients to achieve an 80% power. A p-value less than 0.05 was considered statistically significant.

Results

A total of 300 patients were screened and 141 patients were included in the study. The most common exclusion criteria was spinal surgery associated with trauma. Patients were mostly male (55%) and Caucasian (56%), with an average age of 54 years. Baseline characteristics were similar between all groups. The median oral morphine equivalent consumption at 24 hours was 86 mg and 72 mg for patients in the compliance and non-compliance groups respectively (p=0.224). The median oral morphine equivalent consumption at 48 hours was 190 mg and 146mg for patients in the compliance and non-compliance groups respectively (p=0.303). The median post-operative pain score at 24 hours was 6 in the compliance group and 5 in the non-compliance group (p=0.615). Time to first oral opioid administered was 306 minutes and 377 minutes in the compliance and non-compliance group respectively (p=0.055). The length of stay in the PACU was 144 minutes in the compliance group and 136 minutes in the non-compliance group (p=0.946). Hospital length of stay was reduced in the compliance group (1.45 days) compared to the non-compliance group (2.47 days) (p=0.042).

Conclusions

Patients in the compliance group did not show a difference in OME consumption at 24 or 48 hours compared to the non-compliance group. The compliance group had a reduced hospital length of stay and had a trend toward utilizing oral medications sooner post-operatively. This study has several limitations. One factor that likely contributed significantly was the incomplete documentation of home medication regimens, pain scores, pain goals, and medications received post-operatively. The impact of pre-operative multimodal analgesia regimens in patients who undergo an elective spinal surgery cannot be adequately evaluated from this study due to several limiting factors impacting the outcome.

86 Efficacy of Fremanezumab in Patients With Chronic Migraine Who Had Prior Use of Topiramate or OnabotulinumtoxinA

Paul Yeung¹, Egilius Spierings², Xiaoping Ning¹, Ronghua Yang¹, Yuju Ma¹, Ernesto Aycardi¹, Marcelo Bigal¹

¹Teva Pharmaceuticals, Frazer, PA, USA, ²MedVadis Research Corporation, Watertown, MA, USA

Purpose

A high unmet need exists for patients with CM, most of whom have discontinued currently available preventive migraine therapies. Fremanezumab, a fully-humanized monoclonal antibody(IgG2∆a) targeting calcitonin gene-related peptide (CGRP), has demonstrated efficacy in migraine prevention.

Purpose of this analysis was to determine the efficacy of fremanezumab in patients with chronic migraine (CM) who have previously used topiramate or onabotulinumtoxinA.

Methods

In this Phase III, multicenter, randomized, double-blind, placebo-controlled, parallel-group study, eligible patients with prospectively confirmed CM (≥15 headache days and ≥8 migraine days per month), were randomized 1:1:1 to receive subcutaneous injections of fremanezumab quarterly (675 mg at baseline and placebo at Weeks 4 and 8), fremanezumab monthly (675 mg at baseline and 225 mg at Weeks 4 and 8), or placebo at each time point over a 12-week treatment period. Change from baseline in the monthly average number of headache days of at least moderate severity and migraine days in patients with prior topiramate or onabotulinumtoxinA use were assessed as exploratory endpoints.

Results

This analysis included 338 patients with prior topiramate use (quarterly, N = 106; monthly, N = 115; placebo, N = 117) and 165 patients with prior onabotulinumtoxinA use (quarterly, N = 66; monthly, N = 50; placebo, N = 49).  During the 12-week treatment period, both dosing arms of fremanezumab resulted in significant reductions from baseline in the mean number of monthly headache days of at least moderate severity (quarterly: –4.4 ± 0.57; monthly: –4.7 ± 0.55) versus placebo (–1.7 ± 0.60) in patients with prior topiramate use (both, P < 0.0001), while monthly fremanezumab dosing led to significant reductions in those with prior onabotulinumtoxinA use (monthly: –4.1 ± 0.81; placebo: –2.0 ± 0.78; P = 0.03). Significant reductions were observed as early as 4 weeks after initiation of treatment for patients who previously used topiramate or onabotulinumtoxinA (P < 0.01). Similar reductions in migraine days were also seen with fremanezumab.

Conclusions

Fremanezumab demonstrated efficacy in patients with CM who previously used topiramate or onabotulinumtoxinA.

87 Impact of Fremanezumab on the Number of Days with Use of Acute Headache Medications in Chronic Migraine

Paul Yeung¹, Ernesto Aycardi¹, Tricia Blankenbiller¹, Melissa Grozinski-Wolff¹, Ronghua Yang¹, Yuju Ma¹, Egilius Spierings², Marcelo Bigal¹

¹Teva Pharmaceuticals, Frazer, PA, USA, ²MedVadis Research Corporation, Watertown, MA, USA

Purpose

Overuse of acute headache medications is common in people with CM and can lead to worsening of headaches. Fremanezumab (TEV-48125), a fully humanized monoclonal antibody targeting calcitonin gene-related peptide (CGRP), has demonstrated efficacy in migraine prevention.  The objective was to evaluate the efficacy of fremanezumab in patients with chronic migraine (CM) by assessing the change in use of acute headache medications.

Methods

In this Phase III, multicenter, randomized, double-blind, placebo-controlled, parallel-group study, eligible adult patients with prospectively confirmed CM (≥15 headache days and ≥8 migraine days per month) were randomized 1:1:1 to receive subcutaneous injections of fremanezumab quarterly (675 mg at baseline; placebo at Weeks 4 and 8), fremanezumab monthly (675 mg at baseline; 225 mg at Weeks 4 and 8), or placebo at each time point over a 12-week treatment period. The monthly numbers of days on which patients used either acute headache medications of any type or those specific to migraine (triptans and ergots) were evaluated as secondary and exploratory endpoints.

Results

1130 patients were randomized (quarterly, N = 376; monthly, N = 379; placebo, N = 375). The monthly number of days with use of any acute headache medication was significantly reduced from baseline in both fremanezumab regimens (quarterly: –3.7 ± 0.30 days; monthly: –4.2 ± 0.30 days) versus placebo (–1.9 ± 0.30 days) during the 12-week treatment period (both, P < 0.0001), with significant reductions observed as early as Week 4 (quarterly: –3.9 ± 0.31 days; monthly: –4.1 ± 0.31 days; placebo: –1.6 ± 0.31 days) and at each time point thereafter (all, P < 0.001). Likewise, fremanezumab significantly reduced the use of migraine-specific acute headache medication (quarterly: –3.3 ± 0.35 days; monthly: –3.9 ± 0.35 days) versus placebo (–1.1 ± 0.36 days) over the 12-week period (both, P < 0.0001). As before, these effects were observed as early as Week 4 and sustained until the end of the trial (all, P < 0.0001).

Conclusions

Fremanezumab reduces the need for use of acute headache medications, including migraine-specific medications, in patients with CM.

88 Do Electroceuticals (using physics) treat neuropathic pain better than pharmaceuticals?

Peter Carney¹, Robert Odell², Richard Sorgnard³

¹Cutting Edge Integrative Pain Centers, Elkhart, IN, USA, ²Neuropathy &* Pain Center of Las vegas, Las Vegas, NV, USA, ³Morhea Technologies, Las Vegas, NV, USA

Purpose

1. To show how, for over 50 years, the use of electrical currents and the principles of physics have given, in select cases, results that are superior to pharmaceuticals.

2. To demonstrate why real evidence based medicine makes the ethical care of the patient its top priority

3. To understand how using the principles of physics can regenerate nerves damaged by neuropathy.

4. To prove that refuting the universally held concept that “neuropathic nerves have irreversible damage” revolutionizes how we can now treat neuropathic pain.

Methods

Starting in 2006, an interventional pain specialist and a PhD in molecular biology teamed up to develop a process that not only blocked the perception of pain but also could heal the damaged nerves that caused our perception of pain.  They published a case report and theory on how electroanalgesic nerve blocks could treat pain. (3)  Since then, they and others have published or presented over 30 articles and poster presentations showing how useful electromagnetic energy fields can be.  The technique is termed EST (Electronic Cell Signaling Therapy) which was found to have profound anti-inflammatory effects (4).

In a 2012, Cernak et al published a series of 101 patients with diabetic peripheral neuropathy, Dr. Cernak, et al published “Electric Current and Local Anesthetic Combination Successfully treats Pain Associated with Diabetic Neuropathy” and showed that  89% of their patients reduced their pain by 50% or more.(6)

In 2013 Milne and Sorgnard published “Quantum Theory Underpins the use of Electromagnetic Therapies for Pain Management”. (7)

In 2014, Carney presented and then published that “Quantum Theory Treats Neuropathy Better than Pharmacology(8).”  In 98 patients w/neuropathic pain from a variety of causes, 63% reduced their pain by at least 50% and 79% reduced their pain by at least 30%.  In 2015,  Carney reported how 95 patients with CIPN 55% reduced their pain by at least 50% and 78% reduced their pain by at least 30%  (9).

By 2015, Odell et al summarized current findings in “The Combined Electrochemical Treatment for Peripheral Neuropathy (10).”  Since May 2015, over 15 articles and posters have been published or presented that show how CET restores peroneal palsy (11), mitigates phantom limb pain (12), reduces opioid use (13,14), regenerates nerves (15,16, 17), and helps patients without harming them (18).

Results

Since 2006 presentations and publications describing the use of CET come from small practices without the resources of large academic centers.  These practices may look very much like your practice.  The results are remarkably superior to the largest, most randomized, placebo controlled, double-blinded studies, although “n” in each of these studies is small and the design was sometimes retrospective

The well-respected British authorities, Drs. Greenhalgh et al, while acknowledging two decades of success for EBM, found serious problems with its use, including misappropriation of quality marker(s),  unmanageable volume, statistically significant benefits that were marginal, management driven rather than patient centered and poorly mapped complex multiple morbidities³³.  They recommended five steps to achieve “Real Evidence Based Medicine.”  The most important first step is to make the ethical care of patients its top priority.

Using meta-analysis and systematic reviews to evaluate how to treat patients with neuropathic pain illustrates the difficulty of trying to use Real Evidence Based Medicine and at the same time make “the ethical care of patients [our] top priority.”  Results of these meta-analysis and systematic reviews, according to Finnerup et al. (NSIG of the IASP) stated that the “Inadequate response to drug treatments constitutes substantial unmet needs in patients with neuropathic pain ²².”

Similar results are echoed by members of the interventional pain management community.  Richard Rosenquist, MD, Chairman of the Department of Pain Management at the Cleveland Clinic was quoted in November 2016 as saying: “The evidence is ‘marginal’ and the results of drug treatment ‘frustrating … and maybe even appalling’ ” at a recent meeting of the American Society of Regional Anesthesia and Pain Medicine²³.  The Cochrane Database of Systematic Reviews²⁴reviewed 37 class I-A randomized, placebo controlled, double-blinded trials including 5,914 participants who received either gabapentin at 1,200 mg/day or greater versus placebo.  They found that those who received gabapentin did significantly better than placebo, (38% reduced their pain by at least 50% vs 21% who received placebo); however, more than 60% had one or more side effects.

On the other hand, we have shown that the application of physics and quantum mechanics can regenerate nerves damaged by neuropathy (please refer to Dr. Odell’s oral presentation).  The authors have shown evidence of nerve regrown/regeneration, strongly suggesting that nerve damage is not irreversible (poster examples will be shown).  These results show that the drug treatment comes nowhere near to meeting the standards set by Hippocrates.

Conclusions

Bril has stated that “Interventions aimed specifically at nerve regeneration may need to be employed²⁵.”  Malik stated that disease modifying drugs have not worked²⁶.  Dr. Malik’s observation confirms the universally held premise that “patients with peripheral neuropathy have irreversible nerve damage ²⁷.”

We are not aware of any case reports or articles that support the statements of Malik or Argoff.  These statements have near universal acceptance by those who are acknowledged as authorities in the field of neuropathic pain.  We want to challenge that premise.

Schrodinger pioneered the concept that “Life, at a cellular level is quantum mechanics … pure physics and pure chemistry⁹.”    Built on Schrodinger’s insight, Dr. Sorgnard developed an advanced electromedical cell signaling device that uses the electromagnetic energy created by quantum mechanics to regenerate nerves.

Study results relegate the premise that “Patients with peripheral neuropathy have irreversible nerve damage” to the same scientific dustbin as “The sun revolves around the earth.”  Hard evidence rejects that hypothesis.    We do not just treat the symptoms; now we can regenerate and heal the nerves, and remove the source of patient’s symptoms by treating the primary pain generator.

Finally, given adequate resources, we argue that these results will be scalable.

89 Long-Term Impact of Fremanezumab on Response Rates, Acute Headache Medication Use, and Disability in Patients with Chronic Migraine: Interim Results of A One-Year Study

Peter McAllister¹, Paul Yeung², Joshua Cohen², Sanjay Gandhi², Ronghua Yang², Ernesto Aycardi²

¹New England Institute for Neurology and Headache, Stamfod, CT, USA, ²Teva Pharmaceuticals, Frazer, PA, USA

Purpose

Fremanezumab, a fully-humanized monoclonal antibody(IgG2∆a) targeting the calcitonin gene-related peptide (CGRP) ligand, has demonstrated to be an efficacious and safe preventive therapy in 3-month chronic migraine (CM) studies.  This analysis evaluates the long-term effect of fremanezumab in the prevention of chronic migraine.

The purpose was to investigate the long-term effect of fremanezumab on response rates, acute headache medication, and disability in adults with CM.  

Methods

This is a 52-week, multicenter, randomized, double-blind, parallel-group study to evaluate the long-term safety, tolerability and efficacy of fremanezumab in adults with migraine.   The Headache Impact Test (HIT-6) was used to assess disability.  Patients were assigned to one of two subcutaneous dose groups: (1) monthly dosing: monthly 225 mg of fremanezumab (with a starting dose of 675 mg), or (2) quarterly dosing: a single dose of 675 mg of fremanezumab every 3 months, with placebo injections on months in which fremanuzemab was not injected (to maintain blinding).  Percentage of patients achieving at least a 50% reduction in monthly average number of headache days of at least moderate severity, the mean change from baseline in the monthly number of days of use of any acute headache medications, and the mean change from baseline in HIT-6 score was assessed for both doses.

Results

This study enrolled 1110 patients with CM.  In this interim analysis, the proportion of patients achieving at least a 50% reduction in monthly average number of headache days of at least moderate severity at month 6 was 56% with monthly dosing, and 51% with quarterly dosing.  The mean change in monthly number of days of use of any acute headache medications from baseline to month 6 in patients with CM was −5.8 days in the 225-mg monthly treatment group and −5.2 days in the 675-mg quarterly treatment group.  HIT-6 disability scores decreased by 8.1 and 6.9 at month 6 for patients who received 225 mg monthly and 675 mg quarterly, respectively. These mean changes from baseline met the established criteria of within-person minimally important difference in HIT-6 scores. For a subset of patients who had completed the entire 12 month treatment period, data available at the cutoff date indicated that the response achieved at month 6 was maintained throughout the treatment period to month 12.

Conclusions

Efficacy and disability data from this interim analysis indicated that the level of efficacy observed at month 1 of this study was maintained during the remainder of the study.

90 Kratom and Mitragynines: Nature’s First ‘Atypical Opioids’

Robert Raffa^1,2,3, Joseph Pergolizzi^3,4, Robert Taylor⁴, Michael Ossipov⁵

¹University of Arizona College of Pharmacy, Tucson, AZ, USA, ²Temple university School of Pharmacy, Philadelphia, PA, USA, ³Neumentum Inc, Palo Alto, CA, USA, ⁴NEMA Research Inc, Naples, FL, USA, ⁵University of Arizona College of Medicine, Tucson, AZ, USA

Purpose

Advances in pain research have led to an understanding that many pains are driven by more than one underlying (patho)physiologic cause (i.e., they are ‘multi-mech-anistic’) and that superior pain relief is obtained with fewer adverse effects when an analgesic is correspondingly multi-mechanistic. At least two more-modern analgesics combine opioid and non-opioid mechanisms, and they have become known as ‘atypical opioids’.  Less well known is that just as Nature evolved opioids, it also evolved atypical opioids, presaging modern drug discovery.

Methods

The basic science and clinical literature on kratom and on multi-mechanistic analgesics was summarized and synthesized. The authors’ extensive familiarity with the topics allowed for formulation of the concepts and conclusions.

Results

Traditional (typical) opioids are extracts or analogs of substances derived from the poppy plant.  They produce their analgesic and adverse effects primarily through a single, opioid mechanism (albeit with individual differences). Two of the most recent analgesics were developed to have both an opioid and a second, non-opioid mechanism of action (inhibition of monoamine neurotransmitter reuptake). Little known is that Nature had already evolved a plant source of compounds with the same properties.   

