Dosing and Safety of Methadone Initiation in the Setting of Fentanyl: A Systematic Review
Abstract
BACKGROUND
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.
METHODS
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.
RESULTS
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…
How strong is the evidence?
Evidence Hub reads this as a systematic review, done in people. Its evidence level is 1 of 5 (Highest · pooled evidence). Pooled evidence from several studies sits at the top of the evidence pyramid.
Read the paper
Related studies
- Drug repositioning: a brief overview
- Cyclic nucleotide phosphodiesterases in Drosophila melanogaster
- Time-resolved in silico modeling of fine-tuned cAMP signaling in platelets: feedback loops, titrated phosphorylations and pharmacological modulation
- Current View on Green Tea Catechins Formulations, Their Interactions with Selected Drugs, and Prospective Applications for Various Health Conditions
- In silico Structure-based Identification of Novel Acetylcholinesterase Inhibitors Against Alzheimer’s Disease
- Development and In Vitro Evaluation of Controlled Release Viagra® Containing Poloxamer-188 Using Gastroplus™ PBPK Modeling Software for In Vivo Predictions and Pharmacokinetic Assessments
Go deeper in Evidence Hub
Evidence Hub adds a study data sheet (design, sample size, evidence level, key numbers), an AI summary and a chat grounded in the paper's text.