Methadone for Enhanced Postoperative Analgesia in Intermediate-Risk Noncardiac Surgery (MELODY)

Official title

Methadone for Enhanced Postoperative Analgesia in Intermediate-Risk Noncardiac Surgery: A Multicentre Randomized Controlled Trial (MELODY Trial)

Overview

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.

Detailed description

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.

Interventions

• Drug Intravenous Methadone
  Intervention Description - Intravenous Methadone A single intravenous dose of methadone (0.25 mg/kg based on ideal body weight) administered at induction of anesthesia to provide sustained intraoperative and early postoperative analgesia. Additional short-acting opioids are discouraged but may be administered if clinically required. A supplemental dose of methadone (2 mg) may be given at emergence in case of significant nociceptive signs.
• Drug Short-acting Opioids Intraoperative analgesia
  ntervention Description - Short-acting Opioids Intraoperative analgesia using short-acting opioids (e.g., fentanyl and/or hydromorphone) administered at induction and throughout surgery according to clinician judgment and institutional practice. This approach reflects usual care, with dosing and timing determined pragmatically based on intraoperative needs.

Primary outcome measures

• Quality of Recovery (QoR-15) score on postoperative day 1 [Time frame: Postoperative Day 1 (24 hours after surgery)]

Secondary outcome measures (6)

• QoR-15 score on postoperative day 2 [Time frame: Time Frame: Postoperative Day 2]
• Cumulative opioid consumption (MME) [Time frame: Time Frame: 0-24 hours and 24-48 hours postoperatively]
• Maximum pain scores (Numeric Rating Scale) [Time frame: Time Frame: Postoperative day 1 and 2]
• Opioid-free days [Time frame: Time Frame: Within 7 days postoperatively]
• Opioid-related adverse events [Time frame: Time Frame: Up to 48 hours postoperatively]
• Health-related quality of life (EQ-5D-5L) [Time frame: 30 days post-surgery]

Eligibility criteria

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

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Single blind

Primary purpose

Treatment

Study locations

United States · 1 center

• UCI — Irvine

Identifiers

NCT: NCT07565870 · IRB-25-2394

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