Conclusions

As debate about the use and abuse potential of kratom swirls, conflicting, and often contradicting, opinions are expressed.  A review of the basic pharmacology of kratom reveals the explanation for the bifurcation in viewpoints: kratom has both opioid and non-opioid properties.  Fascinatingly, just as the poppy plant (Papaver) evolved the typical opioids, Mitragyna evolved the mitragynines – Nature’s ‘atypical opioids’.    

91 Indirect-Acting Strategy of Opioid Action Rather Than Direct Receptor Activation: Dual-Acting Enkephalinase Inhibitors (DENKIs)

Robert Raffa^1,2,3, Joseph Pergolizzi^3,4, Robert Taylor⁴, Michael Ossipov⁵

¹University of Arizona College of Pharmacy, Tucson, AZ, USA, ²Temple University School of Pharmacy, Philadelphia, PA, USA, ³Neumentum Inc, Palo Alto, CA, USA, ⁴Nema research Inc, Naples, FL, USA, ⁵University of Arizona College of Medicine, Tucson, AZ, USA

Purpose

Although pain is one of the most common afflictions, it is often inadequately managed because available analgesic options are relatively limited due to insufficient efficacy, unacceptable adverse effects, or the potential for misuse or abuse. However, recent publications suggest that an alternative approach – indirect enhancement of endogenous pain-relieving pathways – might be desirable.  We review this approach, in particular the dual enkephalinase inhibitors (DENKIs).

Methods

Published literature and Internet sources were searched for information related to the basic science and clinical data on inhibition of metabolic pathways of endogenous analgesic agents. The identified sources were reviewed, assessed, and synthesized. Emphasis was placed on the mechanism of the approach, as well as on the individual agents.   

Results

Inhibition of the enzymes that degrade the endogenous opioid ligands Met- and Leu-enkephalin result in an increased synaptic concentration of the enkephalins and an analgesic effect in a variety of animal models of pain and in preliminary trials in humans.  The design of compounds that inhibit both of the two primary enkephalin-degrading enzymes (neprilysin and aminopeptidase N) have been found to be better than those that inhibit only one of the enzymes. These ‘dual-acting’ enkephalinase inhibitors yield analgesia with less adverse effects than current opioid drugs.   

Conclusions

Unlike currently available analgesics, inhibitors of metabolic degradation of endogenous analgesic substances attempt to elicit a more ‘natural’ targeted analgesic effect. This indirect approach offers an opportunity for novel additions to the otherwise relatively limited choice of analgesic classes.  

92 ‘Folded DNA’ Structures in Human Cells: Potential Drug Targets

Robert Raffa^1,2,3, Joseph Pergolizzi^4,1, Robert Taylor⁴, Michael Ossipov⁵

¹Neumentum Inc, Palo Alto, CA, USA, ²Temple University School of Pharmacy, Philadelphia, PA, USA, ³University of Arizona College of Pharmacy, Tucson, AZ, USA, ⁴NEMA Research Inc, Naples, FL, USA, ⁵University of Arizona College of Medicine, Tucson, AZ, USA

Purpose

The double-helical conformation of human DNA (hDNA) is so axiomatic that it is called the ‘canonical’ form. Recently, though, intra-strand folds (termed ‘I-motifs’ and ‘G-quadruplexes’) have been identified in hDNA. These could be targets for novel drug discovery.

Methods

A search was conducted of the published literature (in English) using sources such as PubMed and MedLine. The identified material was reviewed and synthesized. Emphasis was placed on the concept of folded DNA.

Results

Any alteration or interruption in the canonical form of hDNA fundamentally impacts the normal progression of transduction and translation function. In particular, the synthesis of receptors and their cognate protein ligands would be affected, as well as their affinity for – and signal transduction of – pharmacotherapeutic agents. Recent studies have identified normally-occurring, folded structures superimposed on the usual double-helix motif of hDNA.         

Conclusions

Newly-identified ‘folded DNA’ structures (‘G-quadruplexes and ‘I-motifs’) could represent novel drug-discovery targets, possibly for chronic pain conditions.  

93 Lofexidine: Not just your father’s alpha-2 agonist

Robert Raffa^1,2,3, Joseph Pergolizzi^3,4, Robert Taylor⁴, Robert James⁵, Mark Pirner⁵

¹University of Arizona College of Pharmacy, Tucson, AZ, USA, ²Temple University School of PharmacY, Philadelphia, PA, USA, ³Neumentum Inc, Palo Alto, CA, USA, ⁴NEMA Research Inc, Naples, FL, USA, ⁵US Worldmeds, Louisville, KY, USA

Purpose

Lucemyra® (lofexidine hydrochloride) has recently been approved by the U.S. FDA for the mitigation of withdrawal symptoms to facilitate abrupt discontinuation of opioids in adults. Lofexidine is known to be an alpha-2 adrenoceptor agonist. However, its clinical attributes differ in an advantageous way from classical alpha-2 agonists such as clonidine. The receptor binding affinity and intrinsic activity (efficacy) of lofexidine was measured in order to gain insight into the difference(s).

Methods

Lofexidine HCl and clonidine HCl were studied in a broad screen of receptor binding, uptake, and functional assays by Eurofins Scientific.

Results

Clonidine displayed significant functional activity (i.e., pEC50 ≤ 6.5) only at the following receptors: alpha-1, alpha-2A, and alpha-2C. Lofexidine displayed almost the same agonist activity at these sites, but in contrast to clonidine also displayed significant agonist functional activity (pEC50 ≤ 6.5) at the 5-HT-1A receptor.     

Conclusions

Lofexidine’s receptor binding profile includes agonist action at the same alpha-adrenoceptor subtypes as does clonidine (namely alpha-1, alpha-2A, and alpha-2C), but unlike clonidine lofexidine also has agonist action at the 5-HT-1A receptor, a receptor that has been associated with positive effects on withdrawal from opioids. It thus seems possible that lofexidine’s agonist action at the 5-HT-1A receptor could: (1) explain the different clinical profiles of the two drugs, and (2) contribute to a better outcome in the mitigation of withdrawal symptoms to facilitate abrupt discontinuation of opioids.

94 Phrenic Nerve Stimulation as an Alternative Treatment for Central Sleep Apnea: a Review of Literature

Rahul Nalamasu¹, Rohit Nalamasu², Srinivas Nalamachu^3,4, Dhanujaya Lakkireddy⁵

¹Western University of Health Sciences, Pomona, CA, USA, ²University of Nebraska, Omaha, Omaha, NE, USA, ³Kansas City University of Medicine and Biosciences, Kansas City, MO, USA, ⁴Mid-America PolyClinic, Overland Park, KS, USA, ⁵Overland Park Regional Medical Center, Overland Park, KS, USA

Purpose

Chronic pain affects 30-40 million individuals in the United States. As the population ages and medical advances continue to extend our expected lifespan, its prevalence will continue to increase. Although there has been a recent decline, treatment with opioids remains the mainstay. Central sleep apnea (CSA) is one a serious concern in patients treated with opioids, due to opioid-induced respiratory depression that can be even more profound when combined with other CNS depressants, such as benzodiazepines. CSA can lead to serious consequences, including cardiac arrhythmias and sudden death. Therefore, there has been an increased focus to treat CSA in the general population with a greater emphasis on individuals with other risk factors. For the past twenty years there have been many trials and advances in the treatment of CSA ranging from antidiuretic medications to ventilator masks (CPAP), but each have their own disadvantages that make them unfavorable for long term treatment. The newly FDA-approved Remedē® system shows significant potential for effective long-term CSA treatment with little-to-no side effects and better short-term and long-term outcomes compared to traditional methods of treatment. This study serves as a review of clinical relevance, safety, and efficacy for phrenic nerve stimulation via the Remedē® system in CSA patients.

Methods

We have conducted a thorough review of published literature using a variety of databases, using the key terms “central sleep apnea”, “phrenic nerve stimulation”, and “CPAP”. We selected the 5 clinical trials that compared CPAP to phrenic nerve stimulation and CPAP to oral diuretic therapy, and based our selection on number of patients enrolled in each study. To evaluate clinical relevance, we used AHI (apnea/hypopnea index) as the major characteristic of outcome.

Results

Based on our review, phrenic nerve stimulation via the Remedē® system shows similar efficacy to CPAP treatments in terms of decrease in AHI. We conclude that phrenic nerve stimulation is clinically viable option for CSA treatment. Furthermore, phrenic nerve stimulation had the added benefit of increasing left ventricular ejection fraction (LVEF), an important marker of heart failure. The largest problems with CPAP treatment are lack of adherence and data supporting long-term efficacy. Due to its bulky apparatus and high time commitment, roughly 5-10% of patients in each CPAP study dropped out or opted to stop treatment. While there were adverse events involved with the implantation of the Remedē® system, they were non-serious and did not affect the adherence of patients in the studies.

Conclusions

While more studies need to be done regarding the long-term benefits of phrenic nerve stimulation, clinical trials have displayed similar AHI reductions and LVEF increase when compared to CPAP trials without serious adverse events or adherence issues. Therefore, the recently FDA approved Remedē® system can be an effective alternative treatment for CSA.  

95 Efficacy of Intra-articular CNTX-4975 for Knee Osteoarthritis (OA) Pain Varies With Radiographic Presence of OA in the Opposite Knee

Randall M. Stevens¹, James N. Campbell¹, Kimberly Guedes¹, Robin Burges¹, Valerie H. Smith², Peter D. Hanson¹

¹Centrexion Therapeutics Corp, Boston, USA, ²Premier Research, Durham, USA

Purpose

Nearly 60% of patients with knee OA have unilateral OA, and most of those patients will develop bilateral OA. CNTX-4975 is a highly purified, synthetic trans-capsaicin that targets transient receptor potential vanilloid 1 and produces analgesia via reversible desensitization of primary afferent pain fiber terminals after intra-articular (IA) injection. CNTX-4975 1.0 mg was well tolerated and effective in subjects with OA knee pain in the phase 2b TRIUMPH study. The objective of this post hoc analysis was to evaluate the efficacy and safety of CNTX-4975 in subjects with unilateral knee pain with and without radiographic evidence of OA in the opposite knee.

Methods

Subjects aged 45–80 years with chronic knee OA and stable moderate to severe knee OA pain in a single joint (index knee; non-index knee with no to mild pain) who failed oral or IA therapies were randomized 2:1:2 to a single IA injection of placebo, CNTX-4975 0.5 mg, or CNTX-4975 1.0 mg. Randomization was stratified by Kellgren-Lawrence (K-L) grade (2–3 vs 4) and body mass index (<30 vs ≥30 kg/m²). Unilateral OA was defined as K-L grade 0, 1, or missing in the non-index (untreated) knee, and bilateral OA as grades 2–4 in both knees. Area under the curve was assessed for change from baseline in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) question A1, pain with walking on a flat surface (11-point numeric rating scale, 0 [none]–10 [extreme]), daily through week 12 and weekly through week 24. Weekly WOMAC B (stiffness; sum of the 2 stiffness subscale responses [0–20]) and C (physical function; sum of the 17 function subscale responses [0–170]) scores through weeks 12 and 24 were also analyzed. Least squares mean differences (LSMD) for CNTX-4975 groups vs placebo were calculated using analysis of covariance. Statistical tests were 2-sided (alpha, 0.10). Safety assessments included treatment-emergent adverse events (TEAEs).

Results

The safety analysis comprised 175 subjects; unilateral knee OA, n = 52 (placebo, n = 17; CNTX-4975 0.5 mg, n = 18; CNTX-4975 1.0 mg, n = 17) and bilateral knee OA, n = 123 (placebo, n = 53; 0.5 mg, n = 16; 1.0 mg, n = 54). The efficacy analysis included 172 subjects (3 subjects in the bilateral subgroup were excluded before unblinding). Mean baseline WOMAC QA1 pain score (index knee) was 7.3 (numeric rating scale, 0–10) in each subgroup. WOMAC A1 scores were significantly improved vs placebo at weeks 12 and 24 with CNTX-4975 1.0 mg in the unilateral (week 12, LSMD: −2.6; P = 0.0004; week 24, −2.3; P = 0.0017) and bilateral subgroups (week 12, −1.2; P = 0.0053; week 24, −1.0; P = 0.017). Similarly, WOMAC B and C scores were significantly improved with CNTX-4975 1.0 mg vs placebo at weeks 12 and 24: WOMAC B; unilateral (week 12, LSMD: −2.9; P = 0.0098; week 24, −3.2; P = 0.012), bilateral (week 12, −1.3; P = 0.042; week 24, −1.5; P = 0.038); WOMAC C; unilateral (week 12, LSMD: −21; P = 0.024; week 24, −23; P = 0.031), bilateral (week 12, −11; P = 0.038; week 24, −11; P = 0.058). The incidence of TEAEs for CNTX-4975 was similar to placebo through week 24. All TEAEs were mild to moderate, with most unrelated to study treatment.

Conclusions

A single IA injection of CNTX-4975 1.0 mg, the dose used in ongoing phase 3 clinical trials, improved pain with walking, knee stiffness, and physical function vs placebo in the index knee and was well tolerated in subjects with moderate to severe unilateral or bilateral knee OA. Greater absolute improvements in WOMAC QA1, B, and C were seen in subjects with unilateral than with bilateral knee OA, even though the non-index knee had no to mild pain at baseline.

96 Healthcare Resource Use by Disease Severity for Patients with Osteoarthritis in the United States using Adelphi Osteoarthritis Disease Specific Programme

Rebecca Robinson¹, Joel Bobula², Joseph Cappelleri³, Andrew Bushmakin³, Leslie Tive⁴, Lars Viktrup¹, Jennifer Mellor⁵, James Jackson⁵

¹Eli Lilly and Company, Indianapolis, IN, USA, ²Pfizer Inc., Collegeville, PA, USA, ³Pfizer Inc., Groton, CT, USA, ⁴Pfizer Inc., New York, NY, USA, ⁵Adelphi Real World, Bollington, United Kingdom

Purpose

Osteoarthritis (OA) is characterised by cartilage degradation, bone remodeling, osteophyte formation, joint inflammation and loss of normal joint function.¹  OA is the leading cause of chronic disability in older adults and is associated with greater than $185 billion total annual costs (2008 US dollars)^2.  Patients with OA have been found to incur greater direct medical costs than those without^3-5.  Higher direct medical costs also were reported to increase with self-reported pain severity associated with OA in employed respondents of the 2009 National Health and Wellness Survey⁶.  A US study examined the cost of OA among privately insured patients taking pain medications from 2003-2004 and found these costs to be primarily driven by outpatient/non-PCP visits (22.9% of total), hospital inpatient costs (19.8% of total), total drug costs (18.2% of total)⁷.  OA hospitalizations in the US are also reported to be on the rise⁸.  From 2005 to 2014, OA became the fourth most common diagnosis for hospital stays in the US, rising from 715,900 stays in 2005 to 1,070,500 stays in 2014⁸.  Given the rising costs and prevalence of OA, it is important to understand updated healthcare resource use as well as the components and drivers of these costs.  The Adelphi Disease Specific Programme (DSP) is uniquely positioned to provide holistic assessment for illnesses by understanding how diseases are managed in real-world clinical practices based on physician and patient perspectives^9. The objective of this study is to identify and characterize healthcare resource utilization among consulting patients in the US with OA-based disease severity based on physician assessment in real-world, clinical practice using the Adelphi OA DSP.

Methods

Data were drawn from the US Adelphi OA DSP a cross-sectional, online survey of physicians (N=153) measuring their attitudes and behaviors as related to the management of OA from February to May 2017.  Physicians (primary care, rheumatologists, orthopaedists) completed electronic patient record forms for their next nine consecutive adult patients (18 years or older) with a diagnosis of OA.  Physicians invited these same patients to complete paper questionnaires.  Cohorts were formed based on physician-perceived current disease severity (mild, moderate, severe).   OA diagnosis and disease severity were based on the judgement and diagnostic skills of the respondent physicians rather than on formalized diagnostic checklists.  Demographics available in the patient record, clinical profile, and physician-reported and patient-reported healthcare resource utilization (HCRU) were assessed at the time of the survey.  The clinical profile included chief complaint of patient, most troublesome joint, location of this joint, principal diagnosis, time since diagnosis, and comorbidities.  Physician-reported annualized HCRU included frequency and type of the provider visits, outpatient services, emergency room visits, hospitalizations for OA, and procedures for OA.  Nonmedical interventions in relation to drug therapy and use of opioid dose-sparing approaches were also assessed.  HCRU was assessed to understand services used specifically to diagnose and monitor patients and to be considered in future plans for patients based on their current conditions.  Descriptive statistics were used and all data were managed and analysed using SPSS v6 and Stata v14.1.

Results

Patients’ (N=1352) mean (standard deviation) age was 65.2 (11.8) years and time since diagnosis was 2.3 (3.9) years. Current physician-reported OA disease severity included mild (34%), moderate (49%), and severe (17%) classifications.

