Buprenorphine-Naloxone vs Extended-Release Naltrexone Following Opioid Withdrawal Treatment

Buprenorphine-naloxone and extended-release (XR) naltrexone are both efficacious medications for opioid use disorder that reduce unregulated opioid use and improve opioid cravings and treatment retention. While prior comparative effectiveness studies demonstrated superiority of buprenorphine-naloxone over XR naltrexone for relapse and treatment retention, the comparative effectiveness of both treatments for all-cause mortality and nonfatal opioid overdose outcomes has not been rigorously tested.

To compare the effectiveness of buprenorphine-naloxone vs XR naltrexone after medically managed opioid withdrawal (MMOW) treatment.

This observational comparative effectiveness study using a target trial emulation framework leveraged individually linked administrative data from the Massachusetts Public Health Data Warehouse to emulate the protocol of the Extended-Release Naltrexone vs Buprenorphine for Opioid Treatment randomized clinical trial. Participants included adults 18 years or older who were discharged from MMOW in Massachusetts between January 1, 2014, and December 31, 2018. Individuals could meet eligibility criteria more than once. Data were analyzed from December 22, 2023, to January 30, 2025.

Initiation of buprenorphine-naloxone or XR naltrexone therapy within 28 days of MMOW discharge.

Estimated 24-week cumulative incidence of all-cause mortality and nonfatal opioid overdose using inverse probability weighting to adjust for baseline and time-varying confounding.

A total of 36 752 unique individuals who met eligibility criteria were identified and contributed 106 052 MMOW discharge episodes; 79 089 (74.6%) episodes were among individuals who were male and 44 463 (42.1%) were among individuals aged 18 to 29 years. By 28 days after MMOW discharge, initiation of buprenorphine-naloxone was observed among 14 194 discharge episodes (13.4%) and initiation of XR naltrexone was observed among 4734 (4.5%) episodes. The adjusted 24-week cumulative incidence of all-cause mortality after MMOW discharge was 1.4% (95% CI, 1.2%-1.7%) for buprenorphine-naloxone and 1.4% (95% CI, 1.1%-1.8%) for XR naltrexone, corresponding to a risk difference of 0.0 percentage points (pp) (95% CI, -0.4 to 0.4 pp). The adjusted 24-week cumulative incidence of nonfatal opioid overdose after MMOW discharge was 11.6% (95% CI, 10.8%-12.3%) for buprenorphine-naloxone and 13.9% (95% CI, 12.9%-15.0%) for XR naltrexone, corresponding to a risk difference of 2.3 pp (95% CI, 1.2-3.6 pp).

In this comparative effectiveness study of buprenorphine-naloxone vs XR naltrexone, initiating buprenorphine-naloxone after MMOW discharge was associated with a lower risk of nonfatal opioid overdose at 24 weeks than initiating XR naltrexone, but a similar risk of all-cause mortality.