Association of Genetic Variation in Pharmacodynamic Factors with Methadone Dose Required for Effective Treatment of Opioid Addiction

Abstract

Aim: The interindividual variability in the dose required for effective methadone maintenance treatment (MMT) for opioid addiction may be influenced in part by genetic variations in genes encoding pharmacodynamic factors of methadone. This study was conducted to identify some of these variants. Materials & methods: This study focused on 11 genes encoding components of the opioidergic (OPRM1, POMC and ARRB2), the dopaminergic (ANKK1 and DRD2) and the glutamatergic pathways (GRIN1 and GRIN2A), as well as the neurotrophin system (NGFB, BDNF, NTRK1 and NTRK2). The study includes 227 Israeli patients undergoing stable MMT. Results: Out of the 110 variants analyzed, 12 SNPs (in BDNF, NTRK2, OPRM1, DRD2 and ANKK1) were associated with methadone dose (nominal p < 0.05). Of these SNPs, ANKK1 rs7118900 and DRD2 rs2283265 are known to affect gene expression. Logistic regression of five representative SNPs discriminated between individuals requiring a methadone dose of >120 mg/day and <120 mg/day (p = 0.019), and showed moderate sensitivity and specificity (AUC of 0.63 in receiver operating characteristic analysis). Conclusion: This data should stimulate further research on the potential influence and clinical significance of these variants on MMT.

Original submitted 14 November 2012; Revision submitted 12 March 2013

KEYWORDS::

• ANKK1
• BDNF
• DRD2
• methadone maintenance
• NTRK2
• OPRM1
• pharmacogenetics

Acknowledgements

The authors thank and acknowledge the contributions of C Zhao, B Zhang and S Russo.

Financial & competing interests disclosure

Funding was provided by P60-05130 from NIDA (MJ Kreek), grant # 8 UL1 TR000043 from the National Center for Research Resources and the National Center for Advancing Translational Sciences, NIH (pilot award, O Levran) and the Adelson Medical Research Foundation. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

The authors state that they have obtained appropriate institutional review board approval or have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations. In addition, for investigations involving human subjects, informed consent has been obtained from the participants involved.

Additional information

Funding

Funding was provided by P60-05130 from NIDA (MJ Kreek), grant # 8 UL1 TR000043 from the National Center for Research Resources and the National Center for Advancing Translational Sciences, NIH (pilot award, O Levran) and the Adelson Medical Research Foundation. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.