Concerns About Consensus Guidelines for QTc Interval Screening in Methadone Treatment FREE

TO THE EDITOR:

I am Chief Medical Director for Aegis Medical Systems' network of 24 narcotic treatment programs throughout California. I am writing to share my serious reservations regarding the assertions made by Krantz and colleagues (1) in their recent guidelines.

Aegis has been serving California communities for more than 10 years and has been using methadone to safely treat more than 5000 patients on a daily basis. Aegis has not encountered any evidence of torsade de pointes attributable to our patients' treatment with methadone. In fact, over more than 30 years (1969 to 2002), only 43 cases of methadone-associated torsade de pointes and 16 cases of QTc prolongation were reported to the U.S. Food and Drug Administration's MedWatch program. In addition, other risk factors for QTc prolongation and torsade de pointes (for example, taking medications with known drug–drug interactions, low potassium or magnesium levels, and structural heart disease) were found in 75% of such cases.

Furthermore, in the case series (1) mentioned by Krantz and colleagues, approximately 82% (14 of 17) of those patients had known risk factors for arrhythmias, such as hypokalemia, or were concomitantly taking other drugs that could prolong the QTc interval. Therefore, Krantz and colleagues themselves cautioned that “[their] report should not be interpreted to suggest that high-dose methadone cannot be used safely.”

Both Aegis' strict internal policies and state regulatory requirements dictate that Aegis physicians perform a thorough review of all patient deaths. Therefore, Aegis receives and reviews a coroner's report in conjunction with each patient death. Aegis physicians are also in direct communication with the primary care physicians of their patients. Neither the communications concerning the care of thousands of patients nor the reviewed coroners' reports have ever indicated any correlation between QTc prolongation and the treatment of our patients with methadone. Nonetheless, to effectively and reasonably address concerns raised by Krantz and colleagues, Aegis has updated its clinical risk management policy to require ECG for all patients treated with methadone doses greater than 150 mg, or for patients with established cardiovascular disease.

Treatment with methadone has both costs and benefits. Over the past 40 years, methadone has been firmly established as the most effective therapy for opiate addiction and has been linked to a substantial reduction in the mortality rates of patients with opiate addiction. We believe that a broad and sweeping requirement that all prospective and continuing patients undergo ECG is a dangerous obstacle and deterrent to their recovery efforts.

The relatively small potential risk for adverse cardiac effects must be considered against the serious risks that would result from withholding methadone treatment (for example, continued illicit drug use and public health issues). If ECG were required, thousands of patients who are indigent and uninsured would be forced to withdraw from the program, and prospective patients will be unable to access treatment for the same reason.

Furthermore, Krantz and colleagues should have considered other effective measures to ensure the safety of patients, including education of patients on these concerns, collaboration with primary care physicians, and monitoring of patients with a history of cardiac conditions. Such measures would not have a detrimental effect on access to treatment.

Aegis believes that the medical diagnosis and the determination of a patient's fitness for methadone treatment must be left in the hands of patients' treating physicians. Aegis further believes that Krantz and colleagues neglected to consider the various medical, psychological, and cultural considerations that accompany drug addiction.

We would like to point out the following findings from previous studies and publications regarding the relationship between QTc prolongation and methadone. First, much of the evidence to date regarding QTc prolongation and methadone are the result of case reports and small case studies (1 - 2). Second, many of these cases (82%) did not isolate methadone as the triggering element for QTc prolongation; rather, additional factors that could have played important roles in the diagnosis were not ruled out. QTc prolongation often results from a confluence of risk factors rather than a single causative agent.

Third, the prevalence of other substance abuse, such as cocaine, alcohol, and tobacco, would be expected in opioid-dependent persons entering methadone maintenance therapy. Cocaine has long been related to depression of heart rhythms, and alcohol has been shown to prolong QTc by up to 19%. In addition, many patients in methadone maintenance therapy are treated with multiple drugs that may alter electrical conduction in heart muscle tissue.

Fourth, past clinical investigations have shown minimal effects of methadone on QTc prolongation (3 - 4). In a 2003 study of 50 pain patients (5), QTc intervals did not change during oral methadone therapy. Fifth, researchers have noted that 89% of plasma methadone is protein-bound, thereby possibly reducing the in vivo amount of methadone available to inhibit IHERG to 11% (free fraction) and increasing the therapeutic index for methadone approximately 10-fold.

Sixth, laboratory studies are often based on methadone blood concentrations nearly 9 times greater than usual therapeutic levels recommended for patients on methadone maintenance therapy. In addition, past studies have been limited to cell cultures or animals, which do not necessarily translate to clinical effects on patients. Furthermore, in many case studies, high doses of methadone were applied directly to heart tissue on a single-dose basis. This is inconsistent with the actual long half-life of methadone and the steady blood serum levels common with methadone maintenance therapy.

Finally, effects on the heart's electrical conduction are not always harmful. In fact, certain opioids (including methadone) have shown cardioprotective effects and have been important adjuncts in treating heart attacks and coronary artery disease (6 - 7).

The calcium-slowing effects of methadone may be analogous to the actions of certain heart medications that suppress some forms of arrhythmia (8). One study (9) found similarities between methadone and verapamil. Verapamil, a calcium-channel blocker used to treat hypertension and angina, has not appeared on any lists of agents known to prolong QTc or induce torsade de pointes; in fact, calcium-channel blocking may shorten the QTc interval.

Thus, some of methadone's actions demonstrated in laboratory studies actually may provide a degree of cardiac protection in certain patients receiving methadone maintenance therapy. We hope that Annals will recognize these considerations and consider the complexity of this matter. Furthermore, we hope that Annals will present a more balanced view of these matters.

George Girgis, MD

Aegis Medical Systems

Agoura Hills, CA 91376