High-Dose Methadone: management of an opioid-addicted patient

Introduction: Methadone (MT), a synthetic opioid used in racemic form to treat opiate dependence, is metabolized primarily by CYP3A4, CYP2B6 and CYP2D6 enzymes. Interindividual variability in drug response can occur as a consequence of variations in cytochrome P-450 (CYP) isoenzyme activity or in the single nucleotide polymorphisms (SNPs) of drug transport proteins and/or receptors. Genetic variations in the OPRM1 gene locus of mu opioid receptors and/or in P-glycoprotein (ABCB1/MDR1 gene) are thought to play an essential role in interindividual responses to opiates. We investigated how best to make a genetic assessment of an opiate-addicted man who needed a high methadone dose to control withdrawal symptoms. Case presentation: We report the case of a patient in methadone maintenance treatment (MMT) who kept on demanding an increase in methadone dose; he ended up consuming 480 mg of MT daily, with the consequent development of cardiac toxicity. The patient was admitted to our Toxicology Unit to allow us to evaluate plasma MT concentration, to make a genetic evaluation of CYP2B6, CYP3A4, OPRM1 and ABCB1/MDR1, and to allow the patient to undergo a double shift from methadone to buprenorphine via oxycodone, a short-acting opioid. R/S MT plasma concentrations were above the range that corresponds to a normal MT metabolism. Genetic assessment of the opioid receptors revealed a variant G allele of the OPRM1 A118G SNP, thus confirming the patient's poor response to methadone treatment. Conclusions: Some opioid-addicted patients fail to respond adequately to MT treatment, despite their high dosage; in such cases the evaluation of plasma MT concentration, genetic assessment of opioid pharmacokinetic/pharmacodynamics and, possibly, an opiate drug switch may be helpful.