Importance: In opioid treatment programs (OTPs), restarting methadone after missed doses is common. Current guidelines recommend significant dose decreases but do not account for maintained tolerance.

Question: Are individualized higher methadone restart doses after a gap in daily dosing associated with safety and effectiveness?

Findings: In this cohort study, a new clinical protocol that individualized methadone restart doses by accounting for maintenance of opioid tolerance after a gap in methadone treatment was associated with significantly higher restart doses without any changes in opioid-related harms or treatment retention.

Meaning: These results suggest that more individualized methadone restart dosing that accounts for maintenance of opioid tolerance may promote higher restart doses that are closer to therapeutic levels without increased patient harm.