Higher dose extended-release buprenorphine improves outcomes in heavy fentanyl use

1. In this randomized double-blind controlled trial, both the 100-mg and 300-mg doses of buprenorphine were effective and well-tolerated, with substantial and rapid reductions in opioid use in a high-risk population.

2. The higher 300-mg maintenance dose provided greater benefit for people with heavy fentanyl use, improving abstinence rates more significantly compared with the 100-mg dose.

Evidence Rating Level: 1 (Excellent)

Study Rundown: The opioid epidemic continues to be a major public health crisis, driven in part by the widespread use of fentanyl, which accounted for more than 46,000 deaths in the US in 2024. Buprenorphine is an effective first-line treatment for opioid use disorder (OUD); however, fentanyl exposure is associated with worse treatment initiation and retention, increasing the risk of relapse and overdose. As fentanyl use rises, improved treatment strategies are urgently needed. Extended-release buprenorphine is a once-monthly injectable treatment approved for moderate-to-severe OUD that improves abstinence, retention, and quality of life. 

To address whether individuals would benefit from this, this randomized trial compared 100-mg versus 300-mg maintenance doses of extended-release buprenorphine in participants with high-risk opioid use, with post hoc analyses to identify subgroups who may derive greater benefit from the higher dose. Participants first entered an open-label induction phase, randomized 2:1 to rapid or standard buprenorphine induction. Four weeks later, they were re-randomized 1:1 to receive eight monthly maintenance doses of either 100-mg or 300-mg buprenorphine. The primary outcome was the proportion of participants who were abstinent from opioids at 80% or more of visits between weeks 20 and 38. This study found that both extended-release buprenorphine doses were effective and well-tolerated, with the 300-mg maintenance dose showing greater benefit among individuals with heavy fentanyl use. One limitation was that this study was designed before the widespread rise in illicit fentanyl use and before the development of updated guidance for fentanyl testing in clinical trials. Despite this limitation, these findings suggest that future treatment guidelines and trials should consider higher maintenance dosing specifically for patients with heavier fentanyl use. 

Click here to read the study in JAMA Network Open

Relevant Reading: Examining the benefit of a higher maintenance dose of extended-release buprenorphine in opioid-injecting participants treated for opioid use disorder 

In-Depth [randomized controlled trial]:

After meeting the eligibility criteria, 436 participants were randomized. Of these individuals, 435 participants (mean [SD] age, 41.6 [10.9] years, 248 [57.0%] male) received at least one maintenance injection (218 in the 100-mg group and 217 in the 300-mg group). Participants received a similar number of injections in both groups, with a mean of 8.4 injections, and 63.2% (275 participants) completed all 10 planned doses. The average duration of double-blind treatment was 186 days. Use of additional transmucosal buprenorphine was rare (0.5% in the 100-mg group and 2.8% in the 300-mg group), and when used, it occurred only once. In post hoc subgroup analyses, the 300-mg maintenance dose was more effective than the 100-mg dose for achieving treatment response among participants with high fentanyl use. Higher response rates with 300-mg were observed in those reporting daily fentanyl use at screening (difference, 11.1%; 95% CI, 0.4%-21.6%), fentanyl use 14 or more times per week (difference, 12.2%; 95% CI, 2.4%-22.1%), and daily and frequent use (difference, 15.4%; 95% CI, 4.6%-26.1%). Injection-site reactions occurred less frequently in the 100 mg group than in the 300 mg group during maintenance treatment (difference, 9.2%; 95% CI, 3.7%-15.2%). 

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