Buprenorphine vs Naltrexone: A Large Study

Real-world data find slightly fewer overdoses with buprenorphine

STUDY: Hsu HE et al, JAMA Network Open 2026

STUDY TYPE: Observational comparative effectiveness study (target trial emulation)

FUNDING: National Institute on Drug Abuse

Background

Buprenorphine-naloxone (Suboxone, Zubsolv) and naltrexone XR (Vivitrol) both treat opioid use disorder, but head-to-head trials have been too small and short to tell us which is more effective. This large, six-month study compares mortality rates (though without randomization).

The Study

• Over 106,000 discharge episodes from medically managed opioid withdrawal in Massachusetts, 2014 to 2018, involving more than 36,000 adults.
• Compared people who started buprenorphine-naloxone versus XR naltrexone within 28 days of discharge, using statistical methods designed to mimic a randomized trial.
• Followed for 24 weeks, tracking all-cause mortality and nonfatal opioid overdose.

Results

All-cause mortality was essentially identical between the two drugs: 1.4% for buprenorphine-naloxone and 1.4% for naltrexone XR. But nonfatal opioid overdose favored buprenorphine-naloxone: 11.6% versus 13.9% with naltrexone XR, a risk difference of 2.3 percentage points. That difference held up across most subgroups, though it shrank and lost significance when the analysis was restricted to a patient’s first detox episode only.

These overdose and death rates are far higher than what was seen in the X:BOT randomized trial that inspired this study, likely because real-world patients don’t get the extra support and incentives that trial participants receive.

Limitations

Observational data, so residual confounding by indication is possible despite the target trial design. Data misses nonfatal overdoses that didn’t require emergency medical services. Results come from one state (Massachusetts) with unusually high overdose rates and broad insurance coverage, which may limit generalizability.

Practice Implications