Genetic variants at loci related to methadone metabolism may also be clinically relevant, but their study has been complicated by the presence of differently metabolized optical isomers,55 the use of different experimental paradigms,20, 21, 56–58 and the possible tissue specificity of enzymatic activity.59, 60 Our suggestive finding that a CYP2D6 loss of function allele61, 62 decreases required methadone dose is in the expected direction. Future applications of genetics to dosage prediction could incorporate genetic variation at known pharmacokinetic and pharmacodynamic genes, as well as additional genes such as those implicated by the GS. These additional genes point to relevant biology beyond the interface of opioids with metabolizing enzymes or the μ-opioid receptor, illustrating the importance of unbiased GWASs that are not driven by prior hypotheses.
