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Cancer Pain pp 37–46Cite as

Pharmacogenetics of Pain in Cancer

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Abstract

The efficacy of opioids varies between individual cancer pain patients. This relates both to the needed dose and to responses to different opioids. Opioid pharmacology is complex and genes coding several pharmacological elements are proposed to explain some of the variability in opioid response. This includes opioid metabolism, opioid receptors, opioid transport through the blood–brain barrier, inflammation, and mechanisms modifying opioid signalling. Variability in CYP2D6 is established to influence the efficacy from codeine. The two other genes shown in several studies to influence opioids efficacy are the OPRM1 gene and the COMT gene. Variability in other genes are not consistently shown to influence on the efficacy from opioids, and in the only study that included a large patient cohort and a validation sample, no candidate genes were associated with opioid dose. Thus, with the exception of CYP2D6 activity and codeine, there are currently no pharmacogenetic analyses that are able to guide opioid therapy. Still, the biological phenomenon has been established, and it is expected that future research will discover the basis for why individuals vary in terms of opioid response.

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Abbreviations

BBB:

Blood–brain barrier

COMT:

Catechol-O-methyltransferase

CYP:

Cytochrome P

ECF:

Extracellular fluid

GWA:

Genome-wide association

M6G:

Morphine-6-glucuronide

MDR:

Multidrug resistance

NKFBIA:

Nuclear factor of light polypeptide gene enhancer in B-cell inhibitor alpha

PTGS2:

Prostaglandin G/H synthase 2

SNP:

Single-nucleotide polymorphism

UGT2B7:

UDP-glucuronosyltransferase 2B7

WHO:

World Health Organization

References

  1. Klepstad P, Kaasa S, Borchgrevink PC. Start of oral morphine to cancer patients: effective serum morphine concentrations and contribution from morphine-6-glucuronide to the analgesia produced by morphine. Eur J Clin Pharmacol. 2000;55:713–9.

    Article  PubMed  CAS  Google Scholar 

  2. Cepeda MS, Farrar JT, Roa JH, et al. Ethnicity influences morphine pharmacokinetics and pharmacodynamics. Clin Pharmacol Ther. 2001;70:351–61.

    PubMed  CAS  Google Scholar 

  3. Mogil JS. Pain genetics: pre- and post-genomic findings. In IASP Newsletter. International Association for the Study of Pain; 2000.

    Google Scholar 

  4. Lacroix-Fralish ML, Ledoux JB, Mogil JS. The Pain Genes Database: an interactive web browser of pain-related transgenic knockout studies. Pain. 2007;131(3): e1–4.

    PubMed  Google Scholar 

  5. Diatchenko L, Nackley AG, Tchivileva IE, et al. Genetic architecture of human pain perception. Trends Genet. 2007;23:605–13.

    Article  PubMed  CAS  Google Scholar 

  6. Kim H, Clark D, Dionne RA. Genetic contributions to clinical pain and analgesia: avoiding pitfalls in genetic research. J Pain. 2009;10:663–93.

    PubMed  Google Scholar 

  7. Kim H, Ramsay E, Lee H, et al. Genome-wide association study of acute post-surgical pain in humans. Pharmacogenomics. 2009;10:171–9.

    Article  PubMed  CAS  Google Scholar 

  8. Sindrup SH, Brøsen K, Bjerring P, et al. Codeine increases pain thresholds to copper vapor laser stimuli in extensive but not poor metabolizers of sparteine. Clin Pharmacol Ther. 1990;48:686–93.

    Article  PubMed  CAS  Google Scholar 

  9. Poulsen L, Arendt-Nielsen L, Brøsen K, et al. The hypoalgesic effect of tramadol in relation to CYP2D6. Clin Pharmacol Ther. 1996;60:636–44.

    Article  PubMed  CAS  Google Scholar 

  10. Heiskanen T, Olkkola KT, Kalso E. Effects of blocking CYP2D6 on the pharmacokinetics and pharmacodynamics of Oxycodone. Clin Pharmacol Ther. 1998;64:603–11.