  Most were female (60%), white (75%), and insured (97%).  Physicians reported knees as the most common (58%) and troublesome (45%) joint affected.  Patient history and X-ray were used most frequently to diagnose (96%; 89%) and monitor patients (79%; 60%).  Comorbid conditions occurring in >10% of patients included hypertension (58%), dyslipidemia/high cholesterol (21%), diabetes (18%), depression (15%), anxiety (14%), chronic low back pain (CLBP; 13%), thyroid disease (12%), and obesity (10%).  Conditions experienced at least twice as often in moderate or severe cohorts versus mild included arrhythmia, chronic pulmonary disease, CLBP, rheumatoid arthritis, depression, peripheral vascular disease, and constipation.

All HCRU is reported by OA disease severity (mild, moderate, severe), respectively.  Physicians reported that most patients saw health providers every 2-6 months (66%, 67%, 68%).  OA management mostly included primary care physicians (66, 60%, 49%), rheumatologists (22%, 28%, 30%), and orthopedic surgeons (26%, 31%, 51%).  Few reported hospitalizations (5%, 6%%, 13%) or emergency room services (2%, 5%, 8%) over the last 12 months.  The most common reasons for most recent OA-related hospitalization included surgery (81%, 59%, 84%), treatment of OA medication side effects (10%, 8%, 0%), and “other” (5%, 19%, 12%).  Few underwent OA-related surgical procedures (4%, 5%, 12%) and, of those, most involved joint replacement (53%, 51%, 59%) and arthroscopic washout/debridement (20%, 32%, 31%).  Most patients were prescribed OA medications (58%, 79%, 79%) including NSAIDs (traditional: 58%, 51%, 42%; COX-2 inhibitors: 24%, 27%, 22%) and opioids (overall: 17%, 29%, 44%; strong: 0%, 7%, 12%; weak: 14%, 20%, 18%; combination: 3%, 6%, 17%).  Opioid sparing approaches were often considered either previously (6%, 5%, 11%), currently (11%, 21%, 14%), or anticipated in the future (42%, 41%, 36%).  Non-medical interventions were discussed with most patients (69%, 72%, 66%) and primarily in combination with prescription therapies (46%, 41%, 44%).  Interventions discussed in >10% of the overall sample included: fitness/exercise regimen (75%, 73%, 70%), weight loss (54%, 65%, 72%), physical/physiotherapy (53%, 66%, 75%), avoidance of painful activities (31%, 32%, 38%), therapeutic massage (19%, 16%, 16%), acupuncture (9%, 10%, 11%) and use of walking stick/cane (4%, 11%, 18%).  Patient-reported rates of using aids (22%, 34%, 55%) and modifying homes (21%, 27%, 41%) due to OA increased with severity.

Conclusions

Healthcare resource utilization tended to include multiple modalities and varied across patients with mild, moderate or severe OA disease in this real-world study of patients who were consulting with their healthcare providers.  Prescription medication use was frequently used across all disease severity levels as was the discussion of non-medical interventions.  Further research is needed to better understand the impact of various treatment strategies in light of the disease severity.

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97 Assessing Unmet Treatment Needs and Associated Disability in Persons With Migraine: Results from Migraine in America Symptoms and Treatment (MAST) Study

Richard Lipton^1,2,3, Sagar Munjal⁴, Aftab Alam⁴, Dawn Buse¹, Kristina Fanning⁵, Michael Reed⁵, Todd Schwedt⁶, David Dodick⁶

¹Department of Neurology, Albert Einstein College of Medicine, Bronx, NY, USA, ²Montefiore Medical Center, Bronx, NY, USA, ³Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY, USA, ⁴Promius Pharma, a subsidiary of Dr. Reddy’s Laboratories, Princeton, NJ, USA, ⁵Vedanta Research, Chapel Hill, NC, USA, ⁶Department of Neurology, Mayo Clinic, Phoenix, AZ, USA

Purpose

Triptans are the mainstay of acute migraine treatment and are available in oral, injectable, and nasal delivery forms. Many migraine patients have unmet acute treatment needs. Some patients treated with acute medications experience dissatisfaction with their therapy due to less than optimal effectiveness. We administered a 13-item MAST Unmet Treatment Needs (MUTN) questionnaire to migraine patients treating with oral acute prescription medications. Given that oral therapy is most commonly used, the objective was to empirically characterize domains and degrees of unmet acute treatment need and assess rates of migraine-related disability.

Methods

Respondents, ≥18 years, were recruited from a nationwide online research panel, using stratified random sampling. A validated screener used modified ICHD-3-β criteria to identify individuals with migraine. Respondents averaging ≥1 headache day per month (MHD) over the previous 3 months were included in the study. Respondents provided data on sociodemographics (age, gender, race, income, employment, education, BMI, health insurance, smoking status, marital status), medication use, migraine characteristics and burden, and medication response. Eligible respondents used acute oral prescription migraine medications and were excluded if they used nasal or injectable acute treatments. Prior to analysis, 15 unmet needs characteristics were grouped into 3 broad domains based on item face validity and expert clinician judgement: Insufficient Treatment Response, Migraine Attack Characteristic Needs, and Patient Characteristic Needs.

Results

Among 15,133 respondents meeting inclusion criteria, 26% (n = 3930) reported current use of oral acute prescription medications to treat headache. The sample had a mean (SD) age of 45.0 (13.5) years, and most respondents were women (73.6%) and white (81.6%). A total of 95.8% of respondents had at least 1 unmet need; 90.8% reported unmet needs related to migraine attack characteristics, 76% had unmet needs related to insufficient acute treatment response, and 16.1% reported unmet needs associated with respondent characteristics. Common areas of unmet need included rapid onset of headache (65.3%), headache-related disability (55.6%), inadequate pain relief (49.0%), and recurrence of pain within 24 hours of initial relief (38.6%).

Conclusions

Unmet needs among MAST Study respondents using prescription drugs as acute migraine treatments were near universal. There was considerable overlap of unmet needs. Common areas of unmet need, such as inadequate acute treatment response and challenging attack-related characteristics, may be fulfilled by a range of alternative measures and should be a high-priority focus for improving the treatment of people with migraine.

98 The positive impact of fremanezumab on work productivity and activity impairment in patients with chronic migraine

Richard Lipton¹, Sanjay Gandhi², Timothy Fitzgerald², Paul Yeung², Joshua Cohen², Ronghua Yang², Ernesto Aycardi²

¹Albert Einstein College of Medicine, Bronx, NY, USA, ²Teva Pharmaceuticals, Frazer, PA, USA

Purpose

Migraine is a debilitating chronic disease that imparts a substantial indirect cost burden. In clinical trials, fremanezumab, a fully-humanized monoclonal antibody(IgG2∆a) that selectively targets calcitonin gene-related peptide, reduced the frequency, severity, and duration of headaches in patients with chronic migraine (CM).

The objective was to evaluate the effect of fremanezumab on work productivity loss and activity impairment in CM patients. 

Methods

A 16-week, multicenter, randomized double-blind, placebo-controlled, parallel-group adult CM study. Patients assignments were 1:1:1 ratio to 1 of 3 treatment groups: (1) monthly dosing: 675 mg fremanuzemab followed by 225 mg of fremanezumab at months 2 and 3; quarterly dosing:fremanezumab  675 mg at month 1, followed by placebo injections at months 2 and 3; and monthly administration of matching placebo. Change in Work Productivity and Activity Impairment questionnaire (WPAI) scores from baseline to 4 weeks after last dose (weeks 9-12) was evaluated as an exploratory endpoint. Work productivity loss was assessed as the composite of absenteeism and impairment while working (presenteeism).

Results

Fremanezumab treatment led to larger reductions from baseline in overall work productivity loss from baseline to weeks 9–12 (quarterly dosing: −16.6 ± 2.1%, n = 375; monthly dosing: −15.9 ± 2.0%, n = 375) relative to placebo (–9.1 ± 2.0%, n = 371).  Placebo subtracted differences favored quarterly (–7.5 ± 2.2%, P < .001) and monthly: −6.8 ± 2.3%, P = .003). Similarly, changes from baseline in presenteeism were greater with fremanezumab (quarterly: −15.7 ± 1.9%; monthly: −14.9 ± 1.8%) than for placebo (–10.0 ± 1.8%), resulting in significant treatment differences (quarterly: –5.7 ± 2.0%, P = .005; monthly: −4.9 ± 2.1%, P = .02). Fremanezumab also reduced impairment of activity outside of work in the quarterly dosing arm of the study relative to placebo (−15.0 ± 1.7% vs −11.0 ± 1.7%; treatment difference: −4.0 ± 1.9%, P = .03).

Conclusions

In this study, fremanezumab treatment resulted in significant improvements in work productivity and activity impairment, demonstrating the positive impact of fremanezumab on the ability of CM patients to function both at and outside of work.

99 Effect of Baseline Characteristics on Outcomes of Oral Methylnaltrexone for Opioid-Induced Constipation

Richard Rauck¹, Neal E. Slatkin^2,3, Nancy Stambler⁴, Robert J. Israel³

¹Carolinas Pain Institute, Winston-Salem, NC, USA, ²University of California Riverside, School of Medicine, Riverside, CA, USA, ³Salix Pharmaceuticals, Bridgewater, NJ, USA, ⁴Progenics Pharmaceuticals, Inc., New York, NY, USA

Purpose

In July 2016, oral methylnaltrexone (MNTX), a selective, peripherally-acting µ-opioid receptor antagonist, was approved for the treatment of opioid-induced constipation (OIC) in adults with chronic noncancer pain. The purpose of this post hoc analysis was to assess the potential impact of baseline characteristics on the efficacy endpoints and opioid withdrawal in patients treated with oral MNTX from a phase 3 trial.

Methods

A randomized, double-blind, placebo-controlled trial (NCT01186770) was conducted in adults with chronic noncancer pain for ≥2 months who received ≥50 mg/d of oral morphine equivalents for ≥14 days and experienced OIC (confirmed during a 14-day screening period and defined by <3 rescue-free bowel movements [RFBMs] per week, on average, and associated with ≥1 of the following: ≥25% of RFBMs categorized as type 1 or type 2 on the Bristol Stool Form Scale, straining during ≥25% of RFBMs, or ≥25% of RFBMs with a sensation of incomplete evacuation). Patients were randomly assigned to receive oral MNTX (150 mg, 300 mg, or 450 mg) or placebo once daily for 4 weeks, followed by 8 weeks of oral MNTX or placebo taken as needed. Double-blinding was maintained throughout all 12 weeks of the study. Data were analyzed by baseline characteristics including age, sex, and high (average dose ≥150 mg/d) and low (average dose <150 mg/d) opioid morphine equivalent daily doses, for the following endpoints: RFBMs within 4 hours of dosing during weeks 1 to 4; proportion of responders during weeks 1 to 4 (patients with ≥3 RFBM/wk with an increase of ≥1 RFBM/wk for ≥3 of 4 weeks); number of RFBMs over the first 4 weeks of dosing; and Objective and Subjective Opioid Withdrawal Scales (OOWS and SOWS).

Results

Patients (N = 803; males, 37%; aged <65 y, 91%) received ≥1 dose of oral MNTX (150 mg, n = 201; 300 mg, n = 201; 450 mg, n = 200) or placebo (n = 201). Demographic and baseline characteristics were similar among groups. Median baseline opioid morphine equivalents were 132 mg/d (placebo; range, 43–1077 mg/d) and 151 mg/d (MNTX groups; range, 27–2289 mg/d). Differences between endpoints for males and females were not significant for percentage of days with RFBMs within 4 hours of dosing, percentage of patients with ≥3 RFBM/wk and ≥1 RFBM/wk increase from baseline for ≥3 weeks, and change from baseline in weekly RFBMs, with the exception of percentage of patients with ≥3 RFBM/wk and ≥1 RFBM/wk increase from baseline for ≥3 weeks in the MNTX 300 mg group (males 57.5% vs females 43.0%, P<0.05) and change from baseline in weekly RFBMs in the MNTX 300 mg group at week 2 (2.95 vs 2.06), week 3 (3.26 vs 2.10), and week 4 (3.22 vs 1.92; all P<0.05). No significant differences between patients aged <65 and ≥65 y in any treatment groups were noted. An analysis of covariance model with treatment as the main effect and sex and age group as covariates demonstrated that the percentage of dosing days with an RFBM within 4 hours of dosing during weeks 1 to 4 was significantly greater with MNTX 300 mg and 450 mg vs placebo (both P < 0.05). The number of RFBMs/wk was significantly higher with MNTX 300 mg and 450 mg vs placebo at week 1 (both P < 0.05). Opioid withdrawal symptoms were minimal and did not differ significantly in MNTX-treated patients with baseline opioid morphine equivalent < 150 mg/d or ≥150 mg/d, measured with the OOWS and SOWS on postdose days 1, 14, or 28. Similar results were obtained when abdominal cramping was excluded from the analyses.

Conclusions

Once-daily oral MNTX is effective for the treatment of OIC in adults with chronic noncancer pain, and its efficacy is independent of patients’ sex and age. Oral MNTX is not associated with opioid withdrawal.

100 Randomized, Double-Blind, Pilot Study Comparing 3Mg Subcutaneous Sumatriptan With 6Mg Subcutaneous Sumatriptan Using DFN-11 Autoinjector for the Acute Treatment Of Rapidly-Escalating Migraine Attacks

Roger Cady¹, Sagar Munjal², Ryan Cady¹, Heather Manley¹, Elimor Brand-Schieber²

¹Clinvest, A Division of Banyan Group Inc*, Springfield, MO, USA, ²Promius Pharma, a subsidiary of Dr. Reddy’s Laboratories, Princeton, NJ, USA

Purpose

A 6 mg dose of SC sumatriptan is currently considered the fastest and most efficacious acute treatment for migraine, but it is not tolerated by all patients.  SC sumatriptan 3 mg may provide improved tolerability while maintaining efficacy. The objective of this study was to compare 3 mg and 6 mg subcutaneous (SC) sumatriptan using the DFN-11 autoinjector for the acute treatment of rapidly escalating migraine attacks.

Methods

This randomized, double-blind, crossover study compared the efficacy and tolerability of 3 mg SC sumatriptan with 6 mg SC sumatriptan in 20 adults with a history of migraine attacks that typically are associated with moderate to severe headache within 2 hours of onset. Eligible subjects were randomized (1:1) to treat each of two attacks with either a DFN 11 autoinjector plus matching placebo autoinjector (total 3 mg dose) or two DFN 11 autoinjectors (total 6 mg dose). The primary endpoint was pain freedom at 1 hour.

Results

The proportion of subjects pain free at 1 hour postdose was similar following treatment with 3 mg and 6 mg SC sumatriptan (50% vs 52.6%, P   =   .87). Other outcome measures were also comparable for 3 mg and 6 mg SC sumatriptan, including the proportion of subjects experiencing pain relief (P  ≥  .48); reductions in migraine pain intensity (P  ≥  .78); and relief from nausea, photophobia, or phonophobia (P  ≥  .88). Mean patient treatment satisfaction ratings (2.6 vs 2.4, P  =  .81) and the mean number of rescue medications (.11 vs .26, P  =  .32) were also similar, as was the incidence of adverse events (3 mg, n  =  14 [44%]; 6 mg, n  =  18 [56%], P =  .60). Triptan sensations affected 4 subjects with the 6 mg dose only, 1 subject with the 3 mg dose only, and 7 subjects reported triptan sensations with both doses. The reported duration of triptan sensations was 24 minutes with 3 mg and 64 minutes with 6 mg SC sumatriptan (P = .43). Chest pain affected 2 subjects (10%) treated with 6 mg and no subjects (0%) treated with 3 mg SC sumatriptan. There were no serious adverse events.

Conclusions

The 3 mg dose of sumatriptan in DFN-11 provided relief of migraine pain and associated symptoms comparable to a 6 mg SC dose of sumatriptan. Tolerability was similar with both study medications. The 3 mg dose showed a numerical advantage in duration of triptan sensations that requires confirmation in a fully-powered study. DFN 11, a 3 mg SC sumatriptan autoinjector, may be a useful option for the acute treatment of migraine.

101 The Effect of Multidisciplinary Pain Education on Self-Efficacy and Pain Treatment Outcomes in Patients with Chronic Pain

Roslyn Feierstein, Ph.D., ABPP¹, Sondra Adkinson, PharmD, DAIPM, CPE¹, Michael Zaccaro (APPE Student)²

¹CWY Bay Pines VA Healthcare System, Bay Pines, Florida, USA, ²LECOM School of Pharmacy, Bradenton, Florida, USA

Purpose

Individuals with chronic pain and co-morbid medical conditions, such as chronic multi-system pain need to self-manage their health.   Self-management is likely to improve the quality of their life and their ability to cope with their pain.  Recovery and treatment outcomes are a direct consequence of the activation of self-management of health conditions (self-efficacy).  Individuals with higher levels of self-efficacy respond better to treatment and produce higher levels of recovery.   Historically, the Perceived Medical Condition Self-Management Scale (PMCSMS) measure has been used to examine and was validated with the conditions of diabetes, HIV, RA, Fibromyalgia and other medical conditions.  To date it has not been used to examine chronic multi-system pain.

