Genetic Analysis of Mu and Kappa Opioid Receptor and COMT Enzyme in Cancer Pain Tunisian Patients Under Opioid Treatment

  • Imen CHATTI Laboratory of Human Cytogenetics, Molecular Genetics and Reproductive Biology, Farhat Hached Hospital, Sousse, Tunisia
  • Jean-Baptiste WOILLARD U850 INSERM, University of Limoges, CHU Limoges, FHU SUPORT, Limoges, France
  • Amira MILI Laboratory of Human Cytogenetics, Molecular Genetics and Reproductive Biology, Farhat Hached Hospital, Sousse, Tunisia
  • Isabelle CREVEAUX Laboratoire de Biochimie Médicale, Faculté de Médecine, Clermont-Ferrand, France
  • Ilhem BEN CHARFEDDINE Laboratory of Human Cytogenetics, Molecular Genetics and Reproductive Biology, Farhat Hached Hospital, Sousse, Tunisia
  • Jihène FEKI Service d’ Oncologie Médicale et Service de Chirurgie Générale, CHU Habib Bourguiba, Université de Sfax, Sfax, Tunisia
  • Sarah LANGLAIS Laboratoire de Biochimie Médicale, Faculté de Médecine, Clermont-Ferrand, France
  • Leila BEN FATMA Dept. of Medical Oncology, CHU Farhat Hached, Sousse, Tunisia
  • Ali SAAD Laboratory of Human Cytogenetics, Molecular Genetics and Reproductive Biology, Farhat Hached Hospital, Sousse, Tunisia
  • Moez GRIBAA Laboratory of Human Cytogenetics, Molecular Genetics and Reproductive Biology, Farhat Hached Hospital, Sousse, Tunisia
  • Frédéric LIBERT Laboratoire de Pharmacologie et Toxicologie, CHU G. Montpied, Clermont-Ferrand, France Inserm, U1107 NEURO-DOL, Clermont Université, 63001 Clermont-Ferrand, France
Keywords: Polymorphism, OPRM1, OPRK1, COMT, Cancer pain, Genetic heterogeneity


Background: Pain and its opioid treatments are complex measurable traits. Responses to morphine in terms of pain control is likely to be determined by many factors, including the underlying pain sensitivity of the patient, along with nature and extent of the painful process, concomitant medications, genetic and other clinical and environmental factors. This study investigated genetic polymorphisms implicated in the inter-individual pain response variability to opioid treatment in the Tunisian population.Methods: This prospective association study investigated seven variations in the OPRM1, OPRK1 and COMT gene, which encode Mu and KAPPA opioid receptors, and Catechol-O-methyltransferase enzyme respectively, in a cohort of 129 Tunisian cancer pain patients under oral morphine treatment. Genotyping was performed by simple probe probes on Light Cyler for rs17174629, rs1799972, rs1799971, rs1051659, rs1051660 and rs4680 and by PCR assay for the indel in the promoter region of OPRK1 (rs35566036). A statistical associations study between dose (continuous), dose escalation (yes/no) and SNP or haplotypes were investigated using linear multiple regressions and logistic regressions respectively adjusted on metastases and pain covariates in the R software.Results: We detected significant association of the rs1051660 adjusted on metastasis and pain (P=0.02), no other association has been detected between the 7 polymorphisms screened and the dose of morphine needed for pain relief.Conclusion: This can be explained by the strong genetic heterogeneity in the cosmopolitan areas where our patients were recruited for this study, compared to more homegenous population recruited in other studies.  


Meuser T, Pietruck C, Radbruch L et al (2001). Symptoms during cancer pain treatment following WHO-guidelines: a longitudinal follow-up study of symptom prevalence, severity, and etiology. Pain, 93(3): 247-57.

Hoehe MR, Kopke K, Wendel B et al (2000). Sequence variability and candidate gene analysis in complex disease: association of mu opioid receptor gene variation with substance dependence. Hum Mol Genet, 9(19): 2895-908.

Klepstad P, Rakvag TT, Kaasa S et al (2004). The 118 A > G polymorphism in the human mu-opioid receptor gene may increase morphine requirements in patients with pain caused by malignant disease. Acta Anaesthesiol Scand, 48(10): 1232-9.

Chou WY, Yang LC, Lu HF et al (2006). Association of mu-opioid receptor gene polymorphism (A118G) with variations in morphine consumption for analgesia after total knee arthroplasty. Acta Anaesthesiol Scand, 50(7): 787-92.

Reyes-Gibby CC, Shete S, Rakvag T et al (2007). Exploring joint effects of genes and the clinical efficacy of morphine for cancer pain: OPRM1 and COMT gene. Pain, 130(1-2): 25-30.

Gscheidel N, Sander T, Wendel B et al (2000). Five exon 1 variants of mu opioid receptor and vulnerability to alcohol dependence. Pol J Pharmacol, 52(1): 27-31.

Gelernter J, Kranzler H, Cubells J (1999). Genetics of two mu opioid receptor gene (OPRM1) exon I polymorphisms: population studies, and allele frequencies in alcohol- and drug-dependent subjects. Mol Psychiatry, 4(5): 476-83.

Kumar D, Chakraborty J, Das S (2012). Epistatic effects between variants of kappa-opioid receptor gene and A118G of mu-opioid receptor gene increase susceptibility to addiction in Indian population. Prog Neuropsychopharmacol Biol Psychiatry, 36(2): 225-30.

