Progress in Neuro-Psychopharmacology and Biological Psychiatry
Association of dopamine and opioid receptor genetic polymorphisms with response to methadone maintenance treatment
Introduction
Methadone has been demonstrated to be an effective treatment for opiate dependence, reducing illicit opiate abuse, criminality, HIV risks, and mortality, and improving social rehabilitation (Bertschy, 1995). Methadone is a synthetic µ-opioid receptor agonist, which displays a large interindividual variability in its pharmacokinetics (Crettol et al., 2006, Eap et al., 2002) and probably also in its pharmacodynamics, therefore contributing to a high interindividual variability in response to treatment (Eap et al., 2002). We recently evaluated the impact of several pharmacokinetic factors on response to methadone maintenance treatment (MMT) and methadone dose requirement, but none of the analyzed cytochrome P450s nor permeability glycoprotein were found to influence response to treatment, while only a small influence on the dose requirement was observed (Crettol et al., 2006).
Dopamine receptors appear to play a large role in the rewarding effects of drugs of abuse (Kreek et al., 2005) and several studies have looked for an association of dopamine D2 receptor (DRD2) genetic polymorphisms with dependence (Noble, 2003, Young et al., 2004). In particular, the TaqI A single nucleotide polymorphism (SNP) of DRD2 has been widely studied in relation with dependence and other psychiatric disorders (Noble, 2003). Only two studies have investigated the relation between DRD2 SNPs and response to MMT (Barratt et al., 2006, Lawford et al., 2000). The first study reported a significant association of the DRD2 TaqI A1 allele with opioid dependence, as compared to a control group, and within the MMT patients group, with non-response to MMT and higher prior heroin use (Lawford et al., 2000). However, this finding was not confirmed in a recent study, in which a similar TaqI A1 allele frequency was observed in MMT patients and a control group, and in MMT patients responding or not to MMT (Barratt et al., 2006). None of these studies included the analysis of the synonymous DRD2 957C>T SNP, which was shown to be in linkage disequilibrium with the TaqI A SNP (Duan et al., 2003). Surprisingly, the TaqI A SNP has recently been shown to reside in a protein kinase gene (ankyrin repeat and kinase domain containing 1, ANKK1) and not in the DRD2 gene. The non-synonymous change may therefore affect substrate binding specificity of the gene product and might be involved in dopaminergic reward pathway through signal transduction (Neville et al., 2004). Finally, a potential role for the DRD1 gene in addictive behaviors was previously reported (Comings et al., 1997, Limosin et al., 2003, Kim et al., 2007).
The µ-opioid receptor, encoded by the µ-opioid receptor gene (OPRM1), is the pharmacological target of methadone. The non-synonymous 118A>G SNP of OPRM1 has been associated with a decreased potency of several opioids (Klepstad et al., 2004, Lötsch et al., 2002, Oertel et al., 2006, Romberg et al., 2005), including methadone (Lötsch et al., 2006), even though its impact on the binding affinity and potency of several opioid receptors agonists is controversial (Befort et al., 2001, Beyer et al., 2004, Bond et al., 1998, Zhang et al., 2005). In a recent study on healthy volunteers, a lower miotic potency induced by (R)-methadone was observed in carriers of the 118G allele, suggesting that this SNP is associated with a decreased effect of (R)-methadone (Lötsch et al., 2006). In addition, the δ-opioid receptor gene (OPRD1) might be involved in modulating the effects of compounds acting on the µ-opioid receptor (Kreek et al., 2005).
As very few pharmacogenetic studies have been performed on methadone, the main aim of this study was to identify genetic factors involved in response to MMT, focusing on pharmacodynamic factors. The allele and genotype frequencies of several SNPs of the dopamine D1, D2, µ- and δ-opioid receptor genes were compared in a group of MMT patients between the responders to their treatment and the non-responders. In addition, as a secondary aim, the allele and genotype frequencies of the above-mentioned genes were compared between the group of MMT patients and a control group of subjects screened for psychiatric disorders and substance dependence.
Section snippets
Study design and patients
This pharmacogenetic study was conducted in five methadone-dispensing centers in Geneva, Lausanne, Bern and Montreux (Switzerland). All patients fulfilled the DSM-IV criteria for heroin dependence (304.02; Information on possible co morbidities was not available). 238 Caucasian patients in MMT were included into three groups, according to their response to MMT and their methadone daily dose. The first group of patients were responders to treatment, with methadone daily dose comprised between 40
Results
The present results are based on 238 patients in MMT, 54 women and 184 men, all Caucasians. The median age of the patients was 35 years (range: 21–54 years) and 222 patients were smokers (93%). The patients had been in MMT for a median duration of 43 months (range: 2–294 months) and their median methadone daily dose was 125 mg (range: 3–430 mg/day). 87 patients (37%) were included as low-dose responders, 78 patients (33%) were included as high-dose responders and 73 patients (31%) were included
Discussion
The main aim of the present study was to identify genetic factors associated with response to methadone during maintenance treatment, focusing on pharmacodynamic factors. Contradictory data have suggested that SNPs in the genes coding for dopamine receptors might be associated with response to MMT (Barratt et al., 2006, Lawford et al., 2000), while SNPs in the µ-opioid receptor have been associated with a decreased potency of methadone in healthy volunteers (Lötsch et al., 2006). Therefore, we
Acknowledgments
We thank Mr. J Spagnoli for supervising the statistical analyses and Mrs. M Brocard, Mrs. M Delessert, Mrs. N Cochard, Mrs. A-C Aubert, Mrs. K Powell Golay, Mrs. L Koeb and Mrs. M Brawand for analyzing the samples. We are grateful to Dr. A Al Amine, Mr. J Bergeron, Dr. M Bourquin, Mrs. I Girod, Dr. H Hüttemann, Mrs. S Meynet, Mrs. I Soulignac, Dr. R Rajeswaran, and Mr. D Uk for their help in the recruitment of patients. We are also grateful to Prof. M Del Zompo (Cagliari, Italy), Prof. L
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