Methadone enzyme inducers

Interactions are similar to those of opioid analgesics. Methadone has interactions with enzyme inducers. Withdrawal symptoms of methadone are observed upon concurrent administration with phenobarbitone, phenytoin, and rifampicin. Methadone toxicity increases if administered with cimetidine and fluvoxamine. 

Enzyme-inducing drugs, such as carbamazepine, pheno-barbital, phenytoin, and rifampicin, enhance the metabolism of methadone, leading to lower serum methadone concentrations (58). 

Not fully established, but all of these antiepileptics (except larnotrigine and valproate) are recognised enzyme-inducers that can increase the metabolism of other drugs by the liver, thereby hastening their loss from the body. In one study it was found that phenytoin increased the urinary excretion of the main metabolite of methadone. ... 

Information is limited but the interaction between methadone and these enzyme-inducing antiepileptics appears to be established and of clinical importance. Anticipate the need to increase the methadone dosage in patients taking carbamazepine, phenytoin or phenobarbital. It may be necessary to give the methadone twice daily to prevent withdrawal symptoms appearing towards the end of the day. It seems probable that primidone will interact similarly because it is metabolised to phenobarbital. Also be aware of the need to reduce the methadone dose if any enzyme-inducing antiepileptic is stopped. Valproate appears not to interact. 

For comment on the effect of enzyme inducers such as phenobarbital on opioid metabolism, see Opioids + Antiepileptics Enzyme-inducing , p.l62 and Opioids Methadone + Antiepileptics , p.l63. 

Rifampicin is a potent enzyme-inducer, which increases the aetivity of the intestinal and liver enzymes concerned with the metabolism of methadone, resulting in a marked decrease in its levels. In 4 patients in the study cited, the urinary excretion of the major metabolite of methadone rose by 150%. Rifabutin has only a small enzyme-indueing effect and therefore the effects are not as great. 

An inducer of many CYP450 enzymes may result in complaints of withdrawal symptoms in methadone maintenance patients when added to their drug regimen may need to increase methadone dose. ... 

The answer is b. (Katzungr pp 806—807J Rifampin induces cytochrome P450 enzymes, which causes a significant increase in elimination of drugs, such as oral contraceptives, anticoagulants, ketoconazole, cyclosporine, and chloramphenicol. It also promotes urinary excretion of methadone, which may precipitate withdrawal. 

Treatment with the NNRTIs efavirenz and nevirapine was noted to cause methadone withdrawal symptoms in patients with HIV [66, 52], Subsequently, both NNRTIs were shown to induce drug-metabolizing enzymes in cultured hepatocytes due to activation of CAR and weak activation of PXR [37]. 

Rifampin induces the activity of the hepatic microsomal enzyme, metabolizing numerous drugs including acetaminophen, anticoagulants, barbiturates, benzodiazepines, beta-blockers, chloramphenicol, clofibrate, contraceptives, corticosteroids, cyclosporine, digitoxin, disopyramide, estrogens, hydantoins, methadone, mexiletine, quinidine, sulfones, sul-fonylureas, theophyllines, tocainide, and verapamil. The plasma levels and effectiveness of these agents may be decreased. 

Toxicity and interactions Rifampin commonly causes light chain proteinuria and may impair antibody responses. Occasional side effects include skin rashes, thrombocytopenia, nephritis, and hver dysfunction. If given less often than twice weekly, rifampin may cause a flu-hke syndrome and anemia. Rifampin strongly induces liver dmg-metabolizing enzymes and enhances the elimination rate of many drugs including anticonvulsants, contraceptive steroids, cyclosporine, ketoconazole, methadone, and warfarin. 

With the introduction of RiF in 1967, the duration of combination therapy for the treatment of TB was significantiy reduced (from 18 to 9 months). Rifampin is nearly always used in combination with one or more other antitubercuiin agents. The drug is potentially hepatotoxic and may produce Gl disturbances, rash, and thrombocytopenic purpura. Rifampin is known to induce hepatic microsomai enzymes (cytochrome P450) and may decrease the effectiveness of oral contraceptives, corticosteroids, warfarin, quinidine, methadone, zidovudine, clarithromycin, and the azoie antifungai agents (see Chapter 10) (33). 

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