Methods

A Quasi-Experimental Pilot Study with pre- and post-testing format, prior to and following Pain School group education, five consecutive weekly sessions for five total cohorts at the Bay Pines Pain Clinic was implemented from December 2017 through May 2018.  This five-week, multi-disciplinary educational program receives referrals for chronic pain treatment beginning with an orientation to a multi-disciplined approach.  Pre-and Post-testing completed by each individual attendee before the first and after the fifth sessions was facilitated.  The PMCSMS scores range from 0−48, and a higher score indicates better treatment outcomes.  In addition, a self-report NRS pain scale was utilized (0−10) pre- post testing.

Results

The pilot study utilized repeated measures within the same group.   With repeated measures,   a paired t-test was used to determine statistical significance.  The study hypothesized that participation in Pain School positively affects treatment outcomes as evidenced by increased scores on the PMCSMS, and a decrease in pain as identified by the patients (NRS).  Averages of the baseline and post Pain School PMCSMS; and pain scores were calculated and then compared against each other using the paired t-test.  Statistically speaking, a significantly higher difference in PMCSMS score was observed in the post Pain School measurement than at baseline (p = 0.0087).  Conversely, no statistically significant difference in average pain scores (NRS) was observed between measurements (p = 0.339). 

Conclusions

A pilot pain-specific adaptation of the Perceived Medical-Condition Self-Management Scale (PMCSMS) was administered to Pain School individual attendees with chronic multi-symptom pain. The individuals engaged in a brief educational training group e.g., Pain School for five sessions.  Individuals with poor or very poor outcomes at the time of pre-testing showed no improvement; while individuals who scored in the upper two ranges of the scale, had good to very good outcomes, and showed improvement at the time of post-testing. Individuals with pre-test mid-range scores showed fair treatment outcomes, but demonstrated mixed post-testing with improvement vs. a decline.  Individuals who demonstrated negative or no improvement were evaluated to have complex trauma, protracted depression, unresolved substance issues and/or personality disorders.   Those who showed improvement had significantly fewer diagnostic history of co-morbid anxiety and depressive disorders, but no personality disorders or substance abuse history.

102 Mechanisms contributing to the low brain distribution of naldemedine, a peripherally acting μ-opioid receptor antagonist

Ryosuke Watari, Akihiro Matsuda, Shuichi Ohnishi, Hiroshi Hasegawa

Shionogi & Co., Ltd., Toyonaka, Japan

Purpose

Naldemedine tosylate is a peripherally acting μ-opioid receptor antagonist (PAMORA) indicated for the treatment of opioid induced constipation (OIC) in adult patients with chronic non-cancer pain in the US and in patients with chronic non-cancer pain and cancer in Japan. Previous phase 3 studies with naldemedine have demonstrated that naldemedine is not associated with signs or symptoms of opioid withdrawal and has no notable impact on opioid-mediated analgesia. The low brain distribution of naldemedine by adding side chain which result in an increased polar surface area and molecular weight could contribute to such pharmacological property of naldemedine. The brain distribution of drugs or molecules is limited by the blood-brain barrier (BBB) that is formed by intercellular tight junctions of brain capillary endothelial cells. P-glycoprotein (P-gp), one of the adenosine 5’-triphosphate-binding cassette transporters is expressed at the luminal side of brain capillary cells of the BBB and can excrete xenobiotic compounds from brain to systemic blood to protect the brain. Therefore, the brain distribution of P-gp substrates could be increased by the concomitant administration of P-gp inhibitors and/or functional disorders of P-gp. The purpose of this study was to investigate the contribution of P-gp on the brain distribution of naldemedine.

Methods

[14C]-naldemedine tosylate was orally administered to rats and ferrets, and the concentration of radioactivity in the brain was determined by quantitative autoradiography following preparation of sagittal whole-body sections of rats or transverse brain sections of ferrets. Naldemedine tosylate (molecular weight: 742 dalton) was orally administered to multidrug resistance 1a/b (mdr1a/b, P-gp) knockout and wild-type mice to estimate the contribution of P-gp on the brain distribution of naldemeidne. The plasma and brain concentration of naldemedine were determined by high performance liquid chromatography combined with tandem mass spectrometry, and brain-to-plasma concentration ratio (Kp) was calculated to evaluate the brain distribution of naldemedine.

Results

After a single oral administration of [14C]-naldemedine tosylate to rats, the radioactivity was not detected in the cerebrum and cerebellum which are protected by the BBB, yet was detected at the same level as plasma in the hypophysis and pineal body which are lacking the BBB. This result indicates that the brain distribution of naldemedine-related radioactivity through the BBB was minimal. After a single oral administration of [14C]-naldemedine tosylate to ferrets, the radioactivity was minimal in the caudate nucleus, hippocampus, hypothalamus, periaqueductal gray, putamen, and thalamus, which are protected by the BBB and express opioid receptors related to the effect of opioid analgesics. On the other hand, the radioactivity was detected at the same level as plasma in the area postrema, which is not protected by the BBB and is a region existing the chemoreceptor trigger zone (CTZ), also indicating that the brain distribution of naldemedine-related radioactivity through the BBB is minimal. Considering that agonist activity of opioid receptors in CTZ is relevant to emesis, naldemedine tosylate could be effective in the treatment of not only OIC but also opioid induced emesis without affecting the analgesic effect of opioid analgesics and inducing opioid withdrawal symptoms. Since the P-gp is a crucial factor for the brain distribution of P-gp substrates, the impact of P-gp on the brain distribution of naldemedine was clarified by utilizing mdr1a/b knockout mice which lacks P-gp. The brain Kp value of naldemedine in the P-gp knockout mice was 4-fold of that in the wild-type mice, indicating that the P-gp has an effect on the brain distribution of naldemedine. However the brain Kp value of P-gp knockout mice was extremely low (brain Kp

Conclusions

These data demonstrate a low brain distribution of naldemedine. This pharmacokinetic property would be due to the limited ability to cross the BBB rather than the efflux by P-gp. Naldemedine presents negligible brain penetration without inter-individual variability of brain distribution due to drug-drug interactions and/or functional disorders of P-gp. Sequentially, there is a potential for low inhibition of opioid receptors within the CNS. Notably, such pharmacological effect is consistent with clinical evidence of naldemedine which is lack of interference with pain relief or increased safety risk for emergence of opioid withdrawal symptoms and signs.

103 Tolerability of DFN-11, Low Dose (3 mg) Sumatriptan Injection: Focus on Triptan Sensations and Injection Site Reactions in the RESTOR Episodic Migraine Study

Sagar Munjal¹, Stephen Landy², Elimor Brand-Schieber¹, Alan Rapoport³

¹Promius Pharma, a subsidiary of Dr. Reddy’s Laboratories, Princeton, NJ, USA, ²Baptist Medical Group, Memphis, TN, USA, ³David Geffen School of Medicine at UCLA, Woodside, CA, USA

Purpose

Despite the established efficacy of subcutaneous (SC) sumatriptan 6 mg, fewer than 10% of migraine sufferers use it. Among the reasons for this are triptan sensations and the high incidence of injection site reactions (ISR). The objective of this study was to evaluate the efficacy, tolerability and safety of DFN-11, a low-dose (3 mg) sumatriptan autoinjector with a thin-walled 29G needle. This report focuses on two common deterrents to the use of 6 mg SC sumatriptan, triptan sensation AEs and ISR.

Methods

Patients with episodic migraine were enrolled into a multicenter, double-blind (DB), placebo-controlled comparison followed by an 8-week open-label (OL) period. In the DB period, subjects were randomized (1:1) to DFN-11 or placebo to treat one migraine attack. In the OL period subjects treated additional attacks to assess the safety and tolerability of DFN-11 treatment over multiple attacks. Adverse event terms were prespecified for triptan sensations occurring within 2 hours of dosing (eg, tingling/prickling, dizziness/vertigo, warm/hot/burning sensation, cold sensation, heaviness/pressure/tightness, paresthesia, flushing, numbness) and for ISRs occurring within 24 hours after dosing (eg, swelling, irritation, erythema, hemorrhage, pain, and bruising). In addition to the overall incidence, the first four treated attacks were each summarized separately. Subjects recorded ISRs and other adverse events in an eDiary.

Results

In the DB period 7.2% of DFN-11 subjects (8/111) and 1.7% of placebo subjects (2/119) reported triptan treatment emergent adverse events (TEAEs). The most common TEAEs were paresthesia (2.7%) with DFN-11 and noncardiac chest discomfort (1.7%) with placebo. During the 8-week OL period, the overall incidence of triptan TEAEs was 11.4% (25/219) and across attacks 1 through 4, the incidence was 10.2% (n = 216), 8.1% (n = 186), 7.0% (n = 142), and 5.5% (n = 110), respectively. The most common TEAE was chest discomfort (~2% in each attack) and most triptan TEAEs were mild. During the DB period, ISRs were reported by 24 (21.6%) DFN-11 and 14 (11.8%) placebo subjects. The highest incidence DB period TEAE was injection site pain (7.2%) in DFN-11 and (5.9%) in placebo.  During the OL period, the overall incidence of ISRs was 22.8% (n = 50) and across attacks 1 through 4, the incidence was 18.1%, 9.7%, 9.9% and 7.3%, respectively.  The most common ISR was site swelling and pain (~4%-8% across attacks). Most ISRs were mild. In total 3 subjects (all treated with DFN-11) experienced severe TEAEs, 2 in the DB period (injection site pain, nausea) and 1 in the OL period (joint stiffness). There were 3 discontinuations due to triptan TEAEs: 2 subjects with mild throat tightness and one with nausea and injection site swelling.

Conclusions

Triptan-related side effects and injection aversion are concerns to migraine patients that might benefit from SC sumatriptan. In this study, there was a low incidence of triptan-related side effects and injection site reactions with DFN-11. Based on these data DFN-11, a low dose (3 mg) SC sumatriptan autoinjector, may be an alternative to SC 6 mg.

104 Outcome Success for Special Forces: Intensive Outpatient Chronic Pain Management Program for Rehabilitation of Neuro-musculoskeletal Injuries and mTBI

Samantha Parker¹, Jeff Frankart²

¹NMS, Washington, DC, USA, ²Ranson Inc, Landstuhl, Germany

Purpose

The purpose of this study was to compare recovery functional outcomes of Special Operators who received standard TBI treatment only to patients who received traditional TBI rehabilitation in conjunction with the Intensive Movement Recovery Program; yoga being a CAM modality to help facilitate quicker functional recovery times, return to duty status, reduction of opioid medication use as well as controlling and diminishing pain with more holistic treatments. 

Methods

The experimental group consists of (n= 14) service members with comorbid diagnoses of musculoskeletal pain and TBI who received six weeks of intensive outpatient TBI rehabilitation. The intensive outpatient Movement Recovery Program consists of experimental treatment enriched in Neuroplastic-Graded Proprioceptive Stimulation (N-GPS) rehabilitation, vestibulocochlear nerve stimulation, cognitive restructuring, motor function training and task overloading. The control arm consisted of (n = 15) SOF participants who received standard of care TBI treatment. Metrics used to evaluate their improvement included the NSI, WHO-QOL, TMT, PGIC, WAIS, Epworth, NeuroCom SOT, HIT-6, PCL-5, AUDIT, Headaches, Sit/Reach and functional performance metrics. The physical function of the Service member was tested using a FUNCTIONAL MILITARY EXERCISE (FME):  (7-1 PYRAMID TEST 7-1 PYRAMID TEST = The improvement in number of repetitions of push-ups, prone rows, supine rows, squats, dips, burpees complete in a 20 minute test cycle.) PT sessions consisted of 40 minutes total treatment 20 minutes of dynamic warm-ups (YoMo; Yoga in Motion) and 20 minutes of Physical Function Pyramid Test once a day, twice a week for 6 weeks for a total of 12 treatments. Yoga treatments consisted of 5 sessions a week for 6 weeks, for a total of 30 treatments. Yin yoga treatment was implemented immediately after PT sessions for 40 minutes for active recovery and reinforcing cognitive restructuring that was implemented throughout the duration of the activation of the neuroendocrine response. Hatha yoga was taught for 60 minutes the remaining 3 days of the week for the duration of 60 minutes. Practice included a yoga protocol of sequenced asanas, diaphragmatic breathing, guided imaginary and mediation. 

Results

A series of paired-samples t-tests were used to examine pre-post differences in report of headache, dizziness, sleep, cognitive functioning, sensory organization and motor coordination, neurobehavioral symptoms, balance, functional performance as well as report of pain, pain intensity, quality of life, PTSD symptoms and overall behavioral health concerns. A standardized measure of effect size, Cohen’s d, is reported to index the magnitude of the observed differences between pre- and post-treatment scores. The statistical significance level was set at P < 0.05 for all. Preliminary results indicate statistically significant (p<.05) differences on simple paired t-test for all pre-post measures between the two groups. The treatment group evidenced as high as a 188% symptom and functional improvement rate with over 80% of the cohort returning to full active duty. Significant improvement in patient symptom sequelae was observed, however more comprehensive regression analysis of the data is in process.

Conclusions

Interdisciplinary care involving CAM modalities such as yoga that incorporate a more dynamic, interactive delivery model for patients during TBI rehabilitation, achieves greater improvements in TBI symptoms, functional improvement and return success to functional duty 

105 Kambin’s triangle approach for percutaneous transforaminal epidural adhesiolysis with inflatable balloon catheter; a pilot study

Sangmin Jeong, Francis Sahngun Nahm

Seoul National University Bundang Hopital, Bundang-si, Gyeonggi-do, Korea, Republic of

Purpose

Spinal stenosis is a common condition for elderly people, but there are so many patients who are not responsive to conventional treatments. Percutaneous epidural adhesiolysis can relieve nerve root compression and deliver drugs effectively. Recently, it is reported that percutaneous transforaminal epidural adhesiolysis using inflatable balloon catheter can reduce patients’ pain and improve functional capacity. We would like to figure out the effectiveness and significance of Kambin’s trianglular approach as well as traditional safety triangular approach in percutaneous transforaminal epidural adhesiolysis using inflatable balloon catheter.

Methods

24 patients with chronic L5 unilateral radiculopathy who did not respond to conventional treatment were enrolled. They were divided into two groups; safe triangle approach group and Kambin’s triangle approach group. The success rate of the procedure was assessed by dividing each patient into three categories (B, D, F); category B (Ballooning): the instrument enters the target area and the contrast medium spreads after the balloon is inflated; category D (Dye spread): failed in balloon inflation but success in adhesiolysis and spread of contrast media; category F (Fail): failed in balloon inflation and adhesiolysis. Both NRS and ODI were also recorded at three times; before the procedure, one month and three months after the procedure. Basic patients’ demographic data were recorded.

Results

There was no difference in characteristics of patients between the two groups (Table 1). The success rate of the procedure was 80% in safe triangular approach group, and 90% in Kambin’s triangle approach group (Table 2). NRS at 3 months after the procedure showed statistically significant decrease and there was no significant difference between two groups (Table 3). ODI at 3 months after the procedure also showed statistically significant decrease and there was no significant difference between two groups either (Table 4).

Conclusions

For patients who have difficulty in safe triangle approach when performing percutaneous transforaminal epidural adhesiolysis, Kambin’s triangle approach can be an alternative option. A randomized, controlled, double-blind, multi-center study should be followed.

106 Improving the Safety of Intrathecal Drug Delivery for Chronic Pain: A Quality Improvement Initiative

Sarah Yost, Gary MacDonald, Eva Rowles

Intermountain Healthcare, Park City, UT, USA

Purpose

In 2017, the Intermountain Healthcare Pain Management Clinic in Park City, UT and Pharmacy Services within Intermountain Healthcare collaborated to improve the safety of intrathecal drug delivery for chronic pain patients. Intrathecal medications were evaluated for safety and stability and a list of standard concentrations and dosages was compiled. This list is more restrictive and supersedes the 2017 Polyanalgesic Consensus Conference recommendations and guidelines for intrathecal drug delivery. An internal goal was established to have 75% of patients within Intermountain Healthcare intrathecal pump medication standards by July of 2018 and decrease the dose of oral opioids by an average of 15%. 

Methods

As a quality improvement initiative, the primary goal was safety and improved compliance with Intermountain Healthcare standards. Outcome measures were established and measured retrospectively from July 2017 to July 2018. Outcome measures include a signed intrathecal pump management agreement, an up to date urine drug screen, change in oral opioid dosage, the number of patients within intrathecal medication standards, and the number of patients treated with intrathecal monotherapy.

