Review: Electrocardiogram Characteristics of Methadone and Buprenorphine Maintained Subjects

Byrne Review: Electrocardiogram characteristics of methadone and buprenorphine maintained subjects
Comments by A. Byrne
September 22, 2008

Athanasos P, Farquharson AL, Compton P, Psaltis P, Hay J. Journal of Addictive Diseases 2008 27;3:31-35

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 (39%) were female.

No significant difference in QT interval was found between the three groups. There were 2 methadone patients and one control with long QT when defined as 430ms or longer for males (450 for females). None was over 475ms (the threshold at which risk of torsades occurs is believed to be 500ms). There was a trend for longer QT intervals in those on >60mg daily as well as some increased U waves reported in methadone patients. These findings are consistent with Lipsky’s findings from 1973, but the clinical significance, if any, is unclear. Like other prospective studies on this subject, these authors do not report any cases of torsades.

The authors 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 an exercise I contacted two prominent addiction experts in Adelaide on this subject. One had seen no cases and the other was aware of one possible case some years ago. 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 treatment in addiction is accompanied by a significant risk from arrhythmias, including death. Despite there being no body of case reports (or perhaps because of it) a number of authors attempted to assess methadone’s role in cardiotoxicity by using indirect and unconventional methods.

For example, Fanoe (ref below) prefers QT/torsades as an explanation for up to 30% of his subjects reporting syncope on MMT in Copenhagen. Since the incidence of torsades is 0-1% 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. His 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.” [our italics] 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 torsades 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 risk factors, most cases could probably be avoided using good clinical practice (see Sticherling). A pre-treatment cardiograph would not have detected any of these cases.

As well as a dearth of relevant case reports, some have given advice without due consideration of the benefits of methadone treatment in the absence of a suitable alternative in a large proportion of cases, especially high-dose subjects (see Kakko). While methadone induced torsades may indeed occur, it must be in extremely low numbers and would probably be swamped statistically by reductions in endocarditis cases alone (as reported by Krantz in 2001 - ref below).

In practical terms, this means that existing methadone patients needing other medications, methadone doses over 200mg or who develop HIV and/or have other risk factors should have 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.
Redfern Clinic.com News

References:

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, Grönbladh L, Svanborg KD, von Wachenfeldt J, Rück 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. Available from: Addiction Treatment Forum 2001 No 4