Buprenorphine-naloxone tied to lower overdose risk vs extended-release naltrexone

Clinical takeaway: After medically managed opioid withdrawal, buprenorphine-naloxone may be the preferred medication for many patients because it was associated with fewer nonfatal opioid overdoses than extended-release naltrexone, while mortality was similar. Prioritizing rapid treatment initiation and improving retention remain critical regardless of medication choice.

The weeks after medically managed opioid withdrawal are among the highest-risk periods for opioid overdose. Although both buprenorphine-naloxone and extended-release (XR) naltrexone are FDA-approved treatments for opioid use disorder, clinicians have had limited evidence comparing their effects on overdose and mortality in routine practice.

A large target trial emulation using linked Massachusetts administrative data found that patients who initiated buprenorphine-naloxone after discharge from opioid withdrawal treatment experienced fewer nonfatal opioid overdoses over the next 24 weeks than those who started XR naltrexone.

The study included 106,052 withdrawal-treatment discharge episodes among 36,752 adults between 2014 and 2018. The adjusted 24-week risk of nonfatal opioid overdose was 11.6% with buprenorphine-naloxone versus 13.9% with XR naltrexone, an absolute risk difference of 2.3 percentage points. All-cause mortality was identical in both groups at 1.4%.

These findings extend prior randomized trial data, which suggested better treatment retention with buprenorphine but were not large enough to reliably assess overdose or mortality. The authors noted that buprenorphine users were more likely to remain on medication over time, and exploratory analyses showed that overdose and death rates were higher during periods when patients were no longer receiving medication for opioid use disorder.

The results also underscore the substantial ongoing risk after withdrawal treatment regardless of medication choice. More than one in ten patients experienced a nonfatal opioid overdose within 24 weeks, highlighting the importance of rapid treatment initiation, continued engagement in care, and strategies to improve long-term medication retention.

Source: Hsu HE, et al. (2026 Jul 14) JAMA Netw Open. Buprenorphine-Naloxone vs Extended-Release Naltrexone Following Opioid Withdrawal Treatment