OPRM1 and CYP3A4 association with methadone dose in Iranian patients undergoing methadone maintenance therapy

Abstract Background Investigations proposed that genetic polymorphisms within proteins in methadone pharmacokinetic and pharmacodynamics are critical factors in determination of methadone dose in methadone maintenance therapy (MMT). Objective This study aimed to assess the associations between two polymorphisms, CYP3A4 (rs2740574) and OPRM1 (rs1799971), with dose of methadone in Iranian patients undergoing MMT. Methods A total of 124 Iranian male subjects aged 18–65 years old who were confirmed to be addicted by the addiction diagnostic tests and underwent MMT were assessed. Patients were divided into three groups of low (less than 40 mg/day), moderate (more than 40 mg/day and less than 110 mg/day) and high (more than 110 mg/day) methadone dose consumption. DNAs of included patients were extracted from their blood samples and were assessed for CYP3A4 and OPRM1 polymorphisms. Results Results showed that there was no significant association between the studied polymorphisms and methadone dose in Iranian addicted patients underwent MMT (P > 0.05). Conclusions CYP3A4 and OPRM1 single variations cannot explain variability in methadone dosage in MMT. Studying the interactions of more genetic factors in larger samples may elucidate factors influencing the required dose of methadone and better individualized therapy.

[1]  R. Malekzadeh,et al.  Iranome: A catalog of genomic variations in the Iranian population , 2019, Human mutation.

[2]  Abdolrazagh Barzegar,et al.  Characterizing Mortality from Substance Abuse in Iran: An Epidemiological Study during March 2014 to February 2015 , 2017, Addiction & health.

[3]  Winners Monthly,et al.  FEBRUARY 2015 , 2017, No Boston Olympics.

[4]  J. Benumof.  Treatment of Opioid-Use Disorders. , 2016, The New England journal of medicine.

[5]  Johnny C. Tenegra,et al.  Substance Abuse Screening and Treatment. , 2016, Primary care.

[6]  B. Saloner,et al.  Changes in Substance Abuse Treatment Use Among Individuals With Opioid Use Disorders in the United States, 2004-2013. , 2015, JAMA.

[7]  I. Bauer,et al.  The role of opioidergic genes in the treatment outcome of drug addiction pharmacotherapy: A systematic review. , 2014, The American journal on addictions.

[8]  G. Rankin,et al.  Fatal methadone toxicity: potential role of CYP3A4 genetic polymorphism. , 2014, Journal of analytical toxicology.

[9]  J. Ott,et al.  Association of genetic variation in pharmacodynamic factors with methadone dose required for effective treatment of opioid addiction. , 2013, Pharmacogenomics.

[10]  B. Haerian,et al.  OPRM1 rs1799971 polymorphism and opioid dependence: evidence from a meta-analysis. , 2013, Pharmacogenomics.

[11]  Yu-ting Chen,et al.  Genetic polymorphisms in the opioid receptor mu1 gene are associated with changes in libido and insomnia in methadone maintenance patients , 2012, European Neuropsychopharmacology.

[12]  K. Merikangas,et al.  Epidemiology of substance use disorders , 2012, Human Genetics.

[13]  A. Somogyi,et al.  ABCB1 haplotype and OPRM1 118A > G genotype interaction in methadone maintenance treatment pharmacogenetics , 2012, Pharmacogenomics and personalized medicine.

[14]  H. Lane,et al.  Impact of genetic polymorphisms in ABCB1, CYP2B6, OPRM1, ANKK1 and DRD2 genes on methadone therapy in Han Chinese patients. , 2011, Pharmacogenomics.

[15]  M. Preisig,et al.  Association of dopamine and opioid receptor genetic polymorphisms with response to methadone maintenance treatment , 2008, Progress in Neuro-Psychopharmacology and Biological Psychiatry.

[16]  C. Eap,et al.  ABCB1 and cytochrome P450 genotypes and phenotypes: Influence on methadone plasma levels and response to treatment , 2006, Clinical pharmacology and therapeutics.

[17]  E. Kharasch,et al.  Role of hepatic and intestinal cytochrome P450 3A and 2B6 in the metabolism, disposition, and miotic effects of methadone , 2004, Clinical pharmacology and therapeutics.

[18]  L. Wojnowski.  Genetics of the variable expression of CYP3A in humans. , 2004, Therapeutic drug monitoring.

[19]  Ann Daly,et al.  Common allelic variants of cytochrome P4503A4 and their prevalence in different populations. , 2002, Pharmacogenetics.

[20]  F. d’Oleire Uquillas,et al.  Definition of Substance and Non-substance Addiction. , 2017, Advances in experimental medicine and biology.

[21]  S. Spampinato,et al.  Opioid Receptors , 2015, Methods in Molecular Biology.

[22]  D. Oslin,et al.  association analysis of polymorphisms in the delta-opioid receptor , PRD 1 , with cocaine and opioid addicted populations , 2012 .

[23]  P. Whelan,et al.  Buprenorphine vs methadone treatment: A review of evidence in both developed and developing worlds , 2012, Journal of neurosciences in rural practice.

[24]  M. Gratacós,et al.  Response to methadone maintenance treatment is associated with the MYOCD and GRM6 genes. , 2010, Molecular Diagnosis & Therapy.

[25]  T. Rebbeck,et al.  More about: modification of clinical presentation of prostate tumors by a novel genetic variant in CYP3A4. , 2000, Journal of the National Cancer Institute.