Pharmacogenomics of Opioids and Perioperative Pain Management

Senthilkumar Sadhasivam; Vidya Chidambaran


Pharmacogenomics. 2012;13(15):1719-1740. 

In This Article

Abstract and Introduction


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.


One of the fundamental perioperative goals is to optimize pain management with better control of pain without significant adverse effects from pain medications for all patients. Unfortunately, safe and effective analgesia is an important unmet critical medical need[1] and its continued existence is an important clinical, economic and societal problem. This is mainly because of huge and unpredictable interpatient variability and narrow therapeutic indices of currently used perioperative opioids. Each year, in the USA alone, more than 30 million children and adults undergo painful surgical procedures;[2] worldwide more than 250 million patients undergo painful surgery annually. Many patients experience inadequate pain relief[3] and serious side effects with opioids, the most commonly used perioperative analgesics.[4] Inadequate pain relief and serious side effects from perioperative opioids occur frequently in approximately 50% of patients.[4,5]

The goal of personalized analgesia is an appropriate and individualized balance at which a patient experiences maximum desirable analgesic relief and minimal undesirable adverse effects. The current clinical considerations for variability are inadequate: age, weight, gender, race, anxiety and type of surgery. To achieve the goal of personalized analgesia, a better understanding of the genetic contribution to interindividual variability with perioperative analgesics is needed. Recently, a number of small adult studies have shown association of SNPs in genes in the pain pathway with altered pain sensitivity and altered responses to perioperative analgesics. This article is a comprehensive review of the available evidence on improving and personalizing pain management with further focus on the need for pediatric pharmacogenetic studies to maximize analgesia while minimizing adverse effects.

Since its discovery and use in the third century BC, as described by Theophrastus, opium has remained the principal treatment for pain through administration of its many derivatives.[6] Today opioid analgesics remain the primary treatment for pain during the intraoperative and immediate postoperative period among which morphine is the most widely used opioid across all age groups.[7] Morphine, along with the other opioids, have narrow therapeutic indices and high interpatient variability, which often results in inadequate pain relief at one end of the outcome spectrum and adverse effects, including respiratory depression, sedation, dizziness, postoperative nausea and vomiting, pruritus, constipation, physical dependence and tolerance at the other end.[8–16] Adverse events related to morphine in adults were found to significantly increase median total hospital costs by 7.4% and median length of stay by 10.3%.[17] Thus, there is a need for a fine balance aiming to maximize analgesic efficacy without compromising safety.

The clinical practice of perioperative pain management has evolved as an art and a science, but is far from perfect due to the unpredictability and heterogeneity of individual patient responses.[18] These differences lead to unpredictable responses or toxic effects in individuals or subgroups, and can ultimately affect patient outcomes. A priori identification of susceptible individuals could lead to modification of drug dosage or use of an alternate drug, which might prevent serious adverse drug reactions. Moreover, inadequate pain management is also associated with major clinical, financial and societal consequences.[19,20] Recent advances in genomic techniques and molecular biology have enabled researchers to identify associations between an individual's genotype and drug response. Although there have been review articles pertaining to pharmacogenetic effects on analgesia in the past,[18,21–23] evolving genomic technology, identification of newer genotype–phenotype associations, and emerging fields, such as epigenetics and functional genomics, have further expanded the knowledge base. The necessity to recapitulate this knowledge for clinicians cannot be overemphasized as they face an increased likelihood of implementing pharmacogenetics in daily clinical care in the near future.