Precision Medicine for Chronic Pain

In fact, dysregulated expression of circulating microRNAs (miRNAs) in bodily fluids is being explored as a non-invasive clinical biomarker for a variety of disorders including chronic pain. MicroRNAs studies can provide insights on molecular underpinnings influencing treatment outcome or specific therapeutic intervention.

Effective implementation of miRNA-based biomarkers would provide better clinical trial designs, improved pain treatment options, guidance for clinicians, including selection of optimal dose and patient selection, leading to individualized care and better treatment outcome for chronic pain patients.⁸

While clinical application of precision chronic pain management is “still in its infancy,” according to Stephen McMahon, PhD, FMedSci, Sherrington Professor of Physiology at King’s College London, and Director of the London Pain Consortium, specific genes associated with migraine have been identified.^9,10

Given that the current approach to chronic pain management is largely by trial and error, Stephen G. Waxman, MD, PhD, Professor of Neurology at Yale University School of Medicine and VA Connecticut, acknowledges that the need for precision chronic pain medicine is immense.

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Dr Waxman is involved in a research study investigating the Nav1.7 mutations in inherited erythromelalgia as a potential therapeutic target. While clinical application is potentially a decade away, Dr Waxman firmly believes that precision medicine for chronic pain is a realistic and achievable goal. 

“The exciting thing about our study is that it provides proof-of-principle that, using genomics and atomic-level modeling, we could match a specific pain medicine to a particular person’s DNA, and thus, successfully predict that [a specific] medication would reduce pain in [a specific] person.

In the strict sense, our results apply only to the very small number of people carrying a particular gene variant, just a few people in the entire continent. But, in a more general sense, we now have proof-of-principle that a genomically-guided, “precision” approach to pain therapy can work in human beings.I can imagine a time, sometime in the future, when pain management with medications will be transformed from ‘trial and error’ to ‘first time around,’” adds Dr Waxman.

There is evidence to support an association of the TWIK-related spinal cord potassium (K⁺) channel (TRESK) gene, and the methylene tetrahydrofolate reductase (MTHFR) gene in migraine pain.^10,11

Recent efforts have also focused on improved understanding of the role of exogenous aldehydes in pain pathophysiology. Animal models suggest that aldehyde dehydrogenase-2 (ALDH2) may be involved in the regulation of nociception. Data from rodent models suggest that the mitochondrial ALDH2 regulates inflammatory pain by reactive aldehyde metabolism, and therefore could serve as a molecular target for pain control.^12,13

Therapeutics specifically targeting ALDH2 may offer an avenue for precision medicine for pain control and a strategy to treat the approximately 540 million people worldwide who carry the ALDH2*2 variant, which severely limits reactive aldehyde metabolism by over 60% compared to the ALDH2 wild type.¹³

The clinical significance of ALDH2*2 variant is that analgesics such as acetaminophen may not be as effective for pain control since the variant gene may limit further reactive aldehyde metabolism.¹³

Treatments tailored to individuals with reduced aldehyde metabolism may be a first step to delivering precision medicine for those with an ALDH2*2 variant while improving understanding of how pain is regulated.

Studies supporting precision pain management are emerging and are promising, however, a reality check is necessary. Clinical application of gene-targeted precision pain medicine is still a long way ahead.

While the concept of precision medicine for chronic pain is supported by the Federal Government, few clinical studies have been conducted. Much of the necessary methodology remains to be developed.

Funding, time and commitment for complex genetic research, pain biomarker studies and analysis of clinically relevant findings are all required.^14,15

In addition, research collaborations — nationally and internationally –and public participation  will be critical, as identification of relevant gene targets necessitate the study of large numbers of people with a variety of pain conditions.¹⁶

Progress is being made to turn the vision of a precision medicine approach to pain management into reality. The NIH is working with the Department of Health and Human Services to bring the Common Rule, a decades-old rule originally designed to protect research participants, more in line with participants’ desire to be active partners in modern science.

To help speed the translation of such discoveries, the Food and Drug Administration is working with the scientific community to ascertain its oversight of genomic technology supports innovation while ensuring public support through safe and effective technology.¹⁷

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Summary and Clinical Applicability

For the millions of Americans living with chronic pain and suboptimally managed with current therapeutic options, precision pain medicine is an emerging clinical strategy for personalized pain management. 

Optimal precision pain management requires the integration of genomic data, functional studies, and data from biomarker-driven clinical trials to inform clinical decision-making on the best therapeutic options and predict outcomes.

Such measures may lead to improved care, fewer adverse effects and lower cost. The goal is to move away from a “one-size-fits-all” pain treatment strategy. Although still in its infancy, precision medicine, if done right, could transform medicine and patient care, particularly for the millions of Americans with chronic pain.

Limitations and Disclosures

Available studies on precision pain medicine are limited to animal models.

No emerging conflict of interest

References

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