Postoperative pain remains inadequately controlled in a substantial proportion of surgical patients, with more than 40% reporting unsatisfactory analgesia despite advances in perioperative care [1]. Traditional intraoperative opioid strategies rely on short-acting agents such as fentanyl, which may produce fluctuating plasma concentrations. In some cases, methadone, a long-acting µ-opioid agonist with additional N-methyl-D-aspartate (NMDA) receptor antagonism and monoamine reuptake inhibition, is a viable alternative to fentanyl for intraoperative pain management.
A randomized, double-blind trial in 156 cardiac surgical patients compared intraoperative methadone (0.3 mg/kg) with fentanyl (12 µg/kg) [2]. Patients receiving methadone required significantly less morphine in the first 24 postoperative hours (median 6 mg vs 10 mg) and reported lower pain scores with coughing at 12 hours. Methadone-treated patients also reported greater satisfaction with pain management throughout the first three postoperative days, with no corresponding increase in opioid-related adverse events such as nausea, sedation, or hypoventilation. Importantly, despite methadone’s considerably longer half-life, times to extubation and ICU discharge did not differ between groups.
Similar findings have been reported outside cardiac surgery. In morbidly obese patients undergoing open bariatric surgery, intraoperative methadone reduced postoperative morphine consumption by roughly half across multiple time intervals up to 48 hours, lowered pain scores at rest and with coughing, and was associated with less nausea and vomiting and higher satisfaction scores compared with fentanyl—all promising outcomes for pain management [3]. Notably, this trial also found reduced evoked pain at the surgical scar three months after surgery in the methadone group, suggesting a possible effect on the transition to chronic postsurgical pain. In ambulatory surgery, a dose-finding pilot study identified 0.15 mg/kg (ideal body weight) as an effective intraoperative methadone dose that heavily reduced the need for postanesthesia care unit opioids and opioid consumption for up to 30 days after discharge, again without increasing sedation, respiratory depression, or delaying recovery [4].
A systematic review and meta-analysis pooling ten randomized trials (617 patients) across cardiac, orthopedic, and general surgical populations corroborates these individual findings [5]. Patients in this study receiving intraoperative methadone consumed significantly less opioids at 24 hours (mean difference −15.22 mg oral morphine equivalents) and reported greater satisfaction with analgesia, although substantial heterogeneity between studies was noted. Most included trials reported lower pain scores in the methadone group, with no significant differences in nausea, pruritus, sedation, respiratory depression, or hypoxemia compared with shorter-acting opioids. However, the authors caution that the included studies were generally small and underpowered to detect rare but serious adverse events, particularly respiratory depression and arrhythmia, both of which have been reported at much higher rates in larger observational cohorts receiving intraoperative methadone outside the trial setting.
The available evidence suggests that, in certain surgical cases, intraoperative methadone dose can improve surgical pain management compared to fentanyl, without clear evidence of increased short-term opioid-related morbidity. Optimal dosing varies by procedure and population, safety data on rare adverse events remain limited, and high-risk patients have generally been excluded from trials to date. For short procedures in which prolonged opioid effects are undesirable, fentanyl may remain the preferred choice. Clinicians considering intraoperative methadone should weigh these analgesic benefits against the drug’s long and variable half-life, arrhythmia potential, and the relative paucity of large, adequately powered safety data before broader adoption.
References
- Gan, T. J. Poorly controlled postoperative pain: prevalence, consequences, and prevention. J. Pain Res. 10, 2287–2298 (2017). https://doi.org/10.2147/JPR.S144066
- Murphy, G. S. et al. Intraoperative methadone for the prevention of postoperative pain: a randomized, double-blinded clinical trial in cardiac surgical patients. Anesthesiology 122, 1112–1122 (2015). https://doi.org/10.1097/ALN.0000000000000633
- Machado, F. C., Palmeira, C. C. A., Torres, J. N. L., Vieira, J. E. & Ashmawi, H. A. Intraoperative use of methadone improves control of postoperative pain in morbidly obese patients: a randomized controlled study. J. Pain Res. 11, 2123–2129 (2018). https://doi.org/10.2147/JPR.S172235
- Komen, H., Brunt, L. M., Deych, E., Blood, J. & Kharasch, E. D. Intraoperative methadone in same-day ambulatory surgery: a randomized, double-blinded, dose-finding pilot study. Anesth. Analg. (2018). https://doi.org/10.1213/ANE.0000000000003464
- D’Souza, R. S., Gurrieri, C., Johnson, R. L., Warner, N. & Wittwer, E. Intraoperative methadone administration and postoperative pain control: a systematic review and meta-analysis. Pain (2019). https://doi.org/10.1097/j.pain.0000000000001717