Respiratory Depression Following Intraoperative Methadone: A Retrospective Cohort Study

Methadone is used as a perioperative analgesic in the management of postoperative pain. Despite positive outcomes from randomized trials favoring methadone, concerns about its safety persist, particularly regarding respiratory depression (RD) and excessive sedation. In this study, we compared the incidence of naloxone administration between patients administered intraoperative methadone and those administered intraoperative morphine as a measure of severe RD. Time spent at the postanesthesia care unit (PACU) was used as a proxy variable for excessive sedation.

This was a retrospective cohort study including all patients aged ≥18 years who underwent surgery between March 2019 and March 2023 at Aarhus University Hospital, Denmark. We assessed the association between intraoperative administration of either methadone or morphine and postoperative naloxone administration within the first 24 hours using logistic regression (primary outcome). An analogous linear regression model was used for the secondary outcome of time spent in the PACU after surgery. Patients were weighted using propensity scores to adjust for potential confounding variables.

A total of 14,522 patients were included in the analysis. Among the 2437 patients who received intraoperative methadone, 15 (0.62%) patients received naloxone within the first 24 hours after surgery compared to 68 of 12,0885 (0.56%) who received intraoperative morphine. No statistical difference was observed in the odds of naloxone administration between patients administered methadone or morphine (adjusted odds ratio 95% confidence interval [CI], 1.21 [0.40-2.02]). Patients who were administered intraoperative methadone had a mean PACU length of stay (LOS) of 334 minutes (standard deviation [SD], 382) compared to 195 minutes (SD, 228) for those administered intraoperative morphine. The adjusted PACU LOS of patients administered intraoperative methadone was 26% longer compared to those administered intraoperative morphine (adjusted ratio of the geometric means 95% CI, 1.26 [1.22-1.31]).

The incidence of naloxone administration to treat severe RD was low. No difference was observed in the odds of naloxone administration to treat severe RD between patients administered intraoperative methadone or intraoperative morphine. Intraoperative methadone was associated with longer stays at the PACU; however, this result should be interpreted with care. Our findings suggest that intraoperative methadone has a safety profile comparable to that of morphine with regard to severe RD.