Patient Controlled Analgesia Pharmacogenetic Study

Pain management after surgery is not optimal partly due to great interindividual variability in pain perception and coping. This also can lead to persistent pain beyond the healing period and disability. Up to two-thirds of the inter-individual variability result from genetic variations in pain perception as well as response to the pain medicine. The investigators aim to identify genomic (genetic/epigenetic), psychological and drug profiles contributing to this variability. Opioids are the mainstay for treatment of postoperative pain in children. Experience dictates that opioids have narrow therapeutic indices and large inter-patient variability in response. This leads to serious side effects like respiratory depression in up to 50% of children undergoing invasive surgery, which can be fatal. It is evident that there are particular children who are more susceptible to suffering side effects and having inadequate pain relief from opioids.

It is hypothesized that much of the genetic variability can be explained by gene function which is modulated by a) Single Nucleotide Polymorphisms (SNPs) in genes that encode proteins involved in pain perception, opioid transport/metabolism (pharmacokinetics), and opioid receptor signaling (pharmacodynamics); b) epigenetics which modify gene expression without structural changes to the DNA, and c) genes that influence psychological factors.

Identifying genetic and non-genetic predictors for this susceptibility is vital for safe and effective analgesia in children. This is a critical knowledge gap in medical literature that significantly impacts pediatric pain management. The investigators' central hypothesis is that specific genetic polymorphisms in genes involved in pain perception, opioid transport, and opioid receptor signaling pathways contribute significantly to pain sensitivity, opioid side-effects, and analgesic efficacy in children.

The choice and dosing of opioids and pain management approaches have thus far been largely empirical, with a frequent need to switch medications, strategies and alter doses due to inherent differences in individuals. By this study, the investigators hope to develop preemptive approaches and drug targets that can be targeted to individual risk and genomic-psychosocial profiles. The study will help determine the 'right' doses of the 'right' opioids for optimized and safe postoperative analgesia in children. This will be done by first building population pharmacokinetic and pharmacodynamic models for opioid concentration-exposure and then investigating covariates.

Given the unexplored nature of this complex phenomenon, The investigators propose a comprehensive study to evaluate gene, drug, and surgical interactions, in a large sample of 650 children undergoing different surgeries, requiring patient controlled analgesia with opioids.

The investigators' long term goal is to develop more effective, safer, and tailored pediatric opioid analgesia, by contributing to better understanding of the underlying genetic basis for variations in the sensitivity to pain, pain relief, and development of adverse effects from the extended use of postoperative intravenous opioids in children.

The data collected will include acute and long-term pain data, opioid doses, incidence of side-effects of opioids - including respiratory depression, sedation, vomiting, and itching, and blood samples for genetic and pharmacometric analyses. Data analysis will use advanced logistic regression techniques to uncover the association between the SNP variants and the response to specific opioids following various surgeries.