AIMS: To examine mortality during and in the first year following extended-release naltrexone (XR-NTX) treatment in patients with opioid use disorder (OUD).

DESIGN: A prospective registry study. Two clinical trials in Norway. A total of 268 XR-NTX patients from two clinical trials conducted from 2013 to 2022.

MEASUREMENTS: Data from the inclusion interviews were cross-linked with data from the Norwegian Cause of Death Registry. Mortality during treatment was estimated for the first 30 days following a XR-NTX injection, while mortality following treatment cessation was examined from day 31 after the final XR-NTX injection until death or censoring. Surviving individuals were censored at 365 days. Crude mortality rates (CMR) and 95 % Confidence Intervals (CI) were calculated per 100 person-years (PY). We used the Kaplan-Meier method to estimate the survival functions and the log-rank test to compare survival distributions across different groups; male (no/yes), age (<30 years, 30-39 years, >39 years), injecting drug use (IDU) (no/yes), lifetime non-fatal overdose (no/yes), and treatment duration for six months (no/yes).

FINDINGS: Overall, there was only one non-drug-related death during treatment. In the year following treatment cessation,12 individuals died; two within the first 30 days. Ten of these deaths were from accidental poisonings. The overall CMR was 4.6 (95 % CI 2.5-7.5) per 100 PY,

CONCLUSION: The XR-NTX patients in the two clinical trials appeared to be protected from overdose death while in treatment but faced an elevated mortality risk in the year following treatment cessation.