Skip to main content
SpringerLink
Log in

Pharmacogenetics of Methadone Response

  • Review Article
  • Published:
Molecular Diagnosis & Therapy Aims and scope Submit manuscript

Abstract

The efficacy of methadone maintenance treatment (MMT) in opioid use disorder is well established but responses vary. The influence of methadone pharmacodynamics and pharmacokinetics on dose requirements and program outcomes remains controversial despite the increasing number of studies evaluating genetic influences on response to methadone treatment. Furthermore, patients require different doses (usually between 60 and 100 mg/day), and there are no clear data on a plasma concentration associated with treatment success. We review the evidence regarding the influence of genetics on pharmacokinetic and pharmacodynamic factors in terms of MMT outcome. We also analyse the influence of genetics on the occurrence of severe adverse events such as respiratory depression and ventricular arrhythmia in methadone treatment. The outcomes of MMT may be influenced by a combination of environmental, drug-induced, and genetic factors. The influence of pharmacokinetic genetic variability can be clinically managed by modifying the posology. A better understanding of pharmacodynamic factors could help in selecting the best opioid for substitution treatment, but patient phenotype must still be considered when establishing a maintenance treatment. Pharmacogenetic studies represent a promising field that aims to individualize treatments according to genetic backgrounds, adapting medication and doses according to possible outcomes and the risk of adverse events.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. United Nations Office on Drugs and Crime. World Drug Report 2016. Vienna: (United Nations publication, Sales No. E.16.XI.7); 2016.

  2. Koob GF, Volkow ND. Neurobiology of addiction: a neurocircuitry analysis. Lancet Psychiatry. 2016;3:760–73.

    Article  PubMed  Google Scholar 

  3. Sellman D. The 10 most important things known about addiction. Addiction. 2010;105:6–13.

    Article  PubMed  Google Scholar 

  4. Kreek MJ, Levran O, Reed B, Schlussman SD, Zhou Y, Butelman ER. Opiate addiction and cocaine addiction: Underlying molecular neurobiology and genetics. J Clin Invest. 2012;122:3387–935.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Veilleux JC, Colvin PJ, Anderson J, York C, Heinz AJ. A review of opioid dependence treatment: pharmacological and psychosocial interventions to treat opioid addiction. Clin Psychol Rev. 2010;30:155–66.

    Article  PubMed  Google Scholar 

  6. Fiellin DA, Friedland GH, Gourevitch MN. Opioid dependence: rationale for and efficacy of existing and new treatments. Clin Infect Dis. 2006;43(Suppl 4):S173–7.

    Article  CAS  PubMed  Google Scholar 

  7. Mattick RP, Breen C, Kimber J, Davoli M. Methadone maintenance therapy versus no opioid replacement therapy for opioid dependence. Cochrane Database Syst Rev. 2009;(3):CD002209.

  8. Nielsen S, Larance B, Degenhardt L, Gowing L, Kehler C, Lintzeris N. Opioid agonist treatment for pharmaceutical opioid dependent people. Cochrane Database Syst Rev. 2016;(5):CD011117. https://doi.org/10.1002/14651858.CD011117.pub2.

  9. Mattick RP, Breen C, Kimber J, Davoli M, Rp M, Breen C, et al. Buprenorphine maintenance versus placebo or methadone maintenance for opioid dependence. Cochrane Database Syst Rev. 2014; 2:CD002207.

  10. Amato L, Davoli M, Perucci CA, Ferri M, Faggiano F, Mattick RP. An overview of systematic reviews of the effectiveness of opiate maintenance therapies: available evidence to inform clinical practice and research. J Subst Abuse Treat. 2005;28:321–9.

    Article  PubMed  Google Scholar 

  11. Connock M, Juarez-Garcia A, Jowett S, Frew E, Liu Z, Taylor RJ, et al. Methadone and buprenorphine for the management of opioid dependence: a systematic review and economic evaluation. Health Technol. 2007;11:1–171.

    CAS  Google Scholar 

  12. Torrens M, Fonseca F, Castillo C, Domingo-Salvany A. Methadone maintenance treatment in Spain: the success of a harm reduction approach. Bull World Health Organ. 2013;91:136–41.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Dolan KA, Shearer J, White B, Zhou J, Kaldor J, Wodak AD. Four-year follow-up of imprisoned male heroin users and methadone treatment: mortality, re-incarceration and hepatitis C infection. Addiction. 2005;100:820–8.

    Article  PubMed  Google Scholar 

  14. Brugal MT, Domingo-Salvany A, Puig R, Barrio G, Garcia de Olalla P, de la Fuente L. Evaluating the impact of methadone maintenance programmes on mortality due to overdose and aids in a cohort of heroin users in Spain. Addiction. 2005;100:981–9.

    Article  CAS  PubMed  Google Scholar 

  15. Zhou K, Wang D, Li H, Wei X, Yin J, Liang P, et al. Bidirectional relationships between retention and health-related quality of life in Chinese mainland patients receiving methadone maintenance treatment. PLoS One. 2017;12:e0179009 (Le Foll B, editor.).

  16. Eap CB, Buclin T, Baumann P. Interindividual variability of the clinical pharmacokinetics of methadone: implications for the treatment of opioid dependence. Clin Pharmacokinet. 2002;41:1153–93.

