Pharmacogenetics of anesthetic and analgesic agents: CYP2D6 genetic variations.

To the Editor:—We congratulate Palmer et al. for their excellent review on pharmacogenetics of anesthetic and analgesic agents published in the March 2005 issue of ANESTHESIOLOGY. They give a worthreading introduction into basic molecular concepts and include the latest literature on pharmacogenetic aspects of anesthesia and analgesia. Because of this very comprehensive and detailed review, we feel the necessity for a brief specification and correction of their comments on the cytochrome P-450 enzyme system CYP2D6 and its influence on efficacy of tramadol analgesia. Tramadol is a synthetic weak opioid metabolized by CYP2D6. Like codeine, it is a prodrug, considering its -opioid receptor–mediated analgesia. Hepatic cytochrome P-450 metabolizes tramadol to 11-desmethylated compounds, of which M1 (O-desmethyltramadol) predominates and possesses analgesic properties. ( )O-Desmethyltramadol has been demonstrated to have an affinity to -opioid receptors that is approximately 200 times greater than that of the parent compound. Therefore, it is largely responsible for opioid receptor–mediated analgesia, whereas ( )-tramadol and ( )-tramadol inhibit reuptake of neurotransmitters serotonin (5-HT) and noradrenaline. O-Desmethylation to M1 requires CYP2D6 for its formation, a highly polymorphic isoenzyme of the cytochrome P-450 system. This enzyme is deficient in approximately 10% of white individuals. Several mutations causing a decrease in enzyme activity have been described up to now, the most frequent being single base exchanges or deletions within the 2D6 gene locus.* Patients displaying two inactive alleles, so-called poor metabolizers, are characterized by deficient hydroxylation of several classes of commonly used drugs, e.g., -blockers, antiarrhythmics, tramadol, codeine. Extensive metabolizers, displaying two functional alleles (e.g., two wild-type alleles: *1/*1), present normal enzyme activity and are able to metabolize tramadol sufficiently to O-desmethyltramadol. In our study, extensive metabolizers experienced adequate analgesia by tramadol in contrast to poor metabolizers presenting two mutant alleles with deficient enzyme activity. We tested for the seven polymorphisms, *3, *4, *5, *6, *7, *8, and *14; however, further genetic variations with allele frequencies of less than 0.01 (e.g., *11, *12, *13, *15, *16) are known, although they are extremely rare in white individuals. Whether it is worthwhile to test for these rare alleles in a clinical setting remains questionable. We identified 35 poor metabolizers with the CYP*3, *4, *5, or *6 alleles. These poor metabolizers were unable to form the analgesic active M1 metabolite of tramadol. This is why poor metabolizers were found to be twice as likely to require additional rescue medication than patients with at least one wild-type allele. The reason for nonresponse in poor metabolizers has to be assumed as a lack of tramadol metabolism. Therefore, the statement of Palmer et al. that nonresponse in patients with one or more functional CYP2D6*1 alleles require additional postoperative analgesics because of increased tramadol metabolism is incorrect. Correct is that carriers of at least one wild-type allele, CYP2D6*1, were responsive to tramadol treatment. Nonresponse was clearly associated with carriage of two mutant alleles and poor metabolizing status. In contrast to tramadol, which has to be considered as a prodrug for -opioid activity, when administering an active drug such as tricyclic antidepressants or 5-HT3 receptor antagonists ondansetron or tropisetron, ultrarapid metabolizers with increased CYP2D6 activity require additional medication because of subtherapeutic drug concentrations. As outlined in the same issue of ANESTHESIOLOGY, individuals with multiple functional copies of the CYP2D6 allele and ultrarapid metabolizer status had an increased incidence of ondansetron failure. The wide interindividual variability of drug concentrations in blood can often be ascribed to variability in drug-metabolizing enzyme activity. This can have an impact on the therapeutic response and toxicity of drugs with a narrow therapeutic index. Phenotypic or genotypic characterization of individuals is an attempt to predict enzyme activity and thus maximize drug safety and efficacy.