Proove Pain Perception

  • Pain is one of the most common reasons people visit their doctor. It is critically important for a physician to understand and treat a person’s pain appropriately. However, the perception of pain is a complex neuropsychosocial phenomenon: a number of factors can affect how a person experiences pain – not only the severity of the injury or condition. Physicians and scientists now understand that physiologically, people experience pain differently. Even individuals with similar injuries often report different pain levels.
  • Unfortunately, the pain a person feels is extremely difficult to measure objectively. Many of the tools available to physicians for assessing candidates for pain medications are subjective, thereby limiting the utility of these tools.
  • The addition of objective information is essential to guide clinical decisions regarding pain. This profile provides an analysis of the factors found to be most important in the variability of pain sensitivity between people, including several genetic markers. None of these markers are currently assessed as part of standard-of-care pain evaluations.
  • This information provides a physician and the patient with more accurate information about the patient’s pain, which can help mitigate the subjective characteristic of pain perception, and enable the physician to better determine analgesic requirements.
    • For example, a high pain perception result signifies a predisposition to higher catecholamine levels and increased sensitivity to perceived pain. These patients may be more responsive to therapies that target increased catecholamine levels, such as cognitive-behavioral therapies, stress therapy, physical therapy, or non-selective beta blockers. Physicians with concerns surrounding opioid use may use this as a basis to explore adjuvant medications or other multidisciplinary therapies in lieu of escalating opioid doses for those patients not receiving pain relief.
    • For example, a low pain perception result signifies a predisposition to lower catecholamine levels and decreased pain sensitivity. These patients may require lower levels of opioids, but may also benefit from additional examinations for underlying pain generators.
  • Understanding where an individual falls in the spectrum of pain sensitivity can guide decisions about which interventions – be they pharmacological, behavioral, physical – may result in the best outcomes.

  • The Proove Pain Perception test evaluates both genetic and non-genetic factors associated with pain sensitivity and recovery from injury. Genetic factors evaluated are haplotypes of the Catechol-O-Methyltransferase gene (COMT). COMT haplotypes are associated with a profound change in COMT enzymatic activity (up to twenty-fold difference) and correlate strongly with variations in human pain perception1. Low COMT activity – which may occur as a result of genetics and other external factors – is associated with higher sensitivity to painful stimuli due in part to activation of non-selective adrenergic receptors30. COMT genetic associations have been shown in experimentally evoked pain2 and chronic pain, such as fibromyalgia3-7, migraine7-10, cancer pain11-16, shoulder pain17-20, facial pain21 and TMD 1,22,23. Individuals with a COMT pain vulnerable genotypes are also more affected by acute pain, as measured by recovery following a motor vehicle collision24.
  • In 2015, the Proove Pain Perception profile incorporated an enriched COMT haplotype strategy, which analyzes an additional COMT SNP that adds to the effect of the original COMT haplotypes. The inclusion of this data and its association with pain has been replicated in two independent cohorts.25
  • Additional, non-genetic factors evaluated in the profile are stress, gender, and ethnicity. These factors interact with an individual’s genetics to modify sensitivity to pain26-28. For example, exposure to stress and its consequent release of epinephrine largely affects the same pain pathways as COMT genetic variations. Further, COMT expression varies by sex and ethnicity, thereby influencing the COMT activity effect on pain sensitivity. Specifically, factors that decrease or mimic decrease of COMT activity (e.g. stress and decreased expression in females and some minorities) are at higher risk of experiencing pain, which is exacerbated by the low activity COMT haplotype26-29.
  1. Diatchenko, L. et al. Genetic basis for individual variations in pain perception and the development of a chronic pain condition. Hum Mol Genet 14, 135-143, doi:10.1093/hmg/ddi013 (2005).
  2. Zubieta, J. K. et al. COMT val158met genotype affects mu-opioid neurotransmitter responses to a pain stressor. Science 299, 1240-1243, doi:10.1126/science.1078546 (2003).
  3. Cohen, H., Neumann, L., Glazer, Y., Ebstein, R. P. & Buskila, D. The relationship between a common catechol-O-methyltransferase (COMT) polymorphism val(158) met and fibromyalgia. Clin Exp Rheumatol 27, S51-56 (2009).
  4. Desmeules, J. et al. Central pain sensitization, COMT Val158Met polymorphism, and emotional factors in fibromyalgia. J Pain 15, 129-135, doi:10.1016/j.jpain.2013.10.004 (2014).
