Below is an edited excerpt from a chapter titled, Pharmacogenetics and Personalized Medicine in Pain Management, that Inna Belfer, MD PhD and I published in Clinics in Laboratory Medicine, Volume 36, Issue 3, September 2016.
Personalized Pain Medicine
Pharmacogenetic therapy in people with pain requires consideration of 2 different genetic substrates to determine the outcome of pharmacotherapy. The first is the genetic contribution to a variety of different pain types, and the second is the genetic influence on drug effectiveness and safety.
Studies to isolate the genetic risk of inheriting a specific pain condition are plentiful, but scientists are only beginning to examine genetic variations that may influence pain processing. If a genetic basis underlies how pain is expressed and perceived, including the varying mechanisms of nociceptive, neuropathic, and visceral pain, then the potential exists for new analgesic targets affecting these gene products. In the future, the right drug may depend on the patient’s genotype; furthermore, the genetic signature of personal analgesic response may guide both drug and drug dose selection. Pain expression is also influenced by environmental factors, such as cultural attitudes, attention, sleep, and stress. Fibromyalgia (FM), tension headaches, and irritable bowel syndrome are a few of the functional pain conditions influenced by environmental factors. It is increasingly recognized that complex phenotypes encompass genetic and environmental interactions that may shape predisposition to pain processing and perception.
Interindividual Differences in Pain Sensitivity
Clinical observation of patients suggests large interindividual differences in pain sensitivity, and research confirms that view. Examples of pain conditions that persist in a minority of patients include diabetes with diabetic peripheral neuropathy, herpes zoster with postherpetic neuralgia, lumbar disc degeneration with low back pain, and whiplash injuries with cervicalgia. Age, sex, severity of stimulus, and environmental factors explain some of the variance, but not all. A genetic influence is suggested by results showing that inbred mouse strains respond differently to the same acute and chronic pain stimuli. Similarly, studies of sensitivity to painful stimulation showed a great variability in both threshold and tolerance to mechanical, thermal, and chemical stimuli in normal volunteers, only a tiny portion of which is explained by personality or expectations.
Allele-based association studies have been expected to shed light on why pain persists in some patients but not in others after nearly identical tissue damage. Close to 200 candidate genes that may be involved in pain processing have been categorized by their frequency of occurrence in chronic neuropathic pain conditions and by the strength of evidence, frequency of the specific variant, and likelihood that a genetic polymorphism alters function. A polymorphism is a variation in DNA sequencing that occurs in greater than 1% of the population; in contrast, a mutation occurs in less than 1%.
More recent genetic and genomic technologies have allowed a genome-wide association unbiased study approach to complex pain traits. These studies revealed an underlying multilevel genetic architecture of pain control with many loci of different effect sizes, gene-gene interactions, and common pathways among painful diseases. There are studies showing genes that have been associated with pain processing and perception. There are also genes found to reduce pain or be protective from pain.
Separating genetic from environmental factors is usually best explored through twin studies. In a study using classic twin design, a consistent excess concordance in monozygotic compared with dizygotic twins equated to up to 68% heritability for low back pain and up to 58% for neck pain.
Consistent Response to Pain Medications
Clinicians who treat pain have always known that the response to opioids varies widely among patients. Differences in bioavailability and pain stimuli explain some of this difference, but genetic makeup is likely a strong factor. Clinicians struggle with finding a consistent response to pain medications because of this tremendous interpatient response.
There are several ways genetics influence drug response: through drug metabolism enzymes, drug transporters, opioid or other pain medication receptors, or structures involved in the perception and processing of pain. Pharmacogenetics describes the effects of genetics on the pharmacokinetics (e.g., drug absorption, distribution, metabolism, and excretion) and pharmacodynamics (through receptor activity, receptor binding affinity, and receptor density) of drugs.
Genetic variations that impact a patient’s drug sensitivity can lead to adverse reactions, toxicity, or therapeutic failure. Of 27 drugs frequently cited in adverse drug reaction studies, 59% are metabolized by at least one enzyme with a variant allele known to cause poor metabolism. That compares with 7% to 22% of randomly selected drugs. Tailoring therapy based on each individual’s genotype should increase therapeutic effectiveness and minimize adverse effects.
Each person carries his or her own genetic imprint for the risk of more severe or more chronic pain, pain perception, and response to analgesics. The environment may significantly influence how this genetic profile is expressed. Recent progress in genetic research indicates multiple gene-gene and gene environment interactions that influence pain and analgesia as well common pathways among painful diseases. Studies of genetic polymorphisms linked to pain syndromes and medication metabolism herald a fresh therapeutic approach based on genotype with targeted analgesia and fewer side effects. However, genome-wide association studies are needed to complete a pain genome puzzle, identify full genetic signatures for pain and analgesia, and help genetic testing become a widespread part of clinical practice.
In the next few years we should expect to learn how to best treat an individual’s pain based upon their genotype. This will take us one huge step closer to personalized medicine.