Results

In July 2017, we identified 59 patients receiving intrathecal drug therapy. At that time, 19% of patients were within intrathecal drug medication standards, 31% of patients were receiving intrathecal monotherapy, 76% of patients had a current intrathecal pump management agreement on file, and 56% of patients had a current urine drug screen. 83% of patients were co-prescribed oral opioid pain medication with an average milligram morphine equivalent dose of 178 mg/day and a range of 0 to 1,208 mg/day. In July 2018, 72% of patients were within intrathecal drug medication standards, 44% of patients were receiving intrathecal monotherapy, 100% of patients had a current intrathecal pump management agreement on file, and 90% of patients had a current urine drug screen. 85% of patients were co-prescribed oral pain medications with an average milligram morphine equivalent dose of 118 mg/day and a range of 0 to 405 mg/day. The average oral opioid dose decreased by 34%.

Conclusions

The data acquired from the quality improvement initiative demonstrates an increase of patients within intrathecal drug medication standards, a decrease in the average dose of oral opioids, and thus by proxy improved patient safety. Other variables suggest improved compliance with clinic policies and best practices. The primary limitation of our project was the lack of patient-based outcomes for statistical analysis.

107 Real-Word Effectiveness of Fixed-Site High-Frequency Transcutaneous Electrical Nerve Stimulation in Chronic Low Back Pain

Shai Gozani, Xuan Kong

NeuroMetrix, Inc., Waltham, MA, USA

Purpose

Chronic low back pain (CLBP) is a common health problem associated with substantial disability and economic burden. Recent epidemiological studies estimated the point prevalence of CLBP in U.S. adults at 10−13%. In a national health survey, 28% of U.S. adults reported low back pain over the prior 3-months. Annual U.S. health care expenditures for CLBP are over $100B with an additional $100−200 billion in decreased wages and lost productivity. Patients with CLBP are frequently managed with pharmacological therapy, including prescription opioids, however lack of efficacy, adverse events and addiction risk lead many to discontinue treatment. There is a need for non-pharmacological options for CLBP.

Transcutaneous electrical nerve stimulation (TENS) is a non-invasive treatment for chronic pain that has no significant side effects. Conventional TENS is delivered through surface electrodes to generate a strong, nonpainful sensation. The resulting stimulation of large diameter, deep tissue afferents produces widespread pain relief by decreasing central excitability and increasing central inhibition. Although TENS has been used in CLBP for several decades, its efficacy remains controversial due to conflicting conclusions from systematic reviews. Several factors have been identified for negative clinical outcomes including inadequate dose, inappropriate outcome measures and small sample size.

Fixed-site high-frequency TENS (FS-TENS) is an emerging form of TENS in which the stimulator is designed for a predetermined location rather than for co-localization with the patient’s pain. A single target site enables design of small wearable devices that may be used while active and sleeping, thereby facilitating adequate dosing. In a randomized clinical trial of 68 CLBP patients followed for three-months, FS-TENS decreased pain intensity, pain interference, pain catastrophizing and pain-related disability compared to a “treatment as usual” control. The objective of the present study was to evaluate the effectiveness of regular (i.e., daily or near daily) FS-TENS use in a large, real-world CLBP population.

Methods

This retrospective, observational study evaluated users of a FS-TENS device to treat CLBP (Quell®, NeuroMetrix, Waltham, MA) over a 10-week period. The device is placed on the upper-calf and provides semi-continuous stimulation (60-minutes every other hour) of sensory nerves in the S2-L4 dermatomes. The device and companion smartphone app collect utilization data, demographics, pain characteristics and pain ratings (provided at user’s discretion) that are stored in a cloud database. The pain ratings include intensity and interference with activity, sleep and mood on an 11-point NRS. Device users were included iif they provided demographic data and pain characteristics indicative of CLBP (i.e., daily/weekly pain, pain duration >3 months, low back pain and ≥1 self-reported condition among herniated disc, spinal stenosis and previous back injury), baseline and 10-week pain ratings.

Study participants were allocated to the treatment or reference group based on their device utilization (%days with ≥30 minutes of FS-TENS use). Participants with ≥50% utilization were allocated to treatment (adequate dose) and those with <50% utilization were allocated to reference (low dose). The primary study outcome was the baseline to 10-week change in composite pain, which was defined as the average of pain intensity and the three pain interference values.

The treatment effect was estimated by comparing outcomes in the treatment group to a matched reference group constructed by propensity score (PS) matching. PS methods reduce confounding bias in observational studies. The PS model was comprised of demographics, potential confounders and risk factors; the latter two variables were determined by univariate statistical testing. The final model included age, gender, BMI, baseline composite pain, hand/wrist pain, foot pain, diabetes, prior hand/arm injury and prior leg/foot injury. Arm pain was a risk factor but was excluded because it prevented effective matching. The PS was estimated by logistic regression. The matched reference group was created by 1-1 nearest neighbor matching (caliper 0.1) with replacement. Balance between the treatment and reference groups was assessed by the standardized percentage bias (SPB). Differences between groups were tested by the Wilcoxon rank-sum and Pearson chi-square tests.

Results

A total of 834 device users met the inclusion criteria and were assigned to the treatment (671, 80%) or reference (163, 20%) group. With few exceptions, the two groups had similar demographic and pain characteristics at baseline. The treatment group was older (58 ± 13 vs 56 ± 14, p = 0.035) and had lower BMI (30.5 ± 6.8 vs 31.9 ± 7.9, p = 0.043). In addition, the treatment group was more likely to have hip pain (p = 0.037) and less likely to have diabetes (p = 0.002) or a prior neck injury (p = 0.006). There was no difference in the baseline composite pain, which was 6.3 ± 2.1 (treatment) and 6.5 ± 1.9 (reference), p = 0.364.

Device usage was different in the two groups. Utilization was 86 ± 15 (treatment) compared to 31 ± 13 (reference), p<0.001. Weekly therapy was 46 ± 22 hrs/week (treatment) compared to 11 ± 7 hrs/week (reference), p < 0.001. The median stimulation intensity (ratio of stimulation to sensation level expressed in decibels) was 5.3 dB (treatment) compared to 6.0 dB (reference), p = 0.045.

The matched reference group was created using PS matching on the model variables. The median absolute SPB between the treatment and reference groups decreased from 10.3% for the original reference to 2.4% for the matched reference. The absolute SBP was below 10% for all model variables following PS matching. A match was found for each participant in the treatment group. Of the 163 participants in the original reference group, 143 (88%) served as matches for the treatment group. 71% of the reference participants matched 5 or fewer treatment participants.

The baseline to 10-week follow-up change in composite pain was -0.89 ± 2.30 for the treatment group and –0.01 ± 2.3 for the matched reference group. The standardized mean difference between the groups was 0.38 (95%CI 0.27, 0.49).

Conclusions

This study demonstrated that 10-weeks of regular FS-TENS use improved pain outcomes in a real-world sample of CLBP when compared to a reference group with low utilization. The primary study limitations were the possibility of uncorrected bias due to unmeasured confounders and a potential impact of the outcome on group allocation. Study strengths included evaluation of a large real-world sample, use of a concurrent reference group, allocation of participants to treatment or reference based on objective data, and reduction of bias by PS matching. This study suggests that regular FS-TENS use is effective in improving pain outcomes in CLBP.

108 Persistence of Effect of Galcanezumab in Patients with Episodic or Chronic Migraine: Phase3, Randomized, Double-Blind, Placebo-Controlled EVOLVE-1, EVOLVE-2 and REGAIN Studies

Sheena K. Aurora, Qi Zhang, Virginia L. Stauffer, Marissa I. Daniele

Eli Lilly and Company, Indianapolis, IN, USA

Purpose

To describe the persistence of effect following treatment with galcanezumab in adult patients with episodic or chronic migraine.

Methods

Data from two parallel studies of patients with episodic migraine (between 4 and 14 migraine headache days [MHD] and at least 2 migraine attacks per month during baseline) and one study of patients with chronic migraine (headache ≥15 days/month for >3 months, with features of migraine headache ≥8 days/month at baseline) were analyzed. In all three studies, patients randomized in a 1:1:2 ratio received a subcutaneous (SC) injection of galcanezumab at 120 mg/month or 240 mg/month or a SC placebo. Persistence of effect during the double-blind phase was evaluated based on a comparison of the percentages of galcanezumab- and placebo-treated patients with maintenance of ≥50% response (defined as ≥50% reduction from baseline in monthly MHDs) for at least 3 and 6 consecutive months for the episodic study and 3 months for the chronic study. Logistic regression analyses were used for between treatment comparisons.

Results

A total of 1773 adult patients with episodic migraine (n = 444 for galcanezumab 120 mg; n = 435 for galcanezumab 240 mg; n = 894 for placebo for two episodic studies pooled) and 1113 patients with chronic migraine (n = 278 for galcanezumab 120 mg; n = 277 for galcanezumab 240 mg; n = 558 for placebo) were evaluated. In patients with episodic migraine, significantly higher percentages of patients maintained ≥50% response for at least 3 consecutive months in the galcanezumab 120 mg (41.5%; p < .001) and 240 mg (41.1%; p < .001) groups or for 6 consecutive months (19.0% and 20.8%, respectively; p < .001) compared with the placebo group (21.4% at 3 months and 8.0% at 6 months). In patients with chronic migraine, significantly higher percentages of patients in the galcanezumab 120 mg (16.8%) and 240 mg (14.6%) groups maintained ≥50% response for all 3 months of the double-blind treatment phase compared with placebo (6.3%; all p < .001).

Conclusions

Treatment with galcanezumab 120 mg or 240 mg demonstrated statistically significant and clinically meaningful persistence of effect in patients with episodic migraine (at least 3 and 6 consecutive months) and in patients with chronic migraine (for 3 months).

109 Acute Medication Use and Overuse in Patients with Migraine

Shonda Foster, Krista Schroeder, Casey Kar-Chan Choong, Sarah Curtis, Paula Morrow, Janet Ford

Eli Lilly and Company, Indianapolis, Indiana, USA

Purpose

Current evidence-based guidelines for treatment of migraine recommend individualized pharmacological management of acute attacks in addition to preventive intervention as warranted.  Overuse of medications intended for acute or symptomatic treatment of migraine may be associated with medication overuse headache and/or progression from episodic to chronic migraine.   The purpose of this analysis is to describe acute medication use in migraine patients and specifically the frequency of overuse based on number of scripts and days of therapy (DOT) data.  In addition, this study reports acute medication use in patients on preventive therapy and those not on preventive therapy.

Methods

This study was a retrospective, observational, cross-sectional study using the Truven Marketscan Commercial and Medicare-Supplemental administrative claims database.  Patients 18 years and older with continuous medical and prescription enrollment during the 2016 calendar year who had at least one migraine diagnosis (ICD-9: 346.xx; ICD-10: G43.0-G43.9*) during the 2016 calendar year (1/1/2016 – 12/31/2016) were selected. Additionally, to ensure prevalent migraine on Jan 1, 2016, at least one additional migraine diagnosis occurring any time before the 2016 calendar year was required.  Patients were excluded if they had ICD-9/10 codes for HIV, cancer, cluster headache, or epilepsy.  Descriptive analyses were conducted to evaluate prescription acute medication use including DOT and number of claims during the 2016 calendar year.  Frequency of acute medication overuse was assessed. Acute medication overuse was defined as 120+ triptan DOT in a year; 96+ DOT of opioids per year, or barbiturates 60+ DOT per year.  Overuse of NSAIDS/acetaminophen was not reported due to over-the-counter use that cannot be evaluated in claims data.

Results

The cohort included 216,674 patients with prevalent migraine (mean age 44.3 years; 85.9% female; 101,111 on preventives; 115,536 not on preventives).  During the 2016 calendar year, the majority of patients had at least one claim for an acute medication (83.5%).  Almost half had a claim for triptans (49.7%) and 46.9%, 44.3% and 14.2% had a claim for opioids, NSAIDS/acetaminophen, and barbiturates, respectively.  Of the patients with a claim for at least one acute medication, the average acute medication DOT for 2016 was 116 days (31.8% of 2016 days covered with acute medication).   Of those with at least one DOT, average DOT for triptans was 99 days, 67 days for opioids, 60 days for NSAIDs/acetaminophen, and 58 days for barbiturates.  Of those with at least one script of each respective class, the mean (± SD) number of scripts in the calendar year was 4.75 ± 4.84 for triptans, 5.11 ± 6.64 for opioids, 2.98 ± 3.11 for NSAIDs/acetaminophen and 3.99 ± 4.94  for barbiturates.  About 15.7% of the entire cohort had overused triptan therapy over the study period.  Additionally, 9.7% had overused opioids and 3.8% had overused barbiturates.  Out of those who had at least one DOT of triptans, 31.5% had overused the medication.  Similarly, out of those with at least one DOT of opioid use, 20.7% had overused the medication and out of those with at least one DOT of barbiturates, 27% had overused the medication.

Conclusions

The majority of patients with migraine had at least one claim for an acute medication and a subset of patients appeared to have overused triptans, opioids, or barbiturates during the study period.  Effective treatment options that can help to reduce acute medication use are needed in the management of patients with migraine. Understanding current utilization and overuse of acute medications among patients with migraine will better inform potential interventions to improve patient care and outcomes.

110 Pharmacist Awareness of the DEA National Prescription Drug Take Back Day

Stacy Baldridge, Thomas Alfieri, Rupa Shah

Purdue Pharma LP, Stamford, CT, USA

Purpose

According to the National Community Pharmacists Association, up to 40% of dispensed prescription medications are not completely used during the course of treatment, and are likely to remain in the home, where the storage may not be secure. Unnecessary prescription medications kept inside the home pose a risk for unintentional poisoning events or diversion.  The Drug Enforcement Administration (DEA) National Prescription (Rx) Drug Take Back Days address a crucial public safety and public health issue, and provide the opportunity for individuals to properly dispose unused prescription drugs. Since 2010 the DEA has supported disposal efforts and has collected more than 9 million pounds of potentially dangerous, unused, unwanted or expired prescription drugs at biannual National Rx Drug Take Back Days. Pharmacists are well-positioned to educate patients about medication safety, storage, and disposal.  In fact, retail pharmacies, such as Walmart, CVS, and Rite Aid have taken measures to help reduce abuse and misuse of unused medications through patient education, medication drop off sites, and disposal solutions. To raise awareness of the DEA National Rx Drug Take Back Day and to learn of the experience and needs of pharmacists as it relates to medication safety, storage, and disposal, Purdue Pharma Medical Science Liaisons (MSLs) conducted outreach with retail pharmacists.

Methods

Purdue Pharma MSLs are healthcare professionals, including pharmacists, nurses, and physician assistants, with training in pain care. The primary objective of this focused outreach to retail pharmacists was to raise awareness of the DEA National Rx Drug Take Back Day, with the intent of encouraging their patients to participate in proper disposal of their unused, unwanted, or expired medications.  In April 2018, a team of Purdue Pharma MSLs approached a convenience sample of pharmacists in nine states based on the MSL’s metropolitan area, with the goal of increasing awareness of the DEA National Rx Drug Take Back Day on April 28, 2018.  MSLs provided DEA flyers, promoting the DEA National Prescription Drug Take Back Day in English and Spanish, that could be displayed in pharmacies.  Pharmacists voluntarily participated in peer to peer discussions with the MSLs to discuss the needs and challenges of pharmacists and patients as related to controlled substances.  MSLs documented key insights from the discussions into an electronic database. Qualitative exploratory analyses were conducted to identify key themes and patterns in the insights.

Results

MSLs visited138 pharmacies in 9 states (CA, CT, MA, MN, NC, NY, PA, SC, and TX).  Pharmacy settings included national retail chains (n = 53, CVS, Walmart, Rite Aid, Kmart, and chain grocery stores), as well as independent and regional chain pharmacies (n = 85).  Of the 138 pharmacists approached in the retail setting, approximately half (n = 67) engaged in discussions with the MSLs.  Of the pharmacists taking part in detailed discussions, 64% (n = 43) were from independent or regional chain pharmacies.   The most frequently mentioned theme by pharmacists was regarding medication disposal options and patient education on those options, such as the availability of in-pharmacy disposal drop boxes and distribution of medication disposal bags (n = 30). Regarding the upcoming DEA National Rx Drug Take Back day, 72% of pharmacists who engaged in discussions (n = 48) were aware of the upcoming DEA event, but only 13 pharmacists (19%) described active efforts to counsel patients on proper medication disposal, including individual patient education, provision of medication disposal bags, and informing patients of local medication drop-off sites. In the detailed discussions, additional key themes were identified about needs and challenges for pharmacists, including patient education (22%), use of state Prescription Drug Monitoring Programs (21%) naloxone (18%), prior authorizations/insurance (13%), lack of issues with patient access to controlled substances (12%), and the impact of opioid quantity limits (9%).

Conclusions

There is a need for increased awareness and education for pharmacists and consumers regarding proper medication disposal. Pharmacists noted the value of disposal options, such as controlled substance take-back, drop boxes, and disposal bags.  These results highlight an opportunity for ongoing education about the importance of proper disposal of unused medications. Pharmacists play a critical role in educating patients with accurate information about prescription medication safety, storage, and disposal options.

