[Skip to Content]
[Skip to Content Landing]

Clinical Trial Design Challenges and Opportunities for Emerging Treatments for Opioid Use DisorderA Review

To identify the key insights or developments described in this article
1 Credit CME
Abstract

Importance  Novel treatments for opioid use disorder (OUD) are needed to address both the ongoing opioid epidemic and long-standing barriers to existing OUD treatments that target the endogenous μ-opioid receptor (MOR) system. The goal of this review is to highlight unique clinical trial design considerations for the study of emerging treatments for OUD that address targets beyond the MOR system. In November 2019, the Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION) public-private partnership with the US Food and Drug Administration sponsored a meeting to discuss the current evidence regarding potential treatments for OUD, including cannabinoids, psychedelics, sedative-hypnotics, and immunotherapeutics, such as vaccines.

Observations  Consensus recommendations are presented regarding the most critical elements of trial design for the evaluation of novel OUD treatments, such as: (1) stage of treatment that will be targeted (eg, seeking treatment, early abstinence/detoxification, long-term recovery); (2) role of treatment (adjunctive with or independent of existing OUD treatments); (3) primary outcomes informed by patient preferences that assess opioid use (including changes in patterns of use), treatment retention, and/or global functioning and quality of life; and (4) adverse events, including the potential for opioid-related relapse or overdose, especially if the patient is not simultaneously taking maintenance MOR agonist or antagonist medications.

Conclusions and Relevance  Applying the recommendations provided here as well as considering input from people with lived experience in the design phase will accelerate the development, translation, and uptake of effective and safe therapeutics for individuals struggling with OUD.

Sign in to take quiz and track your certificates

Buy This Activity

JN Learning™ is the home for CME and MOC from the JAMA Network. Search by specialty or US state and earn AMA PRA Category 1 Credit(s)™ from articles, audio, Clinical Challenges and more. Learn more about CME/MOC

CME Disclosure Statement: Unless noted, all individuals in control of content reported no relevant financial relationships. If applicable, all relevant financial relationships have been mitigated.

Article Information

Accepted for Publication: October 7, 2022.

Published Online: November 30, 2022. doi:10.1001/jamapsychiatry.2022.4020

Corresponding Author: Brian D. Kiluk, PhD, Department of Psychiatry, Yale School of Medicine, 40 Temple St, Ste 6C, New Haven, CT 06510 (brian.kiluk@yale.edu).

