Evaluation of Analgesia for Spine Fusion Elective Surgery in Children

Phase 3

Not yet recruiting

• Conditions: Idiopathic Scoliosis
• Interventions: Drug: Methadone based ERAS; Drug: Non-methadone based group

• Registration Number: NCT06626503
• Lead Sponsor: Senthil Sadhasivam

Brief Summary

The multicenter PRECISE Analgesia (Prospective Randomized Evaluation of Analgesia for Idiopathic Scoliosis Spine Fusion Elective Surgery in Children) 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 dosing1,2 and c) personalized analgesia for the safe and effective opioid-sparing management of surgical pain after posterior spine fusion (PSF) in children.

Detailed Description

Specific Aims Aim 1. Conduct a randomized clinical trial in posterior spine fusion (PSF) 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).

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 PSF.

Overall Impact The 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 PSF. 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 adverse events (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 PSF. 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, and AAG levels 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: 2024-10-04
• Status Verified: 2025-06
• 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

• Participants aged 10-<18yrs for PSF trial
• ASA physical status 1&2
• Undergoing PSF for idiopathic scoliosis
• Participant or legal guardian can speak and read English or Spanish

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	The comparator standard-of-care non-methadone-based analgesia arm will include 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 at 48-hours timepoint using 0-10, Numerical Rating Scale (NRS), in which 0=no pain at all and 10=worst pain imaginable. Outcome will be reported based on area under the curve (AUC) as mean(SD).
Total postoperative opioid use	Postoperative 48 hours	Number of opioids used in hospital, 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 persistent oxygen desaturation (SpO2) \<90% on room air or respiratory rate \<8 breathes per minute requiring oxygen in the absence of airway obstruction. Outcome will be reported as n(%).
Incidence of Postoperative Nausea and Vomiting (PONV)	Postoperative 120-hours	PONV will be assess by self-report, EMR, and medication use. Outcome 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 will be reported as n(%).
QTc Prolongation	Postoperative 48-hours	QTc prolongation is defined as more than 460 msec based on 12-lead EKG. Outcome will be reported as n(%).
Length of Hospital Stay (LOS)	Up to 30 days	LOS will be measured in days until hospital discharge. Outcome 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 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 Index (FDI). NRS Pain scale is 0=no pain at all and 10=worst pain imaginable. Outcome 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) scales. Outcome will be reported as n(%).

Trial Locations

Locations (1)

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