Skip to main content
Article Publicly Available

Genetic variability of pain – A patient focused end-point

  • EMAIL logo and
Published/Copyright: January 1, 2016
Download Article (PDF)
Become an author with De Gruyter Brill
Author Information Explore this Subject
Scandinavian Journal of Pain
From the journal Scandinavian Journal of Pain Volume 10 Issue 1

In this issue of the Scandinavian Journal of Pain, Martire et al. [1] observed that single nucleotide polymorphism (SNP) variability in the OPRM1 A118G (rs1799971) and COMT Val158Met (rs4680) was related to fluctuations of pain and activity induced pain in patients with knee osteoarthritis.

1 Reasons for inconsistencies of SNP variability in pain-related studies

The potential influence from these two polymorphisms on pain perception and analgesic efficacy from opioids is reported in several studies including patients with chronic pain, postoperative pain, and cancer pain [2,3]. The two polymorphisms are also shown to have a potential gene joint effect [4]. The COMT Val158Met polymorphism is also associated with potential opioid adverse effects representing genetic dispositions that limit the therapeutic window for opioid analgesics [5,6]. Still, findings are inconsistent and large-scale studies or meta-analyses have partly failed to confirm genetic associations [7,8].

1.1 Limited numbers of candidate genes studied in pain and analgesia

The reasons for the inconsistencies between studies are several. First, most studies analyze a limited number of candidate genes and studies with positive associations are usually only able to explain a minor part of the variability of pain or analgesic effects. Pain physiology and opioid pharmacology are complex processes. It is therefore not surprising that variations in multiple genes can be related to experience of pain physiology and response to opioid treatment. Galvan et al. [9] performed a pooled DNA analysis of cancer pain patients using an opioid. They observed that genes related to neuronal processing not usually considered as relevant for pain and opioid studies, were those identified to be different in patients with good pain control versus patients with poor pain control [9].

1.2 Different pain entities, or a mix of pain conditions studied

Second, patients in different studies have different pain entities or are a mix of pain entities. It may well be that the influence from genetic variations are specific for different pain etiologies. Thus, the variation in genetic findings between studies may be a result of poor categorization of pain patients.

1.3 Other causes than SNP of genetic variability

Third, genetic variability in the OPRM1 gene can be caused by other mechanism than SNPs. Variability in selection of exon regions during processing of the primary RNA transcript to a mature mRNA gives rise to multiple OPRM1 receptor variants (splice variants) that may be responsible for varying analgesic response and adverse effects from opioids [10].

Finally, studies are usually of a cross-sectional design giving only a snapshot of the clinical situation [11].

2 Strengths of Martire et al.’s study: pain measured over 3 weeks and activity provoked pain

The study by Martire et al. [1] reports analyses of pain intensities in relation to two genetic variations, OPRM1 A118G and COMT Val158Met, which both are extensively studied. Therefore, a reasonable question is what is the novelty of this paper? The unusual features of this paper are that pain is assessed during a period of 22 days and that pain is analyzed in respect to its relation to activity. For osteoarthritis as for other chronic diseases, pain will fluctuate. The study therefore recognizes that chronic pain should be measured over some time. The importance of this is shown by the contribution of within-person variability of 38%, this is obviously variability that is not caused by genetics in the sense that genes do not change within a single individual. In a cross-sectional study with one measurement of pain this natural fluctuation of pain would have greatly confounded the analyses of inter-person differences caused by genetic variability.

Perhaps the most important consequence of knee osteoarthri-tis pain is that the pain limits activity. Thus, for patients with knee osteoarthritis this study has made an effort to capture from a patient perspective the most relevant and important end-point. This is beneficial from a perspective of measuring what really matters for the patients. It is also an advantage to use an end-point, activity provoked pain, which are more likely to give a better signal strength.

