Therapeutic drug monitoring in methadone maintenance therapy (MMT) : an evaluation of genetic factors influencing clinical outcomes and serum concentrations of methadone
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Date
2013-06
Authors
Mohamed Nazar, Nor Ilyani
Journal Title
Journal ISSN
Volume Title
Publisher
Universiti Sains Malaysia
Abstract
Introduction: Methadone maintenance therapy (MMT) has been widely used to prevent withdrawal symptoms among opiate use disorder patients. It is one of the harm reduction approaches in order to reduce the spread of fatally blood borne diseases in the community especially HIV AIDS. However, determining the optimal dose in patients is somehow difficult and challenging as it shows wide inter-individual variability of pharmacological activity. This study correlates the trough serum methadone concentrations (Ctrough) at steady state with the methadone dose and the clinical outcomes namely severity of withdrawal symptoms and urinalysis for other illicit drugs. The relationship between various CYP2B6 haplotypes with the Ctrough and OPRM1 (A118G) single nucleotide polymorphisms (SNPs) with the clinical outcomes measures were also studied.
Methodology: One hundred and fifteen (115) patients participated in the study after screening and signing the informed consent form. Blood samples were collected for genotype determination (once) and Ctrough determination (each data collection point). The methadone serum concentrations were analyzed by using ELISA (methadone ELISA kit) method and genotyping of CYP2B6 and OPRM1 (A118G) were determined by using validated PCR method. Statistical analysis was applied appropriately.
Results: Methadone dose was found to have moderate and positive correlation with the Ctrough (r=0.4, p<0.001) with only about 20% of changes in Ctrough can be explained by the changes in dose (r2=0.16-0.19, p<0.05) even after considering possible patients characteristics which may influence the two variables. Nevertheless, Ctrough have shown poor correlation with severity of withdrawal symptoms or urinalysis for other illicit drugs. Dose on the other hand did not show any correlation with both of the clinical outcomes measured. Study on CYP2B6 gene shows those patients with CYP2B6*6 variants have significantly higher mean of corrected trough serum concentrations (log Ctrough/dose) compared to the wildtype (CYP2B6*1). Further study on the OPRM1 (A118G) gene further shows those patients with homozygous variants (GG) did not involved in illicit drug use at lower methadone concentration of less than 250ng/ml compared to the wildtype (AA) (p<0.05)
Conclusion: CYP2B6 and OPRM1 gene with A118G SNPs may able to explain some of the variability in Ctrough and clinical outcomes measured in MMT. However, those genes may not be of value in therapeutic drug monitoring for the purpose of personalizing the dose of methadone as based on the clinical outcome measures.
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Keywords
Methadone maintenance therapy (MMT)