4 May 2010

Advice to stop methadone could be dangerous.

Methadone-associated Q-T interval prolongation and torsades de pointes. Stringer J, Welsh C, Tommasello A. American Jour Health System Pharmacy 2009 1;66(9):825-833 [*see new conflict statement]

Dear Readers,

This review examines the literature on cardiac events in methadone patients.  ‘Torsade de pointes’ arrhythmia and its accompanying prolonged, rate-corrected ’QTc’ interval are discussed in detail. The abstract states “A thorough patient history and ECG monitoring are essential for patients treated with [methadone], and alterations in treatment options may be necessary.”  Despite the extensive literature review, they give no specific justification for the controversial advice about ECG and ‘altered treatment options’.  Their own references would seem to indicate the futility of ‘screening’ ECG.

The authors quote 33 published torsade events in dependency subjects from 2002-2008.  My review of these indicates that 24 of the 33 give QTc interval information away from the torsade episode (and therefore away from the precipitating factor/factors which are usually involved).  Of the known 24 QTc intervals, 19 are ‘normal’ (460ms or less when enumerated) while only 3 are over 500ms, the interval where risk is thought to be significant. Hence, according to the case reports quoted by Stringer et al. screening ECG could not possibly detect or prevent cases of torsade de pointes in the great majority of such cases.  This is consistent with Justo’s literature review which also found precipitating events in 85-100% of published torsade cases he examined.  Krook questions the use of screening ECG as being the ‘wrong priority’. 

Stringer and colleagues also discuss in some detail two studies (Fanoe and Chugh), each of which concluded that large numbers of methadone patients may develop torsade.  Surprisingly, Fanoe also reported syncope, much of which he ascribed to torsade, in about 10% of his buprenorphine subjects. Both studies used indirect and ‘circumstantial’ methodologies to implicate methadone. Neither presented any actual cases of torsade de pointes. Nor did Wedam’s important RCT, another plank of this paper’s discussion, report any cases of torsade, despite high rates of QT prolongation (he is quoted here incorrectly as ‘Wedman’ on three occasions).

The conclusions of Chugh and Fanoe must now be in serious doubt after publication of Anckersen’s large national mortality series from Norway. This showed that despite prolonged QT intervals being common, their analysis of 90 deaths over seven years found that none was reportedly due to arrhythmia.  Unexplained deaths were rare with positive coronial findings available for all but four cases (in 2 of the 4 autopsy was not performed). Even if all four of these were due to torsade de pointes, an unlikely event, the incidence would still be extremely low.  Contrary to the claims of Krantz and colleagues (2009), the finding in Norway of so few unexplained deaths in methadone patients (<5%) is also consistent with other reports (Ballesteros 2003; Sorg 2002; Gagajewski 2003; Shah 2005).

From my reading on the subject over the years, I could find no confirmed deaths due to torsade de pointes in a patient being treated with methadone for addiction or pain. When this serious tachycardia does occur, it appears to be in older individuals with more than one risk factor, and, at least in methadone patients, appears to be non-fatal and treatable in most or all reported cases. 

Anckersen’s findings from Norway are also consistent with 40 years of research on methadone treatment showing that it reduces mortality substantially when used according to established guidelines (using adequate doses, supervision and psychosocial supports). 

Stringer, Welsh and Tommasello seem to ignore the potentially fatal consequences of their recommendations about “alterations in treatment options” based on ECG findings alone. Without any detailed explanation they blandly advise that buprenorphine ‘should be used’ in addiction subjects who develop prolonged QTc on methadone, despite the often impractical nature of such advice. Most such patients will be taking dose levels of methadone at which buprenorphine transfer is not recommended by the manufacturer. And this rather controversial advice is supported by just one single case report!

Good therapeutics dictates that successful treatment should only be change based on sound clinical evidence … and this is not produced in this paper. It is clear that for a substantial proportion of the opioid-using population there is simply no treatment that comes close to methadone maintenance regarding attracting, retaining and benefiting opioid dependent patients. And buprenorphine remains an excellent alternative for appropriate subjects.

*Please note also the up-dated conflict statement published in January 2010 edition: 

Am J Health Syst Pharm 2010 67:94
Methadone-associated Q-T interval prolongation and torsades de pointes (May 1, 2009, Clinical Consultation). On page 825, the author identification section should contain the following statement: Dr. Tommasello is Field Medical Advisor, Reckitt Benckiser Pharmaceutical Company, Parsippany, NJ, which manufactures buprenorphine–naloxone (Suboxone).

I hope this summary is of interest to readers.  [NOTE RESPONSE LETTER June 2010] http://byrnehallinanpubs.blogspot.com/2010/06/blog-post.html

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Krook AL, Waal H, Hansteen V. Routine ECG in methadone-assisted rehabilitation is wrong prioritization. Tidsskr Nor Laegeforen 2004 124;22:2940-1

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

Krantz MJ, Martin J, Stimmel B, Mehta D, Haigney MCP. QTc Interval Screening in Methadone Treatment. Ann Intern Med 2009 150;6:387-395

Krantz MJ, Garcia JA, Mehler PS. Effects of buprenorphine on cardiac repolarization in a patient with methadone-related torsade de pointes. Pharmacotherapy 2005 25:611-614

Anchersen K, Clausen T, Gossop M, Hansteen V, Waal H. Prevalence and clinical relevance of QTc interval prolongation during methadone and buprenorphine treatment: a mortality assessment study. Addiction 2009 104;6:993-999

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