3 Proposals for improved future genetic studies of pain

For researchers who are interested in studies of genetic variability related to pain and efficacy of analgesics the paper by Martire at al. [1] illustrates some important key points. First, if possible, use a design that is able to control for within-person fluctuations of pain, thereby, allowing inclusion of only the actual between-person variability in the genetic analyses. Two, try to select pain phenotypes that are relevant for the studied population. This pain phenotype may be different for different pain populations. Examples of relevant pain phenotypes may be activity related pain for osteoarthritis, mobilization after surgery, global satisfaction with pain treatments, or health related quality of life in cancer patients. Of course the present stage the scientific basis does not merit that new endpoints should replace the currently recommended pain assessments [12,13]. Still, researchers can in upcoming studies include and report alternative patient-focused end-points developed specifically for each patient population. Finally, we emphasize that no genetic studies are better than the quality of selection and assessment of the phenotype.

DOI of refers to article: http://dx.doi.org/10.1016/j.sjpain.2015.07.004

Department Intensive Care Medicine, St. Olavs University Hospital, 7006 Trondheim, Norway. Tel.: +47 7257 5709

  1. Conflict of interest

    No conflict of interest declared.

References

[1] Martire LM, Wilson SJ, Small BJ, Conley YP, Janicki PK, Sliwinski MJ. COMT and OPRM 1 genotype associations with daily knee pain variability and activity induced pain. ScandJ Pain 2015;10:6–12.Search in Google Scholar

[2] Andersen S, Skorpen F. Variation in the COMT gene: implications for pain perception and pain treatment. Pharmacogenomics 2009;10:669–84.Search in Google Scholar

[3] Löftsch J. Genetic variability of pain perception and treatment-clinical pharmacological implications. Eur J Clin Pharmacol 2011;67:541–51.Search in Google Scholar

[4] Reyes-Gibby CC, Shete S, Rakvåg T, Bhat SV, Skorpen F, Bruera E, Kaasa S, Klepstad P. Exploring joint effects of genes and the clinical efficacy of morphine for cancer pain: OPRM1 and COMT gene. Pain 2007;130:25–30.Search in Google Scholar

[5] Laugsand EA, Fladvad T, Skorpen F, Maltoni M, Kaaasa S, Fayers P, Klepstad P. Clinical and genetic factors associated with nausea and vomiting in cancer patients receiving opioids. EurJ Cancer 2011;47:1682–91.Search in Google Scholar

[6] Laugsand EA, Skorpen F, Kaasa S, Sabatowski R, Strasser F, Fayers P, Klepstad P. Genetic and non-genetic factors associated with constipation in cancer patients receiving opioids. Clin Transl Gastroeneterol 2015;6:e90.Search in Google Scholar

[7] Klepstad P, Fladvad T, Skorpen F, Bjordal K, Caraceni A, Dale O, Davies A, Kloke M, Lundstrom S, Maltoni M, Radbruch L, Sabatowski R, Sigurdardottir V, Strasser F, Fayers PM, Kaasa S. Influence from genetic variability on opioid use for cancer pain: a European genetic association study of 2294 cancer pain patients. Pain 2011;152:1139–45.Search in Google Scholar

[8] Walter C, Lötsch J. Meta-analysis of the relevance of the OPRM1 A118 Ggenetic variant for pain treatment. Pain 2009;146:270–5.Search in Google Scholar

[9] Galvan A, Skorpen F, Klepstad P, Knudsen AK, Fladvad T, Falvella FS, Pigni A, Brunelli C, Caraceni A, Kaasa S, Dragani TA. Multiple loci modulate opioid therapy response for cancer pain. Clin Cancer Res 2011;17:1682–91.Search in Google Scholar

[10] Pasterna GW. Incomplete cross tolerance and multiple mu opioid peptide receptors. Trends Pharmacol Sci 2001;22:67–70.Search in Google Scholar

[11] Klepstad P, Kaasa S. The importance and pitfalls of correlational science in palliative care research. Curr Opin Support Palliat Care 2012;6:508–13.Search in Google Scholar

[12] Kaasa S, Apolone G, Klepstad P, Loge JH, Hjermstad MJ, Corli O, Strasser F, Heiskanen T, Costantini M, Zagonel V, Groenvold M, Fainsinger R, Jensen MP, Farrar JT, McQuay H, Rothrock NE, Cleary J, Deguines C, Caraceni A. Expert conference on cancer pain assessment and classification - the need for international consensus: working proposals on international standards. BMJ Support Palliat Care 2011;1:281–7.Search in Google Scholar

