Human abuse potential studies of abuse-deterrent opioids: lessons from oral and intranasal studies with morphine abuse-deterrent, extended-release, injection-molded tablets

Abstract

Background: The development and use of abuse-deterrent (AD) opioids is part of a multifaceted strategy to reduce misuse, abuse, and diversion, while maintaining access for patients with severe pain who may benefit from their analgesic efficacy. Morphine AD, extended-release (ER), injection-molded tablets (morphine-ADER-IMT; ARYMO ER; Egalet US Inc., Wayne, PA) is approved by the FDA as an AD opioid. As part of the characterization of AD opioids, assessments of their human abuse potential (HAP) are required. Evidence from HAP studies can guide clinicians on the use of AD opioids in clinical practice. Herein, we describe HAP study design, and how specific AD features can impact the conduct of a study and interpretation of its results.

Objectives: To review the design features and results of the oral and intranasal HAP studies with morphine-ADER-IMT in order to improve the understanding of key elements of HAP studies of AD opioids.

Conclusions: Results from HAP studies with morphine-ADER-IMT and other AD opioids suggest that key study design features include the release profile (immediate-release vs extended-release) of the positive control, study drug doses, and the way the products are manipulated. These elements can directly impact the outcomes of the pharmacokinetic and pharmacodynamic (e.g. Maximum Drug Liking, Overall Drug Liking, and Take Drug Again) results. When evaluating HAP studies, it is important to understand study design features to assist in the interpretation of the results and understand the clinical relevance of the data to help guide clinical decision-making about the use of AD opioids.

Keywords:

• Abuse-deterrent
• extended-release
• human abuse potential
• morphine
• ARYMO ER
• opioid

Transparency

Declaration of funding

Medical writing and editorial support was funded by Egalet US Inc., Wayne, PA. The morphine-ADER-IMT studies were funded by Egalet Corporation.

Declaration of financial/other interests

LRW is an employee of PRA Health Sciences and has the following disclosures: Daiichi Sankyo (Honorarium-Advisory Board-Travel Support), Depomed (Travel Support), Egalet Corporation (Honorarium-Advisory Board Member-Consultant-Travel Support), Elysium (Honorarium-Consultant-Travel Support), Insys (Honorarium-Consultant-Travel Support), Kempharm Inc. (Honorarium-Consultant-Travel Support), Mallinckrodt Pharmaceuticals (Honorarium-Consultant), Pain Therapeutics Inc. (Honorarium-Consultant), Pfizer (Honorarium-Consultant-Travel Support), Shionogi (Honorarium-Consultant), and Teva (Honorarium-Advisory Board Member-Consultant-Travel Support). EV is an employee of Thomas Jefferson University, and has the following disclosures: research grants from Durect and Pacira Pharmaceuticals, consultant for AcelRx Pharmaceuticals, Cara Therapeutics, Egalet Corporation, Frezenius, Heron Therapeutics, Mallinckrodt Pharmaceuticals, Pacira Pharmaceuticals, Pfizer, and Trevena Inc., and is a speaker for Mallinckrodt Pharmaceuticals and Salix Pharmaceuticals. CB is an employee of Egalet US Inc., and may own stock or stock options. JMD is a former employee of Egalet US Inc., and owns stock in the company. A CMRO peer-reviewer on this manuscript declares involvement in a SPRIX (intranasal ketorolac) post-surgical dental pain study funded by Luptpold, now owned by Egalet; however, the reviewer declares no funded research on abuse-deterrent opioids for Egalet directly. The same reviewer declares receipt of funding from the OTC division of Pfizer on OTC NSAIDs (Advil) and topical anesthetic benzocaine toothache products (Anbesol). Pfizer’s Rx division makes a competitor product to Egalet‘s. All other CMRO peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Acknowledgments

The authors would like to thank Patrick Little, PhD, of Complete Publication Solutions, a CHC Group company (North Wales, PA), for providing medical writing support, which was funded by Egalet US Inc. (Wayne, PA). The morphine-ADER-IMT studies were approved by an appropriate ethics committee.