Monday, November 26, 2007


Comments from Dr. Byrne, an Australian colleague based on journal article below:
Krantz MJ, Rowan SB, Schmittner J, Bucher Bartelson B. Physician Awareness of the Cardiac Effects of Methadone: Results of a National Survey. Journal of Addictive Diseases 2007 26;4:79-85

Dear Colleagues,

Krantz and colleagues’ latest foray into the purported cardiac consequences of methadone treatment has mixed messages. Their survey of methadone clinics finds a majority of clinicians have not heard of what might be termed “Krantz syndrome”. The paper states that “only 41% (95% CI, 37- 45) were aware of methadone’s QT-prolonging properties.” Yet further: “emerging evidence suggests [methadone] may … prolong the QT interval.” But then again more forcefully: “methadone is now categorized as a medication definitively linked with torsade de pointes …”. Are they having a bet both ways on causality? The evidence on this is conflicting as Martell apparently found a significant association between dose and QT interval where Peles, Kreek et al found no such correlation, including blood levels, in a large study from Israel . Krantz and colleagues fail to cite the Peles study although it was available on the net in early December 2006.

Most reports of QT prolongation in methadone patients, eg. Pearson; Walker; Krantz; Ehret, involve (1) ‘mega-doses’ (>300mg daily), (2) other cardio-toxic drugs, (3) abnormal metabolic states (such as hypokaloaemia) and/or (4) heart disease. Only a small minority of reported cases could be termed ‘regular’ methadone clinic patients from my reading. And yet it is these very patients who Krantz gives advice to avoid methadone if possible and when it is used to avoid ‘high’ doses.

To most dependency researchers, ‘high dose’ means more than 100mg daily. For discussion of QT problems ‘high dose’ would appear to mean more than 300mg daily, with the highest reports nearly 2000mg daily! The mean daily dose in Krantz’ original study was 397mg; Pearson 410mg; Walker >600mg. These are not the sort of doses dependency doctors are usually familiar with.

Since so many of the cases quoted by Krantz refer to pain management, it is surprising that this survey only involved addiction clinics.

This whole exercise seems to ignore the consequences of NOT giving methadone - which about 1 million people world receive today, and for most there is no alternative, at least none that would be affordable. Even if methadone were a cause of cardiac complications, Krantz gives us no clear strategy to prevent them, short of forgoing treatment with methadone altogether or giving lower (and therefore sometimes inadequate) doses. Hence, apart from raising anxiety levels, it is hard to see how Krantz’s long campaign on this subject has contributed to the field. It is likely that his perspective would be broadened if he had collaborated more closely with dependency specialists. The advice he is giving to the field is contrary to almost all established guidelines which stress adequate doses of methadone to reduce harmful injecting behaviour.

In Lancet Krantz quotes a study of methadone related deaths to justify focusing on this issue. Yet this study finds that only 4% of the deaths occurred in patients in addiction treatment programs (Ballesteros 2003), and there was absolutely nothing to suggest that cardiac effects played any role whatsoever.

It is still likely in my view that the reduced level of cocaine and heroin use with higher methadone doses shown by Dr Lisa Borg some years ago should actually protect against cardiac arrhythmias - to say nothing of the many other life-threatening concomitants of illicit heroin use. Others have written about the cardio-protective effect of methadone in ischaemic heart disease (Marmor).

Adding to the confusion, while stating that doctors should take account of this syndrome when prescribing methadone, Krantz still does not recommend routine ECG before starting methadone treatment. Ellen Pearson agrees with this assessment in her paper with Woosley, stating further that limiting the dose of methadone is unlikely to completely avoid cardiac complications. As far as I am aware nobody has yet reported a series of cases of cardiac arrhythmia in ‘normal’ methadone patients, so how can this be a public health issue?

Although Pearson’s 59 FDA reports did not specify whether methadone was prescribed as part of an addiction program or otherwise, one may deduce that no more than 14 of the cases would likely have been ‘normal’ clinic patients and only one death occurred in this group in a patient reportedly taking 29mg daily (I have never been in a clinic which could measure 29mg, raising the possibility that this is a mistake/typo etc). Even as Krantz states that the FDA reports are an underestimate of the prevalence of this complication, there are still only the most sparse number of cases considering well over a million Americans have been on the treatment over the years (~240,000 currently). I also note that of 5 deaths in Pearson’s excellent report, only one of them had torsades, the fatal arrhythmia associated with QT changes, raising the possibility that there was only one cardiac death out of 59 cases.

In my view it is likely that the 59% of clinic doctors who had not heard of QT changes were possibly giving better quality treatment to their patients than the ‘enlightened’ minority who only reported a handful of cases to the FDA over a 30 year period.

Comments by Andrew Byrne ..

I note that of 7 web citations in this paper, 6 did not link to the correct (or indeed any) site. This may be a common problem with changes to web addresses yet it must also be a weakness of a scientific paper when peer-reviewed published citations are always to be preferred where possible in my view.

Krantz MJ, Rowan SB, Schmittner J, Bucher Bartelson B. Physician Awareness of the Cardiac Effects of Methadone: Results of a National Survey. Journal of Addictive Diseases 2007 26;4:79-85

Pearson EC, Woosley RL. QT prolongation and torsades de pointes among methadone users: reports to the FDA spontaneous reporting system. Pharmcoepidemiol Drug Saf. 2005 14;11:747-753

Martell BA, Arnsten JH, Krantz MJ, Gourevitch MN. Impact of methadone treatment on cardiac repolarization and conduction in opioid users. Am J Cardiol. 2005;95:915-8

Peles E, Bodner G, Kreek MJ, Rados V, Adelson M. Corrected-QT intervals as related to methadone dose and serum level in methadone maintenance treatment (MMT) patients - a cross-sectional study. Addiction 2007 102;2:289-300

Ballesteros MF, Budnitz DS, Sanford CP, Gilchrist J, Agyekum GA, Butts J. Increase in Deaths Due to Methadone in North Carolina. JAMA 2003 290:40

Krantz MJ, Mehler PS. QTc prolongation: methadone's efficacy-safety paradox. Lancet 2006 368:556-557

Byrne A, Stimmel B. Methadone and QTc prolongation. Lancet 2007 369:366

Krantz MJ, Lewkowiez L, Hays H, Woodroffe MA, D. Robertson AD, Mehler PS. Torsade de Pointes Associated with Very-High-Dose Methadone. Ann Intern Med. (2002) 137:501-504

Walker PW, Klein D, Kasze L. High dose methadone and ventricular arrhythimias: a report of three cases. Pain 2003 103:321-4

Ehret GB, Voide C, Gex-Fabry M, Chabert J et al. Drug-Induced Long QT Syndrome in Injection Drug Users Receiving Methadone High Frequency in Hospitalized Patients and Risk Factors. Arch Intern Med 2006 166:1280-1287

Marmor M, Penn A, Widmer K, Levin R, Maslansky R. Coronary artery disease and opioid use. Am J Cardiol. 2004;93:1295-1297


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