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NCT Number: NCT07565870

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

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.

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Key information

Conditions

Postoperative Pain Neurologic Manifestations Pain Pain, Postoperative Pathologic Processes Pathological Conditions, Signs and Symptoms Postoperative Complications Recovery Signs and Symptoms

Age range

18 year and older

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 3

Primary location

About this study

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.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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

Treatment and study plan

Intravenous methadone

Drug

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.

Short-acting Opioids Intraoperative analgesia

Drug

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 outcomes

  1. Quality of Recovery (QoR-15) score on postoperative day 1

    Time frame: Postoperative Day 1 (24 hours after surgery)

    Quality of recovery assessed using the validated 15-item QoR-15 questionnaire. Scores range from 0 to 150, with higher scores indicating better recovery.

Secondary outcomes

  1. QoR-15 score on postoperative day 2

    Time frame: Time Frame: Postoperative Day 2

  2. Cumulative opioid consumption (MME)

    Time frame: Time Frame: 0-24 hours and 24-48 hours postoperatively

  3. Maximum pain scores (Numeric Rating Scale)

    Time frame: Time Frame: Postoperative day 1 and 2

  4. Opioid-free days

    Time frame: Time Frame: Within 7 days postoperatively

  5. Opioid-related adverse events

    Time frame: Time Frame: Up to 48 hours postoperatively

    Includes nausea, vomiting, sedation, respiratory depression

  6. Health-related quality of life (EQ-5D-5L)

    Time frame: 30 days post-surgery

    The EQ-5D-5L (EuroQol 5-Dimension 5-Level Version) is a health-related quality of life assessment tool that measures quality of life across five dimensions:

    Mobility: 1 = No problems, 5 = Extreme problems Self-care: 1 = No problems, 5 = Extreme problems Usual activities: 1 = No problems, 5 = Extreme problems Pain/discomfort: 1 = No problems, 5 = Extreme problems Anxiety/depression: 1 = Not at all, 5 = Extremely severe Each dimension is scored on a 5-level scale, allowing for a detailed assessment of health status.

Study contacts

Contact information is provided by the study sponsor or research team.

alexandre JOOSTEN, MD PhD

CONTACT

[email protected]

+13109627337

Sponsors and collaborators

Lead sponsor

Alexandre P. Joosten

Other

Registry information

Official study title

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

Acronym: MELODY

Important dates

Study start
2026
Primary completion
2026
Study completion
2027
First posted
May 4, 2026
Registry last updated
May 4, 2026

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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