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- 1. Pain…It’s In My DNA: Pharmacogenomic Considerations For Pain Management 1
- 2. Disclosure Statement All relevant financial relationships with any ACPE- defined commercial interests have been mitigated 2
- 3. Objectives Review chronic pain management Discuss CYP2D6, OPRM1, and COMT polymorphism Evaluate literature regarding genomic testing Recommend treatment options based on current literature 3
- 4. Etiology Chronic pain is pain that lasts for over three months. Types of chronic pain Neuropathic Nociceptive Musculoskeletal Inflammatory Psychogenic Mechanical 4
- 5. Knowledge Check Approximately how much does chronic pain cost the United States each year? A. Over 1 billion dollars B. Over 10 billion dollars C. Over 500 billion dollars D. Over 900 billion dollars 5
- 6. Epidemiology Pain is the number 1 reason why Americans access the healthcare system An estimated 50 million adults in the United States experienced chronic pain Chronic pain cost the United States approximately $560 billion to $635 billion per year About 20% of patients with chronic pain who visit physicians’ offices receive an opioid prescription. 6
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- 10. Chronic Pain Management Challenges Diagnosis Multifactorial nature Individual variability Opioid crisis Treatment modalities Side effects and tolerance 10
- 11. What is Pharmacogenomics? The study of how variations in the human genome dictate an individuals response to medications. https://www.zibdy.com/pharmacogenomics-and-the-future-of-medicine/ 11
- 12. Importance of Individualized Medications Improved drug efficacy Avoiding adverse reactions Reducing trial and error Cost savings Greater patient satisfaction 12
- 13. Genetic Testing for Chronic Pain Management Comprehensive pharmacogenomic panels GeneSight Genomind Opioid-specific genetic testing Proove opioid risk Proove pain perception Single gene testing CYP2D6 testing Whole exome sequencing (WES) and whole genome sequencing (WGS) Reserved for complex cases or when broad genetic evaluation is needed 13
- 14. CYP2D6 Polymorphism and Activity Score Ultrarapid metabolizers (UM) have a genotype with an activity score greater than 2.25 Normal metabolizers (NM) have an activity score of 1.25 to 2.25 Intermediate metabolizers (IM) have an activity score of 0.25 to 1 Poor metabolizers (PM) have an activity score of 0 14
- 15. Knowledge Check Patient 1 is found to have the genotype CYP2C9*1/*1 with an activity score of 2 and patient 2 is found to have the genotype CYP2C9*1/*3 with an activity score of 1. How would you classify their phenotypes? A. Ultraraipd and normal metabolizers B. Both normal metabolizers C. Normal and intermediate metabolizers D. Intermediate and poor metabolizers 15
- 16. OPRM1 and COMT Polymorphism Opioid receptor mu 1 (OPRM1) SNP from Asparagines to Aspartate leads to a 3 fold higher binding affinity for opioid ligands Increased sensitivity to opioids Catechol-o-methyltransferase (COMT) S-COMT and MB-COMT SNP from Valine to Methionine leads to a 4 fold reduction in enzymatic activity Increase in dopamine levels in the prefrontal cortex 16
- 17. Knowledge Check What are the receptors that consist of the endogenous opioid system? A. Alpha, Beta1, Beta2 B. Mu, Delta, Kappa, C. Muscarinic and nicotinic D. alpha, lambda, sigma 17
- 18. Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline Recommendations 18
- 19. CYP2D6 Phenotype Codeine Recommendations Tramadol Recommendations Hydrocodone Recommendations Ultra rapid metabolizer Avoid use due to increased metabolism of codeine to morphine Avoid tramadol due to increased metabolism of tramadol to O- desmethyltramadol No recommendation. Limited evidence on pharmacokinetics Normal Metabolizer Use codeine according to pt age/weight Use tramadol according to pt age/weight Use hydrocodone according to pt age/weight Intermediate Metabolizer Use codeine according to pt age/weight. If no response switch to alternative analgesic. Decreased metabolism of codeine to morphine can lead to potentially decreased analgesia Use tramadol according to pt age/weight. If no response switch to alternative analgesic. Decreased metabolism of tramadol to O- desmethyltramadol can lead to potentially decreased analgesia Use hydrocodone according to pt age/weight. If no response switch to alternative analgesic. 19
