Table 2

 Drug interactions associated with enhanced methadone effects

Pharmacokinetic effectsClinical effectsType of evidencePossible mechanismReference
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.
    CiprofloxacinSedation/respiratory depression/confusionSingle case report; ciprofloxocin reintroduced with same outcomeInhibition of CYP1A2 and/or CYP3A439
    Fluconazole35% ↑ AUC; 27% ↑ peak, 48% ↑ trough, 24% ↓ clearance methadoneNo signs/symptoms of methadone overdose reportedRandomised, double blind, placebo controlled trial; 13 participants received fluconazole 200 mg/dayInhibition of CYP3A4, possibly others38
    FluoxetineSome patients had moderate ↑ plasma level, but this was less marked than with fluvoxamine in the two patientsNone reportedNine case reports of serum levels of methadone after addition of fluoxetine; two participants had also use fluvoxamine previouslyInhibition of CYP2D640
    Fluvoxamine↑ serum methadone levelHypoxemia, hypercapniaSingle caseInhibition of one of several enzymes: CYP3A4, CYP1A2, CYP2C9, CYP2C1941
↑ serum methadone levelPatient unable to achieve effective methadone level despite high dose. Had increased methadone level with fluvoxamine and decrease in withdrawal symptomsSingle caseInhibition of one of several enzymes: CYP3A4, CYP1A2, CYP2C9, CYP2C1942
    Paroxetine↑ R-methadone plasma levels in eight CYP2D6 extensive metabolisers but not in poor metabolisersNo side effects reported by patients and no signs of intoxication were notedProspective administration of paroxetine in 10 methadone-using patients (two poor metabolisers, eight extensive metabolisers)Inhibition of CYP2D6; also possibly CYP1A2, CYP2C9, CYP2C19, and CYP3A443
    Sertraline↑ methadone plasma level 26% with addition of sertralineNo significant difference in side effects between groupsProspective, 12 week, randomised, placebo controlled trial; 12 patients received up to sertraline 200 mg/dayInhibition of several isoenzymes (CYP2D6, CYP3A4, CYP1A2, CYP2C9, CYP2C19)44