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

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

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.

Study Overview

• Status: Not yet recruiting
• Conditions: Postoperative Pain; Recovery
• Intervention / Treatment: Drug: Intravenous Methadone; Drug: Short-acting Opioids Intraoperative analgesia

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.

• Study Type: Interventional
• Enrollment (Estimated): 400
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: alexandre JOOSTEN, MD PhD; Phone Number: +13109627337; Email: AJOOSTEN@MEDNET.UCLA.EDU

Study Locations

• United States
  • California
    • Irvine, California, United States, 92697
      • UCI
      • Contact: SEAN COECKELENBERGH, MD PhD; Phone Number: +19496788922; Email: scoeckel@hs.uci.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Experimental Arm: Methadone-Based Anesthesia; Intervention: Drug: Methadone Intravenous methadone 0.25 mg/kg (ideal body weight) administered at induction Optional supplemental dose (2 mg) at emergence if clinically indicated Additional intraoperative short-acting opioids discouraged	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.
Active Comparator: Active Comparator Arm: Standard Opioid-Based Anesthesia; Intervention: Drug: Short-acting opioids Fentanyl and/or hydromorphone administered intraoperatively according to clinician judgment Reflects usual care practice	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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Quality of Recovery (QoR-15) score on postoperative day 1	Quality of recovery assessed using the validated 15-item QoR-15 questionnaire. Scores range from 0 to 150, with higher scores indicating better recovery.	Postoperative Day 1 (24 hours after surgery)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
QoR-15 score on postoperative day 2		Time Frame: Postoperative Day 2
Cumulative opioid consumption (MME)		Time Frame: 0-24 hours and 24-48 hours postoperatively
Maximum pain scores (Numeric Rating Scale)		Time Frame: Postoperative day 1 and 2
Opioid-free days		Time Frame: Within 7 days postoperatively
Opioid-related adverse events	Includes nausea, vomiting, sedation, respiratory depression	Time Frame: Up to 48 hours postoperatively
Health-related quality of life (EQ-5D-5L)	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.	30 days post-surgery

Collaborators and Investigators

• Sponsor: Alexandre P. Joosten
• Investigators: Study Director: Joseph Szokol, MD PhD, University of California, Los Angeles; Study Director: EVAN KARASCH, MD PhD, Duke

Study record dates

Study Major Dates

• Study Start (Estimated): July 1, 2026
• Primary Completion (Estimated): December 31, 2026
• Study Completion (Estimated): March 30, 2027

Study Registration Dates

• First Submitted: April 23, 2026
• First Submitted That Met QC Criteria: April 29, 2026
• First Posted (Actual): May 4, 2026

Study Record Updates

• Last Update Posted (Actual): May 4, 2026
• Last Update Submitted That Met QC Criteria: April 29, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: Methadone; Quality of Recovery; General Anesthesia; QoR-15; Multimodal Analgesia
• Additional Relevant MeSH Terms: Pain; Neurologic Manifestations; Postoperative Complications; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Signs and Symptoms; Pain, Postoperative
• Other Study ID Numbers: IRB-25-2394

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED
• IPD Plan Description: we will decide later

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No