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.