Evaluation of Analgesia for Cardiac Elective Surgery in Children

Phase 3

Not yet recruiting

• Conditions: Pediatric Cardiac Surgery
• Interventions: Drug: Methadone based ERAS; Drug: Non-methadone based group

• Registration Number: NCT06626035
• Lead Sponsor: Senthil Sadhasivam

Brief Summary

The purpose of this study is to look at a standardized methadone-based enhanced recovery after surgery protocol following pediatric cardiac surgery. This study will consist of randomly assigning children to receive the methadone-based recovery procedures or to receive current standard of care recovery procedures. Randomly assigning means that there is a 50/50 chance, like a coin flip, of being assigned to either research group.

Detailed Description

Specific Aims Aim 1. Conduct a randomized clinical trial in cardiac surgery (CS) to compare acute pain relief, opioid-sparing efficacy, and safety of standardized perioperative multidose methadone-based enhanced recovery after surgery (ERAS) vs. standard-of-care non-methadone-based analgesia.

Aim 2. Develop precision methadone dosing based on age, CYP2B6 and ORM1 variants, and alpha acid glycoprotein (AAG) levels, cardio-pulmonary bypass (CPB) related dilution.

Aim 3. Identify patient profiles that predict benefits from the assigned analgesia protocol to optimize clinical outcomes. Personalized risk prediction models will be developed and validated including genetic variants (i.e., CYP2B6, CYP2D6, ABCB1, OPRM1, and FAAH), and psychological and clinical factors to predict benefit with the assigned treatments (methadone or non-methadone) for pre-specified clinical endpoints (i.e., lower acute surgical pain, respiratory depression \[RD\], postoperative nausea and vomiting \[PONV\], opioid dependence \[OD\], and chronic postsurgical pain \[CPSP\]) in cardiac surgery.

Overall Impact Investigators will develop actionable evidence for the efficacy of standardized, multidose, methadone-based ERAS protocols and will harness genetic, clinical, and psychological factors contributing to variability in methadone and oxycodone PK, acute surgical pain, transition to CPSP, opioid-induced PONV, RD, and dependence to develop personalized analgesia strategy and dosing for children undergoing cardiac surgery. Implementation of evidence-based standardized methadone-based ERAS pain management and individualized risk prediction will maximize acute surgical pain relief while minimizing opioid use and AEs in millions of children.

Hypothesis The central hypothesis is that a standardized, multidose, methadone-based ERAS protocol will reduce acute surgical pain, overall opioid use, RD, PONV and CPSP compared with standard-of-care short-acting opioid-based analgesia in children undergoing cardiac surgery. The long-term goal is to proactively improve the safety and efficacy of surgical pain control while reducing opioid AEs and the opioid epidemic burden in all children undergoing inpatient surgeries. Further, we hypothesize that age, CYP2B6 and ORM1 variants, AAG levels, and CPB-related dilution will explain methadone's PK variability and dose adjustments that correlate with optimal clinical outcomes, and that patient profiles based on genetic, psychological, and that clinical factors will predict benefits from the assigned analgesia protocol to optimize clinical outcomes.

Study Timeline

• Study First Submitted: 2024-06-15
• Study First Submitted QC: 2024-10-01
• Study First Posted: 2024-10-03
• Status Verified: 2025-01
• Last Update Submitted: 2025-08-15
• Last Update Posted: 2025-08-22
• Study Start: 2025-10-01
• Primary Completion: 2029-01-31
• Study Completion: 2029-08-31

Recruitment & Eligibility

• Status: NOT_YET_RECRUITING
• Sex: All
• Target Recruitment: 500

Inclusion Criteria

• Children aged 3-years - <18 years
• ASA physical status 1, 2, or 3
• Participant or legal guardian can speak and read English or Spanish
• Undergoing the following cardiac surgeries (Categories 1 & 2) that are associated with significant acute surgical pain

STS Category 1:

• ASD, PFO closure
• VSD repairs,
• Aortic stenosis sub-valvular repair
• ASD and Partial anomalous venous return repair
• AV canal transitional
• Conduit replacement
• Valve replacement (AVR, PVR)
• TOF repair without ventriculostomy

STS Category 2:

• Glenn shunt (on Bypass only)
• Fontan surgery (on Bypass only)
• Pulmonary artery plasty (main)
• Left Atrium (LA) to Pulmonary Artery (PA) conduit replacement.

