Idiopathic Scoliosis
Conditions
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 dosing 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. 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.
Interventions
Methadone intervention includes 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 administered 4 hours after the 1st dose) and postoperatively, up to 4 additional IV or oral 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 intervention includes standard opioid analgesia protocol without intra- and post-operative methadone per the current site standards. Postoperative pain medication is recommended when reported pain level is considered moderate or higher (≥4 on NRS and FLACC).
Sponsors
Senthil Sadhasivam
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Subject)
Intervention model description
Randomized Clinical Trial
Eligibility
Sex/Gender
ALL
Age
10 Years to 18 Years
Healthy volunteers
No
Inclusion criteria
1. Age 10 - \< 18 years 2. American Society of Anesthesiologists (ASA) Physical Status 1 or 2 3. Undergoing PSF for idiopathic scoliosis 4. Participant or legal guardian can speak and read English or Spanish
Exclusion criteria
1. Pregnant patients 2. Methadone allergy 3. Preoperative prolonged QTc more than 460 msec (-30 days to 0 day) 4. 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) 5. Preoperative opioid use within 30 days before surgery 6. History of severe sleep apnea, defined as a prior sleep study demonstrating an apnea-hypopnea index (AHI) greater than 10. 7. Significant liver, kidney, neurological disease, developmental delay, or any other co-existing medical condition per discretion of the clinical investigator
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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 breaths 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 assessed 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 \>460 msec based on 12-lead or 15-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(%). |
Countries
United States
Contacts
CONTACTSenthilkumar Sadhasivam, MD, MPH, MBA, FASA
CONTACTDayana Alsamsam, BSPS, MSc
PRINCIPAL_INVESTIGATORSenthilkumar Sadhasivam, MD
University of Pittsburgh
Outcome results
None listed