Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
Addiction Science & Clinical Practice
Published in: Addiction Science & Clinical Practice 1/2015

Open Access 01-12-2015 | Research

Contribution of BDNF and DRD2 genetic polymorphisms to continued opioid use in patients receiving methadone treatment for opioid use disorder: an observational study

Authors: Monica Bawor, Brittany B. Dennis, Charlie Tan, Guillaume Pare, Michael Varenbut, Jeff Daiter, Carolyn Plater, Andrew Worster, David C. Marsh, Meir Steiner, Rebecca Anglin, Dipika Desai, Lehana Thabane, Zainab Samaan

Published in: Addiction Science & Clinical Practice | Issue 1/2015

Login to get access

Abstract

Background

The heritability of opioid use disorder has been widely investigated; however, the influence of specific genes on methadone treatment outcomes is not well understood. The association between response to methadone treatment and genes that are involved in substance use behaviors and reward mechanisms is poorly understood, despite evidence suggesting their contribution to opioid use disorder. The aim of this study was to investigate the effect of brain-derived neurotrophic factor (BDNF) and dopamine receptor D2 (DRD2) polymorphisms on continued opioid use among patients on methadone treatment for opioid use disorder.

Methods

BDNF 196G>A (rs6265) and DRD2-241A>G (rs1799978) genetic variants were examined in patients with opioid use disorder who were recruited from methadone treatment clinics across Southern Ontario, Canada. We collected demographic information, substance use history, blood for genetic analysis, and urine to measure opioid use. We used regression analysis to examine the association between continued opioid use and genetic variants, adjusting for age, sex, ethnicity, methadone dose, duration in treatment, and number of urine screens.

Results

Among 240 patients treated with methadone for opioid use disorder, 36.3 percent (n = 87) and 11.3 percent (n = 27) had at least one risk allele for rs6265 and rs1799978, respectively. These genetic variants were not significantly associated with continued opioid use while on methadone maintenance treatment [rs6265: odds ratio (OR) = 1.37, 95 % confidence interval (CI) = 0.792, 2.371, p = 0.264; rs1799978: OR 1.27, 95 % CI 0.511, 3.182, p = 0.603].

