Michael D. Smith

A randomized, double-blind, double-dummy study to evaluate the intranasal human abuse potential and pharmacokinetics of a novel extended-release abuse-deterrent formulation of oxycodone

Objective. Evaluate the human abuse potential (HAP) of an experimental, microsphere-in-capsule formulation of extended-release oxycodone (oxycodone DETERx®) (herein “DETERx”). Design. Randomized, double-blind, double-dummy, positive- and placebo-controlled, single-dose, four-phase, four-treatment, crossover study. Setting. Clinical research site. Subjects. There were 39 qualifying subjects (72% male, 85% white, mean age of 27 years) with 36 completing all four Double-blind Treatment Periods. Methods. The four phases encompassed: 1) Screening; 2) Drug Discrimination; 3) Double-blind Treatment; and 4) Follow-up. Drug Discrimination tests ensured that subjects could distinguish placebo from opioid. The four Double-blind Treatments compared DETERx—administered as either a crushed intranasal (IN) or an intact oral (PO) preparation—with immediate-release oxycodone IN (OXY-IR IN) and with an intact IN and PO placebo DETERx control. Results. For primary pharmacokinetic (PK) assessments, abuse quotient (Cmax/Tmax) was lower with DETERx IN than DETERx PO; both treatments were substantially lower than OXY-IR IN (6.24, 8.60, and 69.6 ng/mL/h, respectively). For drug liking, the primary subjective pharmacodynamic (PD) endpoint, both DETERx IN and DETERx PO produced significantly lower scores than OXY-IR IN (P ≤ 0.0001 for each); DETERx IN was less liked than DETERx PO (P ≤ 0.05), mirroring the PK relationships. Objectively assessed pupillometry corroborated the more rapid and significantly greater effect of OXY-IR IN than either DETERx IN or DETERx PO (P ≤ 0.007 for each). Overall safety profiles of DETERx and OXY-IR were comparable and both were well tolerated. Conclusions. Pharmacokinetic and pharmacodynamic outcomes suggest that DETERx IN has relatively low HAP; continued research in larger populations is suggested.

A Randomized, Double-Blind, Double-Dummy, Placebo-Controlled, Intranasal Drug Liking Study on a Novel Abuse-Deterrent Formulation of Morphine-Morphine ARER.

Objective Misuse and abuse of prescription opioids remains a major healthcare concern despite considerable efforts to increase public awareness. Abuse-deterrent formulations of prescription opioids are designed to reduce intentional misuse, abuse, and prescription opioid-related death. A novel extended-release (ER) formulation of morphine (Morphine ARER; MorphaBond™) resists physical manipulation and retains the drugs ER characteristics, even if attempts are made to manipulate the formulation. Design This randomized, double-blind, double-dummy, placebo-controlled, four-way crossover study investigated the abuse potential and safety of crushed intranasal and intact oral Morphine ARER compared with commercially available crushed intranasal ER morphine sulfate (ER morphine). Outcome Measures Endpoints included maximum mean drug liking (E max ) as measured by subjects on a bipolar 100 mm visual analog scale (primary), a subjects desire to take the drug again, good effects of the drug, and drug high. Results Twenty-five subjects completed the treatment phase. There was a 40% reduction in E max for crushed intranasal Morphine ARER compared with crushed intranasal ER morphine ( P  < .0001). There was no significant difference when comparing the E max for crushed intranasal vs intact Morphine ARER. When comparing crushed intranasal Morphine ARER with ER morphine, subjects reported lower mean scores for good effects of the drug, drug high, and overall drug liking, as well as a lower desire to use Morphine ARER again. Other than adverse events associated with intranasal administration of a drug, all adverse events were typical of those reported for opioid-containing drugs. Conclusions Overall, these data suggest that Morphine ARER has a lower abuse potential via the intranasal route of administration when compared with ER morphine.

