PG and PK of Oxycodone to Personalize Post-op Pain Management Following Surgery in Children

Study Overview
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Brief Summary
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Each year, in the U.S. alone, >6 million children undergo painful surgery; up to 50% of them experience significant and serious side effects with opioids and inadequate pain relief. Though 60% of this inter-individual variability in responses results from genetic variations, there is an almost complete lack of understanding of how specific genetic variability affects pain and of the adverse effects of opioids, especially in children. In this project the investigators will focus on oxycodone, a standard and preferred post-surgical oral analgesic in children The purpose of this research is to study serious immediate and long-term clinical problems from both surgical pain and oxycodone use in children and adolescents to improve the safety and effectiveness of surgical pain relief. The long-term goals are to improve the safety and effectiveness of surgical pain relief with opioids (a class of drugs/pain relievers) and to minimize the societal burden of disabling Chronic Persistent Surgical Pain (CPSP, which is pain that persists even after the expected healing time from surgery) and Opioid Dependence (OD) by preoperative risk predictions and personalized care with the right dose of the right pain medication for each child. The overall objective is to determine the impact of risk factors on oxycodone's immediate and long-term negative postoperative outcomes and to personalize dosing in children undergoing outpatient and major inpatient surgery.

Detailed Description
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Research procedures will include: Pre-operative blood draw for genotyping candidate genes and exploratory genes and for future similar studies will be collected. Standardized pre-, intra-, and post-operative care will be received by all participants. The study team will record medical history, demographic information, concomitant medications, vitals, pain scores, post-operative nausea and vomiting, and all medications given post-surgery for pain management throughout the participants in-patient stay. Psychological questionnaires to assess pain, risk of developing OD and chronic pain, anxiety and depression will be administered pre-operatively, and 48-72 hours, 7-14 days, 2 months, 3 months, 6 months and 12 months post-operatively. Quantitative Sensory Testing will be performed on up to 100 participants pre-operatively, and 48-72 hours,3 months and 12 months post-operatively. Serial blood draws for oxycodone and methadone pharmacokinetic modeling will be collected from up to 200 participants. QTc measurements will also be recorded from pre- and post-operative EKGs for those participants in which methadone pharmacokinetic blood samples are collected.

Official Title
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Pharmacogenetics and Pharmacokinetics of Oxycodone to Personalize Postoperative Pain Management Following Major Inpatient Surgery in Children

Conditions
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Postoperative Pain, Opioid Dependence

Intervention / Treatment
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* Drug: Oxycodone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Boy and girls All races ASA physical status 1 and 2 Scheduled for pectus excavatum repair or idiopathic scoliosis spinal fusion Children with OSA will be included but stratified as they have more opioid-related complications. Exclusion Criteria: Allergy to oxycodone or methadone Developmental delay Neurological disorder Renal or liver disease Pre-operative pain requiring analgesics On inhibitors or inducers of CYP2D6 and CYP3A Cannot read, write and speak English fluently

Ages Eligible for Study
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Minimum Age: 8 Years
Maximum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Major Inpatient Surgeries<br>Children ages 8-17.9 undergoing pectus excavatum or idiopathic scoliosis spinal fusion at Riley Hospital for Children, who have consented to participate in an observational clinical study as approved by the IU IRB, protocol #1707525204. | Drug: Oxycodone<br>* Post-op pain management medication<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Look at genetic factors predisposing children to immediate postoperative opioid-adverse effects (RD and PONV). | The investigators will look at specific CYP2D6, ABCB1, FAAH, OPRM1, and COMT variants to find correlations with children who experience RD, and PONV in the immediate post-surgical period (4 days) in the hospital and at home. | Immediately post-surgery during hospital stay and at home up to 1 year post-surgery | 
| Look at genetic factors predisposing children to inadequate surgical pain relief with oxycodone. | The investigators will look at specific CYP2D6, ABCB1, FAAH, OPRM1, and COMT variants to find correlations with children who experience poor pain relief in the immediate post-surgical period (4 days) in the hospital and at home. | Immediately post-surgery during hospital stay and at home up to 1 year post-surgery | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Look at the impact of CYP2D6 variants on oxycodone's clinical dosing in children to see if specific variants correlate with a need for lower or higher doses of analgesic. | The investigators will look at CYP2D6 variants to find correlations in oxycodone's PK variability and the need for dose adjustments that lead to desired clinical outcomes in children undergoing major inpatient surgeries. | Pre-operative to post-operative day 2 |