Download (R)methadone versus racemic methadone: what is best for patient

EDITORIAL
doi:10.1111/j.1360-0443.2011.03374.x
(R)-methadone versus racemic methadone: what is
best for patient care?
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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 nonmalignant [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 Etherà-go-go Related 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
© 2011 The Author, Addiction © 2011 Society for the Study of Addiction
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
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Editorial
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.
© 2011 The Author, Addiction © 2011 Society for the Study of Addiction
Declaration of interests
None.
ELINORE F. MCCANCE-KATZ
University of California San Francisco and
California Department of Alcohol and Drug Programs,
San Francisco General Hospital, 1001 Potrero Avenue, Suite
7M-WD93, San Francisco, CA 94110, USA.
E-mail: [email protected]
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