Conclusions

Despite an association of BDNF rs6265 and DRD2 rs1799978 with addictive behaviors, these variants were not associated with continued illicit opioid use in patients treated with methadone. Problematic use of opioids throughout treatment with methadone may be attributed to nongenetic factors or a polygenic effect requiring further exploration. Additional research should focus on investigating these findings in larger samples and different populations.
Literature
1.
Gomes T, Mamdani MM, Dhalla IA, Cornish S, Paterson JM, Juurlink DN. The burden of premature opioid-related mortality. Addiction. 2014;109(9):1482–8.PubMedCentralCrossRefPubMed
2.
3.
Oviedo-Joekes E, Brissette S, Marsh DC, Lauzon P, Guh D, Anis A, Schechter MT. Diacetylmorphine versus methadone for the treatment of opioid addiction. N Engl J Med. 2009;361(8):777–86.CrossRefPubMed
4.
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.
5.
Li Y, Kantelip JP, Gerritsen-van Schieveen P, Davani S. Interindividual variability of methadone response: impact of genetic polymorphism. Mol Diagn Ther. 2008;12(2):109–24.CrossRefPubMed
6.
Rounsaville BJ, Kosten TR, Weissman MM, Prusoff B, Pauls D, Anton SF, Merikangas K. Psychiatric disorders in relatives of probands with opiate addiction. Arch Gen Psychiatry. 1991;48(1):33–42.CrossRefPubMed
7.
Luthar SS, Anton SF, Merikangas KR, Rounsaville BJ. Vulnerability to substance abuse and psychopathology among siblings of opioid abusers. J Nerv Ment Dis. 1992;180(3):153–61.CrossRefPubMed
8.
Merikangas KR, Stolar M, Stevens DE, Goulet J, Preisig MA, Fenton B, Zhang H, O’Malley SS, Rounsaville BJ. Familial transmission of substance use disorders. Arch Gen Psychiatry. 1998;55(11):973–9.CrossRefPubMed
9.
Grove WM, Eckert ED, Heston L, Bouchard TJ Jr, Segal N, Lykken DT. Heritability of substance abuse and antisocial behavior: a study of monozygotic twins reared apart. Biol Psychiatry. 1990;27(12):1293–304.CrossRefPubMed
10.
Pickens RW, Svikis DS, McGue M, Lykken DT, Heston LL, Clayton PJ. Heterogeneity in the inheritance of alcoholism. A study of male and female twins. Arch Gen Psychiatry. 1991;48(1):19–28.CrossRefPubMed
11.
Kendler KS, Prescott CA. Cannabis use, abuse, and dependence in a population-based sample of female twins. Am J Psychiatry. 1998;155(8):1016–22.CrossRefPubMed
12.
Kendler KS, Prescott CA. Cocaine use, abuse and dependence in a population-based sample of female twins. Br J Psychiatry. 1998;173:345–50.CrossRefPubMed
13.
Cadoret RJ, Troughton E, O’Gorman TW, Heywood E. An adoption study of genetic and environmental factors in drug abuse. Arch Gen Psychiatry. 1986;43(12):1131–6.CrossRefPubMed
14.
Cadoret RJ, Yates WR, Troughton E, Woodworth G, Stewart MA. Adoption study demonstrating two genetic pathways to drug abuse. Arch Gen Psychiatry. 1995;52(1):42–52.CrossRefPubMed
15.
Haile CN, Kosten TA, Kosten TR. Pharmacogenetic treatments for drug addiction: alcohol and opiates. Am J Drug Alcohol Abuse. 2008;34:355–81.CrossRefPubMed
16.
Fonseca F, de la Torre R, Diaz L, Pastor A, Cuyas E, Pizarro N, Khymenets O, Farre M, Torrens M. Contribution of cytochrome P450 and ABCB1 genetic variability on methadone pharmacokinetics, dose requirements, and response. PLoS One. 2011;6(5):e19527.PubMedCentralCrossRefPubMed
17.
Crettol S, Deglon JJ, Besson J, Croquette-Krokkar M, Gothuey I, Hammig R, Monnat M, Huttemann H, Baumann P, Eap CB. Methadone enantiomer plasma levels, CYP2B6, CYP2C19, and CYP2C9 genotypes, and response to treatment. Clin Pharmacol Ther. 2005;78(6):593–604.CrossRefPubMed
18.