    Article  CAS  PubMed  Google Scholar 

  17. Silverman DAN, Nettleton RT, Spencer KB, Wallisch M, Olsen GD. S-Methadone augments R-methadone induced respiratory depression in the neonatal guinea pig. Respir Physiol Neurobiol. 2009;169:252–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Eap CB, Finkbeiner T, Gastpar M, Scherbaum N, Powell K, Baumann P. Replacement of (R)-methadone by a double dose of (R, S)-methadone in addicts: interindividual variability of the (R)/(S) ratios and evidence of adaptive changes in methadone pharmacokinetics. Eur J Clin Pharmacol. 1996;50:385–9.

    Article  CAS  PubMed  Google Scholar 

  19. Beck O, Boreus LO, Lafolie P, Jacobsson G. Chiral analysis of methadone in plasma by high-performance liquid chromatography. J Chromatogr. 1991;570:198–202.

    Article  CAS  PubMed  Google Scholar 

  20. Foster DJ, Somogyi AA, White JM, Bochner F. Population pharmacokinetics of (R)-, (S)- and rac-methadone in methadone maintenance patients. Br J Clin Pharmacol. 2004;57:742–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Mouly S, Bloch V, Peoc’h K, Houze P, Labat L, Ksouda K, et al. Methadone dose in heroin-dependent patients: role of clinical factors, comedications, genetic polymorphisms and enzyme activity. Br J Clin Pharmacol. 2015;79:967–77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Garrido MJ, Aguirre C, Trocóniz IF, Marot M, Valle M, Zamacona MK, et al. Alpha 1-acid glycoprotein (AAG) and serum protein binding of methadone in heroin addicts with abstinence syndrome. Int J Clin Pharmacol Ther. 2000;38:35–40.

    Article  CAS  PubMed  Google Scholar 

  23. Wolff K, Rostami-Hodjegan A, Shires S, Hay AW, Feely M, Calvert R, et al. The pharmacokinetics of methadone in healthy subjects and opiate users. Br J Clin Pharmacol. 1997;44:325–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Bell J, Seres V, Bowron P, Lewis J, Batey R. The use of serum methadone levels in patients receiving methadone maintenance. Clin Pharmacol Ther. 1988;43:623–9.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  26. Torrens M, Castillo C, San L, del Moral E, Gonzalez ML, de la Torre R. Plasma methadone concentrations as an indicator of opioid withdrawal symptoms and heroin use in a methadone maintenance program. Drug Alcohol Depend. 1998;52:193–200.

    Article  CAS  PubMed  Google Scholar 

  27. Borg L, Ho A, Peters JE, Kreek MJ. Availability of reliable serum methadone determination for management of symptomatic patients. J Addict Dis. 1995;14:83–96.

    Article  CAS  PubMed  Google Scholar 

  28. Loimer N, Schmid R, Grunberger J, Jagsch R, Linzmayer L, Presslich O. Psychophysiological reactions in methadone maintenance patients do not correlate with methadone plasma levels. Psychopharmacology. 1991;103:538–40.

    Article  CAS  PubMed  Google Scholar 

  29. Dyer KR, Foster DJ, White JM, Somogyi AA, Menelaou A, Bochner F. Steady-state pharmacokinetics and pharmacodynamics in methadone maintenance patients: comparison of those who do and do not experience withdrawal and concentration-effect relationships. Clin Pharmacol Ther. 1999;65:685–94.

    Article  CAS  PubMed  Google Scholar 

  30. Eap CB, Bourquin M, Martin J, Spagnoli J, Livoti S, Powell K, et al. Plasma concentrations of the enantiomers of methadone and therapeutic response in methadone maintenance treatment. Drug Alcohol Depend. 2000;61:47–54.

    Article  CAS  PubMed  Google Scholar 

  31. Valentová J, Horáková R, Pechová I, Okruhlica L, Devínsky F. Stereoselective determination of methadone and its main metabolite in serum and urine from methadone maintenance patients. Neuroendocrinol Lett. 2006;27(Suppl 2):130–3.

    PubMed  Google Scholar 

  32. Hiltunen AJ, Beck O, Hjemdahl P, Liljeberg P, Almstrom U, Brodin K, et al. Rated well-being in relation to plasma concentrations of l- and d-methadone in satisfied and dissatisfied patients on methadone maintenance treatment. Psychopharmacology. 1999;143:385–93.

    Article  CAS  PubMed  Google Scholar 

  33. Meini M, Moncini M, Daini L, Giarratana T, Scaramelli D, Chericoni S, et al. Relationship between plasma concentrations of the l-enantiomer of methadone and response to methadone maintenance treatment. Eur J Pharmacol. 2015;760:1–6.

    Article  CAS  PubMed  Google Scholar 

  34. Bell J, Burrell T, Indig D, Gilmour S. Cycling in and out of treatment; participation in methadone treatment in NSW, 1990–2002. Drug Alcohol Depend. 2006;81:55–61.

    Article  PubMed  Google Scholar 

  35. Faggiano F, Vigna-Taglianti F, Versino E, Lemma P. Methadone maintenance at different dosages for opioid dependence. Cochrane Database Syst Rev. 2003;(3):CD002208.

  36. Villafranca SW, McKellar JD, Trafton JA, Humphreys K. Predictors of retention in methadone programs: a signal detection analysis. Drug Alcohol Depend. 2006;83:218–24.

    Article  PubMed  Google Scholar 

  37. Trafton JA, Tracy SW, Oliva EM, Humphreys K, et al. Different components of opioid-substitution treatment predict outcomes of patients with and without a parent with substance-use problems. J Stud Alcohol Drugs. 2007;68:165–72.