Human Abuse Potential of an Abuse-Deterrent (AD), Extended-Release (ER) Morphine Product Candidate (Morphine-ADER Injection-Molded Tablets) versus Extended-Release Morphine Administered Orally in Nondependent Recreational Opioid Users

Objective. To compare the relative human abuse potential of intact and manipulated morphine abuse-deterrent, extended-release injection-molded tablets (morphine-ADER-IMT) with that of marketed morphine sulfate ER tablets Methods. This randomized, double-blind, triple-dummy, active- and placebo-controlled, 4-way crossover, single-center study included adult volunteers who were experienced, nondependent, recreational opioid users. Participants were randomized 1:1:1:1 to placebo, morphine-ADER-IMT (60 mg, intact), morphine-ADER-IMT (60 mg, manipulated), and morphine ER (60 mg, manipulated) and received 1 dose of each oral agent in crossover fashion, separated by ≥5 days. Pharmacodynamic and pharmacokinetic endpoints were assessed, including the primary endpoint of peak effect of Drug Liking (Emax) via Drug Liking Visual Analog Scale (VAS) score and the secondary endpoints of time to Emax (TEmax) and mean abuse quotient (AQ; a pharmacokinetic parameter associated with drug liking). Results. Thirty-eight participants completed the study. Median Drug Liking VAS Emax was significantly lower after treatment with manipulated morphine-ADER-IMT (67) compared with manipulated morphine ER (74; P = 0.007). TEmax was significantly shorter after treatment with manipulated morphine ER compared with intact (P < 0.0001) or manipulated (P = 0.004) morphine-ADER-IMT. Mean AQ was lower after treatment with intact (5.7) or manipulated (16.4) morphine-ADER-IMT compared with manipulated morphine ER (45.9). Conclusions. Manipulated morphine-ADER-IMT demonstrated significantly lower Drug Liking Emax compared with manipulated morphine ER when administered orally. Morphine-ADER-IMT would be an important new AD, ER morphine product with lower potential for unintentional misuse by chewing or intentional manipulation for oral abuse than currently available non-AD morphine ER products.

Comparative effects of morning vs. evening dosing of extended-release hydromorphone on sleep physiology in patients with low back pain: a pilot study.

OBJECTIVE To investigate effects of extended-release (ER) hydromorphone dosing time (morning, QAM; evening, QPM) on sleep physiology in patients with chronic low back pain. DESIGN Randomized, double-blind, placebo-controlled, crossover trial. SETTING Clinical research site. PATIENTS Fifteen patients with moderate-to-severe chronic low back pain requiring long-term opioid analgesia. INTERVENTIONS Following an open-label immediate-release (IR) hydromorphone titration phase, patients received once-daily ER hydromorphone QAM or QPM for at least 14 days and then crossed over to the alternate regimen. Overnight polysomnographic sleep studies were performed at baseline, following IR hydromorphone titration, and following each ER hydromorphone dosing period. OUTCOME MEASURES The primary outcome measure was prevalence of nocturnal apnea-hypopnea index (AHI). Other evaluations included central apnea index and obstructive apnea index; Short-Form McGill Pain Questionnaire; a modified Medical Outcomes Study sleep scale, patient responses in a daily diary, and adverse event safety profiles. RESULTS Mean AHI scores were lower following QAM rather than QPM dosing, but not significantly (12.9 vs. 17.1, P > 0.05). Secondarily, QAM dosing resulted in numerically fewer apnea episodes and improvements in pulse oximetry measures; however, these differences were not significant (P > 0.05). Sleep quality/quantity and pain measures were improved with opioid therapy overall, particularly QPM dosing, without significantly compromising safety. CONCLUSIONS ER hydromorphone QAM dosing may be preferred if sleep-disordered breathing associated with ongoing opioid therapy is of concern; however, QPM dosing may be advantageous in terms of pain relief and quality/quantity of sleep. Further research is recommended to provide more definitive clinical guidance.

A Randomized, Double-Blind, Double-Dummy, Placebo-Controlled, Intranasal Human Abuse Potential Study of Oxycodone ARIR, a Novel, Immediate-Release, Abuse-Deterrent Formulation.

Objective. Prescription opioid abuse continues to be a public health concern. Oxycodone ARIR is an immediate‐release (IR) oxycodone tablet composed of multiple overlapping barriers that deter manipulation of the tablet for non‐oral abuse. Design. This randomized, double‐blind, double‐dummy, active‐ and placebo‐controlled, four‐way crossover, intranasal human abuse potential study assessed the pharmacodynamics and pharmacokinetics of crushed intranasal oxycodone ARIR compared with crushed intranasal IR oxycodone and intact oral oxycodone ARIR. Outcome Measures. Pharmacodynamic end points included mean maximum drug liking (Emax), as measured by subjects on a bipolar 100‐mm visual analog scale (primary), and desire to take the drug again, overall drug liking, drug high, and good effects (secondary). Pharmacokinetic assessments included peak concentration and time to peak concentration. Results. Twenty‐nine subjects completed the treatment phase. Crushed intranasal oxycodone ARIR demonstrated a significant reduction of 46.9% and 23.4% in drug liking Emax compared with crushed intranasal IR oxycodone and intact oral oxycodone ARIR, respectively (P < 0.0001 for both). Significant reductions also were observed in desire to take the drug again, drug high, overall drug liking, and good effects when comparing crushed intranasal oxycodone ARIR with crushed intranasal IR oxycodone and intact oral oxycodone ARIR (P < 0.001 for all). Crushed intranasal oxycodone ARIR exhibited lower peak oxycodone plasma concentrations and slower time to peak concentration compared with crushed intranasal IR oxycodone and intact oral oxycodone ARIR. All treatments were well tolerated; adverse effects were typical of opioids or intranasal administration. Conclusions. These data indicate that oxycodone ARIR has the potential to reduce abuse via the intranasal route.