    Article  PubMed  CAS  Google Scholar 

  11. Andreassen TN, Eftedal I, Klepstad P, et al. Do CYP2D6 genotypes reflect oxycodone requirements for cancer patients treated for cancer pain? A cross-sectional multicentre study. Eur J Clin Pharmacol. 2012;68(1):55–64.

    Article  PubMed  CAS  Google Scholar 

  12. Eap CB, Broly F, Mino A, et al. Cytochrome P450 2D6 genotype and methadone steady-state concentrations. J Clin Psychopharmacol. 2001;21:229–34.

    Article  PubMed  CAS  Google Scholar 

  13. Crettol S, Deglon JJ, Besson J, Croquette-Krokar M, et al. ABCB1 and cytochrome P450 genotypes and phenotypes: influence on methadone plasma levels and responses to treatment. Clin Pharmacol Ther. 2006;80:668–81.

    Article  PubMed  CAS  Google Scholar 

  14. Crettol S, Deglon JJ, Besson J, Croquette-Krokar M, et al. Methadone enantiomer plasma levels, CYP2B6, CYP2C19, and CYP2C9 genotypes, and response to treatment. Clin Pharmacol Ther. 2005;78:593–604.

    Article  PubMed  CAS  Google Scholar 

  15. Zhang W, Chang Y-Z, Kan Q-C, et al. CYP3A4*1G genetic polymorphism influences CYP3A activity and response to fentanyl in Chinese gynecologic patients. Eur J Clin Pharmacol. 2010;66:61–6.

    Article  PubMed  CAS  Google Scholar 

  16. Holthe M, Rakvåg TN, Klepstad P, et al. Sequence variation in the UDP-glucuronosyltransferase 2B7 (UGT2B7) gene: identification of 10 novel single nucleotide polymorphisms (SNPs) and analysis of their relevance to morphine glucuronidation in cancer patients. Pharmacogenomics J. 2003;3:17–26.

    Article  PubMed  CAS  Google Scholar 

  17. Sawyer MB, Innoceti F, Das S, et al. A pharmacogenetic study of uridine diphosphate-glucuronosyltransferase 2B7 in patients receiving morphine. Clin Pharmacol Ther. 2003;73:566–74.

    Article  PubMed  CAS  Google Scholar 

  18. Hoehe MR, Köpke K, Wendel B, et al. Sequence variability and candidate gene analysis in complex disease: association of μ opioid receptor gene variation with substance dependence. Hum Mol Genet. 2000;9:2895–908.

    Article  PubMed  CAS  Google Scholar 

  19. Befort K, Filiol D, Decalliot FM, et al. A single nucleotide polymorphic mutation in the human mu-opioid receptor severely impairs receptor signaling. J Biol Chem. 2001;276:3130–7.

    Article  PubMed  CAS  Google Scholar 

  20. Lotsch J, Geisslinger G. Current evidence for a genetic modulation of the response to analgesics. Pain. 2006;121:1–5.

    Article  PubMed  Google Scholar 

  21. Romberg R, Olufsen E, Bijl H, et al. Polymorphism of μ-opioid receptor gene (OPRM1:c.118A>G) does not protect against opioid-induced respiratory depression despite reduced analgesic response. Anesthesiology. 2005;102:522–30.

    Article  PubMed  CAS  Google Scholar 

  22. Lotsch J, Stuck B, Hummel T. The human μ-opioid receptor gene polymorphism 118A>G decreases cortical activation in response to specific nociceptive stimuli. Behav Neurosci. 2006;120:1218–24.

    Article  PubMed  Google Scholar 

  23. Klepstad P, Rakvåg TN, Kaasa S, et al. The 118 A>G polymorphism in the human μ-opioid receptor gene may increase morphine requirements in patients with pain caused by malignant disease. Acta Anaesthesiol Scand. 2004;48:1232–9.

    Article  PubMed  CAS  Google Scholar 

  24. Campa D, Gioia A, Tomei A, et al. Association of ABCB1/MDR1 and OPRM1 gene polymorphisms with morphine pain relief. Clin Pharmacol Ther. 2008;83:559–66.