Conflict of Interest Disclosures: Dr Kiluk has received grants from the National Institute on Drug Abuse and National Institute on Alcohol Abuse and Alcoholism and personal fees from the Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION) during the conduct of the study as well as personal fees from CBT4CBT and Sparian Biosciences outside the submitted work. Dr Kleykamp has received personal fees from ACTTION during the conduct of the study; personal fees from American Society of Addiction Medicine, Pinney Associates, Symplr, ECRI, STATinMED, and Palladian Associates; and honoraria from Filter Magazine and Next Avenue outside the submitted work. Dr Comer has received grants from Alkermes, Lyndra Therapeutics, IntraCellular Therapies, GoMedical, BioXcel, and Janssen as well as consulting fees from Mallinckrodt, Alkermes, Clinilabs, Opiant, Nektar, and Otsuka outside the submitted work. Dr Griffiths has received grants from the Steven and Alexandra Cohen Foundation and from Tim Ferris, Matt Mullenweg, Blake Mycoskie, and Craig Nerenberg during the conduct of the study as well as personal fees from the Heffter Research Institute outside the submitted work. Dr Johnson has received grants from the National Institutes of Health, the Heffter Research Institute, and Mydecine Innovations Group; personal fees from AJNA Labs, AWAKN Life Sciences, Beckley Psychedelic, Entheogen Biomedical, Mind Medicine, Field Trip Psychedelics, Silo Pharma, and Otsuka Pharmaceutical Development and Commercialization; and nonfinancial support from Mydecine Innovations Group outside the submitted work. Dr Kampman has received grants from US World Meds and Alkermes outside the submitted work. Dr Pravetoni has received grants from the National Institutes of Health during the conduct of the study and has a patent pending for disclosing technology related to vaccines and monoclonal antibodies and other treatment strategies for substance use disorders and overdose. Dr Vandrey has received personal fees from Canopy Health Innovations, MyMD Pharmaceuticals, Mira1a Pharmaceuticals, WebMD, Radicle Science, and Syqe Medical during the conduct of the study. Dr Bergeria has received grants from the National Institute on Drug Abuse and ACTTION during the conduct of the study as well as grants from Canopy Growth Corporation outside the submitted work. Dr Bogenschutz has received research funding from the National Institute on Alcohol Abuse and Alcoholism, National Institute on Drug Abuse, Heffter Research Institute, Mind Medicine, Tilray Canada, Multidisciplinary Association for Psychedelic Studies (MAPS), B.More, Turnbull Family Foundation, Fournier Family Foundation, Dr Bronner’s Family Foundation, and Riverstyx Foundation and from Rodrigo Nino, a philanthropic donor, as well as personal fees from the Heffter Research Institute, Ajna Labs, Beckley Psytech, Journey Colab, and Bright Minds Biosciences outside the submitted work. Dr Brown has received grants from the National Institutes of Health, Health Services and Resources Administration, Substance Abuse and Mental Health Services Administration, Usona Institute, Multi-Disciplinary Association for Psychedelic Studies, Etheridge Foundation, and Heffter Research Institute outside the submitted work. Dr Dunn has received grants from the National Institutes of Health as well as personal fees from Mind Medicine, Canopy Corporation, and Canopy-Beckley outside the submitted work. Dr Dworkin has received grants from US Food and Drug Administration and National Institutes of Health during the conduct of the study; personal fees from Abide, Acadia, Adynxx, Analgesic Solutions, Aptinyx, Aquinox, Asahi Kasei, Astellas, Beckley, Biogen, Biohaven, Biosplice, Boston Scientific, Braeburn, Cardialen, Celgene, Centrexion, Chiesi, Chromocell, Clexio, Collegium, Concert, Confo, Decibel, Editas, Eli Lilly, Endo, Eupraxia, Exicure, Glenmark, Gloriana, Grace, Hope, Lotus, Mainstay, Merck, Mind Medicine, Neumentum, Neurana, NeuroBo, Novaremed, Novartis, Oxford Cannabinoid Technologies, OliPass, Pfizer, Q-State, Reckitt Benckiser, Regenacy, Sangamo, Sanifit, Scilex, Semnur, SIMR Biotech, Sinfonia, SK Biopharmaceuticals, Sollis, SPRIM, Teva, Theranexus, Toray, Vertex, Vizuri, and WCG and holds equity in Ethismos, Regenacy, and Mind Medicine outside the submitted work. Dr Finan has received personal fees from Ninnion Therapeutics outside the submitted work. Dr Hendricks has received grants from the Heffter Research Institute and National Institutes of Health as well as personal fees from Bright Minds Biosciences, Eleusis Health Solutions, Reset Pharmaceuticals, and Silo Pharma outside the submitted work. Dr Kosten has received grants from the US Department of Defense, National Institutes of Health, Toomim Family Foundation, and John O’Quinn Foundation as well as personal fees from Alkermes, Amygdala Neurosciences, Aptinyx, Arbor Pharma, Astellas, BioXcel, Boehringer Ingelheim, Braeburn, Data Analytics, Diamond, Embera, Epiodyne, Indivior, Intra-Cellular Therapies, Mallinckrodt, Medscape, Nektar, Nirsum, Novartis, Opiant, Otsuka, Pfizer, Phenex, Promentis, Relmada, Sage, United Neuroscience, US World Meds, and Zynerba. Dr Levin has received grants from US World Meds Medication, Substance Abuse and Mental Health Services Administration, and National Institute on Drug Abuse; personal fees from Major League Baseball; and nonfinancial support from Indivior outside the submitted work; and served on the scientific advisory boards of Alkermes, Indivior, Novartis, Teva, and US World Meds. Dr Raison has received personal fees from Usona Institute, Novartis, Alfasigma, Emory Healthcare, and Otsuka during the conduct of the study. Dr Rasmussen was Director of the Division of Therapeutics and Medical Consequences of the National Institute on Drug Abuse from 2018 to 2021. Dr Turk has received personal fees from GlaxoSmithKline/Novartis and nonfinancial support from Pfizer outside the submitted work and is Editor-in-Chief of the Clinical Journal of Pain and Associate Director of ACTTION. Dr Weiss has received personal fees from Alkermes, Cerevel Therapeutics, Takeda Pharmaceuticals, and Astellas Pharma outside the submitted work. Dr Strain has received personal fees from Caron, Cerevel, Elsevier, Fast Track Drugs and Biologics, Otsuka, Pear Therapeutics, and UpToDate as well as nonfinancial support from Masimo/Innovative Health Solutions outside the submitted work. No other disclosures were reported.

