Respiratory Depression after Perioperative Methadone Administration: A Systematic Review and Meta-analysis

Despite evidence supporting methadone analgesic efficacy, perioperative methadone use remains limited due to concerns regarding respiratory depression. The aim of this systematic review and meta-analysis is to objectively evaluate the current evidence on the association between perioperative intravenous methadone administration and postoperative respiratory depression, compared with other opioids.1.

Ovid MEDLINE, Ovid Embase, Cochrane Central Register of Controlled Trials (CENTRAL), and Scopus were searched from January 1, 1970 to April 5, 2025. Eligible studies were randomized clinical trials (RCT) and retrospective studies comparing perioperative intravenous methadone administration with other opioids in adult or pediatric surgical patients and reporting postoperative respiratory depression events. Summary estimates were calculated as relative risks with a 95% confidence interval for the main analysis. The primary outcome was postoperative respiratory depression, defined as naloxone use, respiratory rate <8 breaths per minute, or SpO2 <90%.

Twenty-five studies comprising 116,815 surgical patients were included. Twelve RCTs (n = 845) contributed data to the primary analysis. Respiratory depression occurred in 7.7% of methadone-treated patients and 6.6% of controls. Methadone was not associated with a significant greater risk of respiratory depression (relative risk [RR] 1.22, 95% confidence interval [CI], 0.76-1.95). Bayesian meta-analysis, subgroup analyses stratified by methadone dose, timing of events, and surgical population, and analyses of retrospective studies did not reveal greater risk of respiratory depression. Certainty of evidence was rated very low due to risk of bias and lack of continuous monitoring strategies in most of the included studies.

Perioperative intravenous methadone was not associated with a higher risk of respiratory depression, compared to other opioids. The available evidence is predominantly derived from retrospective datasets, emphasizing the need for prospective studies with rigorous respiratory monitoring to further validate the safety of perioperative intravenous (i.v.) methadone administration.