Authors: Shiwach R et al.
JAMA Network Open, December 17, 2025
This multicenter, randomized, double-blind trial compared 100-mg versus 300-mg monthly maintenance dosing of extended-release buprenorphine in adults with high-risk opioid use disorder (OUD), many of whom were using fentanyl.
Background
Highly potent synthetic opioids such as fentanyl now dominate the North American opioid supply. Fentanyl exposure is associated with:
• More difficult buprenorphine inductions
• Lower treatment retention
• Higher overdose risk
Although extended-release buprenorphine improves abstinence and retention compared with placebo, optimal maintenance dosing in heavy fentanyl users has been uncertain.
Study Design
• 435 adults with moderate-to-severe OUD
• 28 outpatient centers in the US and Canada
• Mean age 42 years; 43% women
• Nearly 75% fentanyl-positive at screening
• High polysubstance use; one-third with prior overdose
All participants:
• Completed buprenorphine induction
• Received two 300-mg loading injections
They were then randomized to:
• 100 mg monthly maintenance × 8 months
• 300 mg monthly maintenance × 8 months
Primary Outcome
Responder = ≥80% weekly opioid abstinence during weeks 20–38.
Results
Overall Response
• 100 mg: 20.2%
• 300 mg: 23.2%
Difference not statistically significant (P = .48)
Both doses produced:
• Rapid reductions in opioid use (from >43 uses at baseline to <3 by week 3)
• Sustained suppression through week 38
• Decreased cravings and withdrawal symptoms
Fentanyl-Specific Findings (Post Hoc Analysis)
Higher 300 mg dose showed clear benefit in heavy fentanyl users:
Daily fentanyl users
• 300 mg: 24.3%
• 100 mg: 13.3%
≥14 fentanyl uses/week
• 300 mg: 20.2%
• 100 mg: 8.0%
Heavy use subgroup
• 300 mg: 22.2%
• 100 mg: 6.8%
In these groups, the higher dose improved abstinence meaningfully.
Safety
• Both doses well tolerated
• Injection site reactions more common at 300 mg
• No new safety signals
• No increase in discontinuation
Interpretation
In the overall high-risk OUD population, both 100-mg and 300-mg maintenance doses were effective.
However, in individuals with heavy fentanyl exposure, 300 mg maintenance appears more effective in sustaining abstinence.
This is clinically important because fentanyl’s high potency and pharmacodynamics likely necessitate greater receptor occupancy for adequate opioid blockade.
Important Caveat
All participants received two initial 300-mg injections during induction.
This accelerated induction strategy may:
• Improve retention
• Suppress craving more effectively
• Reduce early relapse
However, this approach is not yet standard in most outpatient settings and may face insurance authorization barriers.
Clinical Implications
For clinicians treating OUD in fentanyl-dominant markets:
• Standard dosing may suffice for many patients
• Heavy fentanyl users may benefit from continued 300-mg maintenance
• Rapid induction strategies deserve consideration
• Insurance constraints may limit individualized high-dose therapy
Key Points
• Both 100 mg and 300 mg monthly extended-release buprenorphine reduce opioid use.
• No overall difference in abstinence between doses.
• 300 mg superior in heavy fentanyl users (post hoc).
• Both regimens safe and well tolerated.
• Rapid induction strategy may have enhanced outcomes.
In a fentanyl-driven crisis, this study supports more flexible, higher-dose maintenance strategies for selected high-risk patients rather than a one-size-fits-all dosing approach.