111 Low-Dose (3 Mg) Sumatriptan Injection (DFN-11) Efficacy, Tolerability, and Safety in Episodic Migraine: RESTOR, a Randomized, Double-Blind, Placebo-Controlled Study

Stephen Landy¹, Sagar Munjal², Elimor Brand-Schieber², Alan Rapoport³

¹Baptist Medical Group, Memphis, TN, USA, ²Promius Pharma, a subsidiary of Dr. Reddy’s Laboratories, Princeton, NJ, USA, ³David Geffen School of Medicine at UCLA, Woodside, CA, USA

Purpose

The efficacy of a low dose sumatriptan injection (3 mg) in the acute treatment of migraine has not been previously assessed in a large, placebo-controlled study. This study evaluated the efficacy, safety, and tolerability of DFN-11 (sumatriptan 3 mg) subcutaneous autoinjector for the acute treatment of migraine with or without aura in adults.

Methods

A phase 3, US multicenter, randomized, double-blind (DB), placebo-controlled efficacy, tolerability, and safety study. Adult subjects with a history of episodic migraine (using ICHD II) who experienced 2 to 6 migraine attacks a month for at least the past 12 months with no more than 14 migraine headache days per month, and with 48 hours of headache free time between migraine headaches. DB period subjects self-administered study medication to treat one attack at moderate to severe pain intensity and recorded real-time data in an electronic diary. Primary efficacy was pain freedom at 2 hours (2h) postdose in the DB period. Key secondary endpoints were 1-hour pain freedom, 2-hour pain relief and 2-hour absence of most bothersome symptom (MBS). Following the DB period, an 8-week open-label period was conducted to further assess tolerability and safety of DFN-11 (reported separately).

Results

Of 268 randomized subjects in 16 sites, 208 had DB data postdose (n  =  104 in each treatment arm). The primary endpoint – 2h pain freedom – was met with DFN-11, significantly higher than placebo (51.0% vs 30.8%, P  =  .002). Pain relief at 2h postdose was significant (76.0% vs 60.5%, P  =  .018). Numerically, more DFN-11 subjects were free of their most bothersome symptom (MBS) [nausea, photophobia, phonophobia] at 2h postdose versus placebo (64.1% vs 48.1%; P  = .031). Post hoc analysis using observed cases demonstrated significant separation between DFN-11 and placebo (65.3% vs 47.4%; P  =  .021). At 2h postdose, relief of nausea was numerically but not statistically significantly higher for DFN-11 versus placebo (77.8% vs. 67.3%, P  = .179), and DFN-11 was significantly better than placebo at relieving photophobia and phonophobia (64.5% vs 42.5%; P = .006 and 70.0% vs 50%; P  =  .017. A total of 33.3% (37/111) of DFN-11 subjects and 13.4% (16/119) of placebo subjects in the DB period and 40.6% (89/219) in the OL period experienced treatment-emergent adverse events (TEAEs), none of them serious. The most common TEAEs were injection site pain (7.2% in DFN-11 vs 5.9% in placebo) and injection site swelling (7.2% in DFN-11 vs 0.8% in placebo). Discontinuation due to adverse events occurred in 2 subjects in the DB period and 5 subjects in the OL period (8 week period during which multiple attacks were treated) discontinued due to adverse events, and no new, unexpected, or serious adverse events were observed in the study.

Conclusions

DFN-11, a low dose (3 mg) sumatriptan autoinjector had significantly higher 2-hour pain freedom (51.0% vs 30.8%) and 2-hour pain relief (76.0% vs 61.5%) than placebo. The most common TEAEs were injection site pain (7.2% in DFN-11 vs 5.9% in placebo) and injection site swelling (7.2% in DFN-11 vs 0.8% in placebo). Most bothersome symptom freedom was significantly higher than placebo at 30 minutes and 90 minutes postdose. These results show DFN-11 is effective and well tolerated in the acute treatment of episodic migraine.

112 Efficacy, Tolerability, and Safety of Repeat Dosing With DFN-11, a Low-Dose (3 mg) Sumatriptan Injection, in Episodic Migraine: an Open-Label Extension of RESTOR

Stephen Landy¹, Sagar Munjal², Elimor Brand-Schieber², Alan Rapoport³

¹Baptist Medical Group, Memphis, TN, USA, ²Promius Pharma, a subsidiary of Dr. Reddy’s Laboratories, Princeton, NJ, USA, ³David Geffen School of Medicine at UCLA, Woodside, CA, USA

Purpose

The efficacy, tolerability and safety of DFN-11, a single-use low dose (3 mg) sumatriptan subcutaneous (SC) autoinjector for acute treatment of migraine, has not been previously assessed in multiple attacks in a larger population. The objective of this study was to evaluate the efficacy, tolerability, and safety of DFN-11 for the acute treatment of multiple migraine attacks.

Methods

RESTOR was multicenter, double-blind (DB), placebo-controlled US study. Subjects averaging 2 to 6 episodic migraine attacks per month were initially randomized to DFN-11 or placebo to treat a single migraine attack (DB; data presented elsewhere). The subjects then entered an 8-week, open-label treatment period (OL) to further assess efficacy, tolerability, and safety of DFN-11 in multiple attacks treated at any pain level, rated on a 4-point scale.  Subjects were instructed on autoinjector use and they recorded efficacy data and injection site reactions (ISR) in a real-time eDiary. Efficacy included the proportions of subjects with postdose pain freedom, pain relief, absence of symptoms (including most bothersome symptom, determined at predose [MBS]). Tolerability and safety were assessed by adverse events, vital signs, ECG, physical examination, and clinical laboratory tests.

Results

In the OL period, 219 subjects had safety data and 216 had DFN-11 postdose efficacy data. During the 8-week OL period, 848 migraine episodes were treated with DFN-11; the mean (SD) was 3.9 (2.3) attacks per subject. In attacks number 1 (n = 216), 2 (n = 184), 3 (n = 142) and 4 (n = 110), 2 hour(2h), pain freedom rates were 57.6%, 64.6%, 61.6% and 66.3%; 2h pain relief (pain rating 1 or 0) rates were 83.4%, 88.4%, 84.1%, and 81.7%; and MBS freedom rates were 69.0%, 76.5%, 77.7% and 74.7%, respectively. There were 78.1%, 84.6%, 86.5%, and 85.7% subjects who were free from nausea at 2h; 75.3%, 76.4%, 72.3%, and 77.5% subjects free from photophobia; and 75.2%, 77.5%, 73.6%, and 76.0% subjects who were free from phonophobia, at 2h in attacks 1, 2, 3, and 4, respectively.During the OL period, 89 (40.6%) subjects reported treatment-emergent adverse events (TEAE); the highest incidence was for injection site swelling (12.8%), followed by injection site pain (11.4%), injection site irritation (6.4%), and injection site bruising (6.4%). The majority, (n = 58) had mild severity TEAEs. One subject had severe TEAEs of joint stiffness that were considered definitely related to the study medication. Five subjects discontinued due to AEs (one with moderate hernia pain; 2 subjects with mild throat tightness; one with moderate hypersensitivity; one with both mild nausea and moderate severity injection site swelling). Two subjects had SAEs, none were treatment-emergent (one with severe small intestinal obstruction, considered unrelated to study medication; another with severe rash, moderate dizziness and pyrexia, considered unlikely to be related to study medication). There were no new safety findings during the study.

Conclusions

DFN-11, a low dose (3 mg) SC sumatriptan autoinjector provided consistent efficacy across 4 migraine attacks in an OL study phase. Repeat dosing efficacy was comparable to what was seen in the DB phase (reported elsewhere), with good tolerability and no new safety signals.

113 Overview of Fremanezumab Pooled Safety Data from Placebo-Controlled Phase 2 and 3 Studies

Stephen Silberstein¹, Xiaoping Ning², Paul Yeung², Ronghua Yang², Ernesto Aycardi²

¹Thomas Jefferson University, Philadelphia, PA, USA, ²Teva Pharmaceuticals, Frazer, PA, USA

Purpose

Fremanezumab, a fully-humanized monoclonal antibody (IgG2∆a) that selectively targets calcitonin gene-related peptide (CGRP) ligand that has been shown to be effective in the prevention of episodic migraine (EM) or chronic migraine (CM).

The purpose is to summarize the safety profile of fremanezumab based on all placebo-controlled studies in patients with migraine. 

Methods

Fremanezumab has been studied in four placebo-controlled studies in patients with migraine, including two Phase 2 studies and two Phase 3 studies.  Each study was a 16-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group study to compare the efficacy, safety, and tolerability of fremanezumab and placebo in adults with EM or CM.  The studies evaluated the safety and efficacy of fremanezumab at the proposed doses of 225 mg monthly (Patients with CM received a starting dose of 675 mg), 675 mg quarterly, and at 2 higher doses (675 mg monthly and 900 mg monthly) administered sc for 3 months.

Results

Most patients who received fremanezumab (N = 1702) or placebo (N = 861) were female (87%) with mean age of 41.4 years (range = 18 to 70 years), respectively.  Serious adverse events and adverse events leading to discontinuation occurred infrequently, with similar incidences in patients who received fremanezumab (1% and 2%, respectively) compared with patients who received placebo (2% for both subsets).  The most common adverse events in patients in the placebo-controlled studies who received fremanezumab and placebo were injection site reactions, including induration and erythema, which tended to be transient, mild and slightly more frequent in patients who received fremanezumab.  Upper respiratory tract infection and nasopharyngitis, both reported with similar incidence in patients who received fremanezumab and patients who received placebo, were the next most frequently reported adverse events.   Cardiovascular adverse events occurred infrequently and with a similar incidence in patients who received fremanezumab and patients who received placebo. No signal for hepatoxicity was observed.  No anaphylaxis or severe hypersensitivity occurred, and only 3 patients (2 on placebo, and 1 on fremanezumab) had adverse events of drug hypersensitivity of mild or moderate severity.  Each of these events was not serious and resolved with steroid and/or antihistamine treatment.  Incidence of ADA formation as of the data cut-off date was low, and there were no adverse events related to ADA or Nab development.

Conclusions

Four placebo-controlled studies demonstrate that fremanezumab at the proposed dose regimens of 225 mg monthly (with patients with CM receiving a loading dose of 675 mg) and 675 mg quarterly is an efficacious and generally safe and well tolerated preventive therapy..

114 Targeted Blood Patch for Postdural Puncture Headache following Cervical Epidural Steroid Injection (CESI): A case report.

Steven Punzell¹, Daniel Sainburg¹, Justin Mendoza²

¹UNC Hospital Department of PM&R, Chapel Hill, North Carolina, USA, ²Hackensack University Medical Center Department of PM&R, New York, New York, USA

Purpose

Postdural puncture headache (PDPH) is a major complication of neuraxial anesthesia and epidural injections. PDPHs are thought to occur due to leakage of cerebrospinal fluid from the subarachnoid space leading to both downward traction on intracranial structures and a compensatory veno-dilatation (Turnbull and Shepherd, 2003). 85% of PDPHs will resolve spontaneously so initial treatment is conservative; e.g. bed rest, IV fluids, caffeine, steroids, and NSAIDs (Kwak, 2015; Basurto et al., 2015). If conservative measures fail, an epidural blood patch (EBP) can be used to mechanically close the puncture via coagulation (Kawaguchi et al., 2011; Kwak, 2015; Turnbull and Shepherd, 2003). Classically, EBPs are done in the lumbar spine. There are few cases of targeted EBPs in the thoracic or cervical spine due to the risk of complications such as spinal cord compression (Girgis et al., 2015; Kapoor and Ahmed, 2015). Kapoor (2015) reviewed 19 cases (15 case reports), and demonstrated that the risk of adverse events in targeted cervical EBPs is likely lower than perceived. Girgis (2015) recommended considering targeted EBP after failure of lumbar EBP. Here we present a case of PDPH shortly after CESI which resolved after targeted EBP.

Methods

This is a 66 yo female who presented with neck pain radiating into her left arm consistent with cervical radiculopathy. Prior MRI revealed severe left neural foraminal stenosis at C5-6 and C6-7. The patient failed conservative measures consisting of 3 weeks of physical therapy (PT) and medication management. The patient underwent a CESI with a C7-T1 interlaminar approach utilizing a 20 gauge Tuohy needle. The level was identified with fluoroscopy and depth was confirmed with a contralateral oblique view. The ligamentum flavum was detected through tactile feedback and there was loss of resistance. Intravascular and intrathecal injections were excluded and good epidural flow of contrast was noted. After negative aspiration, 1 mL of 10 mg/mL dexamethasone was injected into the epidural space.

The day following the procedure the patient called the office reporting positional headaches. She was prescribed Fioricet and used it every 4 hours for 2 days without relief. The decision was made to attempt a blood patch and this was scheduled 9 days after her CESI. For the blood patch, venous blood was withdrawn from the antecubital vein. A 20 gauge Tuohy needle was utilized and advanced under fluoroscopic guidance into the epidural space at T1-T2. The epidural space was identified and intravascular and intrathecal injections were excluded as above. Three mL of blood were utilized for our patch

Results

Following CESI the patient’s radicular symptoms resolved. Despite fluoroscopic precautions being taken during the procedure, the patient developed positional headaches the following day. The patient failed conservative treatment for positional headaches and returned 9 days later for EBP. The patient’s postural headaches resolved within a few hours of EBP.

Conclusions

Classically, blood patches have been done in the lumbar spine regardless of dural rupture site. There are few examples in the literature of targeted blood patches in the thoracic or cervical spine. To date, no clear determination can be made regarding efficacy of targeted versus lumbar EBPs due to the paucity of randomized trials (Smith, 2015). Here, we add another successful case of targeted blood patch in treatment of PDPH and we advocate for additional comparative studies.

115 Meloxicam IV in Phase 2 Clinical Studies: A Summary of Safety, Efficacy, and Dose Ranging

Stewart McCallum¹, Randall Mack¹, Sue Hobson¹, Alex Freyer¹, Wei Du²

¹Recro Pharma, Inc., Malvern, PA, USA, ²Clinical Statistics Consulting, Blue Bell, PA, USA

Purpose

Intravenous (IV) meloxicam (Meloxicam IV) is a novel formulation of NanoCrystal Colloidal Dispersion® meloxicam, being developed for the management of moderate to severe pain.  Meloxicam IV has been evaluated across a range of dose levels and adult subject populations in four Phase 2 clinical studies in order to identify a safe and effective dose for evaluation in Phase 3 studies.  The Phase 2 program evaluated dose levels of meloxicam IV ranging from 5 to 60 mg in subject populations including impacted third molar extraction, abdominal hysterectomy, laparoscopic abdominal surgeries, and bunionectomy.

Methods

The meloxicam IV Phase 2 program included a total of four randomized, placebo and/or active controlled studies, with meloxicam IV doses ranging from 5 to 60 mg administered every 12 or 24 hours.  The reported studies (4) were conducted under an FDA IND, IRB approval was obtained prior to study conduct, and all subjects provided written informed consent.  These studies each followed a similar design wherein subjects underwent a protocol defined surgical procedure following a standardized care regimen, with pain assessments performed before and after study treatment to evaluate the impact of treatment on the subject’s pain experience.  Efficacy assessments included pain intensity (via 100 mm visual analog scale [VAS] or 0-10 numeric pain rating scale [NPRS]), as well as assessments of pain relief, and measurements of rescue analgesia use.  Three of the Phase 2 clinical studies completed the planned enrollment, while the fourth study was discontinued early for business reasons after enrolling approximately one-quarter of the planned subjects.

Results

The meloxicam IV Phase 2 program randomized and treated a total of 825 subjects who received at least one study dose.  In the three completed studies, a statistically significant difference was seen favoring meloxicam IV compared with placebo in the primary efficacy endpoint of the summed pain intensity difference over the first 24 or 48 hours (SPID₂₄ or SPID₄₈) (P<0.05).  Within the meloxicam IV treatment groups, increasing dose levels from 5 mg to 30 mg tended to result in increases in pain reduction.  When comparing the 30 mg and 60 mg meloxicam IV dose levels however, SPID results favored the 30 mg dose group in 2 out of 3 completed studies.  Due to the early discontinuation of enrollment in the fourth Phase 2 study, the planned efficacy analyses were not performed.  Co-primary and secondary endpoints provided further evidence of significant pain reductions over numerous other post-dose intervals, as well as improvement in pain relief, and reductions in the use of rescue analgesia compared with placebo.  Study dosing with meloxicam up to 60 mg was well tolerated in Phase 2 studies with six subjects experiencing an SAE (5 meloxicam IV, 1 ketorolac [active control]), two subjects discontinued due to an AE (1 meloxicam IV and 1 placebo), and no deaths.  Adverse events were generally similar between treatment groups, and no dose related increases in the incidence or severity of events was observed. Administration of meloxicam IV was well tolerated across dose levels with a low incidence of injection site events.