The MOBILE Study—A Phase IIa Enriched Enrollment Randomized Withdrawal Trial to Assess the Analgesic Efficacy and Safety of ASP8477, a Fatty Acid Amide Hydrolase Inhibitor, in Patients with Peripheral Neuropathic Pain

Abstract Objective To evaluate the analgesic efficacy and safety of ASP8477 in patients with peripheral neuropathic pain (PNP). Design Enriched enrollment randomized withdrawal. Setting Centers in Poland (four), Czech Republic (six), and the United Kingdom (two). Subjects Patients aged 18 years or older with PNP resulting from painful diabetic peripheral neuropathy or postherpetic neuralgia. Methods A four-week screening period followed by a single-blind period (six-day dose titration and three-week maintenance period with ASP8477 [20/30 mg BID]). Treatment responders (defined as a ≥30% decrease in the mean average daily pain intensity during the last three days of the single-blind period) were stratified by disease and randomized to receive placebo or continue ASP8477 during a three-week, double-blind, randomized withdrawal period. The primary end point was change in mean 24-hour average numeric pain rating scale (NPRS) from baseline to end of double-blind period. Results Among 132 patients who enrolled, 116 entered the single-blind period and 63 (ASP8477, N = 31; placebo, N = 32) completed the double-blind period. There was no difference in mean 24-hour average NPRS score (P = 0.644) or in time-to-treatment failure (P = 0.485) between ASP8477 and placebo. During the single-blind period, 57.8% of patients were treatment responders. ASP8477 was well tolerated. During the single-blind period, 22% of patients experienced at least one treatment-related adverse event (TEAE); during the double-blind period, 8% in the ASP8477 arm and 18% in the placebo arm experienced at least one TEAE. Conclusions ASP8477 was well tolerated in patients with PNP; however, ASP8477 did not demonstrate a significant treatment difference compared with placebo.

Low-dose naloxone provides an abuse-deterrent effect to buprenorphine

In developmental research, plasma buprenorphine concentrations comparable to a 2 mg buprenorphine–naloxone (BN) sublingual tablet have been achieved with a 0.75 mg dose of BN buccal film, a small, bioerodible polymer film for application to mucosal membranes. This was a randomized, double-blind, placebo-controlled, single-dose, four-period crossover study in opioid-dependent subjects with chronic pain receiving >100 mg oral morphine equivalents daily who experienced withdrawal following a naloxone challenge dose. The objective of the study was to determine if intravenous (IV) naloxone doses of 0.1 and 0.2 mg would produce a withdrawal response when coadministered with a 0.75 mg IV dose of buprenorphine. Fifteen subjects receiving 90–1,260 mg oral morphine equivalents per day enrolled and completed the study. Precipitated withdrawal occurred in 13% (2/15) of placebo-treated subjects and 47% (7/15) of buprenorphine-treated subjects. When combined with the 0.75 mg dose of buprenorphine, a 0.1 mg dose of naloxone increased the incidence of precipitated withdrawal to 60%, and a 0.2 mg dose of naloxone increased the incidence to 73%. By 15 minutes postdose, the mean change in Clinical Opioid Withdrawal Scale (COWS) score from predose was 3.0 for placebo, 6.9 for buprenorphine, 9.8 for BN 0.1 mg, and 12.4 for BN 0.2 mg. The mean COWS score with each active treatment was significantly greater than placebo (P<0.001), and the mean COWS score for each of the naloxone-containing treatments was significantly greater than for buprenorphine alone (P<0.001). Naloxone doses as low as 0.1 mg added an abuse-deterrent effect to a 0.75 mg IV dose of buprenorphine.

