Safety and effectiveness of rapid methadone titration protocols in opioid use disorder: A systematic review

Background and aims Methadone is an effective, first‐line treatment for opioid use disorder. Guidelines recommend slow titration to minimize the risk of methadone toxicity, a process exposing patients to sub‐therapeutic doses for weeks to months. Protocols that titrate more rapidly reduce the time to achieving a therapeutic dose. This systematic review evaluated the safety and effectiveness of rapid methadone titrations in patients with opioid use disorder. Method Systematic review of prospective and retrospective studies of patients undergoing rapid methadone titration for treatment of opioid use disorder. Both outpatient and inpatient/acute settings were included. Results A total of 4297 records were screened from MEDLINE, EMBASE, Cochrane CENTRAL and PsycINFO. Following the initial screen, 79 texts were reviewed in full, with 29 studies included in the review, representing 16 154 participants. A wide variety of rapid titration schedules were described across inpatient and outpatient settings. A common protocol (6 studies) started at 30–40 mg, with additional 10 mg every 3–4 hours as needed up to 50–80 mg on day 1. Average dose on day 7 ranged from 53 to 97 mg across 5 randomised controlled trials/cohort studies ( n = 14 758) and from 60 to 200 mg in 5 case series/case reports ( n = 124). Among 26 studies reporting on mortality ( n = 1431), there were 63 deaths in 3 outpatient studies over 2–180 days after starting methadone; 61 deaths were from 2 case series that specifically selected cases of death from coroner reports. Among all 18 studies conducted in the fentanyl era (post‐2013, n = 705), and all 18 inpatient studies from any time period ( n = 604) reporting on mortality, there were no deaths reported. Overdose rates were less than 1% across all studies and sedation events were often mild, with most patients continuing methadone. One study found a correlation between improved retention rates and higher methadone doses during the first week of initiation. Pooled analysis could not be performed due to substantial heterogeneity across studies. Summary A wide range of rapid methadone titration protocols for opioid use disorder are described in the literature, with generally low‐quality evidence and little standardization in protocols or evaluations. Overall adverse events were rare, particularly with rapid methadone titration in the fentanyl era and during inpatient admissions. Data on retention in treatment and changes in unregulated drug use were limited.