Efficacy and safety of intravenous methadone for pain management in cardiac surgery: a systematic review and meta-analysis

Abstract

Objectives To evaluate the analgesic efficacy and safety of intraoperative intravenous methadone compared with conventional opioid-based analgesic regimens in adult patients undergoing cardiac surgery, using data derived from randomized controlled trials and retrospective cohort studies. Methods A comprehensive retrieval of scholarly literature was implemented in Embase, MEDLINE, PubMed, Web of Science, and the Cochrane Library until November 28, 2025. Randomized controlled trials and retrospective cohort studies comparing intraoperative methadone with other opioid analgesics for pain management in patients undergoing cardiac surgical procedures were eligible for inclusion in this meta-analysis. Quality of included studies was independently evaluated by two reviewers, with randomized controlled trials assessed using the Cochrane Risk of Bias tool (version 2.0) and cohort studies appraised using the Newcastle-Ottawa Scale. The primary outcome was postoperative pain intensity at 24 h. Secondary outcomes included postoperative 24-h opioid consumption, time to first rescue morphine administration, time to extubation, ICU length of stay, hospital length of stay, and reported adverse outcomes, including postoperative nausea, vomiting, and postoperative reintubation. Results Eight studies, including 4 randomized controlled trials and 4 retrospective cohort studies, involving 10,203 patients were included. Compared with conventional opioid analgesics, intraoperative methadone was associated with lower postoperative 24-h pain intensity (SMD, −0.44; 95% CI − 0.71 to −0.17; p = 0.001, I2 = 77%). Methadone was also associated with lower postoperative 24-h opioid consumption in the primary analysis (SMD, −0.72; 95% CI, −1.35 to −0.23; p = 0.02; I2 = 97%), No statistically significant differences were observed for overall time to first rescue morphine administration, time to extubation, ICU length of stay, or hospital length of stay. In randomized controlled trials, methadone was not associated with significant differences in postoperative nausea or vomiting, whereas reintubation was less frequent in the methadone group (RR, 0.75; 95% CI, 0.58 to 0.96; p = 0.02). In retrospective cohort studies, postoperative nausea and vomiting were slightly less frequent with methadone (RR, 0.96; 95% CI, 0.93 to 1.00; p = 0.04), but the magnitude of this association was small. Conclusion In adult patients undergoing cardiac surgery, intraoperative intravenous methadone may be associated with lower pain intensity and reduced opioid consumption during the first 24 h after surgery. However, substantial heterogeneity, inconsistent findings between randomized and retrospective studies, and incomplete reporting of key safety outcomes limit the certainty of the evidence. These findings should be interpreted cautiously, and further adequately powered randomized trials with standardized analgesic protocols and safety monitoring are needed. Systematic review registration https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD420251237093, identifier (CRD420251237093).