Medications for Opioid Use Disorder, Opioid Withdrawal, and Opioid Overdose: A Review

# Medications for Opioid Use Disorder, Opioid Withdrawal, and Opioid Overdose: A Review *Published: 2026 Mar 17* Emergency Department-Initiated Buprenorphine for Opioid Use Disorder: A Randomized Clinical Trial. D'Onofrio G(1)(2)(3), Herring AA(4)(5), Hawk KF(1)(3), Perrone J(6), Cowan E(7), McCormack RP(8), Dziura J(1), Matthews AG(9), Pantalon MV(10), Owens P(1), Martel S(1), Coupet E Jr(1), Lofwall MR(11), Walsh SL(11), Edelman EJ(2), Carpenter JE(12), Strout TD(13)(14), Baumann MR(13)(14), Anderson E(15), Barrett TW(16), Dorey A(17), Taillac P(17), Cochran G(18), Crandall CS(19), Wilson J(20), Manteuffel J(21), Cole JB(22), Whiteside LK(23), Jones C(24), Samuels E(25), Huntley K(26), Fiellin DA(1)(2)(27); ED INNOVATION Investigators. Collaborators: Schwarz E, Williamson B, Lee J, Lanter P, Pope J, King A, Stolbach A, Jennings L, Chang B, Kim H, Ketcham E, Wightman R, D'Orazio J, Moore PQ, Lynch M, Sullivan R, O'Connor P. Author information: (1)Department of Emergency Medicine, Yale School of Medicine, New Haven, Connecticut. (2)Department of Medicine, Yale School of Medicine, New Haven, Connecticut. (3)Department of Chronic Disease Epidemiology, School of Public Health, Yale University, New Haven, Connecticut. (4)Department of Emergency Medicine and Division of Addiction Medicine, Highland General Hospital-Alameda Health System, Oakland, California. (5)Department of Emergency Medicine, University of California, San Francisco. (6)Department of Emergency Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia. (7)Department of Emergency Medicine, Rutgers New Jersey Medical School, Newark. (8)Ronald O. Perelman Department of Emergency Medicine, New York University Grossman School of Medicine, New York, New York. (9)The Emmes Company LLC, Rockville, Maryland. (10)School of Health Professions, Long Island University, Brookville, New York. (11)Department of Behavioral Science and Center on Drug and Alcohol Research, University of Kentucky College of Medicine, Lexington. (12)Department of Emergency Medicine, Emory University School of Medicine, Grady Health System, Atlanta, Georgia. (13)Department of Emergency Medicine, MaineHealth Maine Medical Center, Portland. (14)Tufts University School of Medicine, Boston, Massachusetts. (15)Emergency Medicine, Alameda Health System, Oakland, California. (16)Emergency Medicine, Vanderbilt University Medical Center, Nashville, Tennessee. (17)Emergency Medicine, University of Utah Health, Salt Lake City. (18)Department of Internal Medicine, Division of Epidemiology, University of Utah Health, Salt Lake City. (19)Clinical and Translational Science Center, University of New Mexico, Albuquerque. (20)Emergency Medicine, University of South Florida, Tampa. (21)Department of Emergency Medicine, Henry Ford Health, Detroit, Michigan. (22)Minnesota Regional Poison Center, Division of Medical Toxicology, Department of Emergency Medicine, Hennepin Healthcare, Minneapolis. (23)Department of Emergency Medicine, School of Medicine, University of Washington, Seattle. (24)Department of Emergency Medicine, Cooper Medical School of Rowan University, Camden, New Jersey. (25)Department of Emergency Medicine, University of California, Los Angeles. (26)Center for Clinical Trials Network, National Institute on Drug Abuse, Rockville, Maryland (retired). (27)Department of Health Policy and Management, Yale School of Public Health, New Haven, Connecticut. Erratum in JAMA. 2026 Apr 28;335(16):1452. doi: 10.1001/jama.2026.4094. Comment in JAMA. 2026 Mar 17;335(11):945-947. doi: 10.1001/jama.2025.27103. ## IMPORTANCE Extended-release injectable buprenorphine may expand the reach of initiating medications for opioid use disorder in high-risk and hard-to-reach individuals who visit the emergency department (ED) and can be administered in low levels of withdrawal. ## OBJECTIVE To compare the effect of ED-initiated 7-day extended-release injectable buprenorphine vs sublingual buprenorphine on treatment engagement at 7 days. DESIGN, SETTING, AND PARTICIPANTS Multicenter randomized clinical trial enrolling adult patients presenting to the ED with untreated opioid use disorder and a Clinical Opiate Withdrawal Scale (COWS) score of 4 or higher across 29 EDs in the US from July 12, 2020, to August 21, 2024. Final follow-up was completed on October 24, 2024. ## INTERVENTIONS Patients were randomized to receive a 24-mg injection of extended-release buprenorphine (equivalent to 16 mg/d) or sublingual buprenorphine, which included either self-administration instructions if the COWS score was less than 8 or administration of 8 mg of sublingual buprenorphine in the ED if the COWS score was 8 or higher. All sublingual buprenorphine group patients received a 7-day prescription for 16 mg/d. Both groups were provided referral for ongoing medication with a scheduled appointment within 7 days. MAIN OUTCOMES AND MEASURES Engagement in opioid use disorder treatment on day 7 was the primary outcome. Secondary outcomes included engagement at 30 days, precipitated withdrawal and overdose events, craving scores, days of illicit opioid use, and patient satisfaction with treatment. ## RESULTS Among 2000 patients randomized, 6 who were enrolled twice were excluded, resulting in 991 in the extended-release group and 1003 in the sublingual group. The median age was 37 (IQR, 30-47) years, 68% were male, 31% had an initial COWS score of 4 to 7, and 76% tested positive for fentanyl. The adjusted proportion of engagement in opioid use disorder treatment at 7 days was 40.5% with extended-release buprenorphine vs 38.5% with sublingual buprenorphine (adjusted difference, 1.6%; 95% CI, -2.8% to 6.0%). Engagement at 30 days was similar, with adjusted proportions of 43.8% with extended-release buprenorphine vs 44.9% with sublingual buprenorphine (adjusted difference, -1.5%; 95% CI, -6.2% to 3.2%). Precipitated withdrawal was rare: 6 (0.6%) with extended-release buprenorphine and 8 (0.8%) with sublingual buprenorphine. Overdose events within 30 days occurred in 18 participants (2.3%) in each group. Patients receiving extended-release buprenorphine reported lower mean craving scores at 7 days vs those receiving sublingual buprenorphine (scale, 0-100; mean score, 26.5 vs 30.2, respectively; adjusted mean difference, -3.85; 95% CI, -7.08 to -0.63), fewer days of illicit opioid use in the past 7 days (adjusted ratio of means, 0.77; 95% CI, 0.68-0.95), and better treatment satisfaction scores (scale, 1-5; adjusted mean difference, 0.13; 95% CI, 0.01-0.25). CONCLUSIONS AND RELEVANCE No difference was detected in opioid use disorder treatment engagement on day 7 between the 7-day extended-release and sublingual buprenorphine groups. Both buprenorphine formulations were well tolerated; precipitated withdrawal was rare despite a high prevalence of fentanyl. ## TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT04225598. DOI: 10.1001/jama.2025.27019 PMCID: PMC12895321 DOI: 10.1001/jama.2025.26348