Pharmacogenetics of Methadone Response

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.

Relevance of CYP2B6 and CYP2D6 genotypes to methadone pharmacokinetics and response in the OPAL study

“…In their 2018 review, Fonseca and Torrens highlighted the influence of CYP2B6 , and to some extent CYP2D6 and CYP2C19 , genetic variability on methadone pharmacokinetics . Three studies described in that review reported that the CYP2B6 gene had no influence on the methadone response. Nevertheless, the differences in the published study methods may have played a role in the variability of the results, and, thus, the results should be interpreted cautiously.…”

“…Various in vitro and in vivo studies have shown the involvement of different cytochrome P450 (CYP) enzymes, particularly CYP2B6, in methadone metabolism, associated with the CYP2B6‐G516T genetic polymorphism and, to a lesser extent, CYP2D6, CYP3A4, and the gene encoding ATP Binding Cassette Subfamily B Member 1 ( ABCB1 , the permeability glycoprotein [P‐gp] transporter) . The influence of genetic polymorphisms on pharmacodynamic properties and treatment response has been less explored, and is not supported by much evidence . Moreover, the impact of genetic variations could be compounded by interactions between many environmental and individual factors …”

“…The influence of genetic polymorphisms on pharmacodynamic properties and treatment response has been less explored, and is not supported by much evidence . Moreover, the impact of genetic variations could be compounded by interactions between many environmental and individual factors …”

“…The results of pharmacogenomics studies in the field of methadone maintenance treatment (MMT) have been described in terms of dose magnitude, plasma or dose‐adjusted plasma concentrations, responders vs nonresponders, and adverse effects. In these previous studies, the response to treatment was defined by the dose requirement, continued opioid use or composite criteria, including the nonconsumption of heroin and cocaine, the absence of complaints of withdrawal symptoms, the steady and regular attendance at the therapy programme, dropout rate and mean dose …”

Genetic and Pharmacologic Studies Towards Prevention of opioid use disorder

“…Such testing is likely to interrogate several genes, as a multitude of factors (Lu et al, 2003;Badiani and Robinson, 2004;Scherbaum and Specka, 2008;Valentine and Fraser, 2008;Ducci and Goldman, 2012;Kreek et al, 2012;Nielsen and Kreek, 2012;Mistry et al, 2014;Bawor et al, 2015;Curtis et al, 2017;Crist et al, 2018;Fonseca and Torrens, 2018) contribute to OUD predisposition. Several gene variations are associated with predisposition to OUD and/or OUD treatment response (Kreek et al, 2012;Bawor et al, 2015;Curtis et al, 2017;Crist et al, 2018;Fonseca and Torrens, 2018). Environmental factors also contribute to OUD (Lu et al, 2003;Badiani and Robinson, 2004;Scherbaum and Specka, 2008;Valentine and Fraser, 2008), and some environmental factors can affect the influence of genetic factors on predisposition to developing addiction (Ducci and Goldman, 2012).…”