    Article  PubMed  CAS  Google Scholar 

  25. Chou WY, Yang LC, Lu HF, et al. Association of mu opioid receptor gene polymorphism (A118G) with variations in morphine consumption for analgesia after total knee arthroplasties. Acta Anaesthesiol Scand. 2006;50:787–92.

    Article  PubMed  CAS  Google Scholar 

  26. Walter C, Lötsch J. Meta-analysis of the relevance of the OPRM1 118A>G genetic variant for pain treatment. Pain. 2009;146:270–5.

    Article  PubMed  CAS  Google Scholar 

  27. Klepstad P, Fladvad T, Skorpen F, et al. 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.

    Article  PubMed  CAS  Google Scholar 

  28. Pasternak GW. Incomplete cross tolerance and multiple mu opioid peptide receptors. Trends Pharmacol Sci. 2001;22:67–70.

    Article  PubMed  CAS  Google Scholar 

  29. Pan YX, Xu J, Mahurter L, et al. Identification and characterization of two human mu opioid receptor splice variants, hMOR-1O and hMOR-1X. Biochem Biophys Res Commun. 2003;301:1057–61.

    Article  PubMed  CAS  Google Scholar 

  30. Kvam TM, Baar C, Rakvåg TT, et al. Genetic analysis of the murine mu opioid receptor: increased complexity of Oprm gene splicing. J Mol Med. 2004;82:250–5.

    Article  PubMed  CAS  Google Scholar 

  31. Ross JR, Riley J, Taegtmeyer AB, et al. Genetic variation and response to morphine in cancer patients: catechol-O-methyltransferase (COMT) and multi-drug resistance (MDR-1) gene polymorphism are associated with central side-effects. Cancer. 2007;112:1390–403.

    Article  Google Scholar 

  32. Coulbault L, Beaussier M, Verstuyft C, et al. Environmental and genetic factors associated with morphine responses in the postoperative period. Clin Pharmacol Ther. 2006;79:316–24.

    Article  PubMed  CAS  Google Scholar 

  33. Ross JR, Ruttler D, Welsh K, et al. Clinical response to morphine in cancer patients and genetic variation in candidate genes. Pharmacogenomics J. 2005;5:324–36.

    Article  PubMed  CAS  Google Scholar 

  34. Zubieta JK, Heitzeg MM, Smith YR, et al. COMT val 158 met genotype affects μ-opioid neurotransmitter responses to a pain stressor. Science. 2003;299:1240–3.

    Article  PubMed  CAS  Google Scholar 

  35. Kim H, Mittal DP, Iadarola MJ, et al. Genetic predictors for acute experimental cold and heat pain sensitivity in humans. J Med Genet. 2006;43:e40.

    Article  PubMed  CAS  Google Scholar 

  36. Kim H, Lee H, Rowan J, et al. Genetic polymorphisms in monoamine neurotransmittor systems show only weak association with acute post-surgical pain in humans. Mol Pain. 2006;2:24.

    Article  PubMed  Google Scholar 

  37. Rakvåg TT, Klepstad P, Baar C, et al. The Val158Met polymorphism of the human catechol-O-methyltransferase (COMT) gene may influence morphine requirements in cancer pain patients. Pain. 2005;116:73–8.

    Article  PubMed  Google Scholar 

  38. Laugsand EA, Fladvad T, Skorpen F, et al. Clinical and genetic factors associated with nausea and vomiting in cancer patients receiving opioids. Eur J Cancer. 2011;47:1682–91.

    Article  PubMed  CAS  Google Scholar 

  39. Mogil JS, Ritchie J, Smith SB, et al. Melanonocortin-1 receptor gene variants affect pain and μ-opioid analgesia in mice and humans. J Med Genet. 2005;42:583–7.

    Article  PubMed  CAS  Google Scholar 

  40. Crettol S, Besson J, Croquette-Krokar M, et al. Association of dopamine and opioid receptor genetic polymorphisms with response to methadone maintenance treatment. Prog Neuropsychopharmacol Biol Psychiatry. 2008;32:1722–77.