Intranasal Pharmacokinetics of Morphine ARER, a Novel Abuse-Deterrent Formulation: Results from a Randomized, Double-Blind, Four-Way Crossover Study in Nondependent, Opioid-Experienced Subjects

Objective To investigate the pharmacokinetics (PK) of Morphine ARER, an extended-release (ER), abuse-deterrent formulation of morphine sulfate after oral and intranasal administration. Methods This randomized, double-blind, double-dummy, placebo-controlled, four-way crossover study assessed the PK of morphine and its active metabolite, M6G, from crushed intranasal Morphine ARER and intact oral Morphine ARER compared with crushed intranasal ER morphine following administration to nondependent, recreational opioid users. The correlation between morphine PK and the pharmacodynamic parameter of drug liking, a measure of abuse potential, was also evaluated. Results Mean maximum observed plasma concentration (Cmax) for morphine was lower with crushed intranasal Morphine ARER (26.2 ng/mL) and intact oral Morphine ARER (18.6 ng/mL), compared with crushed intranasal ER morphine (49.5 ng/mL). The time to Cmax (Tmax) was the same for intact oral and crushed intranasal Morphine ARER (1.6 hours) and longer for crushed intranasal morphine ER (1.1 hours). Higher mean maximum morphine Cmax, Tmax, and abuse quotient (Cmax/Tmax) were positively correlated with maximum effect for drug liking (R2 ≥ 0.9795). Conclusion These data suggest that Morphine ARER maintains its ER profile despite physical manipulation and intranasal administration, which may be predictive of a lower intranasal abuse potential compared with ER morphine.

Poster 270: Manual Medicine as Effective Treatment for Post-Laminectomy Syndrome Chronic Low Back Pain: A Case Report

upper extremities consistent with neuralgic amyotrophy also known as Parsonage-Turner syndrome. Setting: Tertiary care hospital outpatient clinic. Results: At 4 months after the onset of symptoms the patient regained significant amount of strength and function in bilateral upper extremities. He has continued with his prescribed physical therapy and home exercise program. Discussion: Neuralgic amyotrophy is a rare condition presenting usually unilaterally. It is thought tobecausedby immune-mediatedprocessesbut exact cause is unknown. As per previous studies, the recovery usually takes few years and is associated with residual weakness. This is the first reported case, to my knowledge, of significant recovery in bilateral neuralgic amyotrophy before 6 months after the onset of disease. Conclusions: Recovery of strength and function in bilateral neuralgic amyotrophy may occur earlier in the course of the disease than previously thought. Level of Evidence: Level V

Poster 290: Intramuscular Steroid Injections for the Treatment of Wrist Drop Due to Excessive use of Muscle Enhancement Oil Site Injections: A Case Report

Disclosures: James Meiling: I Have No Relevant Financial Relationships To Disclose Case/Program Description: Slipped capital femoral epiphysis (SCFE) is a unique emergent hip disorder that afflicts children and teenagers. The most common presentation of SCFE is varus slip, a posterior and inferior displacement of the proximal femoral epiphysis on the femoral metaphysis; however, SCFE also presents less frequently as a valgus slip, a posterior and lateral displacement. Bilateral SCFE happens even less often than unilateral SCFE, so a case of simultaneous bilateral valgus SCFE is unique. Setting: Outpatient Primary Care, Outpatient Pediatric Specialty Clinic. Results: An 11-year-old normal weight girl presented with simultaneous bilateral valgus SCFE. She underwent bilateral in situ pinning to prevent further slippage, but post-surgery rapidly developed acute right hip pain caused by retained hardware that inadvertently entered the acetabulum and protruded into the inner wall of the pelvis. An additional operation took place where surgeons dislocated her right hip to remove the retained screw and revised pinnings of both hips. She faced numerous complications, including decreased sensation and numbness on the dorsum of her right foot and decreased peroneal distribution. Almost 2 years later she continues to experience progressive right hip pain, pinpointed to the tip of the greater trochanter on the lateral aspect of her right hip. The hardware irritation pain resolved after the removal of symptomatic hardware in the right hip. However, she still complains of severe radiating right hip pain on the anterior aspect of her hip, which displays significant acetabular dysplasia and a small cystic area on MRI. Discussion: Valgus SCFE is infrequent, but important. Limited available cases for review. Conclusions: Valgus SCFE is a rare presentation of an uncommon musculoskeletal condition. According to the literature, simultaneous bilateral valgus SCFE in a female might be anticipated, but because of the infrequency of such cases the nature of both the presentation and demographics are still being discovered and understood. Level of Evidence: Level V