July 2007

As Depression Becomes More Treatment-Resistant…
For patients who do not respond to initial antidepressant therapy, augmentation, or switch strategies, further augmentation or switching with different agents can bring about remission—but at a lower rate.

New Studies on GAD
Pregabalin and duloxetine (Cymbalta) may be efficacious for adults and venlafaxine (Effexor) for children with generalized anxiety disorder.

Methadone Prolongs QTc Interval
Long-term, high-dose methadone treatment is linked to prolonged QTc intervals.

In Brief
Augmentation for Clozapine Nonresponders; Quetiapine Ineffective for Psychosis/Agitation in Dementia

Effects of Antidepressants on 2D6 Enzymes
Duloxetine (Cymbalta) has substantial and escitalopram (Lexapro) and sertraline (Zoloft and others) more modest inhibiting effects on CYP 2D6.

Methadone Prolongs QTc Interval

July 2007

Since the 1960s, methadone maintenance therapy has been a mainstay in the treatment of heroin addiction. In May and June, we reported on a public health advisory from the US Food and Drug Administration concerning deaths and serious adverse effects, including cardiac arrhythmias, associated with methadone treatment of chronic pain (BTP 2007;30:15,24). A comment in The Lancet discusses prolonged cardiac QTc intervals in heroin addicts treated with methadone.1

Krantz and Mehler note that as long ago as 1973, clinicians in New York observed an increase in sudden deaths among heroin addicts.2 Many of these patients showed prolonged QTc intervals, which were attributed to illicit abuse of many different substances. The editorialists, however, point out that QTc prolongation occurred in 34% of methadone-treated patients in this data set, but in only 3% of heroin addicts who were not taking methadone.

Thirty years later another paper linked high-dose methadone with torsades de pointes, a lethal ventricular arrhythmia associated with prolonged QTc intervals.3 Now, a retrospective study has found QTc intervals above 500 ms (associated with a high risk of torsades de pointes) in 16% of 167 patients with histories of intravenous drug use on long-term methadone maintenance therapy.4 The higher the methadone dose, the longer the QTc tended to be. In another 80 age-matched, intravenous drug-using subjects not receiving methadone, no QTc value exceeded 500 ms.

Krantz and Mehler highlight the clinical implications of this apparent methadone effect.1 On the one hand, 80 to 100 mg/day of methadone appears more effective than lower doses against illicit drug use and for cancer pain. Reducing intravenous drug use reduces accompanying risks, such as the transmission of viral hepatitis and HIV. On the other hand, higher doses of methadone appear to elevate the risk for QTc prolongation and, with it, the potential of torsades de pointes and death.

Buprenorphine (Suboxone and others) is an alternative to methadone and carries a lower overdose risk. The editorialists switched a patient from methadone to buprenorphine, and the QTc interval normalized. However, buprenorphine is expensive, less widely used, and possibly less effective than methadone in severe heroin addiction.

A study by Kakko et al randomly assigned 96 heroin-dependent patients either directly to methadone or to a stepped approach, with buprenorphine plus naltrexone (Depade), with "escalation" to methadone if needed.5 More than half of the subjects had to move up to methadone due to suboptimal response to buprenorphine/naltrexone.

Buprenorphine treatment may be a reasonable, safer, and less stigmatizing first step to try in opiate-dependent people. But it is expensive and may be less effective than methadone. Before starting methadone, consider an electrocardiogram to screen for patients with a prolonged QTc interval.

1Krantz MJ, Mehler S: QTc prolongation: Methadone's efficacy-safety paradox. Lancet 2006;368:556-557.

2Lipski J, Stimmel B, Donoso E: The effect of heroin and multiple drug abuse on the electrocardiogram. Am Heart J 1973;86:663-668.

3Krantz MJ, Lewkowiez L, Hays H, Woodroffe MA, Robertson AD, Mehler PS: Torsade de pointes associated with very-high dose methadone. Ann Intern Med 2002;137:501-504.

4Ehret GB, Voide C, Gex-Fabry M, Chabert J, Shah D, Broers B, Piguet V, Musset T, Gaspoz JM, Perrier A, Dayer P, Desmeules JA: Drug-induced long QT syndrome in injection drug users receiving methadone: High frequency in hospitalized patients and risk factors. Arch Intern Med 2006;166:1280-1287.

5Kakko J, Gronbladh L, Svanborg KD, von Wachenfeldt J, Ruck C, Rawlings B, Nilsson LH, Heilig M: A stepped care strategy using buprenorphine and methadone versus conventional methadone maintenance in heroin dependence: A randomized controlled trial. Am J Psychiatry 2007;164:797-803.