**1.2 Pharmacogenetic of methadone**

Methadone has variable pharmacology. It binds to the µ-opioid receptor, the NMDA ionotropic glutamate receptor to exert its effects. Its metabolism is mediated by several enzymes including CYP3A4, CYP2B6 and CYP2D6, enzymes that are polymorphic and hence exhibit great variability. It is mainly administered through the oral route and adverse effects include hypoventilation, constipation and miosis, in addition to tolerance, dependence and withdrawal difficulties.

As a full µ-opioid agonist, methadone exhibits all the opiate-like effects. Furthermore, its binding to the glutamatergic NMDA (N-methyl-D-aspartate) receptor. This makes it a receptor antagonist against glutamate which is the primary excitatory neurotransmitter in the CNS. NMDA receptors modulate long term excitation and memory formation. NMDA antagonists such as dextromethorphan (DXM), ketamine, tiletamine and ibogaine have been studied for their role in decreasing the development of tolerance to opioids and as possible for eliminating addiction /tolerance /withdrawal. Its action on the NMDA has been proposed as a mechanism by which methadone decreases craving for opioids (Xiao *et al*, 2001).

Methadone is a lipophilic drug and requires biotransformation for elimination. It has a slow metabolism and is longer lasting than morphine-based drugs. Typically its elimination halflife ranges from 15 to 60 hours with a mean of around 22 hours. Due to the polymorphic nature of its metabolism, its metabolism rates vary greatly between individuals, up to a factor of 100. This variability is apparently due to genetic variability in the production of the associated enzymes CYP3A4, CYP2B6 and CYP2D6. Several studies have been conducted to explain the intra- as well as inter-individual variability in methadone's pharmacokinetic and clinical response. Typically, methadone is a substrate for several CYP450 enzymes as well as P-glycoprotein (PGP). Many Single Nucleotide Polymorphisms (SNPs) have been reported to contribute to its variability. Furthermore, as it binds to µ-receptors, SNPs in *OPRM* gene that encodes for these receptors may contribute to the clinical response in MMT patients. Thus, SNPs in *OPRM* gene, *CYP* gene and *ABCB1 (MDR1)* gene may contribute to determine the clinical outcomes of the MMT (Lötsch *et al*, 2009).
