Lesson of the Week: Methadone maintenance and tuberculosis treatment
BMJ 1996; 313 doi: https://doi.org/10.1136/bmj.313.7062.925 (Published 12 October 1996) Cite this as: BMJ 1996;313:925
- Duncan Raistrick, directora,
- Alistair Hay, reader in chemical pathologyb,
- Kim Wolff, research fellowb
- a Leeds Addiction Unit, Leeds LS2 9NG,
- b Division of Clinical Sciences, School of Medicine, University of Leeds, Leeds LS2 9JT
- Correspondence to: Dr Hay.
Rifampicin is a potent inducer of hepatic microsomal enzymes. It increases drug clearance and reduces the half life of a wide range of drugs, including barbiturates, oral contraceptives, propranolol, sulphonylureas, and methadone.1 Without a concomitant increase in methadone dose, patients also taking rifampicin are likely to experience opiate withdrawal symptoms and may stop their antituberculosis drugs or supplement their methadone prescription with illicitly obtained opiates. Failure to comply with antituberculosis treatment compromises recovery and increases the risk of secondary resistance.2 The symptoms of methadone withdrawal usually occur only when intake is reduced and are not expected by a user starting rifampicin. Notifications of tuberculosis in the United Kingdom rose from a plateau of some 5100 in 1987 to over 5700 in 1994. Drug misusers account for only a small number of cases, but they share nationally identified risk factors3; thus high rates of tuberculosis can be expected among drug misusers and especially those who are HIV positive.4
Drug misusers with tuberculosis who are prescribed rifampicin and methadone may require additional methadone to prevent withdrawal symptoms
Case report
A 40 year old woman had first presented for treatment of her opiate dependence at the age of 29. She had experimented with various other drugs, notably amphetamine, since her early 20s. She was judged to have a good prognosis, and after successfully completing an opiate detoxification programme she reported being drug free for four years.
She referred herself back to the clinical service when she was 33 and began a series of methadone maintenance programmes, during which the dose of methadaone was gradually decreased. During this process she stopped using amphetamines and opiates, and her condition was eventually well stabilised with 50 mg methadone daily. When she was 38 a routine chest x ray picture suggested tuberculosis and appropriate treatment was recommended.
The antituberculosis drugs induced an opiate withdrawal state, and she responded by stopping taking rifampicin for a month. When the importance of compliance with the antituberculosis treatment was explained, she restarted the treatment and attended the addiction unit to restabilise her condition with methadone. This was achieved by daily attendance at the unit and incremental increases in the dose of methadone until all withdrawal symptoms were suppressed. Ultimately, she required a dose of 150 mg methadone daily (three times her original maintenance dose).
PHARMACOKINETIC STUDIES
The patient participated in four separate kinetic studies at different daily doses; she had been receiving each of the dosing regimens for at least one week—and in one instance (methadone 80 mg), seven months—before these studies were performed. The sequence of the four regimens was: (a) methadone 110 mg, rifampicin 120 mg four times a day, isoniazid 50 mg three times a day, pyrazinamide 300 mg three times a day; (b) methadone 150 mg (80 mg initially, 70 mg 5 1/2 hours later), rifampicin 150 mg four times a day, isoniazid 100 mg three times a day; (c) methadone 80 mg; and (d) methadone 70 mg. Plasma methadone concentration was measured by high performance liquid chromatography. Blood was collected before the daily dose (methadone was taken by mouth as a single dose except in the second regimen, when the patient split her dose) and at regular intervals for a further 11 to 23 hours.
Figure 1 shows the results of the kinetic studies. The two lower curves were obtained when the patient was receiving antituberculosis treatment; the two upper curves were obtained 11 and 20 months later, when she was taking methadone alone.
Plasma methadone concentrations in patient receiving either methadone and antituberculosis treatment or methadone alone
The dose and the time since the last dose of methadone will affect the blood concentration of methadone at baseline before the daily dose is taken. These are likely to be reasons for the difference between the values in the third and fourth regimens.5 The following pharmacokinetic variables were calculated: oral clearance was 8.97 ml/min/kg for the first regimen, 2.10 ml/min/kg for the third, and 2.12 ml/min/kg for the fourth. We were unable to calculate clearance for the second regimen.
Discussion
So far as we are aware, there are no published reports of an interaction between methadone and isoniazid or pyrazinamide. We assume, therefore, that the lower plasma methadone concentrations during antituberculosis treatment were attributable to the effects of rifampicin. Our methadone measurements agree with those of other clinical reports.1
This case shows that some patients receiving maintenance treatment with methadone cannot tolerate withdrawal symptoms precipitated by rifampicin and that they may not comply with antituberculosis treatment until their methadone is increased.