Methadone-associated long QT syndrome: improving pharmacotherapy for dependence on illegal opioids and lessons learned for pharmacology

Abstract

Methadone is used as the pharmacologic mainstay for substitution for illegal opiates and as analgesic for chronic or cancer-related pain. Given the benefits of methadone substitution for illicit opioids, the finding of an association between methadone and prolongation of cardiac depolarization (QT prolongation) and torsades de pointes is of great concern. QT prolongation can occur with many drugs and is a potentially lethal adverse drug reaction, necessitating risk monitoring and therapeutic alternatives in some patients. Recent studies suggest that QT prolongation with methadone is context dependent: occurrence is more frequent with high doses of methadone, concomitant administration of CYP3A4 inhibitors, hypokalemia, hepatic failure, administration of other QT prolonging drugs and pre-existing heart disease. The valued benefit of methadone substitution therapy on the one hand and the increased cardiovascular risk in particular situations on the other illustrate the difficulties in dealing with drug-induced QT prolongation in general.

Functional Genetic Polymorphisms inCYP2C19Gene in Relation to Cardiac Side Effects and Treatment Dose in a Methadone Maintenance Cohort

“…Although most early studies suggested that the methadone-induced QTc prolongation is dose dependent, the dosage range of methadone required to induce clinically significant QTc prolongation remains unclear (Ehret et al, 2007;Ehret et al, 2006;Kim and Manini, 2008;Piguet et al, 2004;Reddy et al, 2010). Other risk factors such as the concurrent use of CYP450 isoenzyme inhibitors and hepatic insufficiency, which result in an increase in the plasma concentration of methadone, have also been suggested to contribute to QTc prolongation (Piguet et al, 2004).…”

Methadone Deaths: Risk Factors in Pain and Addicted Populations

“…15 Methadone is metabolized primarily in the liver into inactive metabolites by the P450, CYP 3A4 enzymes that are also used by several QTc prolonging medications. 16,17 Methadone is a weak inhibitor of the 3A4 system and a minor weak substrate of 2C89, 2C19 and 2D6. 16 In methadone-naïve persons, it takes approximately two weeks for enzymatic systems to convert methadone into its inactive metabolites.…”

“…16,17 Methadone is a weak inhibitor of the 3A4 system and a minor weak substrate of 2C89, 2C19 and 2D6. 16 In methadone-naïve persons, it takes approximately two weeks for enzymatic systems to convert methadone into its inactive metabolites. 8 Individual differences in methadone metabolism by CYP 3A4 and 2D6 suggest the possibility of drug interactions that may influence sensitivity and risk, especially when methadone is taken in conjunction with drugs that prolong QTc or have respiratory depressive effects on their own.…”

“…Lethal respiratory depressive effects can occur in doses as low as 30 mg in nontolerant persons. 16 These effects can also emerge in persons tolerant to opioids, albeit usually at higher doses. Individual differences in the ability to metabolize methadone, along with imperfect cross-tolerance, may heighten risks of respiratory depression during the methadone induction period.…”

The use of methadone “as needed”, is it justified?

“…Added to the above complexities, methadone has been shown to increase the QT interval to potentially dangerous levels and this must be monitored in all patients on this drug. 19 Further, long-term use of opiates places patients with hypoventilation syndromes and sleep apnea at risk. Methadone specifically may increase the risk of development of de novo central sleep apnea as well.…”