r 60633 a Pharmacogenetics and Methadone Treatment Response May 2011 | Volume 6 | Issue 5 | e19527 Data from the 105 patients included. Bold numbers indicate statistically significant differences between patients. c Plasma Oxyresveratrol cost concentrations were obtained for 79 patients. d Statistical significant differences were found between Ultrarapid compared to Extensive metabolizers p,0.05. doi:10.1371/journal.pone.0019527.t004 b Pharmacogenetics and Methadone Treatment Response medications. The effect of drug interactions could not be discarded in our results as a high proportion of patients were taking concomitant medications. Nevertheless present observations should apply to EM patients, but not to PM patients with a nonfunctional enzyme or to UM the most susceptible to drug interactions but also, those requiring the larger doses. A recent report suggests that CYP2D6, a non-inducible hepatic enzyme, may be induced at 
the brain level by nicotine. As almost all participants 21563277 were smokers, there may be dissociation between plasma concentrations, hepatic metabolism and genotype, and brain drug requirements. According to previous publications there is a pharmacodynamic interaction between methadone treatment and cigarette smoking; methadone and nicotine share some effects: increase the ratings of euphoria and ameliorate negative mood. The contribution of CYP2D6 to methadone metabolism as well the interaction with smoking deserves further studies. Regarding the results of CYP2B6, although non-statistically significant, methadone doses and methadone plasma concentrations are in agreement with previous research reports: patients homozygous for the 6 allele, received lower doses of methadone and those patients showed higher plasma concentrations of -methadone, confirming previous findings. Increased -methadone plasma concentrations are related with an enantioselective methadone metabolic disposition towards the inactive -enantiomer regulated by CYP2B66. Also, in a recent report examining methadone concentrations in post-mortem blood in methadone-related deaths, it was concluded that the risk of methadone fatality may be related in part with the CYP2B66 allele. When we look at responder status, 4 out of 5 slow metabolizers were classified as responders to methadone treatment. It is apparent from the present study that interindividual pharmacokinetic differences among patients can be compensated by clinical management of the doses of methadone. Although the absence of restrictions in methadone dosage in our MMT program, the clinical impression is that some patients with poor response to MMT do not accept increases in their methadone dose. It could be hypothesized that those patients show significant adverse events associated to methadone. -methadone has been previously associated to adverse responses of -methadone as negative mood effects ension, fatigue, confusion…-. No significant differences in the -methadone plasma concentrations have been detected, nor in the / ratio in this sample. Other possible explanations could be a pharmacodynamic influence in the reluctance of a considerable group of patients to increase methadone dose. The candidate gene OPRM1 has previously been related to opioid treatment response, mainly in analgesia and alcohol dependence. The more commonly studied SNP, in the mu-opioid receptor gene can affect opioid function. Carriers of the homozygous variant require higher opiate doses to achieve pain relief when they are treated with m
