Comparison of Extended-Release Buprenorphine Doses for Treating High-Risk Opioid Use: A Randomized Clinical Trial.

Importance: Patients with high-risk opioid use may require higher buprenorphine doses to maximize abstinence and retention in treatment. Objective: To compare the efficacy and safety of 100-mg vs 300-mg once-monthly maintenance doses of extended-release buprenorphine among individuals with high-risk opioid use, including fentanyl. Design, Setting, and Participants: This multicenter, randomized, double-blind clinical trial was conducted from October 26, 2021, to June 26, 2024, at 28 outpatient treatment centers in the US and Canada among treatment-seeking participants with moderate or severe opioid use disorder who injected opioids, used high doses of opioids, or used fentanyl. Interventions: After completing buprenorphine induction and extended-release buprenorphine initiation (week 6), participants were randomized in a 1:1 ratio to receive 8 additional 100-mg or 300-mg extended-release buprenorphine maintenance injections. Main Outcomes and Measures: The primary end point was the proportion of responders for weekly opioid use, defined as participants whose percentage of visits with opioid abstinence was 80% or more over weeks 20 to 38. Post hoc analyses were performed to identify any subgroups that might benefit more from the 300-mg than 100-mg extended-release buprenorphine maintenance dose. Adverse events, including injection-site reactions, were reported. Analysis was conducted on an intent-to-treat basis. Results: Of 436 participants randomized, 435 (mean [SD] age, 41.6 [10.9] years; 248 men [57.0%]) received injections and were analyzed (218 in the 100-mg arm and 217 in the 300-mg arm). There were 44 of 218 responders (20.2%) in the 100-mg arm and 50 of 216 responders (23.2%) in the 300-mg arm (Cochran-Mantel-Haenszel difference, 2.6%; 95% CI, -4.7% to 9.9%). In post hoc analyses, the 300-mg maintenance dose performed significantly better than the 100-mg maintenance dose among participants who used fentanyl daily (difference, 11.1%; 95% CI, 0.4%-21.6%), used fentanyl 14 times or more per week (difference, 12.2%; 95% CI, 2.4%-22.1%), or both (difference, 15.4%; 95% CI, 4.6%-26.1%). With both dosing regimens, the frequency of opioid use decreased from more than 43 instances at screening to fewer than 3 instances by week 3 (through week 38). Extended-release buprenorphine-related adverse events were similar between groups, except for injection-site reactions, which were higher in the 300-mg arm (difference, 9.2%; 95% CI, 3.7%-15.2%). Both maintenance doses were well tolerated with no new safety signals. Conclusions and Relevance: In this randomized clinical trial, both extended-release buprenorphine maintenance doses were well tolerated and effective among participants with high-risk opioid use. The 300-mg maintenance dose may perform better among individuals with heavy fentanyl use. These results are particularly relevant because individuals with opioid use disorder in North America are increasingly exposed to highly potent synthetic opioids, such as fentanyl, a driver of high levels of opioid overdose deaths. Trial Registration: ClinicalTrials.gov Identifier: NCT04995029.