[13] Dworkin RH, Turk DC, Farrar JT, Haythornthwaite JA, Jensen MP, Katz NP, Kerns RD, Stucki G, Allen RR, Bellamy N, Carr DB, Chandler J, Cowan P, Dionne R, Galer BS, Hertz S, Jadad AR, Kramer LD, Manning DC, Martin S, McCormick CG, McDermott MP, McGrath P, Quessy S, Rappaport BA, Robbins W, Robinson JP, Rothman M, Royal MA, Simon L, Stauffer JW, Stein W, Tollett J, Wernicke J, Witter J, IMMPACT. Core outcome measures for chronic pain clinical trials: IMMPACT recommendations. Pain 2005;113:9–19.Search in Google Scholar
Published Online: 2016-01-01
Published in Print: 2016-01-01

© 2015 Scandinavian Association for the Study of Pain

Articles in the same Issue

  1. Editorial comment
  2. Plasma pro-inflammatory markers in chronic neuropathic pain: Why elevated levels may be relevant for diagnosis and treatment of patients suffering chronic pain
  3. Original experimental
  4. Plasma pro-inflammatory markers in chronic neuropathic pain: A multivariate, comparative, cross-sectional pilot study
  5. Editorial comment
  6. Genetic variability of pain – A patient focused end-point
  7. Observational study
  8. COMT and OPRM1 genotype associations with daily knee pain variability and activity induced pain
  9. Editorial comment
  10. Complex Regional Pain Syndrome (CRPS) after viper-bite in a pregnant young woman: Pathophysiology and treatment options
  11. Clinical pain research
  12. Complex regional pain syndrome following viper-bite
  13. Editorial comment
  14. An investigation into enlarging and reducing the size of mirror reflections of the hand on experimentally induced cold-pressor pain in healthy volunteers
  15. Original experimental
  16. An investigation into enlarging and reducing the size of mirror reflections of the hand on experimentally-induced cold-pressor pain in healthy human participants
  17. Editorial comment
  18. Multimodal Rehabilitation Programs (MMRP) for patients with longstanding complex pain conditions – The need for quality control with follow-up studies of patient outcomes
  19. Observational study
  20. Patients with chronic pain: One-year follow-up of a multimodal rehabilitation programme at a pain clinic
  21. Editorial comment
  22. Advancing methods for characterizing structure and functions of small nerve fibres in neuropathic conditions
  23. Clinical pain research
  24. Structural and functional characterization of nerve fibres in polyneuropathy and healthy subjects
  25. Editorial comment
  26. Stimulation-induced expression of immediate early gene proteins in the dorsal horn is increased in neuropathy
  27. Original experimental
  28. Stimulation-induced expression of immediate early gene proteins in the dorsal horn is increased in neuropathy
  29. Editorial comment
  30. Targeting glial dysfunction to treat post-surgical neuropathic pain
  31. Topical review
  32. Glial dysfunction and persistent neuropathic postsurgical pain
  33. Editorial comment
  34. Mechanisms of cognitive impairment in chronic pain patients can now be studied preclinically by inducing cognitive deficits with an experimental animal model of chronic neuropathic pain
  35. Original experimental
  36. Impaired recognition memory and cognitive flexibility in the ratL5–L6 spinal nerve ligation model of neuropathic pain
  37. Editorial comment
  38. Pain treatment with intrathecal corticosteroids: Much ado about nothing? But epidural corticosteroids for radicular pain is still an option
  39. Original experimental
  40. Analgesic properties of intrathecal glucocorticoids in three well established preclinical pain models
  41. Editorial comment
  42. The obesity epidemic makes life difficult for patients with herniated lumbar discs – and for back-surgeons: Increased risk of complications
  43. Observational study
  44. Obesity has an impact on outcome in lumbar disc surgery
  45. Editorial comment
  46. Finnish version of the fear-avoidance-beliefs questionnaire (FABQ) and the importance of validated questionnaires on FAB in clinical praxis and in research on low-back pain
  47. Clinical pain research
  48. Translation and validation of the Finnish version of the Fear-Avoidance Beliefs Questionnaire (FABQ)
  49. Editorial comment
  50. Pain, sleep and catastrophizing: The conceptualization matters Comment on Wilt JA et al. “A multilevel path model analysis of the relations between sleep, pain, and pain catastrophizing in chronic pain rehabilitation patients”
  51. Clinical pain research
  52. A multilevel path model analysis of the relations between sleep, pain, and pain catastrophizing in chronic pain rehabilitation patients
https://doi.org/10.1016/j.sjpain.2015.07.006