  5. Finan, P. H. et al. COMT moderates the relation of daily maladaptive coping and pain in fibromyalgia. Pain 152, 300-307, doi:10.1016/j.pain.2010.10.024 (2011).
  6. Martínez-Jauand, M. et al. Pain sensitivity in fibromyalgia is associated with catechol-O-methyltransferase (COMT) gene. Eur J Pain 17, 16-27, doi:10.1002/j.1532-2149.2012.00153.x (2013).
  7. Tammimäki, A. & Männistö, P. T. Catechol-O-methyltransferase gene polymorphism and chronic human pain: a systematic review and meta-analysis. Pharmacogenet Genomics 22, 673-691, doi:10.1097 FPC.0b013e3283560c46 (2012).
  8. Hagen, K., Pettersen, E., Stovner, L. J., Skorpen, F. & Zwart, J. A. The association between headache and Val158Met polymorphism in the catechol-O-methyltransferase gene: the HUNT Study. J Headache Pain 7, 70-74, doi:10.1007/s10194-006-0281-7 (2006).
  9. Liu, J. et al. Genetic contribution of catechol-O-methyltransferase in hippocampal structural and functional changes of female migraine sufferers. Hum Brain Mapp, doi:10.1002/hbm.22737 (2015).
  10. Park, J. W., Lee, K. S., Kim, J. S., Kim, Y. I. & Shin, H. E. Genetic Contribution of Catechol-O-methyltransferase Polymorphism in Patients with Migraine without Aura. J Clin Neurol 3, 24-30, doi:10.3988/jcn.2007.3.1.24 (2007).
  11. Hickey, O. T. et al. Persistent pain after mastectomy with reconstruction. J Clin Anesth 23, 482-488, doi:10.1016/j.jclinane.2011.01.009 (2011).
  12. Klepstad, P. et al. Influence from genetic variability on opioid use for cancer pain: a European genetic association study of 2294 cancer pain patients. Pain 152, 1139-1145, doi:10.1016/j.pain.2011.01.040 (2011).
  13. Rakvåg, T. T. et al. The Val158Met polymorphism of the human catechol-O-methyltransferase (COMT) gene may influence morphine requirements in cancer pain patients. Pain 116, 73-78, doi:10.1016/j.pain.2005.03.032 (2005).
  14. Rakvåg, T. T. et al. Genetic variation in the catechol-O-methyltransferase (COMT) gene and morphine requirements in cancer patients with pain. Mol Pain 4, 64, doi:10.1186/1744-8069-4-64 (2008).
  15. Reyes-Gibby, C. C. et al. Exploring joint effects of genes and the clinical efficacy of morphine for cancer pain: OPRM1 and COMT gene. Pain 130, 25-30, doi:10.1016/j.pain.2006.10.023 (2007).
  16. Ross, J. R. et al. Genetic variation and response to morphine in cancer patients: catechol-O-methyltransferase and multidrug resistance-1 gene polymorphisms are associated with central side effects. Cancer 112, 1390-1403, doi:10.1002/cncr.23292 (2008).
  17. George, S. Z. et al. Biopsychosocial influence on exercise-induced delayed onset muscle soreness at the shoulder: pain catastrophizing and catechol-o-methyltransferase (COMT) diplotype predict pain ratings. Clin J Pain 24, 793-801, doi:10.1097/AJP.0b013e31817bcb65 (2008).
  18. George, S. Z. et al. Evidence for a biopsychosocial influence on shoulder pain: pain catastrophizing and catechol-O-methyltransferase (COMT) diplotype predict clinical pain ratings. Pain 136, 53-61, doi:10.1016/j.pain.2007.06.019 (2008).
  19. George, S. Z. et al. Biopsychosocial influence on exercise-induced injury: genetic and psychological combinations are predictive of shoulder pain phenotypes. J Pain 15, 68-80, doi:10.1016/j.jpain.2013.09.012 (2014).
  20. George, S. Z. et al. Biopsychosocial influence on shoulder pain: risk subgroups translated across preclinical and clinical prospective cohorts. Pain 156, 148-156, doi:10.1016/j.pain.0000000000000012 (2015).
  21. Marbach, J. J. & Levitt, M. Erythrocyte catechol-O-methyltransferase activity in facial pain patients. J Dent Res 55, 711 (1976).