- 20. CYP2D6 Phenotype Codeine Recommendations Tramadol Recommendations Hydrocodone Recommendations Poor Metabolizer Avoid use due to diminished analgesia. Greatly decreased metabolism of codeine to morphine Avoid use due to diminished analgesia. Greatly decreased metabolism tramadol to O- desmethyltramadol Use hydrocodone according to pt age/weight. If no response switch to an alternative analgesic Indeterminate Metabolizer No recommendation. Effect on codeine unknown No recommendation. Effect on tramadol unknown No recommendation. Effect on hydrocodone unknown 20
- 22. 22
- 23. Agullo et al. 2023 P 60 chronic pain patients who were referred from primary care to pain focused care I Prescribing guided by CYP2D6, OPRM1, and COMT genotypes vs. one with clinical routine C Prescribing guided by clinical routine O Pain intensity, quality of life, average occurrence of clinically relevant adverse events, and total opioid dose 23
- 24. Agullo et al. 2023 Results Reduced pain intensity (76 vs. 59 mm, p < 0.01) by improving pain relief (28 vs. 48 mm, p < 0.05), increased quality of life (43 vs. 56 mm p < 0.001), and lowered the incidence of clinically relevant adverse events (3 [1–5] vs. 1 [0–2], p < 0.01) and 42% opioid dose (35 [22–61] vs. 60 [40–80] mg/day, p < 0.05) as opposed to usual prescribing arm. Limitations Small study group that only included Caucasian pts. Concomitant medications. Pts with psychiatric diagnoses were excluded Conclusions Results support the efficacy and safety of the clinical implementation of genotype-guided opioid use for pain, lowering the risk of adverse effects and opioid dose requirements compared to usual care 24
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- 26. Smith et al. 2020 P 370 pts with chronic pain from 7 pain clinics I CYP2D6-guided prescribing of tramadol/codeine C Standard of care prescribing of tramadol/codeine O Composite pain intensity at baseline and at 3 months 26
- 27. Smith et al. 2020 Results Tramadol/codeine had greater improvement in the CYP2D6-guided versus usual care arm (−1.01±1.59 versus −0.40±1.20; adj-P=0.016); 24% of CYP2D6- guided versus 0% of usual care participants reported ≥30% (clinically meaningful) reduction in the composite outcome. Limitations Non-randomized, pts were not blinded, difficulty in assigning phenotype for heterozygous genotypes with copy number variation, OTC analgesics were not recorded Conclusion The implementation of CYP2D6-guided care was shown to be feasible and yielded clinically relevant improvements in pain control among the subset of patients most expected to benefit. 27
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- 29. Fujita et al. 2023 P 134 morphine-naïve pts with advanced malignancies I C-C motif chemokine ligand 11 (CCL11), histamine N-methyltransferase (HNMT) and transient receptor potential V1 (TRPV1) guided therapy driven morphine and oxycodone prescribing C COMT based morphine and oxycodone prescribing O Pain relief by change in numerical rating scale 29
- 30. Fujita et al. 2023 Results Oxycodone tended to provide superior analgesic effects over morphine in patients carrying the genotype AA for the CCL11 SNP [-0.55 (-0.94 to - 0.16) P=0.012] Limitations SNPs were selected based off sensitivity to morphine, incompatibility between morphine and oxycodone dosage forms Conclusions Successfully identified 3 SNPs as biomarkers, and found that the CCL11 SNP, in particular, was highly correlated with the pain controllability in patients treated with morphine or oxycodone. Further studies using larger sample sizes are needed to analyze and confirm the individual as well as synergistic effects of these SNPs. 30
- 31. Recommendations for the Future Routine clinical integrations Pharmacogenomic testing in the primary care setting Standardization More detailed guideline on pharmacogenomic results Expanded test panels Limited amount of medications that are effected by pharmacogenomics Research and clinical trials PK/PD Cost effectiveness 31
