Doehring A, von 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. Pharmacogenetics Genomics 19: 407-414

Pharmazentrum Frankfurt/ZAFES, Institute of Clinical Pharmacology, Goethe-University, Frankfurt am Main, Germany.
Pharmacogenetics and Genomics (Impact Factor: 3.48). 04/2009; 19(6):407-14. DOI: 10.1097/FPC.0b013e328320a3fd
Source: PubMed


Addictive behavior is importantly mediated by mesolimbic dopaminergic signaling. Here, we comprehensively analyzed the DRD2 gene locus, and in addition, the ANKK1 rs1800497C>T single nucleotide polymorphism (SNP), formerly known as 'dopamine D2 receptor Taq1A C>T polymorphism', for associations with the risk of opiate addiction and the methadone dosage requirements.
Allelic frequencies of DRD2/ANKK1 polymorphisms were compared between 85 methadone-substituted Caucasian patients and a random sample of 99 healthy Caucasian controls. Within patients, the average and maximum daily methadone dose during the first year of treatment and the time when that maximum dose was reached were analyzed for an association with DRD2/ANKK1 genetics.
Compared with the control group, drug users carried more frequently the minor allele of DRD2 SNP rs1076560G>T SNP (P=0.022, odds ratio 2.343) or the ATCT haplotype of DRD2 rs1799978A>G, rs1076560G>T, rs6277C>T, ANKK1 rs1800497C>T (P=0.048, odds ratio 2.23), with similar tendencies for ANKK1 rs1800497C>T (P=0.056, odds ratio 2.12) and the TCCTCTT haplotype of DRD2 rs12364283T>C, rs1799732C del, rs4648317C>T, rs1076560G>T, rs6275C>T, rs6277C>T, and ANKK1 rs1800497C>T (P=0.059, odds ratio 2.31). The average and maximum daily methadone doses were significantly associated with the DRD2 rs6275C>T SNP (P=0.016 and 0.005 for average and maximum dose, respectively). Carriers of the variant rs6275T allele needed higher methadone doses than noncarriers. In addition, this variant was associated with a longer time to reach the maximum methadone dose (P=0.025).
On the basis of an analysis spanning the whole gene locus, from the DRD2 promoter to the ANKK1 rs1800497C>T polymorphism, DRD2 genetic polymorphisms modulate both the risk of opiate addiction, leading to the necessity of methadone substitution therapy, and the course of this therapy in terms of dosage requirements.

