4 March 2009

"Heterogeneous Impact of Methadone on the QTc Interval" what does this mean?

Krantz MJ. Heterogeneous Impact of Methadone on the QTc Interval: What Are the Practical Implications? Journal of Addictive Diseases 2008 27;4:5-9

This article is a confusing amalgam of a rehashed set of figures of little relevance to modern treatment practices. Krantz uses the forum to express strong opinions but he fails to back these up with science. In fact he sometimes quotes other opinion pieces as if they were science. He cites himself 8 times and out of 31 references, he chooses to ignore some of the most solid scientific papers, all of which are reassuring to the standard use of methadone in addiction treatment. For example Justo’s literature review in Addiction, Sticherling’s report of 5 torsades cases from Switzerland.

The most useful fact to my mind is that there were no cases of torsades, like every other prospective study of methadone patients ever performed, to my best knowledge.

Krantz misquotes himself as saying “methadone’s effect on QTc is clearly [sic] dose related” (ref 24) yet the reference (to himself) is only an opinion piece which provides no evidence itself but just quotes a retrospective study of Mehler et al. and two other studies which showed ‘modest concentration-dependent effect’ of dose upon QT and one is a study of LAAM and NOT methadone at all! So Dr Krantz does not even manage to argue cogently for his one contention which is probably correct, a methadone dose effect for QT interval.

In the opening paragraph there is a glaring typo: ‘… QTc prolongation defined as *greater than* 470 msec in men and *less than* 490 msec in women’. (my asterisks) In the concluding paragraph of the piece we are told ‘.. the number of patients who developed critical QTc prolongation defined as *less than* 500 msec …’. This should read *greater than* 500 msec I presume and is yet another sign of the imprecision and therefore the inconsequence of this paper.

Why did reviewers not pick up these flaws? Krantz quotes Wedam on two occasions in the paper but calls him Wedman in error. His use of the word ‘heterogeneous’ does not seem to derive from anything in his paper and it is not clear if he is using the term in its strict electrophysiological sense (see Braunwald's text, 7th edition p705) or the common English usage. Likewise, ‘heterogeneous’ does not seem to apply to these findings or opinions, diverse though they be. It is another sign of a lack of clarity in Krantz’s writing. ‘Dispersion’ is another possible example from another paper (Pharmacotherapy 2005). Further, he used the word ‘paradox’ in Lancet in similar ‘disconnected’ and confusing fashion. All medical prescribing involves balancing therapeutic effects with potential side effects. This is not a ‘paradox’ for most doctors but ‘business as usual’.

There is also a faulty reference to Milon et al, presumably from the French literature but without a year of publication. An author’s name is misspelt (Gouffault with a single F) and the year 1982 is omitted.

His 'piece de resistance' is a careful explanation of why nobody has ever seen a case of torsades in a methadone clinic setting. Just read it!! Because it is so rare (one in a thousand he quotes without any specific reference for methadone) and has a mortality of 20% the 'aggregate' [sic] number of methadone related cardiac deaths in the US is 'relatively small' (does he mean vanishingly small or unmeasurable?). He mentions, accepts, but then dismisses Newman’s contention that many such reports are from outside the ‘addiction realm’. Of course the fact remains that there is a dearth of reports of patients entering ‘normal’ addiction treatment and developing torsades as a result. If there are such reports I have not been able to access them.

In the most quoted and seminal paper on the subject from 2002, Krantz and colleagues do not even inform the reader which of the 17 case reports are addiction clinic patients and which are pain cases. And it is important. He has not responded to my requests for clarification.

Krantz has shown himself to be less than objective in talking up this problem in addiction clinics (see his survey of clinic staff) while not showing as much interest in chronic pain cases. For another example, see Lancet in which he misquoted Lipsky et al. His published response not only fails to address the serious error but tries to justify his stance by emphasising increasing methadone related deaths, nearly all of which came from pain management cases in the reference he cites.

Comments by Andrew Byrne ..


Krantz MJ, Mehler PS. QTc prolongation: methadone’s efficacy-safety paradox. Lancet 2006; 368: 556–57

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

Krantz MJ, Lowery CM, Martell BA, Gourevitch MN, Arnsten JH. Effects of methadone on QT-interval dispersion. Pharmacotherapy. 2005 25;11:1523-9

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

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