Pharmacogenomics of Opioids and Perioperative Pain Management

Abstract

Inadequate pain relief and adverse effects from analgesics remain common in children and adults during the perioperative period. Opioids are the most commonly used analgesics in children and adults to treat perioperative pain. Narrow therapeutic index and a large interpatient variability in response to opioids are clinically significant, with inadequate pain relief at one end of the spectrum and serious side effects, such as respiratory depression and excessive sedation due to relative overdosing, at the other end. Personalizing analgesia during the perioperative period attempts to maximize pain relief while minimizing adverse events from therapy. While various factors influence response to treatment among surgical patients, age, sex, race and pharmacogenetic differences appear to play major roles in predicting outcome. Genetic factors include a subset of genes that modulate the proteins involved in pain perception, pain pathway, analgesic metabolism (pharmacokinetics), transport and receptor signaling (pharmacodynamics). While results from adult genetic studies can provide direction for pediatric studies, they have limited direct applicability, as children's genetic predispositions to analgesic response may be influenced by developmental and behavioral components, altered sensitivity to analgesics and variation in gene-expression patterns. We have reviewed the available evidence on improving and personalizing pain management with opioids and the significance of individualizing analgesia, in order to maximize analgesic effect with minimal adverse effects with opioids. While the early evidence on individual genotype associations with pain, analgesia and opioid adverse outcome are promising, the large amount of conflicting data in the literature suggests that there is a need for larger and more robust studies with appropriate population stratification and consideration of nongenetic and other genetic risk factors. Although the clinical evidence and the prospect of being able to provide point-of-care genotyping to enable clinicians to deliver personalized analgesia for individual patients is still not available, positioning our research to identify all possible major genetic and nongenetic risk factors of an individual patient, advancing less expensive point-of-care genotyping technology and developing easy-to-use personalized clinical decision algorithms will help us to improve current clinical and economic outcomes associated with pain and opioid pain management.

Rescue Morphine in Mechanically Ventilated Newborns Associated with Combined OPRM1 and COMT Genotype

“…The relation between the analyzed SNPs in OPRM1 and COMT on morphine requirement has also been illustrated in different adult studies with postoperative [19,[21][22][23][24][25]37] and cancer related pain [38][39][40], although others failed in finding these associations [41][42][43]. This failure is most likely caused by the polygenic aspect in pain [10], as discussed in the introduction. Our results on the combined genotypic effect are in line with two previously performed studies, in which is concluded that OPRM1 118AA in combination with COMT 158 met have the lowest requirement whereas vice versa (118G and COMT 158 val) have a higher risk for more pain and thus more opioid consumption [20,30].…”

“…The field of pharmacogenetics predicts individual dosing of drugs based on genetic differences affecting disposition and effect. Genetic polymorphisms in several genes have been associated with pain sensitivity and opioid response in both adults [10,11] and children [12]. More recently, genetic variation in newborns with the neonatal abstinence syndrome (NAS) caused by in utero opioid exposure has been related to treatment requirement and length of hospitalization [13].…”

Considerations when using pharmacokinetic/pharmacodynamic modeling to determine the effectiveness of simple analgesics in children

“…The role of pharmacogenomics continues to be investigated and a number of excellent reviews are available [75][76][77][78][79]. While each isolated pharmacogenomics influence may be discerned, the complex interplay of all these influences in any one individual makes clinical interpretation difficult.…”

Pharmacology of Opioids and their Effects on Gastrointestinal Function

“…Polymorphisms in ABCB1, the gene that codes for the effl ux transporter P-glycoprotein, have been shown to have a signifi cant eff ect on the pharmacokinetics of opioids by restricting uptake or enhancing clearance ( 34 ). Variability in ABCB1 has been found to infl uence daily methadone dosage, providing further support for its role in opioid drug transport ( 35 ).…”

“…Polymorphisms in metabolic enzymes, including UDP-glucuronosyl transferase and cytochrome P450 (CYP) 2D6 and CYP3A4, also appear to infl uence the pharmacokinetics of opioids in humans ( 34 ). Specifi cally, UDP-glucuronosyl transferase is involved in metabolizing morphine to the active metabolites morphine-6-glucuronide and morphine-3-glucuronide; variations in the gene coding for this enzyme have been found to correlate with morphine and morphine metabolite concentrations in the serum ( 35 ).…”