Eap CB, Broly F, Mino A, Hammig R, Deglon JJ, Uehlinger C, Meili D, Chevalley AF, Bertschy G, Zullino D, Kosel M, Preisig M, Baumann P. Cytochrome P450 2D6 genotype and methadone steady-state concentrations. J Clin Psychopharmacol. 2001;21(2):229–34.CrossRefPubMed
19.
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.PubMedCentralCrossRefPubMed
20.
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(3):383–9.CrossRefPubMed
21.
Bunten H, Liang WJ, Pounder D, Seneviratne C, Osselton MD. CYP2B6 and OPRM1 gene variations predict methadone-related deaths. Addict Biol. 2011;16(1):142–4.CrossRefPubMed
22.
Bauer IE, Soares JC, Nielsen DA. The role of opioidergic genes in the treatment outcome of drug addiction pharmacotherapy: a systematic review. Am J Addict. 2015;24(1):15–23.CrossRefPubMed
23.
Dalley JW, Fryer TD, Brichard L, Robinson ES, Theobald DE, Laane K, Pena Y, Murphy ER, Shah Y, Probst K, Abakumova I, Aigbirhio FI, Richards HK, Hong Y, Baron JC, Everitt BJ, Robbins TW. Nucleus accumbens D2/3 receptors predict trait impulsivity and cocaine reinforcement. Science. 2007;315(5816):1267–70.PubMedCentralCrossRefPubMed
24.
Lawford BR, Young RM, Noble EP, Sargent J, Rowell J, Shadforth S, Zhang X, Ritchie T. 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(5):592–8.CrossRefPubMed
25.
Russo SJ, Mazei-Robison MS, Ables JL, Nestler EJ. Neurotrophic factors and structural plasticity in addiction. Neuropharmacology. 2009;56(Suppl 1):73–82.PubMedCentralCrossRefPubMed
26.
Beuten J, Ma JZ, Payne TJ, Dupont RT, Quezada P, Huang W, Crews KM, Li MD. Significant association of BDNF haplotypes in European-American male smokers but not in European-American female or African-American smokers. Am J Med Genet B Neuropsychiatr Genet. 2005;139B(1):73–80.CrossRefPubMed
27.
Itoh K, Hashimoto K, Shimizu E, Sekine Y, Ozaki N, Inada T, Harano M, Iwata N, Komiyama T, Yamada M, Sora I, Nakata K, Ujike H, Iyo M. Association study between brain-derived neurotrophic factor gene polymorphisms and methamphetamine abusers in Japan. Am J Med Genet B Neuropsychiatr Genet. 2005;132B(1):70–3.CrossRefPubMed
28.
Jockers-Scherubl MC, Danker-Hopfe H, Mahlberg R, Selig F, Rentzsch J, Schurer F, Lang UE, Hellweg R. Brain-derived neurotrophic factor serum concentrations are increased in drug-naive schizophrenic patients with chronic cannabis abuse and multiple substance abuse. Neurosci Lett. 2004;371(1):79–83.CrossRefPubMed
29.
Gratacòs M, González JR, Mercader JM, de Cid R, Urretavizcaya M, Estivill X. Brain-derived neurotrophic factor Val66Met and psychiatric disorders: meta-analysis of case-control studies confirm association to substance-related disorders, eating disorders, and schizophrenia. Biol Psychiatry. 2007;61(7):911–22.CrossRefPubMed
30.
Chen SL, Lee SY, Chang YH, Wang TY, Chen SH, Chu CH, Chen PS, Yang YK, Hong JS, Lu RB. The BDNF Val66Met polymorphism and plasma brain-derived neurotrophic factor levels in Han Chinese heroin-dependent patients. Sci Rep. 2015;5:8148.PubMedCentralCrossRefPubMed
31.
Jia W, Shi JG, Wu B, Ao L, Zhang R, Zhu YS. Polymorphisms of brain-derived neurotrophic factor associated with heroin dependence. Neurosci Lett. 2011;495(3):221–4.CrossRefPubMed
32.
Cheng CY, Hong CJ, Yu YW, Chen TJ, Wu HC, Tsai SJ. Brain-derived neurotrophic factor (Val66Met) genetic polymorphism is associated with substance abuse in males. Brain Res Mol Brain Res. 2005;140(1–2):86–90.CrossRefPubMed
33.
Greenwald MK, Steinmiller CL, Sliwerska E, Lundahl L, Burmeister M. BDNF Val(66)Met genotype is associated with drug-seeking phenotypes in heroin-dependent individuals: a pilot study. Addict Biol. 2013;18(5):836–45.PubMedCentralCrossRefPubMed