Conclusions

Phase 2 clinical studies of meloxicam IV demonstrated favorable tolerability across a range of doses from 5 to 60 mg daily.  A dose related increase in analgesic effect was generally observed in Phase 2 studies; however, significant differences between 30 and 60 mg dose levels were not observed consistently.  In review of the complete Phase 2 data, the 30 mg dose level of meloxicam IV administered once daily was selected for advancement to Phase 3 evaluation.

116 Racial Disparities in Pain Management in Community-Based Teaching Hospital

Sufana Shikdar, Asim Ruhela, Gurwinder Singh, Amanda Howland, Chad Metzger, Prasad Konda, Reshma Golamari, Surjeet Singh, William Ensor, Eric Green

Mercy Catholic Medical Center, Aldan, PA, USA

Purpose

The growing problem of pain medicine abuse poses a major challenge in prescribing appropriate pain medicine by the physicians. This often results in racial-ethnic disparities especially for conditions that are often associated with drug-seeking behavior. Previous research from the University of Virginia suggests that disparities in pain management may be attributable in part to racial bias. This study examines the racial disparities in pain medicine prescription in a community-based teaching hospital.

Methods

Using inpatient data from two community teaching hospital in Philadelphia for three months between July 2016 to September 2016, the amount of non-opioid and opioid prescription, opioid treatment for more than three days and average daily analgesic dose received during hospital stay received by non-elderly adults aged 18–65 for ‘non-definitive’ conditions (toothache, back pain and abdominal pain) or ‘definitive’ conditions (long-bone fracture and kidney stones) were modeled. In addition, a survey adapted from Hoffman (2016) assessed beliefs associated with racial disparities in pain management by the residents. Survey also included 2 case scenarios of acute painful conditions (eg Nephrolithiasis) asking the kind of pain medication considered appropriate. The factors associated with pain medicine prescription were analyzed using t-test and chi-square test.

Results

The study population was predominantly black (60%), mean patient age was 58 years for the Blacks and 50 years for the Whites. No difference was seen in the percentage of black or white patients who received opioids (42% vs 38%, p = 0.46); however more whites than blacks received opioids for more than 3 days (33% vs 20%, p = 0.023. Based on the survey which was done among the total of 33 residents, 48% believed that blacks have pain medication seeking behavior vs whites and 45% chose NSAIDS before opioids in the case scenarios with no racial bias (23% in blacks and 22% white patients).

Conclusions

In this study, racial disparity was observed in prescribing pain medication by the physicians. Such finding is consistent with other studies and suggesting that improved provider recognition and training in addressing the disparity in pain medicine prescription among racial-ethnic minority groups. These findings should be explored in larger studies.

117 Pilot to Integrate Virginia PDMP Data into Electronic Health Records

Thomas Alfieri, Lisa Miller

Purdue Pharma LP, Stamford, CT, USA

Purpose

Prescription drug monitoring programs (PDMPs) are databases populated by pharmacies and dispensing practitioners that store information about prescriptions of controlled substances.  Health care providers (HCPs) can access PDMPs to identify patients at risk of abusing opioids, drug overdose, or diverting medications. PDMPs include information about patients’ controlled substance prescription doses, morphine milligram equivalence (MME), healthcare prescriber, pharmacies that fulfilled the prescriptions, and potentially harmful co-prescriptions (such as benzodiazepines with opioid analgesics).    

Implementation and use of PDMPs vary from state to state.  The impact of PDMP use on public health outcomes also varies. Some studies have found state legislation mandating use of the PDMP by HCPs is associated with a decrease in the number of opioid prescriptions, MMEs, and the number of opioid and benzodiazepine tablets dispensed. Other studies observed minimal effects of PDMPs on rates of misuse of controlled substances and overdose mortality.

Access to PDMP databases is traditionally granted to authorized users via a web portal, which make them subject to time and technology constraints.  Even when access is successful, PDMPs often produce lengthy patient reports that are difficult to interpret.  These barriers may be preventing HCPs from using PMDPs more frequently. 

In 2017, Purdue Pharma and the Commonwealth of Virginia created a public-private partnership to connect PDMP data with Electronic Health Records (EHR) at pharmacy systems at select healthcare settings. The assumption was that placing PDMP information into these environments carried the potential to make information from the PDMP an integral part of the workflow of prescribing or dispensing controlled substances.

Herein we aim to understand the impact of integrating the PDMP into the EHR by measuring changes in PDMP utilization and prescription patterns.

Methods

The Virginia Department of Health Professions, the administrator of the Virginia PMP, selected Appriss Health to execute the HER-PDMP integration (the “integration”).  Access to the “integration” were granted to 9977 prescribers at one of 11 different healthcare settings between June 1, 2017 and December 31, 2017.  The PDMP web portal was unaffected by the Integration, and authorized users could still access PDMP information via that channel.

This observational study examined PDMP usage data created by Appriss Health regarding the number of requests made of the PDMP and number of unique users accessing it, IQVIA NPA data regarding the number of opioid prescriptions, and statistics published by The Virginia Department of Health Professions regarding opioid prescription-days, multiple provider episodes, and opioid-benzodiazepine overlap during Q1 2018 (Jan, Feb, and March 2018), and compared these statistics to similar metrics during Q1 2017 (Jan, Feb, and March 2017).

Results

PDMP use in Virginia: Q1 2018 versus Q1 2017.

Compared to Q1 2017, mean searches of the Virginia PDMP increased by 27% during Q1 2018, to 409,669.

An 83% increase in the average monthly number of unique individuals interacting with the Virginia PDMP was observed (7,686 in Q1 2017; 14,040 in Q1 2018). Thirty-four percent of the individuals accessed PDMP data via the EHR integration during Q1 2018. Of note, the integration appears to be driving the increased PDMP use. Among the observed increases in Virginia PDMP use (n = 6,353), 76% (n = 4821) was attributable to the individuals accessing the PDMP via the integration.

The average monthly number of prescribers receiving PDMP data increased by 123% (4,663 in Q1 2017; 10,384 in Q1 2018), and the average monthly number of pharmacists increased by 21% (3,024 in Q1 2017; 3,655 in Q1 2018).  The difference between these two increases is consistent with the larger percentage of integration licenses that went to prescribers compared to pharmacists.   

Prescribing behavior in Virginia: Q1 2018 versus Q1 2017

Mean monthly opioid prescriptions decreased by 17% from Q1 2017 (503,552) to Q1 2018 (416,112) in Virginia, which was greater than the 12% national average decrease observed. Over this same period, the number of opioid prescription-days in Virginia decreased by 27%. Multiple provider episodes (MPE; defined as a patient who receives opioids from at least 5 different prescribers and 5 different pharmacists within a 6-month period) in Virginia decreased by 60% from a rate of 22.23 per 100,000 people to 8.79.  The percentage of days that patients in Virginia had overlapping prescriptions for opioids and benzodiazepines decreased by 14%, from 19.3% days to 16.6% days.

Conclusions

Early results from the collaboration of Purdue Pharma, the Commonwealth of Virginia and Appriss Health demonstrated an increase in both the number of people with access to PDMP, and the number of queries made of the PDMP.  At the same time as these observed increases, the Virginia Department of Health Professions reported decreases in opioid prescription-days, MPE, and opioid-benzodiazepine overlaps.  This initiative is one of many in Virginia aimed at lowering the number of opioid prescriptions. Additional research will be needed to determine the direct impact of PDMP use on prescribing behavior and patient outcomes.

118 Initial Opioid Prescription Characteristics and Subsequent Factors Influencing Diagnosed Opioid Use Disorder in a State Medicaid Program

Timothy Pham¹, Grant Skrepnek¹, Christopher Bond², Thomas Alfieri², Terry Cothran³, Shellie Keast¹

¹University of Oklahoma College of Pharmacy, Oklahoma City, OK, USA, ²Purdue Pharma LP, Stamford, CT, USA, ³Pharmacy Management Consultants, Oklahoma City, OK, USA

Purpose

The association between initial prescription opioid exposure and diagnosed opioid use disorders (DOUD) has been studied.[1] However, information is still needed to better understand baseline and post-prescription factors that may modify the association and this was the scope of this study.

References

• Edlund MJ, Martin BC, Russo JE, et al. The role of opioid prescription in incident opioid abuse and dependence among individuals with chronic noncancer pain: the role of opioid prescription. Clin J Pain. 2014;30:557–564.
   PubMed Web of Science ®Google Scholar

Methods

State Medicaid pharmacy and medical claims data from 2011-2017 were used in a random-effects parametric survival model with exponential distribution to evaluate the effect of initial prescription dose on DOUD, adjusted for baseline characteristics and post-index events. Pharmacy claims consisted of individual claims for medications and contain information on member demographics and characteristics of the prescription, such as strength, quantity, days supplied, date of service, prescriber characteristics, and reimbursement amount. Drugs were identified with both national drug code (NDC) and generic product identifier (GPI) numbers.

The initial prescription was classified by total morphine milligram equivalents (MMEs) written (days*dose/day). Date of initial claim was index date. Cause of pain was classified as obstetrical (prescribed by an obstetrician and/or after caesarian section), dental (prescribed by dentist), surgical (prescribed by surgeon), related to trauma or burn, or other specific cause. Baseline characteristics included age, gender, race, residence type (metropolitan, micropolitan, or rural), and proximate cause of pain (by prescriber or claim code). Additional baseline measures were drawn from up to 1 year pre-index: Deyo-Charlson comorbidity score, concomitant liver disease (including hepatitis), previously-diagnosed mental health conditions, prior benzodiazepine use, previously-diagnosed sexually transmitted diseases, and prior non-opioid substance abuse or poisoning. Post-prescription variables included dose escalation >5 MMEs/day, change in opioid type, new prescriber of opioid, benzodiazepine and gabapentin use post-index, ER visits and hospitalizations, and the presence of any opioid-free period (30 days). All members were required to be 18 years of age or older, with no previous cancer diagnosis and no DOUD in the past year, and have at least 60 days of continuous eligibility with no opioid use prior to their index prescription.

Results

There were 147,777 adult members with at least one prescription who met all inclusion criteria. Of these, 7,771 (5.3%) had a DOUD recorded subsequently. The population had a mean (SD) age of 31.0 (11.2), was 79.8% female, 64.7% white, 13.1% black, 10.2% American Indian or Alaskan Native, and 12.0% mixed or other (self-identified).

DOUD cases had a higher mean (SD) age than non-cases (34.9 [11.3] versus 30.8 [11.1], p < 0.001) and were relatively more likely to be white (71.8% versus 64.3%, p < 0.001), male (26.1% versus 19.9%, p < 0.001) and live in metropolitan areas (66.9% versus 58.5%. p < 0.001). DOUD cases were also more likely to have experienced non-opioid substance abuse or poisoning (28.7% versus 16.5%, p < 0.001) and have a prior anxiety diagnosis (14.1% versus 7.5%, p < 0.001) and other mental health conditions (all under 10%). Prior benzodiazepine use was found for 14.5% of cases and 4.9% of non-cases (p < 0.001). Among patients with medical claims before index prescription, DOUD cases were less likely than non-cases to have had their opioid prescribed by an obstetrician or post caesarian delivery (12.8% versus 30.4%, p < 0.001).

Cases were more likely than non-cases to have an index prescription of ≥350 MME (28.1% versus 11.3%). Adjusted hazard ratios (HRs) with accompanying 95% confidence intervals (versus < 150 MME) showed a dose-response, with progressive increases to nearly 3 fold in those using > 2800 MME: 1.06 (0.93-1.20) for 150-349, 1.67 (1.41-1.99) for 350-699, 2.24 (1.80-2.78) for 700-1399, 2.23 (1.62-3.06) for 1400-2799, and 3.03 (2.01-4.57) for ≥2800.  Post-index variables associated with DOUD were dose escalation >5 MME (1.98; 1.67-2.35), subsequent ER visit (1.89; 1.53-2.35), subsequent hospitalization (7.87; 6.65-9.31), change in prescriber (2.13; 1.76-2.59), and subsequent gabapentin use (1.81; 1.19-2.76).

Benzodiazepine use prior to index opioid was associated with subsequent DOUD, but compared to patients who had no benzodiazepine use both before and after index, the HR for those with use only before was lower (1.85; 1.52-2.25) than those with only use after (2.67; 2.26-3.15). The ratio of HRs for interaction for pre- and post-index use was 0.41 (0.31-0.56), indicating that the effect of subsequent use without previous use was larger than previous and subsequent use.

Conclusions

In addition to total MMEs of initial opioid prescription, the adjusted risk for DOUD among opioid-naïve patients is influenced by dose escalation, change in prescriber, ER visits and hospitalization, and subsequent use of gabapentin and benzodiazepines. The results of this study may provide guidance for prescribers seeking to balance benefits and risks for patients newly prescribed opioids or developing early interventions to prevent adverse events.

119 Effects of Naldemedine, a Peripherally-Acting μ-Opioid Receptor Antagonist, in Rat Models of Opioid-Induced Constipation

Toshiyuki Kanemasa¹, Katsumi Koike², Tohko Arai², Narumi Horita², Tsuyoshi Kihara², Eric Krauter³, Minoru Hasegawa¹

¹Shionogi & Co., Ltd., Osaka, Toyonaka, USA, ²Shionogi & Co., Ltd., Osaka, Toyonaka, Japan, ³Shionogi Inc., Florham Park, NJ, USA

Purpose

Opioid analgesics are widely prescribed to manage chronic pain. A common side effect is opioid-induced constipation (OIC) caused by the action of opioids on μ-opioid receptors in the enteric nervous system. Naldemedine (S-297995) is a peripherally-acting, μ-opioid receptor antagonist (PAMORA) being developed to treat OIC. The pharmacological effects of naldemedine in rat models of OIC were evaluated.

Methods

Four experimental models were used. 1) Small intestinal transit: naldemedine-treated rats received morphine subcutaneously (s.c.) or orally (p.o.), or oxycodone s.c. Rats then ingested a dye and its transit (distance traveled relative to small intestine length) was measured. 2) Castor oil-induced diarrhea: naldemedine-treated rats received castor oil p.o. and then morphine s.c. Diarrhea was evaluated using a three-point scale. 3) Anti-analgesic effect: naldemedine-treated rats received morphine s.c. and then thermal stimulation was applied to the tail. Escape latency from the stimulus was recorded. 4) Withdrawal in morphine-dependent rats: rats were infused with morphine s.c. for 5 days and then given naldemedine. Withdrawal symptoms were recorded over 8 hrs.

Results

Naldemedine inhibited morphine- and oxycodone-induced suppression (both s.c.) of dye transit with similar efficacy (ED₅₀, 0.03 mg/kg and 0.02 mg/kg, respectively). Naldemedine also inhibited oral morphine-induced transit suppression (ED₅₀, 0.23 mg/kg). In the castor oil-induced diarrhea model, morphine s.c. inhibited diarrhea, and pre-treatment with naldemedine reversed the effect (ED₅₀, 0.01 mg/kg). In the anti-analgesic model, morphine significantly prolonged escape latency. Pre-treatment with naldemedine (up to 30 mg/kg) did not influence the analgesic effect of morphine. In the withdrawal symptom model, the no-observed-effect-levels (NOEL) of naldemedine for central withdrawal signs were: jumping, > 7 mg/kg; wet dog shakes, 3 mg/kg; and teeth chattering, 1 mg/kg.

Conclusions

Naldemedine potently inhibited the constipating effect of opioids. The analgesic effect of opioids was maintained at very high doses of naldemedine. Central opioid withdrawal symptoms were only observed at doses more than 10 times higher than that required for the anti-constipation effect. These data suggest that naldemedine can be an effective treatment for OIC with little impact on opioid analgesia and with a low risk of central opioid withdrawal.

120 Targeting Peripheral Kappa Opioid Receptors for the Treatment of Chronic Pain

Tyler Beck, Carmela Reichel, Thomas Dix

Medical University of South Carolina, Charleston, South Carolina, USA

Purpose

Pain is the most common symptom that leads people to seek medical intervention in the United States. Currently, there are two major types of chronic pain medications in use – opioids and non-opioids – both of which have limitations. Opioids are the main class of analgesics used in the treatment of moderate to severe chronic pain. These compounds have various side effects, including nausea, vomiting, constipation, depressed breathing, and neurotoxicity. Most significantly, patients can become addicted and tolerant to these agents, thus requiring dose escalations to maintain therapeutic value. Non-opioid analgesics include paracetamol and the non-steroidal anti-inflammatory drugs (NSAIDs), all of which target prostaglandin formation, usually through the inhibition of cyclooxygenase enzymes COX-1 and COX-2.  Nonselective COX inhibitors result in adverse side-effects associated with COX-1 inhibition, including renal dysfunction, GI ulceration, and inhibition of platelet aggregation. Selective COX-2 inhibitors have been associated with increased thromboembolytic risk, which has limited their use.

