Evaluation of Analgesia for Spine Fusion Elective Surgery in Children (PRECISE)

Senthil Sadhasivam

Status and phase: Enrolling; Phase 3

Conditions: Idiopathic Scoliosis

Treatments: Drug: Methadone based ERAS; Drug: Non-methadone based group

Study type: Interventional

Funder types: Other; NIH

Identifiers

NCT06626503

STUDY24040087

1U01HD116257-01 (U.S. NIH Grant/Contract)

Details and patient eligibility

About

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.

Full 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.

Enrollment: 500 estimated patients

Sex: All

Ages: 10 to 18 years old

Volunteers: No Healthy Volunteers

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.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Single Blind

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500 participants in 2 patient groups

Methadone-Based ERAS Group

Experimental group

Description:

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.

Treatment:

Drug: Methadone based ERAS

Non-Methadone-Based Group

Active Comparator group

Description:

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.

Treatment:

Drug: Non-methadone based group