34.
Uhl GR, Liu QR, Walther D, Hess J, Naiman D. Polysubstance abuse-vulnerability genes: genome scans for association, using 1,004 subjects and 1,494 single-nucleotide polymorphisms. Am J Hum Genet. 2001;69(6):1290–300.PubMedCentralCrossRefPubMed
35.
Lang UE, Sander T, Lohoff FW, Hellweg R, Bajbouj M, Winterer G, Gallinat J. Association of the met66 allele of brain-derived neurotrophic factor (BDNF) with smoking. Psychopharmacology. 2007;190(4):433–9.CrossRefPubMed
36.
Egan MF, Kojima M, Callicott JH, Goldberg TE, Kolachana BS, Bertolino A, Zaitsev E, Gold B, Goldman D, Dean M, Lu B, Weinberger DR. The BDNF val66met polymorphism affects activity-dependent secretion of BDNF and human memory and hippocampal function. Cell. 2003;112(2):257–69.CrossRefPubMed
37.
Angelucci F, Ricci V, Pomponi M, Conte G, Mathe AA. Attilio Tonali P, Bria P: Chronic heroin and cocaine abuse is associated with decreased serum concentrations of the nerve growth factor and brain-derived neurotrophic factor. J Psychopharmacol. 2007;21:820–5.CrossRefPubMed
38.
Levran O, Peles E, Randesi M, Shu X, Ott J, Shen PH, Adelson M, Kreek MJ. Association of genetic variation in pharmacodynamic factors with methadone dose required for effective treatment of opioid addiction. Pharmacogenomics. 2013;14(7):755–68.CrossRefPubMed
39.
de Cid R, Fonseca F, Gratacos M, Gutierrez F, Martin-Santos R, Estivill X, Torrens M. BDNF variability in opioid addicts and response to methadone treatment: preliminary findings. Genes Brain Behav. 2008;7(5):515–22.CrossRefPubMed
40.
Hung CC, Chiou MH, Huang BH, Hsieh YW, Hsieh TJ, Huang CL, Lane HY. Impact of genetic polymorphisms in ABCB1, CYP2B6, OPRM1, ANKK1 and DRD2 genes on methadone therapy in Han Chinese patients. Pharmacogenomics. 2011;12(11):1525–33.CrossRefPubMed
41.
Blum K, Braverman ER, Holder JM, Lubar JF, Monastra VJ, Miller D, Lubar JO, Chen TJ, Comings DE. Reward deficiency syndrome: a biogenetic model for the diagnosis and treatment of impulsive, addictive, and compulsive behaviors. J Psychoactive Drugs. 2000;32(Suppl i–iv):1–112.CrossRef
42.
Di Chiara G, Bassareo V, Fenu S, De Luca MA, Spina L, Cadoni C, Acquas E, Carboni E, Valentini V, Lecca D. Dopamine and drug addiction: the nucleus accumbens shell connection. Neuropharmacology. 2004;47(Suppl 1):227–41.CrossRefPubMed
43.
Doehring A, Hentig N, Graff J, Salamat S, Schmidt M, Geisslinger G, Harder S, Lotsch J. 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(6):407–14.CrossRefPubMed
44.
Munafo M, Clark T, Johnstone E, Murphy M, Walton R. The genetic basis for smoking behavior: a systematic review and meta-analysis. Nicotine Tob Res. 2004;6:583–97.CrossRefPubMed
45.
Munafo MR, Matheson IJ, Flint J. Association of the DRD2 gene Taq1A polymorphism and alcoholism: a meta-analysis of case-control studies and evidence of publication bias. Mol Psychiatry. 2007;12(5):454–61.PubMed
46.
Nacak M, Isir AB, Balci SO, Pehlivan S, Benlier N, Aynacioglu S. Analysis of dopamine D2 receptor (DRD2) gene polymorphisms in cannabinoid addicts. J Forensic Sci. 2012;57(6):1621–4.CrossRefPubMed
47.
Crettol S, Besson J, Croquette-Krokar M, Hammig R, Gothuey I, Monnat M, Deglon JJ, Preisig M, Eap CB. Association of dopamine and opioid receptor genetic polymorphisms with response to methadone maintenance treatment. Prog Neuropsychopharmacol Biol Psychiatry. 2008;32(7):1722–7.CrossRefPubMed
48.
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(4):323–31.CrossRefPubMed
49.