    Article  PubMed  Google Scholar 

  38. Li Y, Kantelip JP, Gerritsen-van Schieveen P, Davani S. Interindividual variability of methadone response: impact of genetic polymorphism. Mol Diagn Ther. 2008;12:109–24.

    Article  CAS  PubMed  Google Scholar 

  39. Somogyi AA, Barratt DT, Ali RL, Coller JK. Pharmacogenomics of methadone maintenance treatment. Pharmacogenomics. 2014;15:1007–27.

    Article  CAS  PubMed  Google Scholar 

  40. Attia J, Ioannidis JPA, Thakkinstian A, McEvoy M, Scott RJ, Minelli C, et al. How to use an article about genetic association: B: are the results of the study valid? JAMA. 2009;301:191–7.

    Article  CAS  PubMed  Google Scholar 

  41. Wang JB, Johnson PS, Persico AM, Hawkins AL, Griffin CA, Uhl GR. Human mu opiate receptor. cDNA and genomic clones, pharmacologic characterization and chromosomal assignment. FEBS Lett. 1994;338:217–22.

    Article  CAS  PubMed  Google Scholar 

  42. Bond C, LaForge KS, Tian M, Melia D, Zhang S, Borg L, et al. Single-nucleotide polymorphism in the human mu opioid receptor gene alters beta-endorphin binding and activity: possible implications for opiate addiction. Proc Natl Acad Sci USA. 1998;95:9608–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Zhang Y, Wang D, Johnson AD, Papp AC, Sadee W. Allelic expression imbalance of human mu opioid receptor (OPRM1) caused by variant A118G. J Biol Chem. 2005;280:32618–24.

    Article  CAS  PubMed  Google Scholar 

  44. Oertel BG, Kettner M, Scholich K, Renne C, Roskam B, Geisslinger G, et al. A common human micro-opioid receptor genetic variant diminishes the receptor signaling efficacy in brain regions processing the sensory information of pain. J Biol Chem. 2009;284:6530–5.

    Article  CAS  PubMed  Google Scholar 

  45. Kroslak T, Laforge KS, Gianotti RJ, Ho A, Nielsen DA, Kreek MJ. The single nucleotide polymorphism A118G alters functional properties of the human mu opioid receptor. J Neurochem. 2007;103:77–87.

    CAS  PubMed  Google Scholar 

  46. Hernandez-Avila CA, Wand G, Luo X, Gelernter J, Kranzler HR. Association between the cortisol response to opioid blockade and the Asn40Asp polymorphism at the mu-opioid receptor locus (OPRM1). Am J Med Genet B Neuropsychiatr Genet. 2003;118B:60–5.

  47. Schwantes-An TH, Zhang J, Chen LS, Hartz SM, Culverhouse RC, Chen X, et al. Association of the OPRM1 variant rs1799971 (A118G) with non-specific liability to substance dependence in a collaborative de novo meta-analysis of european-ancestry cohorts. Behav Genet. 2016;46:151–69.

    Article  PubMed  Google Scholar 

  48. Wu WD, Wang Y, Fang YM, Zhou HY. Polymorphism of the micro-opioid receptor gene (OPRM1 118A>G) affects fentanyl-induced analgesia during anesthesia and recovery. Mol Diagn Ther. 2009;13:331–7.

    Article  CAS  PubMed  Google Scholar 

  49. De Capraris A, Cinnella G, Marolla A, Salatto P, Da Lima S, Vetuschi P, et al. Micro opioid receptor A118G polymorphism and post-operative pain: opioids’ effects on heterozigous patients. Int J Immunopathol Pharmacol. 2011;24:993–1004.

    Article  PubMed  Google Scholar 

  50. Mura E, Govoni S, Racchi M, Carossa V, Nadia Ranzani G, Allegri M, et al. Consequences of the 118A>G polymorphism in the OPRMI gene: translation from bench to bedside? J Pain Res. 2013;6:331–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Smith AH, Jensen KP, Li J, Nunez Y, Farrer LA, Hakonarson H, et al. Genome-wide association study of therapeutic opioid dosing identifies a novel locus upstream of OPRM1. Mol Psychiatry. 2017;22:346–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Hwang IC, Park JY, Myung SK, Ahn HY, Fukuda K, Liao Q. OPRM1 A118G gene variant and postoperative opioid requirement: a systematic review and meta-analysis. Anesthesiology. 2014;121:825–34.

    Article  PubMed  Google Scholar 

  53. Lotsch J, Skarke C, Wieting J, Oertel BG, Schmidt H, Brockmoller J, et al. Modulation of the central nervous effects of levomethadone by genetic polymorphisms potentially affecting its metabolism, distribution, and drug action. Clin Pharmacol Ther. 2006;79:72–89.

    Article  PubMed  CAS  Google Scholar 

  54. Barratt DT, Coller JK, Hallinan R, Byrne A, White JM, Foster DJR, et al. ABCB1 haplotype and OPRM1 118A>G genotype interaction in methadone maintenance treatment pharmacogenetics. Pharmacogenomics. 2012;5:53–62.

    CAS  Google Scholar 

  55. Hung CC, Chiou MH, Huang BH, Hsieh YW, Hsieh TJ, Huang CL, et al. Impact of genetic polymorphisms in ABCB1, CYP2B6, OPRM1, ANKK1 and DRD2 genes on methadone therapy in Han Chinese patients. Pharmacogenomics. 2011;12:1525–33.

