12 November 2008

Methadone safe in young uncomplicated patients; check QT in older folk and those taking other drugs or alcohol, or with HIV.

Electrocardiogram characteristics of methadone and buprenorphine maintained subjects. Athanasos P, Farquharson AL, Compton P, Psaltis P, Hay J. Journal of Addictive Diseases 2008 27;3:31-35

Dear Colleagues,

These authors from Adelaide, South Australia report a relevant and reassuring ECG study from a 'normal' addiction clinic setting.

We are presented with a comparison of 35 methadone maintained patients, 19 on buprenorphine and 17 controls. Methadone doses varied from 15-145mg daily, being in the common range used clinically around the world. Most subjects were in their 30s and 28 of 71 subjects (39%) were female.

They report no significant difference between the mean corrected QT interval (QTc) of the three groups (407, 407 and 397 milliseconds). There was also no correlation found between methadone dose and QT interval. The QTc in those taking more than 60mg daily were slightly longer (405ms or 6.3%) than for those taking less than 60mg (381ms) (p=0.02). There were also some 'U' waves reported in the methadone patients. Two methadone patients and one control had prolonged QTc when defined as 430ms or longer for males (450 for females). No result was over 475ms. The threshold above which risk of torsade rises significantly is believed to be 500ms.

These findings are all consistent with the report of Lipsky et al. 35 years ago linking methadone prescription with QT prolongation and U waves. The clinical significance of these findings is still uncertain. These authors report no cases of torsade arrhythmia.

They conclude: 'Although an association is thought to exist between high methadone doses and elongated QTc, methadone and buprenorphine, at commonly used daily doses, remain safe agents for opioid substitution therapy.'

As a further exercise I contacted two prominent addiction experts in Adelaide (pop 1.2 million) on this subject. One had seen no cases and the other was aware of one possible case some years before. This is on a long background of good quality methadone treatment, both private and public, in that city.

It may be timely to examine the evidence for claims that methadone prescription in addiction treatment is accompanied by a significant risk from arrhythmias, including death. Despite there being no body of case reports in such guideline-treated subjects (or perhaps because of it) a number of authors have attempted to assess methadone's role in cardiotoxicity by using indirect and unconventional methods.

For example, Fanoe (ref below) prefers QT/torsade as an explanation for up to 30% of his subjects reporting syncope on MMT in Copenhagen. Since the incidence of torsade is certainly less than 1% annually, this explanation is not credible, especially coming from a country with extremely high alcohol statistics.

Chugh (ref below) used a methodology looking at post mortem structural heart disease in those dying suddenly with or without therapeutic levels of methadone in the blood. Their deduction for QT changes without a single case report seems hard to understand.

Wedam (ref below) wrote 'To compare the effects of [methadone] on the corrected QT (QTc), we conducted a randomized, controlled trial of opioid addicted subjects.' In fact they performed a retrospective re-analysis of old analogue ECG tracings from a 1990s RCT, finding more than 10% had QTc over 500ms. This is not consistent with other reports on the subject. No torsade cases were reported in the study groups.

A review of the world literature by Justo (ref below) found only 40 documented cases, 85% of whom had two or more risk factors. Few of these reported cases bear much similarity to those commencing 'normal' clinic or community addiction treatment. The QT/torsade cases tend to be significantly older, female sex, and to involve co-medications, very high methadone doses (up to 1200mg daily or ten-fold 'normal' doses) as well as certain metabolic (potassium or magnesium deficiencies) and genetic states (familial long QT syndrome).

I believe that it is now possible to restate unequivocally that 'normal', guideline-based methadone treatment is safe and effective. The cardiac arrhythmia issue appears to be based on a combination of factors rather than a consequence of standard methadone treatment. Knowing the other risk factors, most cases could probably be avoided using good clinical practice (see Sticherling). Routine pre-treatment cardiographs would have been unlikely to have detect any of these latter cases.

Even in the face of a dearth of relevant case reports, some have given advice to avoid methadone without due consideration of its benefits and the absence of a suitable alternative in a large proportion of cases, especially high-dose subjects (see Kakko). While methadone-induced torsade clearly can occur, the numbers appear to be exceedingly low and would probably be swamped statistically by reductions in endocarditis cases alone in those taking methadone (these and other benefits are eloquently reported by Krantz in 2001 - ref below).

In practical terms, this means that existing methadone patients needing other strong medications, methadone doses over 200mg or who develop HIV and/or have other risk factors should be recommended a cardiograph, just as they should have electrolytes, liver function tests, etc performed as a matter of clinical course.

We need to ensure that as clinicians we continue to ask the question: what is the evidence?

Comments by Andrew Byrne ..



Fanoe S, Hvidt C, Ege P, Jensen GB. Syncope and QT prolongation among patients treated with methadone for heroin dependence in the city of Copenhagen. Heart 2007;93;1051-1055

Chugh SS, Socoteanu C, Reinier K, Waltz J, Jui J, Gunson K. A Community-Based Evaluation of Sudden Death Associated with Therapeutic Levels of Methadone. American Journal of Medicine 2008 121: 66-71

Wedam EF, Bigelow GE, Johnson RE, Nuzzo PA, Haigney MCP. QT-Interval Effects of Methadone, Levomethadyl, and Buprenorphine in a Randomized Trial. Arch Intern Med 2007 167;22:2469-2473

Justo D, Gal-Oz A, Paran Y, Goldin Y, Zeltser D. Methadone-associated Torsades de Pointes (polymorphic ventricular tachycardia) in opioid-dependent patients. Addiction. 2006;101:1333-1338

Sticherling C, Schaer BA, Ammann P, Maeder M, Osswald S. Methadone-induced Torsade de Pointes tachycardias. Swiss Med Wkly 2005;135:282-285

Kakko J, Gronbladh L, Svanborg KD, von Wachenfeldt J, R�ck C, Rawlings B, Nilsson L-H, 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;5:797-803

Krantz MJ. Clinical Concepts- Cardiovascular Health in MMT Patients. Addiction Treatment Forum 2001 No 4 http://www.atforum.com/SiteRoot/pages/current_pastissues/fall2001.shtml