Safety of rapid inpatient methadone initiation protocol: A retrospective cohort study

Background: Current methadone titration guidelines recommend low initial doses (15–40 mg) and slow increases (10–20 mg every 3 to 7 days) to prevent dose accumulation and oversedation until reaching a target therapeutic dose between 60 and 120 mg. These guidelines were created primarily for outpatient settings in the pre-fentanyl era. Methadone initiations are becoming more common in hospitals, but no titration guidelines exist specific to this treatment setting, which has capacity for increased monitoring. Our objective was to assess the safety of rapid inpatient methadone initiation with regard to mortality, overdose, and serious adverse outcomes both in-hospital and postdischarge. Methods: This is a retrospective, observational, cohort study conducted at an urban, academic medical center in the United States. We queried our electronic medical record for hospitalized adults with moderate to severe opioid use disorder admitted between July 1, 2018, and November 30, 2021. Included patients were rapidly initiated on methadone with 30 mg as the initial dose and 10 mg increases daily until reaching 60 mg. The study extracted thirty-day post-discharge opioid overdose and mortality data from the CRISP database. Results: Twenty-five hospitalized patients received rapid methadone initiation during the study period. The study had no major adverse events including in-hospital or thirty-day post-discharge overdoses or deaths. The study did have two instances of sedation, but neither led to methadone dose holds. There were no instances of QTc prolongation. The study had one patient-directed discharge. Conclusions: This study demonstrated that a small subset of hospitalized patients tolerated rapid methadone initiation. More rapid titrations can be utilized in a monitored inpatient setting to retain patients in the hospital and allow providers to account for increased tolerance in the fentanyl era. Guidelines should be updated to reflect the capabilities of inpatient settings to safely initiate and rapidly titrate methadone. Further work should determine optimal methadone initiation protocols in the fentanyl era.