Methadone serum levels may rise if fluvoxamine is added,sometimes resulting in increased adverse effects. Sertraline,paroxetine, and possibly fluoxetine, may also modestly increase methadone levels.
Methadone 30 to 100mg daily,and fluoxetine 20mg daily were given to 9 patients (two of them were also taking fluvoxamine). Although there were possible compliance problems with some of patients, methadone plasma/dose ratio of group as a whole was not altered by addition of fluoxetine (See reference number 1). This is consistent with results of two other studies, which found that fluoxetine did not appear to alter plasma methadone levels of patients treated for cocaine dependence (See reference number 2,3). However, plasma samples for 7 of 9 patients in first study(See reference number 1) were subsequently analysed again to measure S-and R-enantiomers of methadone separately. This analysis revealed that fluoxetine 20mg daily modestly increased levels-to-dose ratio of active R-methadone (by 33%) without significantly changing either total or inactive S-methadone level-to-dose ratios (See reference number 4). Moreover,a patient taking methadone developed opioid toxicity when given ciprofloxacin and fluoxetine, see Opioids; Methadone + Ciprofloxacin interaction.
Five patients taking maintenance doses of methadone were given fluvoxamine. Two of them had an increase of about 20 % in methadone plasma/dose ratio, while other 3 showed 40 to 100 % rises (suggesting increased methadone levels). One of them developed asthenia,marked drowsiness and nausea, which disappeared when both drug dosages were reduced (See reference number 5). A subsequent analysis of enantiomers of methadone revealed that fluvoxamine increased levels of both R– and S-methadone (See reference number 4). A report describes one patient who was unable to maintain adequate methadone levels,despite a daily dosage of 200 mg, and experienced withdrawal symptoms until fluvoxamine was added (See reference number 6). Another patient taking methadone 70mg daily and diazepam 2mg twice daily was admitted to hospital with an acute exacerbation of asthma and intractable cough 3 weeks after starting fluvoxamine 100mg daily. Blood gas measurements indicated severe hypoxaemia and hypercapnia. The symptoms resolved when methadone dose was reduced to 50mg daily and diazepam was gradually withdrawn, at which point methadone levels fell by about 23 % (from 262 to 202 nanograms/mL) (See reference number 7).
Paroxetine 20mg daily increased steady-state methadone levels by 35 % in 10 patients taking maintenance doses of methadone. Both R– and S-methadone levels were increased in 8 patients who were extensive metabolisers of cytochrome P450 isoenzyme CYP2D6 (see Genetic factors, ), but in 2 patients who were poor metabolisers, only S-methadone levels were increased. Apart from one patient who reported feeling high during first night after starting paroxetine, no symptoms of over-medication or toxicity were noted (See reference number 8).
A placebo-controlled study in 31 depressed methadone-maintained patients found that sertraline significantly increased methadone plasma level/dose ratio by 26 % while patients on placebo had a 16 % decrease after 6 weeks treatment, but by 12 weeks ratios had shifted towards baseline values. Adverse effects were similar in both groups (See reference number 9). A 31-year-old woman taking methadone 230mg daily was found to have a prolonged QT interval after taking sertraline 50mg daily was added to her medications,although she was asymptomatic. The QT interval returned to normal when methadone and sertraline were stopped and her methadone was replaced with morphine (See reference number 10).
Fluvoxamine, and to a lesser extent fluoxetine, paroxetine, and sertraline, can inhibit liver metabolism of methadone (possibly by cytochrome P450 isoenzymes CYP3A4,(See reference number 11) CYP2D6,(See reference number 11,12) and/or CYP1A2(See reference number 4)) thereby allowing it to accumulate in body.
Information is limited, but it indicates that effects of starting or stopping fluvoxamine should be monitored in patients taking methadone, being alert for need to adjust methadone dosage. Although increase in methadone levels with sertraline and paroxetine, and possibly also fluoxetine, is unlikely to have clinical effects in most patients, possibility should be borne in mind, especially if high doses of methadone are being used. Note that methadone can prolong QT-interval in high doses, see drugs that prolong QT-interval, .
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