Rapid Inpatient Methadone Induction in the Fentanyl Era: A Systematic Review of Safety, Efficacy, and Protocols for Hospitalized Patients with Opioid Use Disorder

Abstract Purpose of Review The potency of illicit fentanyl has rendered standard methadone inductions inadequate for many hospitalized adults with opioid use disorder. Standard protocols often fail to achieve therapeutic doses quickly enough to manage withdrawal and cravings in fentanyl-tolerant individuals, contributing to poor retention and higher self-discharge rates. This review examines emerging evidence on dosing strategies, outcomes, and safety of rapid methadone inductions in acute-care hospitals. Recent Findings Nine studies (five retrospective cohorts, four case series/reports) encompassing 380 patients met inclusion criteria. Median starting doses were 30–40 mg (range 20–90 mg), with daily or symptom-triggered increases achieving 60–100 mg within 5–7 days—substantially faster than outpatient schedules. Sedation occurred in 6.4% of patients, while severe sedation requiring naloxone or ICU transfer was rare (0.4%). No in-hospital deaths, malignant arrhythmias, or torsades de pointes were reported. The only study assessing post-discharge outcomes found no overdoses within 30 days. Rapid titration improved retention, with self-discharge against medical advice ranging from 4 to 19% overall and significantly lower among pregnant patients than with slower titration (23.0% vs. 37.9%). Pregnant individuals, those with infections, and polysubstance users tolerated rapid induction without excess adverse events. Summary Observational data suggest that rapid inpatient methadone titration can safely and effectively reach therapeutic doses within one week, even in fentanyl-tolerant patients. The approach may enhance hospital retention and facilitate smoother transitions to outpatient care. Controlled prospective trials are necessary to determine optimal dosing algorithms, monitor adverse effects, and assess long-term outcomes following discharge.