Kreek MJ (1997). Opiate and cocaine addictions: challenge for pharmacotherapies Pharmacol Biochem Behav, 57(3): 551-69.

Bayerer B, Stamer U, Hoeft A, Stuber F (2007). Genomic variations and transcriptional regulation of the human mu-opioid receptor gene. Eur J Pain, 11(4): 421-7.

Gerra G, Leonardi C, Cortese E et al (2007). Human kappa opioid receptor gene (OPRK1) polymorphism is associated with opiate addiction. Am J Med Genet B Neuropsychiatr Genet,144B(6): 771-5.

Butelman ER, Yuferov V, Kreek MJ (2012). κ-opioid receptor/dynorphin system: genetic and pharmacotherapeutic implications for addiction. Trends Neurosci, 35(10): 587-96.

Droney JM, Gretton SK, Sato H et al (2013). Anal-gesia and central side-effects: two separate di-mensions of morphine response. Br J Clin Phar-macol, 75(5): 1340-50.

Thomazeau J, Rouquette A, Martinez V et al (2016). Acute pain Factors predictive of post-operative pain and opioid requirement in multimodal an-algesia following knee replacement. Eur J Pain, 20(5): 822-32.

Crowley JJ, Oslin DW, Patkar AA et al (2003). A genetic association study of the mu opioid receptor and severe opioid dependence. Psychiatr Genet,13(3): 169-73.

Ross JR, Rutter D, Welsh K et al (2005). Clinical response to morphine in cancer patients and genetic variation in candidate genes. Pharmacogenomics J, 5(5): 324-36.

Matsuoka H, Arao T, Makimura C et al (2012). Expression changes in arrestin beta 1 and genetic variation in catechol-O-methyltransferase are biomarkers for the response to morphine treatment in cancer patients. Oncol Rep, 27(5): 1393-9.

Morris JF, Hromas R, Rauscher FJ 3rd (1994). Characterization of the DNA-binding properties of the myeloid zinc finger protein MZF1: two independent DNA-binding domains recognize two DNA consensus sequences with a common G-rich core. Mol Cell Biol,14(3): 1786-95.

Rommelspacher H, Smolka M, Schmidt LG et al (2001). Genetic analysis of the mu-opioid receptor in alcohol-dependent individuals. Alcohol, 24(2): 129-35.

Tan EC, Chong SA, Mahendran R et al (2003). Mu opioid receptor gene polymorphism and neuroleptic-induced tardive dyskinesia in patients with schizophrenia. Schizophr Res, 65(1): 61-3.

Kapur S, Sharad S, Singh RA, Gupta AK (2007). A118g polymorphism in mu opioid receptor gene (oprm1): association with opiate addiction in subjects of Indian origin. J Integr Neurosci, 6(4): 511-22.

Crystal HA, Hamon S, Randesi M et al (2012). A C17T polymorphism in the mu opiate receptor is associated with quantitative measures of drug use in African American women. Addict Biol,17(1): 181-91.

Xuei X, Dick D, Flury-Wetherill L et al (2006). Association of the kappa-opioid system with alcohol dependence. Mol Psychiatry,11(11): 1016-24.

Wang SC, Tsou HH, Chung RH et al (2014). The association of genetic polymorphisms in the kappa-opioid receptor 1 gene with body weight, alcohol use, and withdrawal symptoms in patients with methadone maintenance. J Clin Psychopharmacol, 34(2): 205-11.

Mayer P, Hollt V (2001). Allelic and somatic variations in the endogenous opioid system of humans. Pharmacol Ther, 91(3): 167-77.

Turabi A, Plunkett AR (2012). The application of genomic and molecular data in the treatment of chronic cancer pain. J Surg Oncol, 105(5): 494-501.

Zubieta JK, Heitzeg MM, Smith YR et al (2003). COMT val158met genotype affects mu-opioid neurotransmitter responses to a pain stressor. Science, 299(5610): 1240-3.

Rakvag TT, Klepstad P, Baar C et al (2005). The Val158Met polymorphism of the human catechol-O-methyltransferase (COMT) gene may influence morphine requirements in cancer pain patients. Pain,116(1-2): 73-8.

Oliveira A, Dinis-Oliveira RJ, Nogueira A, et al (2014). Genetic profile and cancer-related pain: a tale from two outlier cases with bone metastatic disease. Pain Med,15(4):710-2.

Candiotti KA, Yang Z, Buric D, et al (2014). Cate-chol-omethyltransferase polymorphisms predict opioid consumption in postoperative pain. Anesth Analg, 119(5): 1194-200.

Fadhlaoui-Zid K, Garcia-Bertrand R, Alfonso-Sanchez MA, et al (2015). Sousse: extreme genetic heterogeneity in North Africa. J Hum Genet, 60(1): 41-9.

How to Cite
CHATTI I, WOILLARD J-B, MILI A, CREVEAUX I, CHARFEDDINE IB, FEKI J, LANGLAIS S, BEN FATMA L, SAAD A, GRIBAA M, LIBERT F. Genetic Analysis of Mu and Kappa Opioid Receptor and COMT Enzyme in Cancer Pain Tunisian Patients Under Opioid Treatment. IJPH. 46(12):1704-11.
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