Torsades de PointesAssociated with High Dose Levomethadyl Acetate (ORLAAM®)

Abstract

A patient undergoing management of heroin dependency with high dosages of the long-acting methadone derivative, levomethadyl acetate HCl (LAAM; ORLAAM) developed a prolonged QTc interval and polymorphic QRS complexes on EKG consistent with torsades de pointes (TdP). The patient was taking other drugs known to prolong the QTc interval (fluoxetine and IV cocaine), and those known to antagonize the activity of the P450 enzymes responsible for the metabolism of LAAM and its active metabolite (fluoxetine, cocaine and marijuana). No previous reports have appeared in the literature attributing this adverse event to LAAM therapy; however, five similar cases have been reported to the manufacturer. Animal studies indicate that LAAM and metabolites prolong the action potential duration of myocardial cells. We propose that predisposed patients on high doses of LAAM may be at risk for developing TdP. Patients being treated with LAAM should receive dosages consistent with guidelines and be evaluated for concomitant diseases, interacting drug therapies, and EKG abnormalities.

Influence of Opioid Agonists on Cardiac HumanEther-a-go-go-related Gene K+Currents

“…In April 2001, the United States Food and Drug Administration issued a new warning about adverse cardiac events (Deamer et al, 2001) associated with the use of L-␣-acetylmethadol hydrochloride (LAAM), a -opioid agonist licensed for the treatment of narcotic addiction (Prendergast et al, 1995). This warning was prompted by 10 cases of serious cardiac arrhythmias reported to the Food and Drug Administration through their MedWatch surveillance program.…”

“…Remarkably, many different types of drugs, including some antiarrhythmics, antihistamines, antibiotics, gastrointestinal prokinetics, and antipsychotics (Faber et al, 1994;De Ponti et al, 2001), have been shown to cause QT prolongation, primarily through interference with the rapid component of the delayed rectifier potassium current, I Kr (Antzelevitch et al, 1996;January et al, 2000;Tamargo, 2000;Tseng, 2001). The human ether-a-go-go-related gene (HERG) gene encodes for the major channel protein that underlies I Kr , and a recently developed cell line that was stably transfected with the HERG gene (Zhou et al, 1998) has proven useful for evaluating drugs suspected of causing delays in cardiac repolarization (Mohammad et al, 1997;Ferreira et al, 2001).In April 2001, the United States Food and Drug Administration issued a new warning about adverse cardiac events (Deamer et al, 2001) associated with the use of L-␣-acetylmethadol hydrochloride (LAAM), a -opioid agonist licensed for the treatment of narcotic addiction (Prendergast et al, 1995). This warning was prompted by 10 cases of serious cardiac arrhythmias reported to the Food and Drug Administration through their MedWatch surveillance program.…”

Methadone and its effect on QTc prolongation

“…6 The CPQ is divided into two sections: 1) basic patient information, 2) factors associated with community placement, including the patient's social functioning, problem behaviours, physical disability, and daytime activity levels. An overall index of the patient's level of social functioning can be derived and patients can be classified into one of five categories ranging from very poor to high.…”

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

“…A cogener of methadone, levo-α-acetyl-methadol (LAAM), binds to the KCNH2 channel in a dose-dependent manner [76] and prolongs the QT interval, and treatment by LAAM is associated with TdP [77]. This has led to the withdrawal of the substance from the European and US market in 2001 and 2003, respectively.…”