Mediation of opioid analgesia occurs through three receptors: mu-, kappa-, and delta-. Activation of these receptors was originally thought to occur only centrally; however, receptors have been found in peripheral sensory neurons that are modulated by endogenous opioids or opioid drugs. Opioids differentially target the three opioid receptors, both in the CNS and peripherally, which can lead to untoward side-effects. Agonists at the mu-receptor are the most currently used opioids, but suffer from induction of euphoria, addiction, respiratory depression, and GI tract inhibition. Kappa-opioid agonists are efficacious in peripheral pain models but suffer from centrally-mediated effects. Derivatives of the tetrapeptide D-Phe-D-Phe-D-Nle-D-Arg-NH₂, such as CR665, exhibit high peripheral to central selectivity in analgesic models when administered IV; however, they are inactive when administered orally. Application of the JT Pharmaceuticals non-natural amino acid technology to CR665 produced derivatives that exhibit peripheral analgesic activity when dosed orally but do not promote CNS-based effects. This abstract presents data supporting the analgesic properties of an orally available, peripherally-restricted, kappa-opioid agonist for peripheral pain. A potential out-patient pharmaceutical that demonstrates efficacy in alleviating peripheral pain, while failing to produce undesired CNS-mediated effects, could help reduce the current healthcare burden associated with prescription opioids.

Methods

The Position 4 D-Arg residue of CR665 was converted to derivatives containing modified D-Arg or D-Lys residues. The strategy was to slightly modify the structure of the proven active compound CR665 to see if improvements in oral activity and selectivity against peripheral pain can be elicited. All tested compounds featured modifications to the Position 4 D-Arg residue, and were chosen to provide a range of structures to initially probe potential structure-activity relationships (SARs) at this position.

All animal work was reviewed and approved by the Institutional Animal Care and Use Committee (IACUC) at the Medical University of South Carolina. All protocols were performed on male Sprague-Dawley rats (Harlan, Prattville AL, 240-280g), which were housed in an AAALAC-approved colony room maintained at a constant temperature and humidity. Experiments were performed to assess pain modulation using the acetic acid-induced writhing model and the hot plate model. The acetic acid-induced writhing assay is a measure of peripheral pain modulation, whereas the hot plate model is a measure of central pain modulation. The efficacy of JT09 in alleviating pain was subsequently assessed and compared to both saline and morphine as controls. Behavioral assays were performed in order to determine the abuse liability and side-effect profile associated with lead compound JT09. Rats were first studied in a self-administration model, which was utilized in order to assess the abuse liability associated with JT09.  Additionally, rats were studied in a conditioned place preference model, which also assessed the abuse liability associated with JT09. Next, we studied JT09 in a forced swim assay, which assesses dysphoria, a common side-effect associated with centrally-acting kappa-opioid agonists. Additionally, we studied JT09 in a locomotor open field test in order to assess the sedative effects of JT09 when compared to other well-known sedatives, such as morphine. Lastly, the side-effect profile of JT09 was assessed using a multiple dose study and maximum tolerated dose study. Animals received various doses of JT09 for 14 days and were subsequently sacrificed and studied via histological analysis.

Results

Lead compound JT09 activates the kappa-opioid receptor with EC₅₀s in the low nM range, while agonist selectivity for kappa over other peripheral opioid receptors was >11,000-200,000-fold. To assess pain modulation, a rat writhing model of peripheral pain and a hotplate model of CNS-mediated pain were performed. Results indicate that JT09 acts as efficacious as morphine in alleviating peripheral pain, while failing to produce undesired CNS-mediated activity. In an operant self-administration procedure, where rats are required to press a lever to receive an intravenous drug infusion, JT09 failed to maintain lever responding, indicating no abuse liability. In contrast, highly salient rewards readily maintained operant responding.  Additionally, JT09 did not promote other CNS-mediated effects associated with morphine (sedation, dysphoria, tolerance, addiction).

Conclusions

In conclusion, this study provides data to demonstrate that JT09 is orally active and peripherally restricted, with the potential for clinical and out-patient use as an analgesic. The EC₅₀ of JT09 is at a druggable level for an oral analgesic, and appears as efficacious as morphine in alleviating peripheral pain. In addition, JT09 does not promote the negative CNS-mediated effects associated with morphine, including sedation, dysphoria, tolerance, and addiction. Thus, we suggest that JT09 is a candidate for development as a novel analgesic for chronic peripheral pain that would not have the negative side-effects of currently used analgesics.

121 A Prospective Clinical Trial to Assess High Frequency Spinal Cord Stimulation (HF-SCS) at 10 kHz in the Treatment of Chronic Intractable Pain from Peripheral Polyneuropathy

Vincent Galan¹, Paul Chang¹, James Scowcroft², Sean Li³, Peter Staats³, Jeyakumar Subbaroyan⁴

¹Georgia Pain Care, Stockbridge, GA, USA, ²KC Pain Centers, Lee's Summit, MO, USA, ³Premier Pain Centers, Shrewsbury, NJ, USA, ⁴Nevro Corp., Redwood City, Ca, USA

Purpose

Current treatment options for neuropathic pain conditions are primarily pharmacological and have demonstrated limited effectiveness with sometimes intolerable side effects.¹ The goal of this study is to document the safety and effectiveness of paresthesia-independent, high frequency SCS (HF-SCS) at 10 kHz in the treatment of chronic intractable pain from peripheral polyneuropathy (PPN).

Methods

Subjects with chronic, intractable pain of ≥ 5 cm (on a 0-10 cm visual analog scale) of the upper or the lower limb from PPN were enrolled in a prospective, multi-center study following Institutional Review Board approval. Each subject was implanted with two epidural leads spanning C2-C6 or T8-T11 vertebral bodies for upper limb pain or lower limb pain, respectively. Subjects with successful trial stimulation were implanted with a Senza system. Interim results are presented as mean ± standard deviation in the permanent implant population.

Results

A total of 28 subjects were enrolled in the study and 2 were screen failures. Majority of the subjects presented with lower limb pain (n = 27). Common diagnoses include idiopathic polyneuropathy (n = 15) and painful diabetic neuropathy (PDN, n = 9).

Twenty-two of the 26 subjects (84.6%) trialed had a successful trial and 18 received a permanent implant (declined to proceed to the permanent implant-3, withdrawn by investigator-1). Five procedure-related adverse events (AEs) or serious adverse events (SAEs) were reported.

The average baseline VAS score was 8.2 ± 1.0 cm. At 3 months, the average VAS score was reduced to 1.8 ± 2.1 cm with a 78% responder rate (subjects with ≥ 50% pain relief) and at 6 months the average VAS score was 2.7 ± 2.3 cm with a 76% responder rate. Sub-analysis of 8 PDN subjects demonstrated similar improvements with an average baseline VAS score of 8.1 ± 1.0 cm decreasing to 1.9 ± 1.4 cm at 3 months (88% responder rate) and 2.0 ± 1.3 cm at 6 months (88% responder rate).

Subjects also demonstrated decreased disability as measured by the Pain Disability Index (PDI). At baseline, the average score was 38.7 ± 17.1 and improved to 19.1 ± 16.3 at 6 months. Neurological assessment demonstrated either sensory, motor or reflex improvements in 12 and 14 subjects at end of trial and 3 months, respectively.

Conclusions

HF-SCS at 10 kHz resulted in clinically meaningful improvements in pain scores, disability and interference measures that were sustained over long-term follow-up with concomitant improvements in subjects’ neurological status.

Reference

• Finnerup NB, Attal N, Haroutounian S, et al., Pharmacotherapy for neuropathic pain in adults: a systematic review and meta-analysis. Lancet Neurol. 2015;14(2):162–173.
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122 Effectiveness of Fixed-Site High-Frequency Transcutaneous Electrical Nerve Stimulation among Individuals with Chronic Pain and Abnormal Sleep

Xuan Kong, Thomas Ferree, Martin Moynihan, Shai Gozani

NeuroMetrix, Inc., Waltham, MA, USA

Purpose

Most people with chronic pain complain of disturbed sleep and daytime lethargy. Polysomnography studies show that chronic pain patients have shorter sleep duration, less REM sleep, lower sleep efficiency and greater numbers of periodic leg movements compared to healthy controls. Inadequate sleep is associated with poor health including cardiovascular disease, diabetes and obesity. Moreover, compromised sleep increases pain sensitivity and may reduce the efficacy of pain treatment, including opioids. One mechanistic explanation may be that sleep abnormalities impair opioidergic pathways mediating descending pain inhibition.

Prescription pain medications are frequently used to treat chronic pain despite concerns about adverse effects and addiction. Transcutaneous electrical nerve stimulation (TENS) is a non-invasive treatment for chronic pain without significant side effects. Conventional TENS is delivered through surface electrodes to generate a strong, nonpainful sensation. The resulting stimulation of large diameter, deep tissue afferents produces widespread pain relief by decreasing central excitability and activating the descending pain inhibition system. Fixed-site high-frequency TENS (FS-TENS) is an emerging form of TENS in which the stimulator is designed for a predetermined location rather than for co-localization with the patient’s pain. A single target site enables design of small wearable devices that may be used nearly continuously, including while sleeping. FS-TENS has been shown to improve pain outcomes in multi-site chronic pain and chronic low back pain.

The objective of this study was to evaluate whether sleep abnormalities moderate the effectiveness of FS-TENS, possibly through an interaction within the descending pain inhibition system. To address this question, we compared pain outcomes in a large, real-world population of FS-TENS users stratified by objective sleep measurements.

Methods

This retrospective, observational study evaluated users of a FS-TENS device to treat chronic pain (Quell®, NeuroMetrix,Waltham, MA) over a 10-week period. In addition to providing neurostimulation, the device and a companion smartphone app collect utilization data, demographics, self-reported pain characteristics, pain ratings, and objective sleep data using actigraphy techniques (from an embedded accelerometer) that are stored in a cloud database. The pain ratings included pain intensity and pain interference with activity, sleep and mood on an 11-point numerical rating scale. The primary study outcome was the baseline to 10-week change in composite pain, which was defined as the average of pain intensity and the three pain interference values. Device users were included in the study if they provided demographic data and pain characteristics indicative of chronic pain (i.e., daily/weekly pain with duration >3 months), baseline pain ratings, and wore their device at least 3 nights during weeks 1−2. The subset of users that also provided a 10-week follow-up pain rating were used for evaluation of pain outcomes.

The sleep measurements included time in bed (TIB, measured in minutes), total sleep time (TST, time within TIB spent sleeping measured in minutes), sleep latency (SL, time from going to bed to falling asleep in minutes), sleep efficiency (SE, defined as TST/TIB), and the periodic leg movement index (PLMI, defined as number of periodic leg movements per hour of sleep). The sleep assessment was based on the median of nights during weeks 1–2 of the study period. Participants were allocated to an impaired sleep (IS) group if TST < 360 or to an acceptable sleep (AS) group if TST ≥ 360. Differences between groups or between baseline and follow-up composite pain were evaluated by the Wilcoxon rank-sum test. Differences among proportions were evaluated by the Pearson chi-square test.

Results

The inclusion criteria were met by 2034 device users; 471 (23%) in the IS group and 1563 (77%) in the AS group. The IS group was older (55 ± 12 vs 53 ± 14 years, p = 0.003), less likely to be female (53% vs 60%, p = 0.004), had higher BMI (32 ± 8 vs 30 ± 7 kg/m2, p = 0.001) and had longer pain duration (42% vs 36% >10 years, p = 0.027). In addition, the IS group was more likely to have foot pain and diabetes. The IS group had higher pain interference with sleep (5.9 ± 2.9 vs 5.4 ± 2.9, p = 0.001) and activity (7.1 ± 2.4 vs 6.7 ± 2.4, p = 0.006) at baseline. The IS group was also less active than the AS group during the first two weeks (316 ± 217 steps/hour vs 371 ± 205 steps/hour, p < 0.001).

Sleep data were estimated from 7 ± 3 (IS) and 8 ± 4 (AS) nights. There were significant differences for all metrics. TST was 313 ± 31 (IS) compared to 444 ± 56 (AS), p < 0.001. TIB was 371 ± 46 (IS) compared to 497 ± 62 (AS), p < 0.001. SL was 33 ± 31 (IS) compared to 26 ± 26 (AS), p < 0.001. SE was 85.0 ± 7.3 (IS) compared to 89.4 ± 5.0 (AS), p < 0.001. PLMI was 10.6 ± 12.8 (IS) compared to 6.7 ± 8.0 (AS), p < 0.001.

Utilization (%days using device) was 73 ± 25 (IS) compared to 75 ± 25 (AS), p = 0.287. Weekly therapy was 41 ± 24 hrs/week (IS) compared to 43 ± 24 hrs/week (AS), p = 0.230. The median stimulation intensity (ratio of stimulation to sensation level expressed in decibels; 6 dB = 2 times) was lower in the IS group (4.9 dB) compared to the AS group (5.6 dB), p = 0.007.

A subset of 755 device users met the inclusion criteria that included a 10-week follow-up pain rating; 178 (24%) in the IS group and 577 (76%) in the AS group. Composite pain decreased by 0.8 ± 2.4 (IS) and 0.8 ± 2.3 (AS), p = 0.432. The combined effect size was 0.35 (95%CI 0.25−0.46). In a subset of participants with daily FS-TENS use (utilization ≥90%, 48% of IS group and 52% of AS group), composite pain decreased by 1.2 ± 2.5 (IS) and 1.2 ± 2.5 (AS), p = 0.421. The combined effect size was 0.52 (95%CI 0.38−0.67).

Although there was no overall difference in pain outcomes between groups, trends were found between IS and AS participants for self-reported fibromyalgia (−0.3 ± 2.2 vs −0.8 ± 2.2, p = 0.094), previous arm/hand injury (−0.4 ± 2.1 vs −1.0 ± 2.2, p = 0.056) and previous foot/leg injury (−0.1 ± 2.5 vs −0.9 ± 2.1, p = 0.001). There were no differences for other high prevalence health conditions including arthritis, herniated disc, spinal stenosis, previous back injury, previous neck injury and headaches/migraine.

Conclusions

In this study, one-quarter of real-world FS-TENS users had impaired sleep based on objective measurements. The abnormalities included low sleep time, low sleep efficiency and elevated periodic leg movements. The primary finding was that FS-TENS effectiveness was generally independent of sleep characteristics. Participants with impaired and acceptable baseline sleep had similar outcomes after 10-weeks of FS-TENS therapy as assessed by composite pain. The effect size among all participants was 0.35 and increased to 0.52 for daily FS-TENS users.

A subset of participants with self-reported fibromyalgia, previous hand/arm injury or previous foot/leg injury and abnormal sleep exhibited trends towards less effective outcomes when compared to participants with acceptable sleep. Patients with fibromyalgia and extremity injuries are susceptible to central sensitization and deficient descending pain inhibition. It is possible that the impact of impaired sleep and pathological alternations in central pain processing combine to render therapeutic interventions that activate descending pain inhibition less effective.

The importance of sleep to chronic pain management and overall health highlights the need for sleep monitoring and treatment personalization. Integration of therapeutic and digital health tools, such as the FS-TENS device used in this study, may be beneficial in achieving this goal.

123 The effect of botulinum toxin type A in rats with neuropathic pain after spinal cord injury

You Chul Chung¹, Myungeun Chung²

¹Jeju Regional Rehabilitation Hospital, Seogwiposi, Korea, Republic of, ²The Catholic University of Korea, Seoul, Korea, Republic of

Purpose

The application of botulinum toxin type A (BTX-A) has been recently explored in a number of painful neuropathic conditions. We aim to determine the changes in pain behavior after spinal cord injury, and the effects of botulinum toxin type A (BTX-A) on the pain threshold and sensory evoked potential.

Methods

Thoracic spinal cord injury of 12 male Sprague-Dawley rats(300-350g) was induced by contusion method. One week after injury, BTX-A (20U/kg) or saline was administered to the plantar surface by subcutaneous injection. Behavioral tests were conducted preoperatively and weekly for 5 weeks postoperatively. Mechanical allodynia was measured using von Frey filament, and thermal hyperalgesia was measured on a hot plate analgesia meter. Sensory evoked potential was detected in the cortex by stimulating the posterior tibial nerve. Two-way analysis of variance (ANOVA) with repeated measures was used to detect statistical significance.

Results

The paw withdrawal threshold (PWT) to mechanical stimulation decreased immediately and significantly after spinal cord injury. The paw withdrawal latency (PWL) to thermal stimulation gradually decreased to the lowest level at 3 weeks after injury. Amplitude of sensory evoked potential gradually decreased after spinal cord injury. Subcutaneous injection of BTX-A reversed the reduction of PWT to mechanical stimulation induced by the spinal cord injury. Compared with the pre-injection value, the PWT was increased after the BTX-A injection. Similarly, the PWL to thermal stimulation was measured to be higher in the BTX-A injection group. Subcutaneous injection of BTX-A reversed the amplitude of sensory evoked potential. But, there was no statistically significant differences in all parameters.

Conclusions

Subcutaneous injection of BTX-A tended to be effective in neuropathic pain. It is necessary to evaluate the effect of BTX-A on neuropathic pain through a large sample study in the future.