OBJECTIVE Determine if a standardized methadone and lorazepam weaning protocol that is based on dose and duration of exposure can reduce the length of opioid and benzodiazepine weaning and shorten hospital stay. METHODS Retrospective cohort study performed in a 24-bed medical/surgical PICU. A total of 177 patients on opioid and/or benzodiazepine infusions for >3 days were included; 75 patients pre protocol (June 2012– June 2013) were compared with 102 patients post implementation of a standardized weaning protocol of methadone and lorazepam (March 2014–March 2015). The recommended wean was based on duration of infusions of >3 days up to 5 days (no wean), 5 to 13 days (short wean), and ≥14 days (long wean). RESULTS Median number of days on methadone for patients on opioid infusions for 5 to 13 days was reduced from 8.5 to 5.7 days (p = 0.001; n = 45 [pre], n = 68 [post]) and for patients on opioid infusions for ≥14 days, from 29.7 to 11.5 days (p = 0.003; n = 9 [pre], n = 9 [post]) after protocol implementation. The median number of days on lorazepam for patients on benzodiazepine infusions for 5 to 13 days was reduced from 8.1 to 5.2 days (p = 0.020; n = 43 [pre], n = 55 [post]) and for patients on benzodiazepine infusions for ≥14 days, from 27.4 to 9.3 days (p = 0.011; n = 9 [pre], n = 8 [post]). There was no difference in methadone or lorazepam wean length for patients on 3 to 5 days of infusions. There was no difference in adverse events or hospital length of stay. CONCLUSIONS A methadone and lorazepam weaning protocol based on patient's exposure to opioids and benzodiazepines (dose and duration) reduces weaning length.