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Managing Methadone and Non-Nucleoside Reverse Transcriptase Inhibitors: Guidelines for Clinical Practice S. Clarke1, F. Mulcahy1, D. Back2, S. Gibbons2, J. Tjia2, and M. Barry1.
1St. James's Hosp., Dublin, Ireland and 2Univ. of Liverpool, UK Nevirapine and Efavirenz are potent inducers of the Cytochrome P450 enzyme system, and anecdotal reports suggest they may produce symptoms of methadone withdrawal when prescribed to injection drug users on methadone maintenance therapy. Two studies were designed to determine the pharmacokinetics of methadone when combined with either EFV or NVP.
Twenty five patients receiving stable methadone maintenance therapy were studied. All commenced ART with dual NRTI’s and either EFV(n=15) or NVP(n=10). Pharmacokinetics before and two to three weeks (pending the onset of withdrawal symptoms) after initiating 600mgs EFV or NVP 200-400mgs OD were determined. Blood samples were obtained at times 0,1,2,3,4,5,6,7,8, and 24 hours post dosing.
When EFV was combined with methadone, there was a decrease in the mean maximum plasma concentration of methadone from 689 (range 212-1568) to 358 (205-706) ng/ml; p=0.007, 95% CI 112 to 549. The mean AUC0-24h for methadone also significantly reduced in the presence of EFV from 12341 (range 3682-34147) to 5309 (2430-10349) ng.h/ml; p=0.011, 95%, CI 1921 to 12143. Initial data on the interaction between NVP and methadone shows a mean reduction in AUC0-24h for methadone of 46% (range 23-80%). Seventeen patients complained of symptoms consistent with methadone withdrawal from day 8-10 onward, requiring a mean increase in methadone dose of 21.65% (mean increase 16 mg, range 15-30 mg).
An immediate increase and a substantial increase in methadone is therefore not appropriate as during the first 1-2 weeks of therapy there appears to be a process of ‘induction –detoxification’ whereby the increase in methadone dose required is not as great as might be expected from an individual’s pharmacokinetic data. We recommend frequent medical assessments for such patients to monitor withdrawal symptoms, increasing methadone dose in increments of 10mgs from day 8-10 onwards.
Key Words: efavirenz, methadone, nevirapine
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