Treating Chronic Pain Doesn’t Need to be Painful: A Case for Pharmacogenetics

Chronic pain is a common reason why people seek medical care and is estimated to affect about 11% to 40% of adults in the United States1,2.  With over 100 million Americans suffering from pain in the U.S., it is one of the most prevalent medical conditions in the country3.  Chronic pain has been linked to restrictions in mobility and daily activities as well as to several comorbidities such as depression, anxiety, and addiction4,5.  In order to treat pain, medical experts can prescribe anything from nonsteroidal anti-inflammatory drugs, to muscle relaxants, to stronger medications such as opioids.  Although not all these medications work with every patient.  Recent studies have shown that one out of five patients that see a clinician for pain receive a prescription for opioids, but long-term opioid therapy had also shown to be ineffective or poorly tolerated by a third of patients who have nonmalignant chronic pain6–8.  Sadly, short term opioid treatment has been shown to be associated with several adverse drug effects such as, but not limited to, nausea, dizziness, constipation, and drowsiness in about 50‑80% of patients8–10.  These statistics call attention for the need for a new type of standard of care treatment for pain management.

Pain management drugs are regularly metabolized by enzymes into their active form and then subsequently into an inactive one that is excreted from the body. Additionally, pain management drugs act by binding to central nervous system receptors to reduce pain. However, molecular variations in the genes responsible for coding these enzymes and receptors can lead to unfavorable treatment outcomes. For example, the Cytochrome P450 2D6 (CYP2D6)  enzyme is involved in the conversion of opioids (e.g. codeine, tramadol, oxycodone) from the (inactive form) into their active forms11. In the case of codeine, CYP2D6 metabolizes it into morphine, which  has about a 200 fold greater affinity to its target  receptor than  codeine, making it a more effective treatment8. Furthermore, the CYPD26 gene is highly variable and can lead to very different phenotypes, e.g. poor metabolizer, intermediate metabolizer, normal metabolizer, and ultrarapid metabolizer. Patients who are classified as poor metabolizers have reduced concentrations of the active drug and an increased concentration of the prodrug, potentially resulting reduced pain relief.  Similarly, patients who are classified as an ultrarapid metabolizer have an increased concentration of the active drug and a decreased concentration of the prodrug, and while resulting in a faster rach of therapeutic level, it can also increased risk of toxicity8,12


Not unlike CYP2D6, patients with a molecular variation in the µ-opioid receptor 1 (OPRM1) may have an increased affinity to morphine, this can result in achieving the desired therapeutic effect at a lower dose (assuming the pharmacokinetics of codeine is normal for the patient). Conversely, patients with decreased affinity will require a higher dose under the same pharmacokinetics conditions13. However, it is important to remember that drug response is the combined effect of multiple genetic and non-genetic factors.

With medical advancements, increased understanding of genetics, and genetic sequencing capabilities, patients with unexpected responses to these drugs can be identified. Pharmacogenomics (PGx) combines the study of genetics with the science of drug delivery. Everyone responds differently to certain treatment options. The goal of pharmacogenomics is to personalize medications to a patient in order to improve the efficacy and reduce the risks of adverse drug effects. By understanding a patient’s genetic profile, clinicians are provided with tools to gain insight on certain pain medications and how effective or dangerous they could be to a patient and can make more informed treatment decisions8

 

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About the Author: 

shalis_ammons-1 Shalis is an Associate Product Manager for the PGxOne(TM) test at Admera Health. She has earned her doctoral degree in Genetics, Cell Biology and Anatomy at the University of Nebraska Medical Center. After graduation, she transitioned into the commercial side of the life science industry and has been working in marketing for about 3 years. She can be contacted at shalis.ammons@admerahealth.com or 908-222-0533 ext. 3880.

 


 

References: 

1) Dahlhamer, J. et al. Prevalence of Chronic Pain and High-Impact Chronic Pain Among Adults — United States, 2016. MMWR. Morb. Mortal. Wkly. Rep. 67, 1001–1006 (2018).

2) NIH Interagency Pain Research Coordinating Committee. National Pain Strategy Overview | Interagency Pain Research Coordinating Committee. Available at: https://www.iprcc.nih.gov/National-Pain-Strategy/Overview. (Accessed: 23rd September 2019)

3) Smith, D. M. et al. CYP2D6-guided opioid therapy improves pain control in CYP2D6 intermediate and poor metabolizers: a pragmatic clinical trial. Genet. Med. 21, 1842–1850 (2019).

4) Smith, B. H. et al. The impact of chronic pain in the community. Fam. Pract. 18, 292–299 (2001).

5) Gureje, O., Von Korff, M., Simon, G. E. & Gater, R. Persistent Pain and Well-being. JAMA 280, 147 (1998).

6) Noble, M. et al. Long-term opioid management for chronic noncancer pain. Cochrane Database Syst. Rev. CD006605 (2010). doi:10.1002/14651858.CD006605.pub2

7) Daubresse, M. et al. Ambulatory Diagnosis and Treatment of Nonmalignant Pain in the United States, 2000–2010. Med. Care 51, 870–878 (2013).

8) Smith, D. M., Weitzel, K. W., Cavallari, L. H., Elsey, A. R. & Schmidt, S. O. Clinical application of pharmacogenetics in pain management. Per. Med. 15, 117–126 (2018).

9) Chou, R. et al. Clinical Guidelines for the Use of Chronic Opioid Therapy in Chronic Noncancer Pain. J. Pain 10, 113-130.e22 (2009).

10) Manchikanti, L. et al. Responsible, Safe, and Effective Prescription of Opioids for Chronic Non-Cancer Pain: American Society of Interventional Pain Physicians (ASIPP) Guidelines. Pain Physician 20, S3–S92 (2017).

11) St. Sauver, J. et al. <em>CYP2D6</em> phenotypes are associated with adverse outcomes related to opioid medications. Pharmgenomics. Pers. Med. Volume 10, 217–227 (2017).

12) Crews, K. R. et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) Guidelines for Codeine Therapy in the Context of Cytochrome P450 2D6 (CYP2D6) Genotype. Clin. Pharmacol. Ther. 91, 321–326 (2012).

13) Campa, D., Gioia, A., Tomei, A., Poli, P. & Barale, R. Association of ABCB1/MDR1 and OPRM1 Gene Polymorphisms With Morphine Pain Relief. Clin. Pharmacol. Ther. 83, 559–566 (2008).