    Article  CAS  PubMed  Google Scholar 

  56. Crettol S, Besson J, Croquette-Krokar M, Hammig R, Gothuey I, Monnat M, et al. Association of dopamine and opioid receptor genetic polymorphisms with response to methadone maintenance treatment. Prog Neuropsychopharmacol. 2008;32:1722–7.

    Article  CAS  Google Scholar 

  57. Nielsen D, Ji F, Yuferov V, Ho A, Chen A, Levran O, et al. Genotype patterns that contribute to increased risk for or protection from developing heroin addiction. Mol Psychiatry. 2008;13:417–28.

    Article  CAS  PubMed  Google Scholar 

  58. Fonseca F, Gratacòs M, Escaramís G, De Cid R, Martín-Santos R, Fernández-Espejo E, et al. Response to methadone maintenance treatment is associated with the MYOCD and GRM6 genes. Mol Diagn Ther. 2010;14:171–8.

    Article  CAS  PubMed  Google Scholar 

  59. Wang SC, Tsou HH, Chen CH, Chen YT, Ho IK, Hsiao CF, et al. Genetic polymorphisms in the opioid receptor mu1 gene are associated with changes in libido and insomnia in methadone maintenance patients. Eur Neuropsychopharmacol. 2012;22:695–703.

    Article  PubMed  CAS  Google Scholar 

  60. Levran O, Peles E, Randesi M, Shu X, Ott J, Shen P-H, et al. Association of genetic variation in pharmacodynamic factors with methadone dose required for effective treatment of opioid addiction. Pharmacogenomics. 2013;14:755–68.

    Article  CAS  PubMed  Google Scholar 

  61. Crist RC, Doyle GA, Nelson EC, Degenhardt L, Martin NG, Montgomery GW, et al. A polymorphism in the OPRM1 3′-untranslated region is associated with methadone efficacy in treating opioid dependence. Pharmacogenomics J. 2016. https://doi.org/10.1038/tpj.2016.89 (epub ahead of print).

  62. Hastie BA, Riley JL, Kaplan L, Herrera DG, Campbell CM, Virtusio K, et al. Ethnicity interacts with the OPRM1 gene in experimental pain sensitivity. Pain. 2012;153:1610–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Lutz P-E, Kieffer BL. Opioid receptors: distinct roles in mood disorders. Trends Neurosci. 2013;36:195–206.

    Article  CAS  PubMed  Google Scholar 

  64. Lutz P-E, Kieffer BL. The multiple facets of opioid receptor function: implications for addiction. Curr Opin Neurobiol. 2013;23:473–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. LaForge KS, Yuferov V, Kreek MJ. Opioid receptor and peptide gene polymorphisms: potential implications for addictions. Eur J Pharmacol. 2000;410:249–68.

    Article  CAS  PubMed  Google Scholar 

  66. Crist RC, Clarke TK, Ang A, Ambrose-Lanci LM, Lohoff FW, Saxon AJ, et al. An intronic variant in OPRD1 predicts treatment outcome for opioid dependence in African-Americans. Neuropsychopharmacology. 2013;38:2003–10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Patriquin MA, Bauer IE, Soares JC, Graham DP, Nielsen DA. Addiction pharmacogenetics: a systematic review of the genetic variation of the dopaminergic system. Psychiatr Genet. 2015;25:181–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Doehring A, Hentig N, Graff J, Salamat S, Schmidt M, Geisslinger G, et al. Genetic variants altering dopamine D2 receptor expression or function modulate the risk of opiate addiction and the dosage requirements of methadone substitution. Pharmacogenet Genomics. 2009;19:407–14.

    Article  CAS  PubMed  Google Scholar 

  69. Bawor M, Dennis BB, Tan C, Pare G, Varenbut M, Daiter J, et al. Contribution of BDNF and DRD2 genetic polymorphisms to continued opioid use in patients receiving methadone treatment for opioid use disorder: an observational study. Addict Sci Clin Pract. 2015;10:19.

    Article  PubMed  PubMed Central  Google Scholar 

  70. Huang M, Chiang T, Lo P, Huang C. Relationship among methadone dose, polymorphisms of dopamine D2 receptor and tri-dimensional personality questionnaire in heroin-addicted patients. Behav Brain Funct. 2016;12:24.

    Article  PubMed  PubMed Central  Google Scholar 

  71. Lawford BR, Young RM, Noble EP, Sargent J, Rowell J, Shadforth S, et al. The D(2) dopamine receptor A(1) allele and opioid dependence: association with heroin use and response to methadone treatment. Am J Med Genet. 2000;96:592–8.

    Article  CAS  PubMed  Google Scholar 

  72. Barratt DT, Coller JK, Somogyi AA. Association between the DRD2 A1 allele and response to methadone and buprenorphine maintenance treatments. Am J Med Genet B Neuropsychiatr Genet. 2006;141B:323–31.

  73. Porter-Stransky KA, Weinshenker D. Arresting the development of addiction: the role of β-arrestin 2 in drug abuse. J Pharmacol Exp Ther. 2017;361:341–8.

    Article  CAS  PubMed  Google Scholar 

  74. Ambrose-Lanci LM, Vaswani M, Clarke T-K, Zeng A, Lohoff FW, Ferraro TN, et al. Association study of the β-arrestin 2 gene (ARRB2) with opioid and cocaine dependence in a European American population. Psychiatr Genet. 2012;22:141–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Sun D, Ma JZ, Payne TJ, Li MD. Beta-arrestins 1 and 2 are associated with nicotine dependence in European American smokers. Mol Psychiatry. 2008;13:398–406.