- 32. References Robinson, Ann. “Causes and Management of Chronic Pain.” Prescriber, vol. 27, no. 7, July 2016, pp. 39–43, https://doi.org/10.1002/psb.1482 Whirl-Carrillo, M, et al. “Pharmacogenomics Knowledge for Personalized Medicine.” Clinical Pharmacology and Therapeutics, vol. 92, no. 4, 2012, pp. 414–7, www.ncbi.nlm.nih.gov/pubmed/22992668, https://doi.org/10.1038/clpt.2012.96. Accessed 19 Aug. 2019. Schug, Stephan, and Sonya Ting. “The Pharmacogenomics of Pain Management: Prospects for Personalized Medicine.” Journal of Pain Research, Feb. 2016, p. 49, https://doi.org/10.2147/jpr.s55595. Accessed 4 May 2020. Cornett, Elyse M., et al. “Pharmacogenomics of Pain Management: The Impact of Specific Biological Polymorphisms on Drugs and Metabolism.” Current Oncology Reports, vol. 22, no. 2, 6 Feb. 2020, p. 18, pubmed.ncbi.nlm.nih.gov/32030524/, https://doi.org/10.1007/s11912-020-0865-4. Crews, Kristine R., et al. “Clinical Pharmacogenetics Implementation Consortium Guideline for CYP2D6 , OPRM1 , and COMT Genotypes and Select Opioid Therapy.” Clinical Pharmacology & Therapeutics, vol. 110, no. 4, Wiley, Feb. 2021, pp. 888– 96. https://doi.org/10.1002/cpt.2149. Agulló, Laura et al. “Pharmacogenetic Guided Opioid Therapy Improves Chronic Pain Outcomes and Comorbid Mental Health: A Randomized, Double-Blind, Controlled Study.” International journal of molecular sciences vol. 24,13 10754. 28 Jun. 2023, doi:10.3390/ijms241310754 Smith, D Max et al. “CYP2D6-guided opioid therapy improves pain control in CYP2D6 intermediate and poor metabolizers: a pragmatic clinical trial.” Genetics in medicine : official journal of the American College of Medical Genetics vol. 21,8 (2020): 1842- 1850. doi:10.1038/s41436-018-0431-8 Fujita, Yoshihiko et al. “Novel single nucleotide polymorphism biomarkers to predict opioid effects for cancer pain.” Oncology letters vol. 26,2 355. 4 Jul. 2023, doi:10.3892/ol.2023.13941 Lauschke, Volker M., et al. “Pharmacogenomic Biomarkers for Improved Drug Therapy—Recent Progress and Future Developments.” The AAPS Journal, vol. 20, no. 1, 27 Nov. 2017, https://doi.org/10.1208/s12248-017-0161-x. Accessed 22 Nov. 2020. Kennedy, Mary Jayne. “Personalized Medicines – Are Pharmacists Ready for the Challenge?” Integrated Pharmacy Research and Practice, vol. Volume 7, Sept. 2018, pp. 113–123, www.ncbi.nlm.nih.gov/pmc/articles/PMC6166757/, https://doi.org/10.2147/iprp.s133083. Accessed 26 May 2019. 32
Editor's Notes
- Chronic pain (i.e., pain lasting ≥3 months) is a debilitating condition that affects daily work and life activities for many adults in the United States and has been linked with depression (1), Alzheimer disease and related dementias (2), higher suicide risk (3), and substance use and misuse (4). Neuropathic Pain Peripheral neuropathic pain as the case post-herpetic neuralgia or diabetic neuropathy Central neuropathic pain - cerebral vascular accident sequella Nociceptive Pain Pain due to actual tissue injuries such as burns, bruises, or sprains Musculoskeletal Pain Back pain Myofascial pain Inflammatory Pain Autoimmune disorders (rheumatoid arthritis) Infection Psychogenic Pain Pain caused by psychologic factors such as headaches or abdominal pain caused by emotional, psychological, or behavioral factors Mechanical Pain Expanding malignancy
- estimated cost was $560 billion to $635 billion per year,2 composed of direct health care costs ($261 billion to $300 billion), days of work missed ($11.6 billion to $12.7 billion), hours of work missed ($95.2 billion to $96.5 billion), and lower wages ($190.6 billion to $226.3 billion.) T
- painful stimuli arising in the periphery are received by specialized nociceptors that selectively respond to a range of aversive stimuli (eg, temperature, pressure, pH). Peripheral nociceptive input is transmitted through the dorsal horn of the spinal column where interneurons modulate and project signals to a distributed range of central nervous system (CNS) structures, including brainstem, limbic, subcortical, associative, and somatosensory brain regions. Pain is a dynamically linked spatiotemporal event, experienced through multi-segmental [20] descending inhibitory and facilitatory signals arising from both the periphery and from the brain https://pubmed.ncbi.nlm.nih.gov/25240653/ Transmission of pain and modulatory signaling involves multiple dynamic and widely distributed bidirectional pathways of excitatory and inhibitory receptors and neurotransmitters, which are targets for the treatment of pain. Drug treatment for chronic pain can target several sites, including neuroreceptors (eg, opioid receptors), ion channels (eg, calcium and sodium channels), and neurotransmitters (eg, norepinephrine and serotonin). While the exact cellular mechanisms of chronic pain can vary depending on the specific condition, there are some common cellular causes and processes associated with chronic pain. For example: peripheral and central nerves can be overly sensitive after an initial injury, neurotransmitters such a substance P or glutamate can be over produces leading to increased pain perception, or receptors such as NMDA can be upregulated which will yield greater pain receptions
