Dosing and Safety of Methadone Initiation in the Setting of Fentanyl: A Systematic Review

The rise of high-potency synthetic opioids such as fentanyl in the illicit opioid supply has contributed to increased overdose deaths and complicated methadone initiation for opioid use disorder (OUD). Traditional methadone initiation protocols may be insufficient in the context of fentanyl's high potency and pharmacokinetics. This systematic review evaluates current evidence on accelerated (≥60 mg within the first 7 d of treatment) methadone initiation strategies.

Following PRISMA guidelines, we conducted a comprehensive search of databases for studies from 2013 to June 16, 2025, reporting on methadone initiation in fentanyl-exposed patients. Key outcomes included patient selection, dosing, retention, and adverse events.

Ten observational studies met the inclusion criteria, with 8 inpatient, 2 outpatient, and 2 studies focused on pregnant individuals. Studies selected for 18- to 65-year-olds without end-organ failure, QTc prolongation, or medications affecting methadone metabolism. The mean and median dose on day 1 ranged from 30 to 53.4 mg (pooled weighted mean=40.7 mg). By day 5, doses increased to 59.2-90 mg (pooled weighted mean=70.2 mg), and by day 7 to 65-100 mg (pooled weighted mean=81.9 mg). Patient-directed discharge occurred in 0%-31% of patients. Sedation occurred in 0%-28.6% of patients, while severe adverse events (requiring naloxone, ICU admission, intubation, or death) occurred in 1.08% of treatment episodes. The certainty of evidence was very low using a GRADE framework.

The current observational literature is limited, with some support for accelerated methadone initiation in inpatient and outpatient settings for appropriately selected patients exposed to fentanyl.