Articles in the same Issue

  1. Editorial comment
  2. Plasma pro-inflammatory markers in chronic neuropathic pain: Why elevated levels may be relevant for diagnosis and treatment of patients suffering chronic pain
  3. Original experimental
  4. Plasma pro-inflammatory markers in chronic neuropathic pain: A multivariate, comparative, cross-sectional pilot study
  5. Editorial comment
  6. Genetic variability of pain – A patient focused end-point
  7. Observational study
  8. COMT and OPRM1 genotype associations with daily knee pain variability and activity induced pain
  9. Editorial comment
  10. Complex Regional Pain Syndrome (CRPS) after viper-bite in a pregnant young woman: Pathophysiology and treatment options
  11. Clinical pain research
  12. Complex regional pain syndrome following viper-bite
  13. Editorial comment
  14. An investigation into enlarging and reducing the size of mirror reflections of the hand on experimentally induced cold-pressor pain in healthy volunteers
  15. Original experimental
  16. An investigation into enlarging and reducing the size of mirror reflections of the hand on experimentally-induced cold-pressor pain in healthy human participants
  17. Editorial comment
  18. Multimodal Rehabilitation Programs (MMRP) for patients with longstanding complex pain conditions – The need for quality control with follow-up studies of patient outcomes
  19. Observational study
  20. Patients with chronic pain: One-year follow-up of a multimodal rehabilitation programme at a pain clinic
  21. Editorial comment
  22. Advancing methods for characterizing structure and functions of small nerve fibres in neuropathic conditions
  23. Clinical pain research
  24. Structural and functional characterization of nerve fibres in polyneuropathy and healthy subjects
  25. Editorial comment
  26. Stimulation-induced expression of immediate early gene proteins in the dorsal horn is increased in neuropathy
  27. Original experimental
  28. Stimulation-induced expression of immediate early gene proteins in the dorsal horn is increased in neuropathy
  29. Editorial comment
  30. Targeting glial dysfunction to treat post-surgical neuropathic pain
  31. Topical review
  32. Glial dysfunction and persistent neuropathic postsurgical pain
  33. Editorial comment
  34. Mechanisms of cognitive impairment in chronic pain patients can now be studied preclinically by inducing cognitive deficits with an experimental animal model of chronic neuropathic pain
  35. Original experimental
  36. Impaired recognition memory and cognitive flexibility in the ratL5–L6 spinal nerve ligation model of neuropathic pain
  37. Editorial comment
  38. Pain treatment with intrathecal corticosteroids: Much ado about nothing? But epidural corticosteroids for radicular pain is still an option
  39. Original experimental
  40. Analgesic properties of intrathecal glucocorticoids in three well established preclinical pain models
  41. Editorial comment
  42. The obesity epidemic makes life difficult for patients with herniated lumbar discs – and for back-surgeons: Increased risk of complications
  43. Observational study
  44. Obesity has an impact on outcome in lumbar disc surgery
  45. Editorial comment
  46. Finnish version of the fear-avoidance-beliefs questionnaire (FABQ) and the importance of validated questionnaires on FAB in clinical praxis and in research on low-back pain
  47. Clinical pain research
  48. Translation and validation of the Finnish version of the Fear-Avoidance Beliefs Questionnaire (FABQ)
  49. Editorial comment
  50. Pain, sleep and catastrophizing: The conceptualization matters Comment on Wilt JA et al. “A multilevel path model analysis of the relations between sleep, pain, and pain catastrophizing in chronic pain rehabilitation patients”
  51. Clinical pain research
  52. A multilevel path model analysis of the relations between sleep, pain, and pain catastrophizing in chronic pain rehabilitation patients
Downloaded on 26.4.2026 from https://www.degruyterbrill.com/document/doi/10.1016/j.sjpain.2015.07.006/html?lang=en
Scroll to top button