High doses of methadone are suggested if the patient is concurrently treated with carbamazepine acc

Fråga: High doses of methadone are suggested if the patient is concurrently treated with carbamazepine according to a specified schedule. What is the background of this dosage recommendation?

Sammanfattning: Methadone is mainly metabolised in the liver, and can, therefore, apart from the interindividual differences in metabolism, be affected by other drugs stimulating or inhibiting the hepatic cytochrome P450 enzymes. Two small studies have indicated that carbamazepine can induce methadone metabolism and that dosage adjustment of methadone may be required when the two drugs are combined. This indicates that methadone treatment should be individualized and that measurement of plasma concentrations of the drugs involved should be taken into consideration.

Svar: This question has been dealt with previously (1). Methadone isextensively biotransformed in the liver (2) and liver enzyme inducing-drugs such as rifampicin (3,4), phenytoin (3,5) and presumably other enzyme-inducing agents (3), can decrease plasma concentrations of methadone. Cimetidine, on the other hand, has been reported to presumably inhibit the metabolism of methadone (4). A Medline search has revealed two articles (6,7) concerning a possible interaction between methadone and carbamazepine. Carbamazepine is a well-known inducer of the P450 microsomal hepatic enzymes (7).

Bell et al (6) measured trough serum methadone concentrations in 43 patients under treatment for heroin addiction and complaining of withdrawal symptoms. Low methadone concentrations (below 100 ng/ml) were noted only in patients taking very low doses and in 10 patients using "enzyme-inducing drugs" (phenytoin, four patients, phenobarbital, five patients and carbamazepine, one patient). According to the authors, carbamazepine had not previously been reported to enhance methadone metabolism. The mechanism was not further discussed but concurrent drug administration was said to be a major determinant in methadone pharmacokinetics.

In a study by Kuhn et al (7) 12 cocaine-dependent patients on methadone maintenance were offered carbamazepine as a pharmacological adjunct in the treatment of cocaine dependence. Patients reported mild opiate withdrawal symptoms after initiation of CBZ treatment. Methadone serum trough levels decreased about 60 per cent after 7-10 days of CBZ treatment. Pre-CBZ methadone concentrations were above 120 ng/ml and methadone dose increases of 10 mg were recommended when concentrations fell below 80 ng/ml. According to the authors, the specific interaction between carbamazepine and methadone was being investigated further in a controlled setting, but we have not yet found any published results. 1 Drugline nr 07509 (year 1990)

2 Goodman and Gilman, The pharmacological basis of therapeutics. 1990; 8th ed. 508-509
3 Avery, Drug treatment. 11987; 3rd ed: 1385
4 FASS 1992; page 548, 948
5 Hansten, Horn, Drug interactions & updates. 1971-; page 188

6 Bell J, Seres V, Bowron P, Lewis J, Batey R: The use of serum methadone levels in patients receiving methadone maintenance. Clin Pharmacol Ther 1988; 43: 623-629 7 Kuhn KL, Halikas JA, Kemp KD: Carbamazepine treatment of cocaine dependence in methadone maintenance patients with dual opiate-cocaine addiction. NIDA Res Monogr 1989; 95: 316-317