  22. Slade, G. D., Diatchenko, L., Ohrbach, R. & Maixner, W. Orthodontic Treatment, Genetic Factors and Risk of Temporomandibular Disorder. Semin Orthod 14, 146-156, doi:10.1053/j.sodo.2008.02.005 (2008).
  23. Smith, S. B. et al. Potential genetic risk factors for chronic TMD: genetic associations from the OPPERA case control study. J Pain 12, T92-101, doi:10.1016/j.jpain.2011.08.005 (2011).
  24. McLean, S. A. et al. Catechol O-methyltransferase haplotype predicts immediate musculoskeletal neck pain and psychological symptoms after motor vehicle collision. J Pain 12, 101-107, doi:10.1016/j.jpain.2010.05.008 (2011).
  25. Meloto CB, Segall SK, Smith S, et al. COMT gene locus: new functional variants. Pain 2015;156(10):2072-83.
  26. Meloto CB, Bortsov AV, Bair E, et al. Modiciation of COMT-dependent pain sensitivity by psychological stress and sex. Pain 2016;157:858-867
  27. Rahim-Williams B, Riley JL, 3rd, Williams AK, Fillingim RB. A quantitative review of ethnic group differences in experimental pain response: do biology, psychology, and culture matter? Pain Med 2012;13(4):522-40.
  28. Fillingim RB, Ohrbach R, Greenspan JD, et al. Potential psychosocial risk factors for chronic TMD: descriptive data and empirically identified domains from the OPPERA case-control study. J Pain 2011;12(11 Suppl):T46-60.
  29. Slade GD, Sanders AE, Ohrbach R, et al. COMT Diplotype Amplifies Effect of Stress on Risk of Temporomandibular Pain. J Dent Res. 2015; 94(9):1187-1195.
  30. Nackley AG, Tan KS, Fecho K, Flood P, Diatchenko L, Maixner W. Catechol-O-Methyltransferase inhibition increases pain sensitivity through activation of both beta2- and beta3 adrenergic receptors. Pain 2007. 128(3):199-208.
  • A prospective, longitudinal study was conducted with 134 chronic non-cancer pain patients genotyped for pain perception-related catechol-O-methyltransferase haplotypes. Physicians were provided with patients’ results for the Proove Pain Perception profile and asked to document 1) their assessment of benefit of the genetic test; 2) treatment changes made based on the genetic test; and 3) patient clinical responses to changes implemented. Based on genetic testing results, physicians adjusted treatment plans for 40% of patients. When medication changes were made based on genetic testing results, 72% of patients showed improvement in clinical status. When non-pharmacological actions were performed, 69% of physicians felt their patients’ clinical status improved. Moreover, physicians believed the genetic test results were consistent with patient pain levels in 85% of cases. These results demonstrate that providing personalized medicine with genetic information related to pain perception affected physician clinical decision-making for a substantial proportion of patients in this study, and that the availability and utilization of this information was a contributing factor in clinical improvement.
    • Reference: Sharma M, Kantorovich S, et al. An Observational Study of the Impact of Genetic Testing for Pain Perception in the Clinical Management of Chronic Non-Cancer Pain. J Psychiatric Res. 2017. In Press.
  • 40 female Caucasian participants meeting the Research Diagnostic Criteria for TMD were genotyped for COMT polymorphisms and completed a randomized, double–blind, placebo- controlled, two-period crossover pilot study. Each period consisted of a baseline assessment week followed by an intervention week (propranolol or placebo). Changes in clinical pain ratings, psychological status, and responses to heat and pressure stimuli between baseline and intervention weeks were compared across periods. When stratified by the COMT haplotype, a beneficial effect of propranolol on pain perception was noted in subjects with low COMT activity, a diminished benefit was observed in those with average activity, and no benefit was noted in those with high COMT activity diplotypes. These results demonstrate the COMT haplotypes may serve as genetic predictors of propranolol treatment outcome, identifying a subgroup of chronic pain patients who will benefit from propranolol therapy.
    • Reference: Tchivileva IE, Lim PF, Smith SB, et al. Effect of catechol-O-methyltransferase polymorphism on response to propranolol therapy in chronic musculoskeletal pain: A randomized double-blind, placebo-controlled, crossover pilot study. Pharmacogenet Genomics. 2010 20(4): 239-248.