Exclusion Criteria

• Pregnant patients
• Methadone allergy
• Preoperative prolonged QTc more than 460 msec (-30 days to 0 day)
• Subjects undergoing concomitant treatment with known cytochrome P450 inhibitors included in methadone labeling (i.e. macrolides (e.g. erythromycin), azole-antifungal agents (e.g. ketoconazole, voriconazole), protease inhibitors (e.g. ritonavir), fluconazole, SSRIs (e.g. sertraline, fluvoxamine)
• Preoperative opioid use within 30 days before surgery
• History of severe sleep apnea (have a sleep study with an AHI index score more than 10 or clinical signs of sleep disordered breathing - snoring, daytime drowsiness)
• Significant liver, kidney, neurological disease, developmental delay, or any other co-existing medical condition per discretion of the clinical investigator

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Methadone-Based ERAS Group	Methadone based ERAS	The methadone-based standardized analgesia intervention arm will include standardized perioperative care and analgesia, including intraoperative intravenous methadone (1st dose: 0.1 mg/kg up to a maximum of 5 mg before incision; 2nd dose: 0.1 mg/kg up to a maximum of 5 mg 4 hours after 1st dose) and postoperatively, up to 4 oral or IV doses of methadone (0.1 mg/kg up to a maximum of 5 mg) every 12 hours before discharge as part of standardized multimodal analgesia in the hospital setting.
Non-Methadone-Based Group	Non-methadone based group	Children randomized to the standard-of-care arm will receive standard opioid analgesia protocol without intra- and post-operative methadone per the current site standards.

Primary Outcome Measures

Name	Time	Method
Average postoperative pain scores	Postoperative 48 hours	Average postoperative pain scores within 48 hours of surgery (Numerical Rating Scale \[NRS\], or Facial expression, Leg movement, Activity, Cry, and Consolability \[FLACC\], both 0-10). Outcome will be reported based on area under the curve (AUC) as mean(SD).
Total postoperative opioid use	Postoperative 48 hours	Total Opioid use in Morphine Milligram Equivalents (MME) (mg), will be reported as mean (SD).

Secondary Outcome Measures

Name	Time	Method
Incidence of Inpatient Respiratory Depression (RD)	Postoperative 120-hours	RD is defined as respiratory rate \<8 breaths per minute requiring oxygen in the absence of airway obstruction. Outcome measure will be reported as n(%).
Incidence of Inpatient Postoperative Nausea and Vomiting (PONV)	Postoperative 120-hours	PONV will be assessed by self-report, EMR, and medication use. Outcome measure will be reported as n(%).
Incidence of Inpatient Sedation	Postoperative 120-hours	Sedation will be assessed using the Ramsay Sedation Scale (RSS) and validated sedation scales extracted from the EMR. Outcome measure will be reported as n(%)
QTc Prolongation	Postoperative 48-hours	QTc prolongation is defined as more than 460 msec. Outcome measure will be reported as n(%).
Length of Hospital Stay (LOS)	Up to 30 days	LOS will be recorded in days. Outcome measure will be reported as mean(SD).
Persistent Opioid Use	1-week, 1-month, and 3-months post-surgery	Based on Prescription Drug Monitoring Program (PDMP) and self-report data. Outcome measure will be reported as n(%)
Presence of Chronic Postsurgical Pain (CPSP) at 3-months	3-months post-surgery	CPSP incidence will be defined using NRS pain \>3/10 and functional limitations based on Functional Disability Inventory (FDI). NRS pain scores are on a scale of 0=no pain at all and 10=worst pain imaginable. Outcome measure will be reported as n(%)
Presence of Opioid Dependence (OD) at 3-months	3-months post-surgery	OD will be assessed using PROMIS and Prescription Pain Medication Misuse (PPMM). Outcome measure will be reported as n(%).

Trial Locations

Locations (1)

UPMC Children's Hospital; 🇺🇸 Pittsburgh, Pennsylvania, United States