Personalized Pain Medicine

Personalized Pain Medicine – By Lynn Webster, M.D. – October, 2018

Here Dr. Webster explains how our genes control both pain sensitivity and drug sensitivity. Many of us with EDS find ourselves with the most unfortunate combination of high pain sensitivity and low drug sensitivity (due to metabolic issues).

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.

Pharmacogenetic therapy in people with pain requires consideration of 2 different genetic substrates to determine the outcome of pharmacotherapy.

1. The first is the genetic contribution to a variety of different pain types, and
2. 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.

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

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%.

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.

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.

Genetic Imprint

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.

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.

Author: Lynn Webster M.D., FACPM, FASAM is Vice President of Scientific Affairs at PRA Healthsciences and a Past President of AAPM. He is board certified in anesthesiology and pain medicine and also is certified in addiction medicine.