Authors: Croft Z A et al.
Cureus 18(2): e102846, February 02, 2026
In this retrospective matched cohort exploratory study, Croft and colleagues evaluated whether a single intraoperative dose of methadone improves post-craniotomy pain control compared with conventional short-acting opioid regimens. Thirty-two adult patients undergoing supratentorial craniotomy for tumor resection were analyzed, including eight who received intraoperative IV methadone (10–20 mg) and 24 matched controls.
The rationale centers on methadone’s dual mechanism: μ-opioid receptor agonism and NMDA receptor antagonism. This combination may reduce central sensitization and opioid-induced hyperalgesia while providing prolonged analgesia due to methadone’s long and variable half-life. In contrast to fentanyl and other short-acting opioids, methadone’s clinical effect can extend 24–36 hours or longer following a single intraoperative dose.
Pain scores and opioid use (converted to morphine milligram equivalents, MMEs) were measured at 24, 48, and 72 hours. At 24 hours, pain scores and opioid consumption were similar between groups. By 48 hours, the methadone group showed numerically lower pain scores and reduced opioid use, though these differences did not reach statistical significance. At 72 hours, outcomes were again comparable. The study was clearly underpowered, with only eight methadone patients, limiting interpretation of effect size.
Importantly, no methadone-specific adverse events were identified. Minor complication rates were similar between groups, and serious complications occurred only in the control group. However, with such small sample sizes, definitive safety comparisons cannot be made. The investigators appropriately emphasize that MME comparisons may underestimate methadone’s analgesic contribution because MME conversion does not account for pharmacokinetic duration or receptor kinetics of long-acting opioids.
Clinically, the exploratory signal suggests that intraoperative methadone may provide durable analgesia through the high-risk postoperative window (48–72 hours), potentially reducing repeated short-acting opioid dosing. In neurosurgical patients—where sedation must be minimized to allow reliable neurologic assessments—this is particularly relevant. However, the authors correctly frame methadone here as hypothesis-generating rather than practice-defining.
Key Points
• Post-craniotomy pain remains common and often undertreated due to concerns about neurologic assessment and opioid side effects.
• A single intraoperative dose of methadone (10–20 mg) was feasible and showed trends toward lower pain and opioid use at 48 hours.
• No safety signal attributable to methadone was observed in this small cohort.
• MME comparisons may underestimate the contribution of long-acting opioids like methadone.
• Larger, prospective randomized trials are required before routine adoption in neurosurgical anesthesia.
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