Intraoperative Methadone for Post-craniotomy Pain Control: A Matched Cohort Exploratory Framework Study

Background Postoperative pain following craniotomy is commonly treated with multimodal analgesic regimens requiring frequent dosing, which contributes to an increased opioid burden. Methadone, a μ-opioid receptor agonist and N-methyl-D-aspartate (NMDA) receptor antagonist, may provide extended analgesia in craniotomy patients from a single intraoperative dose. Methods We performed a single-center feasibility retrospective matched cohort study of adult patients undergoing craniotomy for tumor resection between October 2024 and March 2025. Primary outcomes included postoperative pain scores and opioid consumption at 24, 48, and 72 hours. Results Thirty-two patients (eight methadone, 24 controls) were analyzed. Baseline demographics and perioperative characteristics were comparable. At 24 hours, pain scores and opioid use were similar between groups. At 48 and 72 hours, the methadone group demonstrated numerically lower pain scores and opioid consumption, though the study was underpowered to interpret these differences. No methadone-associated safety concerns were identified. Conclusions Intraoperative methadone was feasible and appeared comparable to conventional opioid regimens, with trends toward reduced pain and opioid use at later timepoints. These exploratory findings support further prospective trials to clarify the role of methadone in neurosurgical analgesia.