A Phase 3 interventional study of Methadone based ERAS and Non-methadone based group in Pediatric Cardiac Surgery, sponsored by Senthil Sadhasivam. Recruiting at 3 sites in United States. Open to participants aged 3 Years to 18 Years. Per ClinicalTrials.gov, last updated 2026-08-07.
Sponsored by Senthil Sadhasivam · Phase 3, Interventional, and Treatment
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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.
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.
Senthil Sadhasivam is the lead sponsor of 8 studies on the registry; 6 are open to participants now.
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STS Category 1:
STS Category 2:
Exclusion Criteria:
Underlined terms in the criteria open these too. Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
The anaesthetists’ scale of health before surgery: I is healthy, II has a mild illness that is under control, III a severe one, IV a severe illness that is a constant threat to life. V and VI are used for the critically ill and for organ donors.
On an ECG, the QT interval is the time the heart’s lower chambers take to activate electrically and recover in each beat. QTc is that time adjusted for heart rate (QTcF by Fridericia’s formula, QTcB by Bazett’s). Some medicines lengthen it, and a long QTc can raise the risk of a dangerous heart rhythm.
The study may name a correction formula and a limit in milliseconds, often around 450–480.
ASA physical status
The anaesthetists’ scale of health before surgery: I is healthy, II has a mild illness that is under control, III a severe one, IV a severe illness that is a constant threat to life. V and VI are used for the critically ill and for organ donors.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
QT and QTc
On an ECG, the QT interval is the time the heart’s lower chambers take to activate electrically and recover in each beat. QTc is that time adjusted for heart rate (QTcF by Fridericia’s formula, QTcB by Bazett’s). Some medicines lengthen it, and a long QTc can raise the risk of a dangerous heart rhythm.
The study may name a correction formula and a limit in milliseconds, often around 450–480.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
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 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 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.
Also known as: Methadone-Based
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.
Also known as: Standard Care
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).
Time frame: Postoperative 48 hours
Total postoperative opioid use
Total Opioid use in Morphine Milligram Equivalents (MME), will be reported as mean (SD).
Time frame: Postoperative 48 hours
Incidence of Inpatient Respiratory Depression (RD)
RD is defined as respiratory rate \<8 breaths per minute requiring oxygen in the absence of airway obstruction.
Time frame: Postoperative 120-hours
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(%).
Time frame: 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(%)
Time frame: Postoperative 120-hours
QTc Prolongation
QTc prolongation is defined as more than 460 msec. Outcome measure will be reported as n(%).
Time frame: Postoperative 48-hours
Length of Hospital Stay (LOS)
LOS will be recorded in days. Outcome measure will be reported as mean(SD).
Time frame: 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(%)
Time frame: 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(%)
Time frame: 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(%).
Time frame: 3-months post-surgery
Plan to share: Yes — 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.
Supporting information: Study protocol, Statistical analysis plan
Time frame: Time frame is within 5-years of study completion.
Access criteria: Online collaborative tools to facilitate data sharing such as SharePoint or Xythos
No publications or documents are linked to this record.
Started Dec 2025 (actual). Primary completion is estimated for Jan 2029, 37 months after the start.
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Senthil Sadhasivam