Postoperative pain control remains suboptimal for a large proportion of surgical patients and is frequently associated with slower recovery and higher reliance on opioids after surgery. Current intraoperative analgesic approaches predominantly use short-acting opioids, whose rapid pharmacokinetics can lead to variable drug exposure and inconsistent control of nociceptive stimuli.

Methadone has a different pharmacologic profile, combining prolonged μ-opioid receptor activity with N-methyl-D-aspartate receptor antagonism, allowing sustained analgesia following a single intraoperative administration and potentially enhancing postoperative recovery.

The MELODY trial is a multicentre, randomized, patient-blinded clinical study designed to compare a single intravenous dose of methadone given at induction with conventional short-acting opioid-based anesthesia in adults undergoing intermediate-risk noncardiac surgery. The primary aim is to evaluate whether this strategy leads to improved quality of recovery on the first postoperative day.

Acute postoperative pain remains insufficiently controlled in a substantial proportion of surgical patients, with more than half reporting moderate-to-severe pain after surgery. Standard intraoperative opioid strategies rely on short-acting agents such as fentanyl or hydromorphone, which are associated with rapid clearance and fluctuating plasma concentrations that may contribute to variability in nociceptive control and increased postoperative opioid requirements.

Methadone offers a pharmacologic profile that may address these limitations. It provides prolonged analgesic effect due to its long elimination half-life, rapid effect-site equilibration, and additional N-methyl-D-aspartate receptor antagonism, potentially reducing central sensitization and improving postoperative pain control.

The MELODY trial is a multicentre, patient-blinded, randomized, parallel-group superiority trial conducted across University of California hospitals. Participants are randomized in a 1:1 ratio to receive either intravenous methadone at induction or standard short-acting opioid-based anesthesia.

All patients receive a standardized multimodal analgesic regimen to isolate the effect of the intraoperative opioid strategy. The primary outcome is quality of recovery on postoperative day 1, assessed using the validated Quality of Recovery-15 (QoR-15) questionnaire. Secondary outcomes include opioid consumption, pain scores, opioid-related adverse events, and health-related quality of life.

Inclusion Criteria

• Age ≥18 years
• Elective intermediate-risk noncardiac surgery under general anesthesia
• ASA physical status I-III
• Expected hospital stay ≥24 hours
• Ability to provide informed consent

Exclusion Criteria

• Severe hepatic dysfunction (Child-Pugh C)
• Severe renal impairment (eGFR <30 mL/min/1.73 m²)
• Known allergy to methadone or opioids
• Pregnancy or breastfeeding
• Chronic opioid use or opioid use disorder
• Planned use of epidural or regional analgesia
• Inability to complete study assessments

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Participants will be blinded to treatment allocation. The intraoperative anesthesiologist cannot be blinded due to the nature of drug preparation and administration. Postoperative care providers, including PACU nurses and surgical teams, may have access to the anesthesia record and are therefore not blinded. Outcome assessment is based on patient-reported measures (QoR-15), which are collected without disclosure of group assignment. Data analysis will be conducted using de-identified datasets.