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      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

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          Abstract

          Background

          Genetic variability may influence methadone metabolism, dose requirements, and risk of relapse.

          Objectives

          To determine whether the CYP2B6*6 or ABCB1 (rs1045642) polymorphisms are associated with variation in methadone response (plasma concentration, dose, or response to treatment).

          Methods

          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.

          Results

          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.

          Conclusion

          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.

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          Most cited references 49

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          The genetics of addictions: uncovering the genes.

          The addictions are common chronic psychiatric diseases that today are prevented and treated using relatively untargeted and only partially effective methods. The addictions are moderately to highly heritable, which is paradoxical because these disorders require use; a choice that is itself modulated by both genes and environment. The addictions are interrelated and related to other psychiatric diseases by common neurobiological pathways, including those that modulate reward, behavioural control and the anxiety or stress response. Our future understanding of addictions will be enhanced by the identification of genes that have a role in altered substance-specific vulnerabilities such as variation in drug metabolism or drug receptors and a role in shared vulnerabilities such as variation in reward or stress resiliency.
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            The efficacy of methadone maintenance interventions in reducing illicit opiate use, HIV risk behavior and criminality: a meta-analysis.

             Lisa A Marsch (1998)
            To provide empirically based evaluation data regarding the efficacy of psychopharmacological interventions in opiate substance abuse, the present study employed meta-analytic statistical procedures to determine the effectiveness of methadone hydrochloride as a pharmacotherapeutic agent. Empirical research findings from 11 studies investigating the effect of methadone maintenance treatment (MMT) on illicit opiate use, and eight and 24 studies investigating the effect of MMT on HIV risk behaviors and criminal activities, respectively, by individuals in such treatment were addressed. Results demonstrate a consistent, statistically significant relationship between MMT and the reduction of illicit opiate use, HIV risk behaviors and drug and property-related criminal behaviors. The effectiveness of MMT is most apparent in its ability to reduce drug-related criminal behaviors. MMT had a moderate effect in reducing illicit opiate use and drug and property-related criminal behaviors, and a small to moderate effect in reducing HIV risk behaviors. Results clarify discrepancies in the literature and are useful in predicting the outcomes of individuals in treatment. The treatment's effectiveness is evident among opiate-dependent individuals across a variety of contexts, cultural and ethnic groups, and study designs.
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              A comparison of levomethadyl acetate, buprenorphine, and methadone for opioid dependence.

              Opioid dependence is a chronic, relapsing disorder with important public health implications. In a 17-week randomized study of 220 patients, we compared levomethadyl acetate (75 to 115 mg), buprenorphine (16 to 32 mg), and high-dose (60 to 100 mg) and low-dose (20 mg) methadone as treatments for opioid dependence. Levomethadyl acetate and buprenorphine were administered three times a week. Methadone was administered daily. Doses were individualized except in the group assigned to low-dose methadone. Patients with poor responses to treatment were switched to methadone. There were 55 patients in each group; 51 percent completed the trial. The mean (+/-SE) number of days that a patient remained in the study was significantly higher for those receiving levomethadyl acetate (89+/-6), buprenorphine (96+/-4), and high-dose methadone (105+/-4) than for those receiving low-dose methadone (70+/-4, P<0.001). Continued participation was also significantly more frequent among patients receiving high-dose methadone than among those receiving levomethadyl acetate (P=0.02). The percentage of patients with 12 or more consecutive opioid-negative urine specimens was 36 percent in the levomethadyl acetate group, 26 percent in the buprenorphine group, 28 percent in the high-dose methadone group, and 8 percent in the low-dose methadone group (P=0.005). At the time of their last report, patients reported on a scale of 0 to 100 that their drug problem had a mean severity of 35 with levomethadyl acetate, 34 with buprenorphine, 38 with high-dose methadone, and 53 with low-dose methadone (P=0.002). As compared with low-dose methadone, levomethadyl acetate, buprenorphine, and high-dose methadone substantially reduce the use of illicit opioids.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2014
                29 January 2014
                : 9
                : 1
                Affiliations
                [1 ]Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Ontario, Canada
                [2 ]Biostatistics Unit, Father Sean O'Sullivan Research Centre, St Joseph's Healthcare, Hamilton, Ontario, Canada
                [3 ]Population Genomics Program, McMaster University, Hamilton, Ontario, Canada
                [4 ]McMaster Integrative Neuroscience Discovery & Study (MiNDS) Program, McMaster University, Hamilton, Ontario, Canada
                [5 ]Departments of Pediatrics and Anesthesia, McMaster University, Hamilton, Ontario, Canada
                [6 ]Population Health Research Institute, Hamilton Health Sciences, Hamilton, Ontario, Canada
                [7 ]Department of Psychiatry and Behavioral Neurosciences, McMaster University, Hamilton, Ontario, Canada
                Yale University, United States of America
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: BBD LT Z. Samaan. Performed the experiments: BBD MB LT Z. Samaan. Analyzed the data: BBD Z. Sohani Z. Samaan. Wrote the paper: BBD MB LT Z. Sohani Z. Samaan.

                Article
                PONE-D-13-29310
                10.1371/journal.pone.0086114
                3906028
                cebf2533-db03-44cd-92e9-ae172482e6e7

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                Page count
                Pages: 17
                Funding
                This work was supported by CIHR Drug Safety and Effectiveness Network (DSEN) grant (grant number: 126639). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology
                Genetics
                Population Genetics
                Genetic Polymorphism
                Human Genetics
                Population Biology
                Population Genetics
                Genetic Polymorphism
                Medicine
                Clinical Research Design
                Cross-Sectional Studies
                Meta-Analyses
                Systematic Reviews
                Drugs and Devices
                Pharmacogenetics
                Mental Health
                Psychiatry
                Therapies

                Uncategorized

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