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Objective: Immediate-release (IR) oxycodone formulations may be manipulated for nonoral routes of administration. Oxycodone abuse-resistant immediate-release (ARIR) is a novel abuse-deterrent formulation (ADF) of IR oxycodone. This study aimed to assess the intravenous (IV) abuse potential of oxycodone ARIR relative to commercially available IR oxycodone tablets using in vitro laboratory studies., Design: Intact or manipulated tablets were incubated in 5 or 10 mL of room temperature water for increasing amounts of time. For each timepoint, syringeability, defined as the ability to draw up water-immersed intact or manipulated tablets into a syringe, was assessed on a scale of 1 (very easy) to 10 (impossible). If the prepared sample could be drawn into a syringe, the proportion of syringeable oxycodone was measured analytically., Results: In all conditions, it was nearly impossible to draw any liquid into a syringe from samples containing manipulated oxycodone ARIR tablets (N = 5/group), and most samples released very low concentrations (<10 percent) of their total oxycodone content, regardless of sample volume. In contrast, samples containing crushed IR oxycodone (N = 5/group) in small volumes of fluid were easily drawn into a syringe through the smallest needle, and more than 90 percent of the oxycodone content was released from relatively small sample volumes (5 mL)., Conclusion: The difficulty required to prepare an injectable solution from oxycodone ARIR when manipulated suggests that oxycodone ARIR has abuse-deterrent properties that may deter IV abuse.

Introduction: Food can alter the pharmacokinetics of certain abuse-deterrent formulations. Morphine ARER is an oral abuse-deterrent formulation of ER morphine sulfate tablets formulated with physical and chemical properties that contribute to the abuse-deterrent aspects of the drug. This study compared the relative bioavailability of Morphine ARER in the presence and absence of food., Methods: This was a randomized, single-dose, two-treatment, crossover study in which healthy adults received Morphine ARER 100 mg under fasting and fed conditions. Subjects were given naltrexone 50 mg to limit opioid effects. Plasma concentrations of morphine and its active metabolite morphine-6-glucuronide (M6G) were obtained up to 48 h post-dose; area under the plasma concentration-time curve (AUC) from time 0 extrapolated to infinity (AUC 0-∞ ), maximum observed plasma concentration (C max ) and time to C max (T max ) were calculated. Safety was evaluated by observation or report of adverse events, which were monitored during the treatment periods., Results: Of 28 enrolled subjects, 27 completed all treatments; 1 subject in the fasted group withdrew voluntarily. Under fed conditions, the C max for morphine was 33% higher (44.78 vs. 33.30 ng/ml for fed and fasted conditions, respectively) and the median T max was 30 min longer than under fasted conditions. The overall morphine exposure (AUC 0-∞ ) was similar for fed (440.6 ng · h/ml) vs. fasted conditions (395.1 ng · h/ml). For M6G, the C max and AUC 0-∞ were similar under both conditions, and the median T max for M6G was 60 min longer under fed conditions. Common adverse events were somnolence and nausea., Conclusion: Morphine ARER can be administered without regard to food. Plain language summary available for this article., Funding: Inspirion Delivery Sciences, LLC.

Introduction: Oxycodone ARIR is a novel oral, abuse-deterrent, immediate-release (IR) formulation with physical and chemical properties that deter misuse and abuse by non-oral routes. In this single-dose pharmacokinetic study, we assessed the relative bioavailability of oxycodone for Oxycodone ARIR and IR oxycodone, and the effect of food on Oxycodone ARIR following oral administration., Methods: This open-label, randomized study in healthy adults compared the relative bioavailability of Oxycodone ARIR 30 mg to IR oxycodone 30 mg under fasted conditions, and Oxycodone ARIR under fed versus fasted conditions. Pharmacokinetic parameters included area under the concentration-time curve from time 0 to the last measured concentration (AUC 0-t ) and the maximum oxycodone plasma concentration (C max ). Equivalence was determined using an analysis of variance of the least-squares means., Results: Fifty-eight subjects completed the study. Under fasted conditions, AUC 0-t was 4% lower (90% CI 92.5-98.7%) and mean C max was 14% lower (90% CI 78.8-94.3%) for Oxycodone ARIR versus IR oxycodone. AUC 0-t was 23% higher (90% CI 119.1-127.0%) and mean C max was higher (90% CI 108.6-129.4%) when Oxycodone ARIR was administered in the fed versus fasted state. Common adverse events included nausea, headache, and dizziness., Conclusion: In this single-dose pharmacokinetic evaluation, fasted Oxycodone ARIR 30 mg had similar bioavailability to and is expected to have the same efficacy and safety profile as IR oxycodone. When administered in the fed state, pharmacokinetic parameters were slightly higher; however, these differences were considered not clinically meaningful and show that Oxycodone ARIR can be administered with or without food., Funding: This study was funded by Inspirion Delivery Sciences, LLC. Daiichi Sankyo, Inc. funded the journal's article processing charges and open access fee. Plain language summary available for this article.

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., (© 2018 American Academy of Pain Medicine.)

Purpose: Morphine ARER is a novel oral, abuse-deterrent, extended-release (ER) formulation of morphine sulfate with physical and chemical properties that deter misuse and abuse by nonoral routes of administration. Here we evaluate the relative bioavailability of morphine ARER and extended-release morphine., Methods: This single-dose, 2-treatment, 2-period, 2-sequence, randomized crossover study in healthy adult subjects compared the relative bioavailability of morphine ARER 100 mg to that of ER morphine 100 mg in the fasted condition. At 12 and 1.5 hours before dosing and 12 hours after dosing, all subjects received a 50-mg oral naltrexone tablet to minimize opioid-related side effects. Pharmacokinetic parameters including the AUC 0-t , AUC 0-∞ , and C max of morphine and its metabolite morphine-6-glucuronide (M6G) were determined at various times up to 48 hours postdose. The bioequivalence of morphine ARER and ER morphine was determined using an ANOVA of the least-squares mean values of morphine and M6G bioavailability., Findings: Forty-nine subjects completed the study. Both morphine ARER and ER morphine exhibited peak plasma morphine and M6G concentrations of ∼30 ng/mL and ∼200 ng/mL, respectively, at 3 hours postdose. The 90% CIs of the ln-transformed values of morphine AUC 0-t , AUC 0-∞ , and C max were within the 80% to 125% range for bioequivalence. M6G values also indicated bioequivalence of morphine ARER and ER morphine. The most common adverse events were nausea and somnolence., Implications: These data show that, in these subjects, morphine ARER was bioequivalent to ER morphine, a treatment for pain with well-established efficacy and safety profiles., (Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.)

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 ( C max ) 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 C max ( T max ) 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 C max , T max , and abuse quotient ( C max / T max ) were positively correlated with maximum effect for drug liking ( R 2  ≥ 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.

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 drug's 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 subject's 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., (© 2016 American Academy of Pain Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com)