Human abuse potential of immediate-release/extended-release versus immediate-release hydrocodone bitartrate/acetaminophen: a randomized controlled trial in recreational users of prescription opioids

Abstract

Background. The abuse potential of prescription opioids is well established. This study compared positive, subjective drug effects of single, equal doses of biphasic immediate release (IR)/extended release (ER) hydrocodone bitartrate (HB)/acetaminophen (acetyl-p-aminophenol [APAP]) 7.5/325 mg tablets versus IR HB/APAP 7.5/325-mg tablets and placebo. Methods: Healthy adult recreational users of prescription opioids entered this randomized, double-blind, double-dummy, active- and placebo-controlled, seven-way crossover study. Participants received single, total doses of IR/ER HB/APAP 22.5/975 mg (intact; three active tablets) and 45/1950 mg (intact and crushed [encapsulated]; six active tablets), IR HB/APAP 22.5/975 mg (intact; three active tablets) and 45/1950 mg (intact and crushed [encapsulated]; six active tablets), and placebo. Peak subjective effects (E_max); time to peak effects (TE_max); and area under the drug–effect curves for drug liking, high, and good drug effects were measured using visual analog scales. Median values with 95% confidence interval (CI) were compared using analysis of variance. Results: Among completers (n = 52), IR/ER HB/APAP produced delayed and lower peak effects compared to equal doses of IR HB/APAP. Comparing intact tablets, the drug liking E_max (median [95% CI]) was significantly lower for IR/ER HB/APAP 45/1950 mg (78.0 [73.0, 81.0]) than an equal dose of IR HB/APAP (89.5 [85.0, 93.0]; difference, –8.5 [–12.0, –6.0]; P < 0.001). Similar results were observed for intact IR/ER HB/APAP and IR HB/APAP 22.5/975 mg. Crushing IR/ER HB/APAP 45/1950 mg delayed these effects compared with an equal dose of crushed IR HB/APAP and intact IR/ER HB/APAP. Conclusion. IR/ER HB/APAP resulted in lower subjective positive drug effects than an equal dose of IR HB/APAP. Crushing IR/ER HB/APAP also delayed the onset of subjective effects compared with intact IR/ER HB/APAP. These findings suggest that biphasic IR/ER HB/APAP has lower abuse potential than IR HB/APAP in single equal doses. Registration: This Phase I clinical trial conducted in the USA was not registered.

Keywords:

• acetaminophen
• extended release
• fixed-dose combination
• human abuse potential
• hydrocodone
• opioid

Acknowledgments

Mallinckrodt Pharmaceuticals (Hazelwood, MO, USA) sponsored this research and funded editorial support provided by Jeffrey Coleman, MA, and Robert Axford-Gatley, MD, of C4 MedSolutions, LLC (Yardley, PA, USA), a CHC Group company.

Declaration of interest: K. Devarakonda, Y. Zheng, J. Montgomery, T. Barrett, and J. Young are employees of Mallinckrodt. K. Kostenbader is a paid contract employee of Mallinckrodt. L. R. Webster reports receiving honoraria, serving as a consultant, and being a member of the advisory boards for Acura Pharmaceuticals, AstraZeneca, BioDelivery Sciences International, Bristol-Myers Squibb, CVS Caremark, Depomed, Egalet, Grunenthal USA, Inspiron Pharmaceuticals, Insys Therapeutics, Jazz Pharmaceuticals, Kaleo, Mallinckrodt, Nektar Therapeutics, Nevro Corporation, Orexo Pharmaceuticals, Synchrony Healthcare, Teva Pharmaceuticals, Trevena and Theravance. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

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