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Available from: Jörn Lötsch, Jul 02, 2015
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    • "The influence of genetic variability on required methadone dose is well known [14-16], but may not explain all of the variance [13]. Besides genetic and neurochemical factors, multidimensional psychosocial disease severity may have an effect on required dosing. "
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    ABSTRACT: Opioid replacement treatment (ORT) with methadone is regarded as gold standard in the treatment of opioid addiction. Treatment doses of 60 mg methadone per day and above are associated with better treatment retention and reduction in the use of heroin and cocaine. However, an absolute dose level cannot function as parameter for adequate dosing. This study aims to determine dose adequacy in a sample of patients on stable methadone treatment, and to relate dose adequacy to disease severity. This study was designed as open prospective cohort study over 12 months, with baseline data reported here. Patients on stable substitution treatment with methadone (Eptadone(R)) were consecutively included. Medical and socio-demographic data were gathered and the instruments Opiate Dosage Adequacy Scale (ODAS), European Addiction Severity Index (EuropASI) and the Derogatis Interview for Sexual Functioning - Self Report (DISF-SR) were applied. Five hundred and sixteen subjects, who received on average 60.3 (+/-30.4) mg methadone per day, were included. According to ODAS, 40.6% suffered from an inadequate dosing, and 59.4% had an adequate dose. Patients with an adequate dose received on average 57.8 (+/-27.5) mg methadone per day, whilst patients with an inadequate dose received on average 70.6 (+/-33.0) mg per day. The frequencies of patients with methadone doses of less than 60 mg per were 45.4% in the inadequate and 60.6% in the adequate group. The inadequate group suffered from a statistically significant higher burden of addiction related problems in all EuropASI domains. Sexual functioning did not differ by adequacy group, but women suffered from more pronounced sexual dysfunction as compared to men. A high frequency of inadequate dosing was found in this sample of patients on ORT. Higher disease severity should alert for possible need of even higher methadone doses. The tendency to low methadone doses warrants further research in the treatment system. Higher methadone doses are not related to increased sexual dysfunction. Sexual dysfunction, especially in women, should be considered in treatment.
    Full-text · Article · Feb 2014 · Substance Abuse Treatment Prevention and Policy
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    • "The MMT response outcomes focused on in this review include: methadone dose, continued illicit opioid abuse, and methadone metabolism or methadone plasma concentrations. Currently, methadone dose is defined in the literature as an average or maximum daily dose during the first year of treatment, where it is treated as a continuous variable that can be measured through self-report or chart review in mg/day [17], [18], [21], [22], [30], [33], [40], [41]. Methadone metabolism is defined as plasma concentrations in methadone patients measured during the steady-state in the trough (R), (S), and (RS) forms, where it is a continuous variable measured in ng*kg/mL [8], [17], [18], [20], [24]. "
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    ABSTRACT: Genetic variability may influence methadone metabolism, dose requirements, and risk of relapse. To determine whether the CYP2B6*6 or ABCB1 (rs1045642) polymorphisms are associated with variation in methadone response (plasma concentration, dose, or response to treatment). Two independent reviewers searched Medline, EMBASE, CINAHL, PsycINFO, and Web of Science databases. We included studies that reported methadone plasma concentration, methadone response, or methadone dose in relation to the CYP2B6*6 or ABCB1 polymorphisms. We screened 182 articles and extracted 7 articles for inclusion in the meta-analysis. Considerable agreement was observed between the two independent raters on the title (kappa, 0.82), abstract (kappa, 0.43), and full text screening (kappa, 0.43). Trough (R) methadone plasma concentration was significantly higher in CYP2B6*6 homozygous carriers when compared to non-carriers (standardized mean difference [SMD] = 0.53, 95% confidence interval [CI], 0.05-1.00, p = 0.03) with minimal heterogeneity (I(2) = 0%). Similarly, trough (S) methadone plasma concentration was higher in homozygous carriers of the *6 haplotype when compared to non-carriers, (SMD = 1.44, 95% CI 0.27-2.61, p = 0.02) however significant heterogeneity was observed (I(2) = 69%). Carriers of the CYP2B6*6 haplotype were not found to be significantly different from non-carriers with respect to dose or response to treatment. We found no significant association between the ABCB1 polymorphism and the trough (R), (S) plasma concentrations, methadone dose, or methadone response. Although the number of studies included and sample size were modest, this is the first meta analysis to show participants homozygous for the CYP2B6*6 genotype have higher trough (R) and (S) methadone plasma concentrations, suggesting that methadone metabolism is significantly slower in *6 homozygous carriers.
    Full-text · Article · Jan 2014 · PLoS ONE
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    • "rs1076560 increases risk for drug dependence in general or has specific effects depending on the drug type remains to be elucidated. Other dopaminergic gene variants have been associated with substance addiction with varying success (Gelernter et al., 1994; Guindalini et al., 2006; Doehring et al., 2009; Hou & Li, 2009). These include a variable nucleotide tandem repeat (VNTR) polymorphism in the 3 UTR (rs28363170) of the dopamine transporter gene (DAT1) and the Taq1A allele now known to reside upstream of DRD2 in ANKK1. "
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    ABSTRACT: The risk for drug addiction is partially heritable. Genes of the dopamine system are likely candidates to harbour risk variants, as dopamine neurotransmission is involved in mediating the rewarding effects of drugs of abuse. One functional single nucleotide polymorphism in dopamine receptor D2 (DRD2), rs1076560, is involved in regulating splicing of the gene and alters the ratio of DRD2 isoforms located pre- and postsynaptically. rs1076560 has been previously associated with cocaine abuse and we set out to confirm this association in a sample of European American (EA) (n = 336) and African American (AA) (n = 1034) cocaine addicts and EA (n = 656) and AA (n = 668) controls. We also analysed the role of rs1076560 in opioid dependence by genotyping EA (n = 1041) and AA (n = 284) opioid addicts. rs1076560 was found to be nominally associated with opioid dependence in EAs (p = 0.02, OR = 1.27) and AAs (p = 0.03, OR = 1.43). When both opioid-addicted ancestral samples were combined, rs1076560 was significantly associated with increased risk for drug dependence (p = 0.0038, OR = 1.29). This association remained significant after correction for multiple testing. No association was found with cocaine dependence. These data demonstrate the importance of dopamine gene variants in the risk for opioid dependence and highlight a functional polymorphism that warrants further study.
    Full-text · Article · Jan 2014 · Annals of Human Genetics
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