Table 3

 Drug interactions associated with diminished methadone effects

Pharmacokinetic effectsClinical effectsType of evidencePossible mechanismReferences
Adapted with permission from Eap CB, Buclin T, Baumann P. Interindividual variability of clinical pharmacokinetics of methadone. Clin Pharmacokinet 2002;41:1153–93.15
AUC, area under the curve.
Antibiotics
    Fusidic acidTotal clearance antipyrine ↑ in group using fusidic acid × 28 daysNo side effects were reported by patients; some patients in 28 day group developed signs of underdosageRandomised, prospective trial, placebo controlled. Ten patients received fusidic acid 500 mg/day × 14 days; 10 patients with same dose × 28 days; 10 patients received no additional meds. Antipyrine clearance used to assess effect on CYP450 systemInduction of CYP450 enzymes46
    Rifampin↓ methadone plasma levelMethadone withdrawal symptomsCaseInduction of CYP3A412, 47
Antivirals/non-nucleoside reverse transcriptase inhibitors
    EfavirenzMarked ↓ maximum plasma methadone concentration, ↓ AUCNine patients described symptoms of methadone withdrawalProspective trial of 11 patients using methadone and beginning therapy with efavirenzInduction of CYP3A448
    NevirapineThree of seven records had a documented decrease in methadone trough level or subtherapeutic levelAll seven records had evidence of opiate withdrawalRetrospective chart review of 800 records of HIV-infected patientsInduction of CYP3A449
36% reduction in maximal concentration of methadone, significant ↓ AUCSix of eight patients reported withdrawal symptomsProspective administration of nevirapine to eight patientsInduction of CYP3A450
Antivirals/nucleoside reverse transcriptase inhibitors
    AbacavirAdministration of both abacavir and ampenavir associated with median 65% decrease in methadone concentrationTwo patients of the five reported symptoms consistent with withdrawalProspective administration of abacavir and ampenavir to five patients using methadoneAbacavir not expected to induce CYP3A4 activity; the protease inhibitor, ampenavir, is a known inducer of CYP3A4 and more likely the cause of ↓ methadone concentration51
Antivirals/protease inhibitors
    Amprenavir (see abacavir statement)
    NelfinavirComplaint of opiate withdrawal within six weeksSingle case report nelfinavir 750 mg three times a day added to drug regimenInduction of CYP3A4, possible induction of P-glycoprotein52
    Ritonavir/saquinavir40% ↓ AUC in S-methadone and 32% ↓ AUC in R-methadoneNo evidence of withdrawal reportedProspective pharmacokinetic study of 12 patients using methadone who began 400 mg ritonavir and 400 mg saquinavir twice dailyRitonavir: induction of CYP3A4; possible induction of P-glycoprotein, induction of CYP2C19 and/or CYP2B6 to explain greater induction of S-methadone v R-methadone. In vitro comparison of inhibition protency against metabolism of methadone is ritonavir > indinavir > saquinavir53, 54