    Article  CAS  PubMed  Google Scholar 

  76. Oneda B, Crettol S, Bochud M, Besson J, Croquette-Krokar M, Hammig R, et al. beta-Arrestin2 influences the response to methadone in opioid-dependent patients. Pharmacogenom J. 2011;11:258–66.

    Article  CAS  Google Scholar 

  77. Chao MV, Rajagopal R, Lee FS. Neurotrophin signalling in health and disease. Clin Sci. 2006;110:167–73.

    Article  CAS  PubMed  Google Scholar 

  78. Grimm JW, Lu L, Hayashi T, Hope BT, Su TP, Shaham Y. Time-dependent increases in brain-derived neurotrophic factor protein levels within the mesolimbic dopamine system after withdrawal from cocaine: implications for incubation of cocaine craving. J Neurosci. 2003;23:742–7.

    CAS  PubMed  Google Scholar 

  79. Koskela M, Bäck S, Võikar V, Richie CT, Domanskyi A, Harvey BK, et al. Update of neurotrophic factors in neurobiology of addiction and future directions. Neurobiol Dis. 2017 97(Pt B):189–200.

  80. de Cid R, Fonseca F, Gratacos M, Gutierrez F, Martin-Santos R, Estivill X, et al. BDNF variability in opioid addicts and response to methadone treatment: preliminary findings. Genes Brain Behav. 2008;7:515–22.

    Article  PubMed  CAS  Google Scholar 

  81. Bie B, Zhang Z, Cai YQ, Zhu W, Zhang Y, Dai J, et al. Nerve growth factor-regulated emergence of functional delta-opioid receptors. J Neurosci. 2010;30:5617–28.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Levran O, Peles E, Hamon S, Randesi M, Zhao C, Zhang B, et al. Nerve growth factor beta polypeptide (NGFB) genetic variability: association with the methadone dose required for effective maintenance treatment. Pharmacogenomics. 2012;12:319–27.

    Article  CAS  Google Scholar 

  83. Fonseca F, Gratacòs M, Escaramís G, De Cid R, Martín-Santos R, Farré M, et al. ALDH5A1 variability in opioid dependent patients could influence response to methadone treatment. Eur Neuropsychopharmacol. 2014;24:420–4.

    Article  CAS  PubMed  Google Scholar 

  84. Lötsch J, Prüss H, Veh RW, Doehring A. 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.

    Google Scholar 

  85. Gerber JG, Rhodes RJ, Gal J. Stereoselective metabolism of methadone N-demethylation by cytochrome P4502B6 and 2C19. Chirality. 2004;16:36–44.

    Article  CAS  PubMed  Google Scholar 

  86. Su Y, Zhan Y, Wang B, Wang SC, Dai D, Hu G, et al. In vitro assessment of 24 CYP2D6 allelic isoforms on the metabolism of methadone. Drug Test Anal. 2017;9:216–20.

    Article  CAS  PubMed  Google Scholar 

  87. Lan T, Yuan L-J, Hu X-X, Zhou Q, Wang J, Huang X-X, et al. Effects of CYP2C19 variants on methadone metabolism in vitro. Drug Test Anal. 2017;9:634–9.

    Article  CAS  PubMed  Google Scholar 

  88. Foster DJ, Somogyi AA, Bochner F. Methadone N-demethylation in human liver microsomes: lack of stereoselectivity and involvement of CYP3A4. Br J Clin Pharmacol. 1999;47:403–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Kharasch ED. Current concepts in methadone metabolism and transport. Clin Pharmacol Drug Dev. 2017;6:125–34.

    Article  CAS  PubMed  Google Scholar 

  90. Shiran MR, Lennard MS, Iqbal MZ, Lagundoye O, Seivewright N, Tucker GT, et al. Contribution of the activities of CYP3A, CYP2D6, CYP1A2 and other potential covariates to the disposition of methadone in patients undergoing methadone maintenance treatment. Br J Clin Pharmacol. 2009;67:29–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Totah RA, Allen KE, Sheffels P, Whittington D, Kharasch ED. Enantiomeric metabolic interactions and stereoselective human methadone metabolism. J Pharmacol Exp Ther. 2007;321:389–99.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  93. Fonseca F, de la Torre R, Diaz L, Pastor A, Cuyas E, Pizarro N, et al. Contribution of cytochrome P450 and ABCB1 genetic variability on methadone pharmacokinetics, dose requirements, and response. PLoS One. 2011;6:e19527.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Levran O, Peles E, Hamon S, Randesi M, Adelson M, Kreek MJ. CYP2B6 SNPs are associated with methadone dose required for effective treatment of opioid addiction. Addict Biol. 2013;18:709–16.

    Article  CAS  PubMed  Google Scholar 

  95. Totah RA, Sheffels P, Roberts T, Whittington D, Thummel K, Kharasch ED. Role of CYP2B6 in stereoselective human methadone metabolism. Anesthesiology. 2008;108:363–74.

    Article  CAS  PubMed  Google Scholar 

  96. Wang SC, Tsou HH, Ho IK, Lin KM, Liu YL. Pharmacogenomics study in a Taiwan methadone maintenance cohort. J Food Drug Anal. 2013;21:S62–8 (Internet).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Zanger UM, Klein K. Pharmacogenetics of cytochrome P450 2B6 (CYP2B6): advances on polymorphisms, mechanisms, and clinical relevance. Front Genet. 2013;4:24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Wang SC, Ho IK, Tsou HH, Tian JN, Hsiao CF, Chen CH, et al. CYP2B6 polymorphisms influence the plasma concentration and clearance of the methadone S-enantiomer. J Clin Psychopharmacol. 2011;31:463–9.

