Precision Medicine for Chronic Pain

genetic susceptibility
genetic susceptibility
An emerging clinical strategy for personalized pain management.

According to the Institute of Medicine, pain affects more than one-third of all Americans and costs more than $600 billion annually.1 Specifically, chronic pain, broadly categorized as non-cancer and cancer pain, is notoriously challenging to treat, and its poor management resulting from a “one-size-fits-all” strategy, remains a significant cause of misery with huge socioeconomic costs. The need for new molecular targets to design more effective pain treatments options is evident. 

Over the past decade, improved understanding of the genetic underpinning of many diseases have resulted in the explosion of targeted therapies that have paved the way to personalized, and precision medicine.

Emerging evidence indicates that pain has an underlying genetic and hereditary association, and may help to explain the observation that pain stimulus from the same origin can produce wide differences in different individuals with respect to how much pain is felt, how long it lasts, and the quality of response to treatment.

Indeed, evidence is accumulating for “pain-enhancing” and “pain-reducing” genes, as well as genes that may confer effectiveness of a pain drug to one person but intolerance or toxicity to another person.

For example, recent evidence show that the hyperpolarization-activated cyclic nucleotide-gated channels subtype 2 (HCN2) ion channel family – known for their role in the pacemaker potential of the heart – play important roles in both inflammatory and neuropathic pain.

Studies in animal models suggest that selective blockers of HCN2 may have value as analgesics in the treatment of inflammatory and neuropathic pain.2,3

Furthermore, cytochrome P450 2D6 (CYP2D6) genotype has been identified as having important clinical relevance for response to opioid analgesics that depend on CYP2D6 metabolism for bio-activation.4,5

Variation in the CYP2D6 genotype may determine how well individuals respond to opioids analgesic. For example, poor metabolizers (PMs) have lower concentrations of active metabolites of codeine (morphine), tramadol (O-desmethyltramadol), oxycodone (oxymorphone) and hydrocodone (hydromorphone), compared to extensive metabolizers (EMs).

Consequently, PMs may fail to derive pain relief from these opioids compared to EMs. Intermediate metabolizers (IMs) are also expected to have reduced analgesic response based on their significant reduction in enzyme activity, while individuals with ultrarapid metabolizer (UM) phenotype may have toxic concentrations of active opioid metabolites, with reports of life-threatening toxicity and death.

An ongoing study is examining the effect of CYP2D6 genotype-guided pain management on cancer pain control.Unraveling the genes involved in the pathological mechanisms of chronic pain is a formidable task that has begun with studies on migraine, a condition that is ranked as the 6th most disabling condition in the world.7

In the United States, migraine affects 38 million adults and children, significantly impacts quality of life, and imposes major economic and societal burden.7

Recent efforts focused on improved understanding of the genotype–phenotype associations of migraine pain has important implications for precision pain management, by determining the clinical utility of gene targeting, identifying clinically relevant biomarkers, and paves a path for safer personalized pain management.