Opioid Agonist Therapy for Fentanyl-Related Opioid Use Disorder: A Systematic Review

While treatment guidelines for opioid use disorder (OUD) are well-established, specific guidance for people who use fentanyl remains limited. This systematic review is the first to examine effectiveness and safety outcomes associated with opioid agonist therapy (OAT), specifically buprenorphine, methadone, and slow-release oral morphine, in this patient population.

Following PRISMA guidelines, we systematically searched EMBASE, Medline, PsycINFO, CENTRAL (all via Ovid), and Scopus from inception to April 2025 for studies reporting OAT for fentanyl-related OUD. Primary outcomes included OAT titration time, treatment retention, withdrawal symptoms, remission, nonprescribed fentanyl use, and mortality. Risk of bias was assessed using the Cochrane risk of bias tools. Results were synthesized narratively.

We identified 180 studies for inclusion (sample sizes ranging from 1 to 150,000). Several reports described treatment success using novel strategies, including low-dose ("microdosing," Bernese method) and high-dose buprenorphine ("macrodosing"), and rapid high-dose methadone protocols that deviate from standard guidelines.

Emerging, yet primarily low-quality evidence suggests novel OAT induction strategies for fentanyl-related OUD are feasible and show a consistent direction toward positive clinical and safety outcomes. High-quality research specific to this population, comparing conventional to novel strategies, is needed.