    Article  CAS  PubMed  Google Scholar 

  99. Kharasch ED, Regina KJ, Blood J, Friedel C. Methadone pharmacogenetics: CYP2B6 polymorphisms determine plasma concentrations, clearance, and metabolism. Anesthesiology. 2015;123:1142–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Dobrinas M, Crettol S, Oneda B, Lahyani R, Rotger M, Choong E, et al. Contribution of CYP2B6 alleles in explaining extreme (S)-methadone plasma levels: a CYP2B6 gene resequencing study. Pharmacogenet Genom. 2013;23:84–93.

    Article  CAS  Google Scholar 

  101. Tsai HJ, Wang SC, Tian JN, Chang TK, Ho IK, Hsiao CF, et al. PXR polymorphisms interacted with CYP2B6 polymorphisms on methadone metabolites. J Clin Psychopharmacol. 2013;33:137–40.

    Article  PubMed  Google Scholar 

  102. Lee HY, Li JH, Sheu YL, Tang HP, Chang WC, Tang TC, et al. Moving toward personalized medicine in the methadone maintenance treatment program: a pilot study on the evaluation of treatment responses in Taiwan. Biomed Res Int. 2013;2013:741403.

    PubMed  PubMed Central  Google Scholar 

  103. Dennis BB, Bawor M, Thabane L, Sohani Z, Samaan Z. Impact of ABCB1 and CYP2B6 genetic polymorphisms on methadone metabolism, dose and treatment response in patients with opioid addiction: a systematic review and meta-analysis. PLoS One. 2014;9:e86114.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  104. Wang JS, DeVane CL. Involvement of CYP3A4, CYP2C8, and CYP2D6 in the metabolism of (R)- and (S)-methadone in vitro. Drug Metab Dispos. 2003;31:742–7.

    Article  CAS  PubMed  Google Scholar 

  105. Gelston EA, Coller JK, Lopatko OV, James HM, Schmidt H, White JM, et al. Methadone inhibits CYP2D6 and UGT2B7/2B4 in vivo: a study using codeine in methadone- and buprenorphine-maintained subjects. Br J Clin Pharmacol. 2012;73:786–94.

    Article  CAS  PubMed  Google Scholar 

  106. Teh LK, Bertilsson L. Pharmacogenomics of CYP2D6: molecular genetics, interethnic differences and clinical importance. Drug Metab Pharmacokinet. 2012;27:55–67.

    Article  CAS  PubMed  Google Scholar 

  107. Eap CB, Broly F, Mino A, Hammig R, Deglon JJ, Uehlinger C, et al. Cytochrome P450 2D6 genotype and methadone steady-state concentrations. J Clin Psychopharmacol. 2001;21:229–34.

    Article  CAS  PubMed  Google Scholar 

  108. Coller JK, Joergensen C, Foster DJ, James H, Gillis D, Christrup L, et al. Lack of influence of CYP2D6 genotype on the clearance of (R)-, (S)- and racemic-methadone. Int J Clin Pharmacol Ther. 2007;45:410–7.

    Article  CAS  PubMed  Google Scholar 

  109. Wang S-C, Ho I-K, Tsou H-H, Liu S-W, Hsiao C-F, Chen C-H, et al. Functional genetic polymorphisms in CYP2C19 gene in relation to cardiac side effects and treatment dose in a methadone maintenance cohort. OMICS. 2013;17:519–26.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  110. Crettol S, Digon P, Golay KP, Brawand M, Eap CB. In vitro P-glycoprotein-mediated transport of (R)-, (S)-, (R, S)-methadone, LAAM and their main metabolites. Pharmacology. 2007;80:304–11.

    Article  CAS  PubMed  Google Scholar 

  111. Zhou S-F. Structure, function and regulation of P-glycoprotein and its clinical relevance in drug disposition. Xenobiotica. 2008;38:802–32.

    Article  CAS  PubMed  Google Scholar 

  112. Callaghan R, Riordan JR. Synthetic and natural opiates interact with P-glycoprotein in multidrug- resistant cells. J Biol Chem. 1993;268:16059–64.

    CAS  PubMed  Google Scholar 

  113. Hung CC, Chiou MH, Teng YN, Hsieh YW, Huang CL, Lane HY. Functional impact of ABCB1 variants on interactions between P-glycoprotein and methadone. PLoS One. 2013;8:e59419.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Hoffmeyer S, Burk O, von Richter O, Arnold HP, Brockmoller J, Johne A, et al. Functional polymorphisms of the human multidrug-resistance gene: multiple sequence variations and correlation of one allele with P-glycoprotein expression and activity in vivo. Proc Natl Acad Sci USA. 2000;97:3473–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Coller JK, Barratt DT, Dahlen K, Loennechen MH, Somogyi AA. ABCB1 genetic variability and methadone dosage requirements in opioid-dependent individuals. Clin Pharmacol Ther. 2006;80:682–90.

    Article  CAS  PubMed  Google Scholar 

  116. Levran O, O’Hara K, Peles E, Li D, Barral S, Ray B, et al. ABCB1 (MDR1) genetic variants are associated with methadone doses required for effective treatment of heroin dependence. Hum Mol Genet. 2008;17:2219–27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Zahari Z, Lee CS, Ibrahim MA, Musa N, Mohd Yasin MA, Lee YY, et al. Relationship between ABCB1 polymorphisms and serum methadone concentration in patients undergoing methadone maintenance therapy (MMT). Am J Drug Alcohol Abuse. 2016;42:587–96.