Funding/Support: Financial support for this article was provided by the Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION) public-private partnership with the US Food and Drug Administration (grant U01-FD005936).

Role of the Funder/Sponsor: The Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION) public-private partnership had a role in the preparation and review of the manuscript and decision to submit the manuscript for publication, and the ACTTION Executive Committee approved the manuscript.

Disclaimer: The views expressed in this article are those of the authors and no official endorsement by the US Food and Drug Administration or the pharmaceutical and device companies that provided unrestricted grants to support the activities of the Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION) public-private partnership should be inferred.

Additional Contributions: We acknowledge the following members from the National Institute on Drug Abuse and the US Food and Drug Administration who were in attendance at the Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION)–sponsored meeting and participated in discussion but were not involved in the development of this article: Jane Acri, PhD (National Institute on Drug Abuse [NIDA], Bethesda, Maryland), Maryam Afshar, MD (US Food and Drug Administration [FDA], Silver Spring, Maryland), Sarah Arnold, MD (FDA), Sean Belouin, PharmD (FDA), Katherine Bonson, PhD (FDA), Emily Deng, MD (FDA), Guerrieri Gioia, DO (FDA), Allison Lin, PharmD, PhD (FDA), Naomi Lowy, MD (FDA), Javier Muniz, MD (FDA), Tanya Ramey, MD, PhD (NIDA), David Shurtleff, PhD (NIDA), Juliette Toure, PharmD (FDA), Robert Walsh, BS, RAC (NIDA), Kevin Walton, PhD (NIDA), and Celia Winchell, MD (FDA). Contributors were not compensated for their work.

AMA CME Accreditation Information

Credit Designation Statement: The American Medical Association designates this Journal-based CME activity activity for a maximum of 1.00  AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Successful completion of this CME activity, which includes participation in the evaluation component, enables the participant to earn up to:

  • 1.00 Medical Knowledge MOC points in the American Board of Internal Medicine's (ABIM) Maintenance of Certification (MOC) program;;
  • 1.00 Self-Assessment points in the American Board of Otolaryngology – Head and Neck Surgery’s (ABOHNS) Continuing Certification program;
  • 1.00 MOC points in the American Board of Pediatrics’ (ABP) Maintenance of Certification (MOC) program;
  • 1.00 Lifelong Learning points in the American Board of Pathology’s (ABPath) Continuing Certification program; and
  • 1.00 credit toward the CME [and Self-Assessment requirements] of the American Board of Surgery’s Continuous Certification program

It is the CME activity provider's responsibility to submit participant completion information to ACCME for the purpose of granting MOC credit.

Close
Want full access to the AMA Ed Hub?
After you sign up for AMA Membership, make sure you sign in or create a Physician account with the AMA in order to access all learning activities on the AMA Ed Hub
Buy this activity
Close
Want full access to the AMA Ed Hub?
After you sign up for AMA Membership, make sure you sign in or create a Physician account with the AMA in order to access all learning activities on the AMA Ed Hub
Buy this activity
Close
With a personal account, you can:
  • Access free activities and track your credits
  • Personalize content alerts
  • Customize your interests
  • Fully personalize your learning experience
Education Center Collection Sign In Modal Right
Close

Name Your Search

Save Search
With a personal account, you can:
  • Access free activities and track your credits
  • Personalize content alerts
  • Customize your interests
  • Fully personalize your learning experience
Close
Close

Lookup An Activity

or

My Saved Searches

You currently have no searches saved.

Close

My Saved Courses

You currently have no courses saved.

Close