Evaluation of Analgesia for Cardiac Elective Surgery in Children (PRECISE)

Prospective Randomized Evaluation of Analgesia for Cardiac Elective Surgery in Children (PRECISE Cardiac Trial)

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.

Study Overview

• Status: Recruiting
• Conditions: Pediatric Cardiac Surgery
• Intervention / Treatment: Drug: Methadone based ERAS; Drug: Non-methadone based group

Detailed Description

SPECIFIC AIMS. The multicenter PRECISE Analgesia (Prospective Randomized Evaluation of Analgesia for Cardiac) trials will a) implement and investigate the efficacy and safety of multidose methadone-based standardized enhanced recovery after surgery (ERAS) protocol, and b) develop personalized ERAS protocols including precision methadone and oxycodone dosing, and c) personalized analgesia for the safe and effective opioid-sparing management of surgical pain after cardiac surgery (CS) in children.

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. 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 CS (Aim 1). Investigators will use PK and genetic variations along with CPB-related dilution and clinical factors to develop optimal intra- and post-operative methadone dosing in children to enable precision analgesia in the future (Aim 2). Finally, the study team will identify patient profiles with genetic, epigenetic, PK, clinical, and psychological factors to predict benefit from assigned analgesia for optimal clinical outcomes (Aim 3). The expert multidisciplinary and multicenter team will enroll a total of 1000 children to conduct two parallel randomized clinical trials for CS (500 children 1 month-18 yrs from 5 clinical sites). In this study, specifically, Investigators will:

Aim 1. Conduct a randomized trial in CS to compare acute pain relief, opioid-sparing efficacy, and safety of standardized perioperative multidose methadone-based ERAS vs. standard-of-care non-methadone-based analgesia. Acute surgical pain, opioid needs (morphine equivalents), RD, PONV, and CPSP will be lower in methadone-based analgesia compared to short-acting opioid-based analgesia.

Aim 2. Develop precision methadone dosing based on age, CYP2B6 and ORM1 variants, AAG, and CPB. 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 among 500 children receiving methadone.

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, RD, PONV, OD, and CPSP).

Overall Impact: The study team 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 CS. 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.

• Study Type: Interventional
• Enrollment (Estimated): 500
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Dayana Alsamsam, BSPS, MSc; Email: alsamsamd@upmc.edu
• Study Contact Backup: Name: Senthilkumar Sadhasivam, MD,MPH, MBA, FASA; Phone Number: 4126474484; Email: sadhasivams@upmc.edu

Study Locations

• United States
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15213
      • Recruiting
      • UPMC Children's Hospital
      • Contact: Senthilkumar Sadhasivam, MD, MPH; Phone Number: 412-647-4484; Email: sadhasivams@upmc.edu
      • Contact: Amy Monroe, MPH; Phone Number: 4126236283; Email: monroeal@upmc.edu
      • Principal Investigator: Senthilkumar Sadhasivam, MD

Participation Criteria

Eligibility Criteria

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

Description

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 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: Methadone-Based ERAS Group; 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.	Drug: Methadone based ERAS; Children randomized to the methadone 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.; Other Names: Methadone-Based
Active Comparator: 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.	Drug: 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.; Other Names: Standard Care

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Average postoperative pain scores	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).	Postoperative 48 hours
Total postoperative opioid use	Total Opioid use in Morphine Milligram Equivalents (MME), will be reported as mean (SD).	Postoperative 48 hours

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of Inpatient Postoperative Nausea and Vomiting (PONV)	PONV will be assessed by self-report, EMR, and medication use. Outcome measure will be reported as n(%).	Postoperative 120-hours
Incidence of Inpatient Sedation	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(%)	Postoperative 120-hours
QTc Prolongation	QTc prolongation is defined as more than 460 msec. Outcome measure will be reported as n(%).	Postoperative 48-hours
Length of Hospital Stay (LOS)	LOS will be recorded in days. Outcome measure will be reported as mean(SD).	Up to 30 days
Persistent Opioid Use	Based on Prescription Drug Monitoring Program (PDMP) and self-report data. Outcome measure will be reported as n(%)	1-week, 1-month, and 3-months post-surgery
Presence of Chronic Postsurgical Pain (CPSP) at 3-months	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(%)	3-months post-surgery
Presence of Opioid Dependence (OD) at 3-months	OD will be assessed using PROMIS and Prescription Pain Medication Misuse (PPMM). Outcome measure will be reported as n(%).	3-months post-surgery
Incidence of Inpatient Respiratory Depression (RD)	RD is defined as respiratory rate <8 breaths per minute requiring oxygen in the absence of airway obstruction.	Postoperative 120-hours

Collaborators and Investigators

• Sponsor: Senthil Sadhasivam
• Collaborators: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
• Investigators: Principal Investigator: Senthilkumar Sadhasivam, MD, University of Pittsburgh

Study record dates

Study Major Dates

• Study Start (Actual): December 17, 2025
• Primary Completion (Estimated): January 31, 2029
• Study Completion (Estimated): August 31, 2029

Study Registration Dates

• First Submitted: June 15, 2024
• First Submitted That Met QC Criteria: October 1, 2024
• First Posted (Actual): October 3, 2024

Study Record Updates

• Last Update Posted (Actual): May 5, 2026
• Last Update Submitted That Met QC Criteria: April 30, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Health Services Administration; Health Care Quality, Access, and Evaluation; Quality of Health Care; Quality Indicators, Health Care; Standard of Care
• Other Study ID Numbers: STUDY24040108; U01HD116257 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Identifiable data and specimens will be shared with the sponsor of the study. The investigators and the study team will comply with all the NIH's Public Access and Data Sharing requirements including Release of Publications and Sharing of Underlying Primary Data. Release of Publications: The investigators will publish their results in open access journals for broad and free availability immediately without any embargo period. Electronic copies of publications will be deposited within four weeks of acceptance by a journal in PubMed Central with proper metadata to be made discoverable and accessible upon publication.
• IPD Sharing Time Frame: Time frame is within 5-years of study completion.
• IPD Sharing Access Criteria: Online collaborative tools to facilitate data sharing such as SharePoint or Xythos
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP

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