Postoperative Pain, Recovery
Conditions
Keywords
Methadone, QoR-15, Quality of Recovery, Multimodal Analgesia, General Anesthesia
Brief summary
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
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.
DRUGShort-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.
Sponsors
Alexandre P. Joosten
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Subject)
Masking description
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.
Intervention model description
randomized, parralle-group, superiority study
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Quality of Recovery (QoR-15) score on postoperative day 1 | 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
| Measure | Time frame | Description |
|---|---|---|
| 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 | Time Frame: Up to 48 hours postoperatively | Includes nausea, vomiting, sedation, respiratory depression |
| Health-related quality of life (EQ-5D-5L) | 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. |
Countries
United States
Contacts
CONTACTalexandre JOOSTEN, MD PhD
STUDY_DIRECTORJoseph Szokol, MD PhD
University of California, Los Angeles
STUDY_DIRECTOREVAN KARASCH, MD PhD
DUKE
Outcome results
None listed