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

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

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Postoperative Pain; Opioid Dependence
• Intervention / Treatment: Drug: Oxycodone

Detailed Description

Research procedures will include:

1. Pre-operative blood draw for genotyping candidate genes and exploratory genes and for future similar studies will be collected.
2. 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.
3. 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.
4. Quantitative Sensory Testing will be performed on up to 100 participants pre-operatively, and 48-72 hours,3 months and 12 months post-operatively.
5. 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.

• Study Type: Observational
• Enrollment (Estimated): 500

Contacts and Locations

Study Locations

• United States
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15224
      • UPMC Children's Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 8 years to 18 years (Child, Adult)
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

Pectus excavatum repair and spinal fusions are two of the most painful surgery children and adolescents undergo. Therefore, the investigators aim to recruit 500 children and adolescents, 8-17.9 years of age, undergoing inpatient pectus excavatum repair or idiopathic scoliosis spinal fusions at Riley Hospital for Children.

Description

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

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Major Inpatient Surgeries; 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; Post-op pain management medication

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Look at genetic oxycodone-related perioperative and bio-psychological factors predisposing children to long-term adverse outcomes such as chronic persistant surgical pain and opioid dependence.	The investigators will look at OPRM1 epigenetics and OPRM1, FAAH, GCH1, DRD2 variants to find correlations with chronic persistent surgical pain and opioid dependence up to 1 year post-surgery. Children will also be asked to complete psychological questionnaires pre-surgery, and at 4 time points post-surgery to assess psycho-psychological factors that may correlate with chronic persistent surgical pain or opioid dependence.	Pre-operative to 12 months post-operative

Collaborators and Investigators

• Sponsor: Senthil Sadhasivam
• Collaborators: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD); Children's Hospital Medical Center, Cincinnati
• Investigators: Principal Investigator: Senthilkumar Sadhasivam, MD, MPH, University of Pittsburgh, UPMC

Publications and helpful links

General Publications

• Packiasabapathy S, Aruldhas BW, Zhang P, Overholser BR, Quinney SK, Sadhasivam S. Novel associations between CYP2B6 polymorphisms, perioperative methadone metabolism and clinical outcomes in children. Pharmacogenomics. 2021 Jul;22(10):591-602. doi: 10.2217/pgs-2021-0039. Epub 2021 Jun 8.
• Sadhasivam S, Aruldhas BW, Packiasabapathy S, Overholser BR, Zhang P, Zang Y, Renschler JS, Fitzgerald RE, Quinney SK. A Novel Perioperative Multidose Methadone-Based Multimodal Analgesic Strategy in Children Achieved Safe and Low Analgesic Blood Methadone Levels Enabling Opioid-Sparing Sustained Analgesia With Minimal Adverse Effects. Anesth Analg. 2021 Aug 1;133(2):327-337. doi: 10.1213/ANE.0000000000005366.

Study record dates

Study Major Dates

• Study Start (Actual): April 1, 2018
• Primary Completion (Actual): August 15, 2022
• Study Completion (Estimated): December 1, 2024

Study Registration Dates

• First Submitted: March 28, 2018
• First Submitted That Met QC Criteria: April 4, 2018
• First Posted (Actual): April 12, 2018

Study Record Updates

• Last Update Posted (Actual): February 12, 2024
• Last Update Submitted That Met QC Criteria: February 8, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Mental Disorders; Chemically-Induced Disorders; Pathologic Processes; Substance-Related Disorders; Postoperative Complications; Pain; Neurologic Manifestations; Narcotic-Related Disorders; Pain, Postoperative; Opioid-Related Disorders; Physiological Effects of Drugs; Central Nervous System Depressants; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Analgesics, Opioid; Narcotics; Oxycodone
• Other Study ID Numbers: STUDY21070170; 7R01HD089458-02 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No