    Article  PubMed  CAS  Google Scholar 

  41. Lötsch J, Klepstad P, Doehring A, et al. A GTP cyclohydrolase 1 genetic variant delays cancer pain. Pain. 2010;148:103–6.

    Article  PubMed  Google Scholar 

  42. Kohli U, Muszkat M, Sofowora GG, et al. Effects of variation in the human α2A- and α2C-adrenoceptor genes on cognitive tasks and pain perception. Eur J Pain. 2010;14:154–9.

    Article  PubMed  CAS  Google Scholar 

  43. Lötsch J, Prüss H, Veh RW, et al. A KCNJ6 (Kir3.2, GIRK2) gene polymorphism modulates opioid effects on analgesia and addiction but not on pupil size. Pharmacogenet Genomics. 2010;20:291–7.

    Article  PubMed  Google Scholar 

  44. Galvan A, Skorpen F, Klepstad P, et al. Multiple loci modulate opioid therapy response for cancer pain. Clin Cancer Res. 2011;17(13):4581–7.

    Article  PubMed  CAS  Google Scholar 

  45. Hutchinson MR, Shavit Y, Grace PM, et al. Exploring the neuroimmunopharmacology of opioids: an integrative review of mechanisms of central immune signaling and their implications for opioid analgesia. Pharmacol Rev. 2011;63:772–810.

    Article  PubMed  CAS  Google Scholar 

  46. Lewis SS, Hutchinson MR, Rezvani N, et al. Evidence that intrathecal morphine-3-glucuronide may cause pain enhancement via toll-like receptor 4/MD-2 and interleukin-1beta. Neuroscience. 2010;165:569–83.

    Article  PubMed  CAS  Google Scholar 

  47. Bessler H, Shavit Y, Mayburd E, et al. Postoperative pain, morphine consumption, and genetic polymorphism of IL-1beta and IL-1 receptor antagonist. Neurosci Lett. 2006;404:154–8.

    Article  PubMed  CAS  Google Scholar 

  48. Candiotti KA, Yang Z, Morris R, et al. Polymorphism in the interleukin-1 receptor antagonist gene is associated with serum interleukin-1 receptor antagonist concentrations and postoperative opioid consumption. Anesthesiology. 2011;114:1162–8.

    Article  PubMed  CAS  Google Scholar 

  49. Reyes-Gibby CC, El Osta B, et al. The influence of tumor necrosis factor-alpha −308 G/A and IL-6–174 G/C on pain and analgesia response in lung cancer patients receiving supportive care. Cancer Epidemiol Biomarkers Prev. 2008;17:3262–7.

    Article  PubMed  CAS  Google Scholar 

  50. Reyes-Gibby CC, Spitz MR, Yennurajalingam S, et al. Role of inflammation gene polymorphisms on pain severity in lung cancer patients. Cancer Epidemiol Biomarkers Prev. 2009;18:2636–42.

    Article  PubMed  CAS  Google Scholar 

  51. Caraceni A, Hanks G, Kaasa S, et al. Use of opioid analgesics in the treatment of cancer pain: evidenced-based recommendation from the EAPC. Lancet Oncol. 2012;13:e58–68.

    Article  PubMed  CAS  Google Scholar 

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Author information

Authors and Affiliations

  1. Department of Intensive Care Medicine, St. Olavs University Hospital, Trondheim, 7006, Norway

    Pål Klepstad MD, PhD

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  1. Pål Klepstad MD, PhD
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Correspondence to Pål Klepstad MD, PhD .

Editor information

Editors and Affiliations

  1. Analgesics & Pain Research Ltd, Beckenham, United Kingdom

    Magdi Hanna

  2. Hildegard Hospiz, Basel, Switzerland

    Zbigniew (Ben) Zylicz

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Klepstad, P. (2013). Pharmacogenetics of Pain in Cancer. In: Hanna, M., Zylicz, Z. (eds) Cancer Pain. Springer, London. https://doi.org/10.1007/978-0-85729-230-8_4

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  • DOI: https://doi.org/10.1007/978-0-85729-230-8_4

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