Rapid vs Standard Induction to Injectable Extended-Release Buprenorphine

Importance: Standard induction (SI) using transmucosal buprenorphine-naloxone is challenging in individuals who inject opioids, use high doses of opioids, or use synthetic opioids (eg, fentanyl). Objective: To compare the effectiveness and safety of rapid induction (RI; single 4-mg dose of buprenorphine-naloxone) vs SI (≥7 days of buprenorphine-naloxone) followed by extended-release buprenorphine injection. Design, Setting, and Participants: This multicenter, open-label randomized clinical trial was conducted from October 26, 2021, to January 19, 2024, at 28 outpatient treatment centers in the US and Canada. Treatment-seeking participants with moderate or severe opioid use disorder who inject opioids, use high doses of opioids, or use fentanyl were studied. Interventions: Participants were randomized 2:1 to RI or SI before 300-mg injection of extended-release buprenorphine. Main Outcomes and Measures: The primary end point, retention rate difference at injection 2 (1 week after injection 1), was estimated by a bayesian approach. Posterior probability was estimated for noninferiority of RI to SI (RI - SI >-10%) and superiority (RI - SI >0%). Adverse events (AEs), including investigator-assessed opioid withdrawal symptoms, were reported. Subgroup analyses compared participants with positive or negative fentanyl urine drug screen results. Results: Analyses included 729 randomized participants (mean SD age, 40.7 10.4 years; 406 55.7% male) who initiated transmucosal buprenorphine per protocol, including 474 in the RI arm and 255 in the SI arm. A total of 560 participants received extended-release buprenorphine injection 1 (409 86.3% in the RI arm and 151 59.2% in the SI arm), and 452 received injection 2 (314 66.2% in the RI arm and 138 54.1% in the SI arm). At injection 2, RI was noninferior with higher retention than SI (difference, 11.8%; 95% credible interval CrI, 4.3%-19.0%; posterior probability greater than 0 was 99.9%). Similarly, among participants with a positive test result for fentanyl, the retention rate differential in favor of RI was 14.8% (95% CrI, 6.5%-23.7%; posterior probability greater than 0 was greater than 99.9%). AE incidence was not statistically different between RI and SI participants (202 42.6% vs 93 35.5%; difference, 6.1%; 95% CrI, -1.3% to 13.4%). Up to injection 2, most AEs were associated with opioid withdrawal. Conclusions and Relevance: In this multicenter randomized clinical trial, RI had higher retention than SI overall and in patients who tested positive for fentanyl through extended-release buprenorphine injection 2. Administration of injection 2 after 1 week was well tolerated and minimized time below target therapeutic levels of 2 ng/mL or greater compared with injection after 1 month. Trial Registration: ClinicalTrials.gov Identifier: NCT04995029.