Clinical trial NCT03495388: PG and PK of Oxycodone to Personalize Post-op Pain Management Following Surgery in Children
Official title: Pharmacogenetics and Pharmacokinetics of Oxycodone to Personalize Postoperative Pain Management Following Major Inpatient Surgery in Children
Study type: OBSERVATIONAL
Overall status: ACTIVE_NOT_RECRUITING
Conditions: Postoperative Pain
Opioid Dependence
Lead sponsor: University of Pittsburgh
Sponsor class: OTHER
Collaborators: name: Children's Hospital Medical Center, Cincinnati
name: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
First posted: 2018-04-12
Enrollment: 500
Sex: ALL
Minimum age (years): 8
Maximum age (years): 18
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Observational model: OTHER
Time perspective: PROSPECTIVE
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.

Brief summary: 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: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Look at genetic factors predisposing children to immediate postoperative opioid-adverse effects (RD and PONV).
timeFrame: Immediately post-surgery during hospital stay and at home up to 1 year post-surgery
measure: Look at genetic factors predisposing children to inadequate surgical pain relief with oxycodone.
timeFrame: Immediately post-surgery during hospital stay and at home up to 1 year post-surgery
Secondary outcomes:
measure: 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.
timeFrame: Pre-operative to post-operative day 2
Other outcomes:
measure: 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.
timeFrame: Pre-operative to 12 months post-operative
Locations:
city: Pittsburgh
country: United States
facility: UPMC Children's Hospital
state: Pennsylvania
Study officials:
affiliation: University of Pittsburgh, UPMC
name: Senthilkumar Sadhasivam, MD, MPH
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.