Evaluation of Analgesia for Spine Fusion Elective Surgery in Children

SPECIFIC AIMS. 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 dosing, and c) personalized analgesia for the safe and effective opioid-sparing management of surgical pain after posterior spine fusion (PSF) 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 PSF (Aim 1). Investigators will use PK and genetic variations along with clinical factors to develop optimal intra- and post-operative methadone dosing in children to enable precision analgesia in the future (Aim 2). Finally, Investigators 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 a randomized clinical trial for PSF (500 children 10-\<18 yrs from 4 clinical sites). In this study, specifically, Investigators will:

Aim 1. Conduct a randomized clinical trial in PSF 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, and AAG. Age, CYP2B6 and ORM1 variants, AAG levels, and 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) in PSF.

Overall Impact: 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 AEs in millions of children.

• Incidence of inpatient respiratory depression (RD) [Срок оценки: Postoperative 120-hours]
• Incidence of Postoperative Nausea and Vomiting (PONV) [Срок оценки: Postoperative 120-hours]
• Incidence of Inpatient Sedation [Срок оценки: Postoperative 120-hours]
• QTc Prolongation [Срок оценки: Postoperative 48-hours]
• Length of Hospital Stay (LOS) [Срок оценки: Up to 30 days]
• Persistent opioid use [Срок оценки: 1-week, 1-month, and 3-months post-surgery]
• Presence of Chronic Postsurgical Pain (CPSP) at 3-months [Срок оценки: 3-months post-surgery]
• Presence of Opioid Dependence (OD) at 3-months [Срок оценки: 3-months post-surgery]