Importance: Injectable extended-release (XR)-naltrexone is an effective treatment option for opioid use disorder (OUD), but the need to withdraw patients from opioid treatment prior to initiation is a barrier to implementation.

Question: Can the opioid antagonist injectable extended-release (XR)-naltrexone be started in patients with active opioid use disorder (OUD) with a rapid (5-7 days) procedure?

Findings: In a 6-site stepped wedge cluster randomized clinical trial that included 415 individuals with OUD, more patients successfully initiated XR-naltrexone using the rapid procedure (62.7%) compared with a standard (12-14 days) procedure (35.8%). The rapid procedure was shown to be both noninferior and superior, but had a higher number of safety events and serious adverse events and required more staff attention.

Meaning: The findings of this trial suggest that a rapid approach to withdrawal management should be considered for patients with OUD attempting to start treatment with XR-naltrexone, but more intensive staffing needs may be a barrier to implementation.