Samaan Z, Bawor M, Dennis BB, Plater C, Varenbut M, Daiter J, Worster A, Marsh DC, Tan C, Desai D, Thabane L, Pare G. Genetic influence on methadone treatment outcomes in patients undergoing methadone maintenance treatment for opioid addiction: a pilot study. Neuropsychiatr Dis Treat. 2014;10:1503–8.PubMedCentralCrossRefPubMed
50.
Hamidovic A, Dlugos A, Skol A, Palmer AA, de Wit H. Evaluation of genetic variability in the dopamine receptor D2 in relation to behavioral inhibition and impulsivity/sensation seeking: an exploratory study with d-amphetamine in healthy participants. Exp Clin Psychopharmacol. 2009;17:374–83.PubMedCentralCrossRefPubMed
51.
Laucht M, Becker K, Frank J, Schmidt MH, Esser G, Treutlein J, Skowronek MH, Schumann G. Genetic variation in dopamine pathways differentially associated with smoking progression in adolescence. J Am Acad Child Adolesc Psychiatry. 2008;47:673–81.CrossRefPubMed
52.
Morton LM, Wang SS, Bergen AW, Chatterjee N, Kvale P, Welch R, Yeager M, Hayes RB, Chanock SJ, Caporaso NE. DRD2 genetic variation in relation to smoking and obesity in the prostate, lung, colorectal, and ovarian cancer screening trial. Pharmacogenet Genomics. 2006;16:901–10.CrossRefPubMed
53.
Schottenfeld RS, Pakes JR, Kosten TR. Prognostic factors in buprenorphine-versus methadone-maintained patients. J Nerv Ment Dis. 1998;186(1):35–43.CrossRefPubMed
54.
Mulvaney FD, Brown LS Jr, Alterman AI, Sage RE, Cnaan A, Cacciola J, Rutherford M. Methadone-maintenance outcomes for Hispanic and African-American men and women. Drug Alcohol Depend. 1999;54(1):11–8.CrossRefPubMed
55.
Jones HE, Fitzgerald H, Johnson RE. Males and females differ in response to opioid agonist medications. Am J Addict. 2005;14(3):223–33.CrossRefPubMed
56.
von Elm E, Altman DG, Egger M, Pocock SJ, Gotzsche PC, Vandenbroucke JP. The strengthening the reporting of observational studies in epidemiology (STROBE) statement: guidelines for reporting observational studies. Lancet. 2007;370(9596):1453–7.CrossRef
57.
Bao YP, Liu ZM, Epstein DH, Du C, Shi J, Lu L. A meta-analysis of retention in methadone maintenance by dose and dosing strategy. Am J Drug Alcohol Abuse. 2009;35:28–33.PubMedCentralCrossRefPubMed
Metadata
Title
Contribution of BDNF and DRD2 genetic polymorphisms to continued opioid use in patients receiving methadone treatment for opioid use disorder: an observational study
Authors
Monica Bawor
Brittany B. Dennis
Charlie Tan
Guillaume Pare
Michael Varenbut
Jeff Daiter
Carolyn Plater
Andrew Worster
David C. Marsh
Meir Steiner
Rebecca Anglin
Dipika Desai
Lehana Thabane
Zainab Samaan
Publication date
01-12-2015
Publisher
BioMed Central
Published in
Addiction Science & Clinical Practice / Issue 1/2015
Electronic ISSN: 1940-0640
DOI
https://doi.org/10.1186/s13722-015-0040-7

Other articles of this Issue 1/2015

Addiction Science & Clinical Practice 1/2015 Go to the issue

Research

A qualitative study of treatment-seeking heroin users in contemporary China

Research

Physician versus non-physician delivery of alcohol screening, brief intervention and referral to treatment in adult primary care: the ADVISe cluster randomized controlled implementation trial

Research

Impact of hepatitis C status on 20-year mortality of patients with substance use disorders

Research

Predictive validity of two process-of-care quality measures for residential substance use disorder treatment

Research

The management of opiate use disorders in France: results of an observational survey of general practitioners

Research

Release from incarceration, relapse to opioid use and the potential for buprenorphine maintenance treatment: a qualitative study of the perceptions of former inmates with opioid use disorder