Managed-care pharmacy benefit programs and many state Medicaid pharmacy formularies are choosing to promote the prescribing of methadone as an opioid of choice because of the drug’s low acquisition cost for managing pain. Some programs advise the analgesic use of methadone in place of long-acting and long-term opioids. However, neither the drug’s effectiveness nor efficacy has been exposed to rigorous, double-blind, placebo-controlled trials—and many pre scribers remain unaware of an important labeling change introduced last fall.
Methadone has been used for decades for managing substance abuse disorders in patients with a chemical dependency or addiction to opioids. It is indicated for the treatment of moderate-to-severe pain, detoxification therapy for opioid addiction, and maintenance treatment of opioid addiction, in conjunction with social and medical services.
Clinical concerns have arisen because of the association of methadone with prolongation or dispersion of the corrected QT (QTc) interval. When the drug is prescribed without careful monitoring, it has the potential to contribute to morbidity and/or mortality. Several reports describe adverse outcomes in patients who have exceeded the normal therapeutic dose range; who have used other pharmacotherapeutic agents with QTc-prolonging effects; or who have phar-macokinetic, pharmacodynamic, or patho physiological co morbidities.
Patients with risk factors for QTc prolongation would benefit from a cardiac evaluation or at least a baseline electrocardiogram before methadone therapy begin s.
In November 2006, the FDA notified health care professionals of reports of death and life-threatening adverse events, such as respiratory depression and cardiac arrhythmias in patients receiving methadone.
The warning noted that the elimination half-life of methadone (from 8 to 59 hours) is considerably longer than its analgesic action (four to eight hours). The FDA recommended that the dose of methadone for pain be carefully selected and slowly titrated to anagesic effect, even in patients who are opioid-tolerant. Physicians should closely monitor patients when switching them from other opioids and when changing their methadone dose; they should also carefully instruct patients on how to take this medication.
The most feared cardiac consequence of methadone is sudden cardiac death resulting from torsade de pointes that degenerates into ventricular fibrillation. Other cardiac adverse events associated with methadone include syncope, hypotension, and ventricular ectopy.
The new boxed warning in the prescribing information is stated as follows:
“Cardiac conduction effects: Laboratory studies, both in vivo and in vitro, have demonstrated that methadone inhibits cardiac potassium channels and prolongs the QT interval. Cases of QT interval prolongation and serious arrhythmia (torsades de pointes) have been observed during treatment with methadone. These cases appear to be more commonly associated with, but not limited to, higher-dose treatment (greater than 200 mg/day). Most cases involve patients being treated for pain with large, multiple daily doses of methadone, although cases have been reported in patients receiving doses commonly used for maintenance treatment of opioid addiction.”
Patients should avoid consuming grapefruit juice concurrently because it decreases the clearance of the metha-done enantiomers.