- For example, a randomized controlled trial published in Pain Medicine in 2020 investigated the efficacy of paravertebral block (PVB) in managing cancer-related pain in patients with advanced lung cancer. The study found that PVB provided significant pain relief and improved functional status, with a lower opioid consumption ( bupivacaine or levobupivacaine 0.5% and ropivacaine)
- Pharmacogenomics refers to the role of various components of the genome on response to a drug. Among the most commonly studied are genetic sequence variants, structural changes in chromosomes (eg, translocations), epigenetic variants (eg, changes in gene methylation), and variation in the expression profile of genes (changes in messenger RNA [mRNA] levels) or noncoding RNA (eg, changes in microRNA). The genetic variation can be inherited through the germline or acquired (eg, somatic mutation in a tumor). The availability of high-throughput techniques to interrogate the entire genome has facilitated many pharmacogenomic studies.
- In a validation study with 258 subjects with diagnosed opioid use disorder (OUD) and 650 controls who reported using opioids, the POR successfully categorized patients at high and moderate risks of opioid misuse or abuse with 95.7% sensitivity.
- The combination of CYP2D6 alleles a person harbors determines their genotype. Examples are CYP2D6*1/*2 or CYP2D6*4/*5. Based on function, each allele can be assigned a value to calculate the activity score of the genotype, which in turn is often used to assign phenotype. Briefly, a value of 1 is assigned to each allele of a CYP2D6*1/*2 genotype giving rise to an activity score of 2 (NM), while both alleles of the CYP2D6*4/*5 diplotype receive a value of 0, which results in an activity score of 0 (PM). If an individual has a gene duplication at the CYP2D6 locus, then the additional copy is also counted toward the total activity score. An individual who has no detected variants and is determined to have triplication of the CYP2D6 gene would thus be genotyped as CYP2D6*1x3 and have an activity score of 3. This CPIC-recommended genotype to phenotype translation method was developed to facilitate standardization, it is however, not consistently utilized across clinical laboratories for reporting CYP2D6 pharmacogenetic test results.
- COMT is an enzyme that is involved in metabolizing various catecholamine neurotransmitters, including dopamine and epinephrine. There are two isoforms expressed from two promoters, the soluble S-COMT isoform that is expressed in most tissues, such as liver, blood, and kidneys, and the membrane-bound form MB-COMT that is more common in the brain. The MB-COMT form is of particular interest because of its role in regulating extracellular dopamine levels in the prefrontal cortex. A common SNP changes the 158th amino acid residue of the membrane-bound isoform (or 108th amino acid of the soluble form) from Valine (Val) to Methionine (Met). The presence of the Met variant leads to a four-fold reduction in COMT enzyme activity due to increased thermolability at physiological temperature. This in turn increases the dopamine levels in the prefrontal cortex The endogenous opioid system consists of Mu (µ), delta (δ) and kappa (κ) receptorsThe polymorphism is located within exon 1 region of the OPRM1 gene and causes amino acid exchange from asparagines to aspartate at position 40 of the µ opioid receptor. µ opioid receptors carrying aspartate instead of asparagines receptors demonstrate increased sensitivity to opioids which contributes towards the development of opioid addiction
- Half of the individuals who work to develop these guidelines are actually pharmacist