(R)-methadone versus racemic methadone: what is best for patient care?


Methadone has been linked to cardiac arrhythmia. (R)-methadone appears to confer a lower risk of QT interval prolongation, resulting in debate over how best to treat patients needing this medication. A discussion of salient aspects of selecting therapy for opioid dependence and pain management and decision-making regarding methadone formulation follows.

Since the groundbreaking work of Dole & Nyswander in the 1960s [1], methadone has been a life-saving treatment for heroin and, more recently, prescription opioid analgesic addiction. Methadone is used increasingly as a treatment for chronic pain, both malignant and non-malignant [2]. As methadone use has increased, associated toxicities and overdose deaths have risen. Methadone confers some risk for cardiac adverse events and sudden death. Its use has been associated with arrhythmias, particularly torsade de pointes [3]. This effect is mediated through the ability of methadone to bind to human Ether-à-go-goRelated Gene (hERG) channels in cardiac myocytes [4], resulting in delayed repolarization. The risk is thought to result mainly from the use of a racemic methadone formulation that contains both (R)- and (S)-enantiomers. The (R)-enantiomer is a mu opioid agonist responsible for therapeutic effects. The (S)-enantiomer is a poor mu agonist and can block hERG channels to a greater degree than the (R)-enantiomer, which has been postulated to be responsible for cardiac adverse events in methadone use [5]. This information, in the context of recent studies showing a reduced effect of (R)- methadone on QTc interval [6] has generated discussion of the consideration of eliminating racemic methadone in favor of the exclusive use of (R)-methadone or buprenorphine as a means of resolving the cardiac safety issues related to current methadone treatment. However, this is a multi-faceted problem that deserves further consideration.

To address the cardiac safety issues with methadone in the United States, the Substance Abuse and Mental Health Services Administration (SAMHSA) convened a panel of experts who made recommendations aimed at enhancing safety for those needing chronic methadone treatment. Recommendations included disclosure of arrhythmia risk with methadone and obtaining a clinical history of risk factors, including structural heart disease, syncope and arrhythmia. Recommendations for monitoring of cardiac QTc interval prior to and following methadone therapy were included. Clinician attention to potential drug interactions that might be associated with delayed methadone clearance and higher plasma concentrations was advised [3]. Concerns regarding some recommendations were voiced within the treatment community [7]. These included questions about the interpretation of currently available data and need for recommended interventions, concerns regarding implementation barriers, the creation of undue anxiety in patients and unnecessary evaluation procedures and delaying or denying treatment to those needing methadone. To date, SAMHSA has not adopted these recommendations.

A proposed solution is the use of a form of methadone that contains only the (R)-enantiomer. This methadone formulation is available in the European Union and is in widespread use in Germany. The use of a pure (R)-formulation of methadone results in lower effective doses, but its cost is up to 20% higher than the racemic formulation (S. Walcher MD, personal communication).

Some in the United States have suggested that racemic methadone be replaced by (R)-methadone. However, this formulation of methadone is not US Food and Drug Administration (FDA)-approved and, therefore, cannot be prescribed in the United States. As a new drug, it is likely that the FDA will require safety testing and clinical trials to show its equivalence to the currently available racemic mixture. Even if the FDA were to expedite the approval process, substantial costs would be incurred by a pharmaceutical manufacturer undertaking this drug development. It is likely that this methadone formulation would be significantly more expensive than currently available methadone in the United States. Further, the use of (R)-methadone would probably increase the cost of methadone treatment in developing nations, for whom this intervention is critically important and for whom higher costs may result in either a reluctance to provide the treatment or to expand the capacity of existing treatment facilities.

It makes good clinical sense to evaluate each patient and to determine an individualized treatment plan based both on clinical need and patient choice. The question then becomes who would benefit from racemic methadone versus who needs the (R)-methadone formulation. Any patient identified with pre-existing structural heart disease or those receiving medications for co-occurring disorders which may inhibit methadone metabolism would benefit from (R)-methadone. Those without co-occurring medical or mental illness, in otherwise good health, with no evidence for prolongation of cardiac QT interval, and receiving moderate doses of methadone (less than 100 mg daily) would, in most cases, be able to be maintained on the currently available and less expensive racemic methadone formulation.

It is also important to consider alternative medication treatments for those with opioid addiction. Buprenorphine has less effect on QT interval at standard clinical doses [8], but a recently approved transdermal formulation has a ‘black box’ warning related to QT interval lengthening with high doses [9]. Naltrexone, an opioid antagonist medication which blocks the effects of an ingested opioid, has been used far less widely in the treatment of opioid dependence. While useful in motivated populations such as health-care professionals [10], it has had more limited success in less motivated groups [11]. However, it is now available as an oral formulation or as a once-monthly injectable that might have better acceptability with patients and, therefore, be associated with greater adherence in those with opioid dependence.

As health-care reform progresses in the United States, the integration of substance abuse, medical and mental health services will be required. Current narcotic treatment program services will, of necessity, need to evolve to provide safer, more effective and integrated care. Methadone is a drug that confers significant medical risk, and the ability to assess that risk and provide the best treatment for individual patients is essential. This tenet will not be altered whether or not (R)-methadone is adopted in the United States. However, the development of new medications and the increasing options for those who suffer with opioid dependence or who require chronic methadone treatment to manage pain, as well as an increasing understanding of how to manage the use of these medications medically, can only benefit those requiring these treatments. The clinical pharmacology of (R)-methadone appears to present important medical advantages for some patients. Studies should be undertaken in the United States to demonstrate its clinical efficacy and safety relative to the racemic formulation of methadone so that this medication can proceed to FDA approval for clinical use. The availability of multiple forms of methadone will permit clinicians to match treatments to individual patient need resulting in improved clinical outcomes.

Declaration of interests