    Article  PubMed  Google Scholar 

  118. Bart G, Lenz S, Straka RJ, Brundage RC. Ethnic and genetic factors in methadone pharmacokinetics: a population pharmacokinetic study. Drug Alcohol Depend. 2014;145:185–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Crettol S, Deglon JJ, Besson J, Croquette-Krokar M, Hammig R, Gothuey I, et al. No influence of ABCB1 haplotypes on methadone dosage requirement. Clin Pharmacol Ther. 2008;83:668–70.

    Article  CAS  PubMed  Google Scholar 

  120. Yang HC, Chu SK, Huang CL, Kuo HW, Wang SC, Liu SW, et al. Genome-wide pharmacogenomic study on methadone maintenance treatment identifies SNP rs17180299 and multiple haplotypes on CYP2B6, SPON1, and GSG1L associated with plasma concentrations of methadone R- and S-enantiomers in heroin-dependent patients. PLoS Genet. 2016;12:e1005910.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  121. van Leeuwen EM, Kanterakis A, Deelen P, Kattenberg MV, Slagboom PE, de Bakker PIW, et al. Population-specific genotype imputations using minimac or IMPUTE2. Nat Protoc. 2015;10:1285–96.

    Article  PubMed  CAS  Google Scholar 

  122. Torrens M, Fonseca F, Galindo L, Farré M. Opioid addiction: short- and long-acting opioids. In: el-Guebaly N, Carrà G, Galanter M, editors. Textb. Addiciont Treat. Int. Prespectives. Milan: Springer; 2015. p. 367–80.

    Google Scholar 

  123. Wachman EM, Hayes MJ, Sherva R, Brown MS, Davis JM, Farrer LA, et al. Variations in opioid receptor genes in neonatal abstinence syndrome. Drug Alcohol Depend. 2015;155:253–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Zahari Z, Lee CS, Ibrahim MA, Musa N, Mohd Yasin MA, Lee YY, et al. The AC/AG diplotype for the 118A>G and IVS2 + 691G>C polymorphisms of OPRM1 gene is associated with sleep quality among opioid-dependent patients on methadone maintenance therapy. Pain Ther. 2016;5:43–54.

    Article  PubMed  PubMed Central  Google Scholar 

  125. Wang S-C, Tsou H-H, Chung R-H, Chang Y-S, Fang C-P, Chen C-H, et al. The association of genetic polymorphisms in the κ-opioid receptor 1 gene with body weight, alcohol use, and withdrawal symptoms in patients with methadone maintenance. J Clin Psychopharmacol. 2014;34:205–11.

    Article  CAS  PubMed  Google Scholar 

  126. Chen CH, Wang SC, Tsou HH, Ho IK, Tian JN, Yu CJ, et al. Genetic polymorphisms in CYP3A4 are associated with withdrawal symptoms and adverse reactions in methadone maintenance patients. Pharmacogenomics. 2011;12:1397–406.

    Article  CAS  PubMed  Google Scholar 

  127. Tian J-N, Ho I-K, Tsou H-H, Fang C-P, Hsiao C-F, Chen C-H, et al. UGT2B7 genetic polymorphisms are associated with the withdrawal symptoms in methadone maintenance patients. Pharmacogenomics. 2012;13:879–88.

    Article  CAS  PubMed  Google Scholar 

  128. Zahari Z, Lee CS, Ibrahim MA, Musa N, Mohd Yasin MA, Lee YY, et al. Relationship between CYP2B6*6 and cold pressor pain sensitivity in opioid dependent patients on methadone maintenance therapy (MMT). Drug Alcohol Depend. 2016;165:143–50.

    Article  CAS  PubMed  Google Scholar 

  129. Morrish GA, Foster DJR, Somogyi AA. Differential in vitro inhibition of M3G and M6G formation from morphine by (R)- and (S)-methadone and structurally related opioids. Br J Clin Pharmacol. 2006;61:326–35.

    Article  CAS  PubMed  Google Scholar 

  130. Wong SH, Wagner MA, Jentzen JM, Schur C, Bjerke J, Gock SB, et al. Pharmacogenomics as an aspect of molecular autopsy for forensic pathology/toxicology: does genotyping CYP 2D6 serve as an adjunct for certifying methadone toxicity? J Forensic Sci. 2003;48:1406–15.

    Article  CAS  PubMed  Google Scholar 

  131. Bunten H, Liang WJ, Pounder D, Seneviratne C, Osselton MD. CYP2B6 and OPRM1 gene variations predict methadone-related deaths. Addict Biol. 2011;16:142–4.

    Article  CAS  PubMed  Google Scholar 

  132. Bunten H, Liang WJ, Pounder DJ, Seneviratne C, Osselton D. OPRM1 and CYP2B6 gene variants as risk factors in methadone-related deaths. Clin Pharmacol Ther. 2010;88:383–9.

    Article  CAS  PubMed  Google Scholar 

  133. Richards-Waugh LL, Primerano DA, Dementieva Y, Kraner JC, Rankin GO. Fatal methadone toxicity: potential role of CYP3A4 genetic polymorphism. J Anal Toxicol. 2014;38:541–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Ahmad T, Sabet S, Primerano DA, Richards-Waugh LL, Rankin GO. Tell-tale SNPs: the role of CYP2B6 in methadone fatalities. J Anal Toxicol. 2017;41:325–33.

