Incidence of Precipitated Withdrawal During a Multisite Emergency Department–Initiated Buprenorphine Clinical Trial in the Era of Fentanyl

Buprenorphine treatment is associated with decreased mortality and morbidity,¹ yet the treatment gap remains wide. Emergency departments (EDs) offer an effective, low-barrier setting in which to initiate buprenorphine.² Retrospective case series³ have raised concerns about increased incidence of precipitated withdrawal (PW) when buprenorphine is initiated in persons using fentanyl, a high-potency μ-opioid agonist with high affinity and slow dissociation from the μ receptor. With long-term use, its high lipophilicity leads to bioaccumulation and prolonged metabolite excretion. As confidence in standard buprenorphine inductions has eroded, alternative strategies, such as low-dose buprenorphine, have emerged, often prompting continued use of illicit opioids. Thus, there is a need for high-quality evidence from prospective studies using uniform surveillance and operational definitions of PW. We report the incidence of PW as part of an ongoing randomized clinical trial⁴ comparing traditional sublingual buprenorphine with CAM2038, a 7-day extended-release injectable form of buprenorphine, conducted in sites with high prevalence of fentanyl.

This observational cohort study using data from an ongoing clinical trial⁴ included patients aged 18 years or older with moderate-to-severe opioid use disorder, opioid-positive and methadone-negative urine tests, and a Clinical Opiate Withdrawal Scale (COWS) score of 4 or higher. Pregnant or admitted patients were excluded. Twenty-eight geographically diverse EDs participated from June 30, 2020, to October 26, 2022. Patients were randomized to standard sublingual buprenorphine inductions or extended-release buprenorphine and were observed for 2 hours. PW was defined⁵ a priori and was considered when a marked escalation in objective COWS scores (score ≥5) occurred, requiring additional buprenorphine and ancillary medications, often within 2 hours of buprenorphine administration. Suspected PW cases were documented prospectively and adjudicated by expert consultants (S.L.W. and M.R.L.). This study was reported according to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline for cohort studies and was approved by the WCG institutional review board. Participants provided written consent.

Patients with a COWS score of 8 or higher received 8 mg of sublingual buprenorphine in the ED and were discharged with a prescription for 16 mg/day. Individuals with COWS scores of 4 to 7 received uniform instructions for unobserved induction, up to 12 mg the first day, and then 16 mg/day. In the extended-release buprenorphine group, on the basis of dose equivalency to 16 mg of sublingual buprenorphine, patients received 24 mg of injectable CAM2038 in the ED during the index visit and follow-up.³ Data analysis was performed with SAS statistical software version 9.4 (SAS Institute).

Among 1200 enrolled patients (800 men [66.7%]; mean [SD] age, 38.4 [12.0] years), there were 9 cases of PW, or 0.76% (95% CI, 0.35%-1.43%) of the overall sample. Patient characteristics (total and PW) are presented in Table 1. The PW cases were enrolled from diverse locations; 5 received sublingual buprenorphine and 4 received extended-release buprenorphine. Detailed data from the PW cases are reported in Table 2. All patients had urine tests positive for fentanyl, 7 with multiple drugs. Routes of use, changes in baseline and peak COWS scores, and time elapsed from buprenorphine administration to PW varied. Time since last use ranged from 8 to more than 24 hours. All patients experiencing PW were discharged after symptoms resolved, with 1 self-directed discharge. Follow-up rates at 7 days after the ED visit were 86%.

This cohort study used data from the first, to our knowledge, prospective trial⁴ using uniform surveillance, operational definitions, and adjudicated outcomes to document buprenorphine-induced PW in persons using fentanyl. Despite high fentanyl prevalence, the incidence of PW in this multisite trial⁴ of ED-initiated buprenorphine was less than 1%, similar to reported rates among persons using heroin or prescription opioids.⁶ All 9 patients with PW used fentanyl, most without PW also used fentanyl, and no factors suggest a specific phenotype for PW. The discordance between our findings and those of retrospective studies is striking.

Limitations include possible undetected fentanyl analogues or nitazenes leading to PW. We may have missed PW after discharge, although follow-up rates at 7 days after the ED visit were 86% and likely would be captured as adverse events.

In this geographically diverse observational cohort, buprenorphine induction in the ED remained safe and effective, even with fentanyl present. Continued access to buprenorphine for opioid use disorder treatment is essential given the ongoing overdose crisis.

Accepted for Publication: February 16, 2023.

Published: March 30, 2023. doi:10.1001/jamanetworkopen.2023.6108

Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2023 D’Onofrio G et al. JAMA Network Open.

Corresponding Author: Gail D’Onofrio, MD, MS, Department of Emergency Medicine, Yale School of Medicine, 464 Congress Ave, Ste 260, New Haven, CT 06519 (gail.donofrio@yale.edu).

Author Contributions: Drs D’Onofrio and Fiellin had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: D’Onofrio, Hawk, Perrone, Lofwall, Fiellin, Herring.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: D’Onofrio, Walsh, Lofwall, Herring.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: D’Onofrio, Herring.

Obtained funding: D’Onofrio, Fiellin.

Administrative, technical, or material support: D’Onofrio, Hawk, Walsh, Lofwall, Fiellin, Herring.

Supervision: D’Onofrio, Hawk, Fiellin.

Conflict of Interest Disclosures: Dr D’Onofrio reported receiving grants from the National Institutes of Health (NIH) National Institute on Drug Abuse (NIDA) Clinical Trials Network (CTN) during the conduct of the study. Dr Hawk reported receiving grants from NIDA CTN during the conduct of the study. Dr Walsh reported receiving personal fees from Astra Zeneca, Cerevel, and Titan outside the submitted work. Dr Lofwall reported serving as a consultant to Journey Colab Scientific, advising on medications in development for non–opioid use disorder indications outside the submitted work. Dr Fiellin reported grants from NIDA during the conduct of the study. No other disclosures were reported.

Funding/Support: This research was supported by the NIH through the NIH HEAL Initiative under award number UG1DA015831-18S7. Support by the NIDA CTN Data and Statistics Center was provided by the NIDA under contracts 271201500065C, 75N95020D00012, and 75N95019D00013.

Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Disclaimer: This manuscript reflects the views of the authors and may not reflect the opinions, views, and official policy or position of the US Department of Health and Human Services or any of its affiliated institutions or agencies.

Data Sharing Statement: See the Supplement.

Additional Contributions: James Dziura, PhD, MPH (Departments of Emergency Medicine and Internal Medicine, Yale School of Medicine), assisted with statistical review. Ethan Cowan, MD (Department of Emergency Medicine, Icahn School of Medicine at Mount Sinai New York), and Ryan McCormack, MD (Department of Emergency Medicine, NYU Langone Medical Center), provided supervision of sites. Shara Martel, MPH, MS, and Patricia Owens, MS (both from Department of Emergency Medicine, Yale School of Medicine), provided technical and administrative support. These individuals were not compensated for their contributions. We also thank the ED INNOVATION Investigators.

Additional Information: The Emergency Department-Initiated Buprenorphine Validation Network Trial is registered under ClinicalTrials.gov identifier NCT04225598.