Drug Interactions between Methadone Diskets and Prozac

MONITOR CLOSELY: Methadone may cause dose-related prolongation of the QT interval. Theoretically, coadministration with other agents that can prolong the QT interval such as fluoxetine may result in additive effects and increased risk of ventricular arrhythmias including torsade de pointes and sudden death. High dosages of methadone alone have been associated with QT interval prolongation and torsade de pointes. In a retrospective study of 17 methadone-treated patients who developed torsade de pointes, the mean daily dose was approximately 400 mg (range 65 to 1000 mg) and the mean corrected QT (QTc) interval on presentation was 615 msec. The daily methadone dose correlated positively with the QTc interval. Fourteen patients had at least one predisposing risk factor for arrhythmia (hypokalemia, hypomagnesemia, concomitant use of a medication known to prolong the QT interval or inhibit the metabolism of methadone, and structural heart disease), but these were not predictive of QTc interval. It is not known if any of the patients had congenital long QT syndrome.

The clinical significance of a pharmacokinetic interaction between fluoxetine and methadone is unclear. Fluoxetine has demonstrated weak inhibitory effect on CYP450 3A4, an isoenzyme responsible for the metabolism of methadone. In nine patients receiving methadone maintenance 30 to 100 mg/day, the addition of fluoxetine 20 mg/day for the treatment of affective disorders did not significantly alter the methadone plasma concentration-to-dose ratio for the group. Other studies of patients in methadone maintenance programs also reported no significant effect of fluoxetine on methadone plasma concentrations. However, fluoxetine is also a potent inhibitor of CYP450 2D6, which is partially involved in the metabolism of methadone. When plasma samples were assayed for the individual enantiomers of methadone, investigators found that fluoxetine 20 mg/day increased the plasma concentration-to-dose ratio of the pharmacologically active R(+) enantiomer by 33%, but had no significant effect on that of the inactive S(-) enantiomer or the racemate. In one case report, a 42-year-old woman who had been on long-term methadone 140 mg/day for pain developed profound sedation and respiratory depression during coadministration with ciprofloxacin and fluoxetine and required treatment with naloxone 0.4 mg intramuscularly. The interaction was primarily attributed to ciprofloxacin, since the patient had experienced sedation on three previous occasions during concomitant use of ciprofloxacin and regained normal alertness each time after its discontinuation. Nevertheless, the apparent increase in severity of interaction during the final episode of ciprofloxacin exposure coincided with a replacement of venlafaxine with fluoxetine, which would suggest some involvement of fluoxetine. According to the prescribing information for methadone, concomitant use with CYP450 3A4 and/or 2D6 inhibitors can increase methadone's risk of toxicity.

MANAGEMENT: Caution is recommended during concomitant use of methadone and fluoxetine, particularly in the setting of chronic pain management or methadone maintenance for opioid dependency where high dosages may be employed. Patients should be advised to seek prompt medical attention if they experience symptoms that could indicate the occurrence of torsade de pointes such as dizziness, lightheadedness, fainting, palpitation, irregular heart rhythm, shortness of breath, or syncope. The possibility of prolonged and/or increased pharmacologic effects of methadone, such as central nervous system and respiratory depression, should be considered.