    Article  PubMed  Google Scholar 

  135. Icick R, Peoc’h K, Ksouda K, Bloch V, Laplanche JL, Lépine JP, et al. OPRM1 polymorphism and lifetime suicide attempts among stabilized, methadone-maintained outpatients. Psychiatry Res. 2014;218:259–60.

    Article  CAS  PubMed  Google Scholar 

  136. Krantz MJ, Lewkowiez L, Hays H, Woodroffe MA, Robertson AD, Mehler PS. Torsade de pointes associated with very-high-dose methadone. Ann Intern Med. 2002;137:501–4.

    Article  CAS  PubMed  Google Scholar 

  137. Chou R, Cruciani RA, Fiellin DA, Compton P, Farrar JT, Haigney MC, et al. Methadone safety: a clinical practice guideline from the american pain society and college on problems of drug dependence, in collaboration with the heart rhythm society. J Pain. 2014;15:321–37.

    Article  CAS  PubMed  Google Scholar 

  138. Mujtaba S, Romero J, Taub CC. Methadone, QTc prolongation and torsades de pointes: current concepts, management and a hidden twist in the tale? J Cardiovasc Dis Res. 2013;4:229–35.

    PubMed  PubMed Central  Google Scholar 

  139. Martell BA, Arnsten JH, Ray B, Gourevitch MN. The impact of methadone induction on cardiac conduction in opiate users. Ann Intern Med United States. 2003;139:154–5.

    Article  Google Scholar 

  140. Butler B, Rubin G, Lawrance A, Batey R, Bell J. Estimating the risk of fatal arrhythmia in patients in methadone maintenance treatment for heroin addiction. Drug Alcohol Rev. 2011;30:173–80.

    Article  PubMed  Google Scholar 

  141. Fonseca F, Marti-Almor J, Pastor A, Cladellas M, Farré M, de la Torre R, et al. Prevalence of long QTc interval in methadone maintenance patients. Drug Alcohol Depend. 2009;99:327–32.

    Article  PubMed  Google Scholar 

  142. Csajka C, Crettol S, Guidi M, Eap CB. Population genetic-based pharmacokinetic modeling of methadone and its relationship with the QTc interval in opioid-dependent patients. Clin Pharmacokinet. 2016;55:1521–33.

    Article  CAS  PubMed  Google Scholar 

  143. Hajj A, Ksouda K, Peoc’h K, Curis E, Messali A, v LL, et al. KCNH2 polymorphism and methadone dosage interact to enhance QT duration. Drug Alcohol Depend. 2014;141:34–8.

    Article  CAS  PubMed  Google Scholar 

  144. Eap CB, Crettol S, Rougier JS, Schlapfer J, Sintra Grilo L, Deglon JJ, et al. Stereoselective block of hERG channel by (S)-methadone and QT interval prolongation in CYP2B6 slow metabolizers. Clin Pharmacol Ther. 2007;81:719–28.

    Article  CAS  PubMed  Google Scholar 

  145. Ansermot N, Albayrak O, Schlapfer J, Crettol S, Croquette-Krokar M, Bourquin M, et al. Substitution of (R, S)-methadone by (R)-methadone: impact on QTc interval. Arch Intern Med. 2010;170:529–36.

    Article  CAS  PubMed  Google Scholar 

  146. Carlquist JF, Moody DE, Knight S, Johnson EG, Fang WB, Huntinghouse JA, et al. A possible mechanistic link between the CYP2C19 genotype, the methadone metabolite ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidene (EDDP), and methadone-induced corrected QT interval prolongation in a pilot study. Mol Diagn Ther. 2015;19:131–8.

    Article  CAS  PubMed  Google Scholar 

  147. Eap CB, Cuendet C, Baumann P. Binding of d-methadone, l-methadone, and dl-methadone to proteins in plasma of healthy volunteers: role of the variants of alpha 1-acid glycoprotein. Clin Pharmacol Ther. 1990;47:338–46.

    Article  CAS  PubMed  Google Scholar 

  148. Crowley NA, Kash TL. Kappa opioid receptor signaling in the brain: circuitry and implications for treatment. Prog Neuro Psychopharmacol Biol Psychiatry. 2015;62:51–60.

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Institut de Neuropsiquiatria i Addiccions, Hospital del Mar, Passeig Marítim 25-29, 08003, Barcelona, Spain

    Francina Fonseca & Marta Torrens

  2. IMIM (Institut Hospital del Mar d’Investigacions Mèdiques), Barcelona, Spain

    Francina Fonseca & Marta Torrens

  3. Department of Psychiatry, Universitat Autònoma de Barcelona, Barcelona, Spain

    Francina Fonseca & Marta Torrens

Authors
  1. Francina Fonseca
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Marta Torrens
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Marta Torrens.

Ethics declarations

Funding

This study was funded in part by Instituto de Salud Carlos III, Red de Trastornos Adictivos UE-FEDER 2012 (RD12/0028/0009); Instituto de Salud Carlos III–FEDER-Red de Trastornos Adictivos UE-FEDER 2016 RD16/0017/0010; and AGAUR-Suport Grups de Recerca (2014 SGR790).

Conflict of interest

Dr. Francina Fonseca and Dr. Marta Torrens have no conflicts of interest.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 25 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Fonseca, F., Torrens, M. Pharmacogenetics of Methadone Response. Mol Diagn Ther 22, 57–78 (2018). https://doi.org/10.1007/s40291-017-0311-y

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40291-017-0311-y

Search

Navigation