28 August 2012

Rare non-fatal cardiac risk should not discourage the use of adequate supervised methadone doses which save lives.

Increased incidence of QT interval prolongation in a population receiving lower doses of methadone maintenance therapy. Roy A, McCarthy C, Kiernan G, McGorrian C, Keenan E, Mahon N, Sweeney B. Addiction 2012 107;6:1132-9

Dear Readers,

These Irish researchers examine QT intervals in relation to methadone dose, cocaine, opiates and benzodiazepine use in 180 stable maintenance patients (total clinic population 376). They find that 9-11% have ‘drug induced’ QT prolongation despite finding no relation to daily methadone dose (which was a healthy mean of 80mg, SD 27mg) and no control group. Nor was there any relation between QT interval and the presence of cocaine in toxicology tests.

The article’s title makes an implication about the relevance of high versus low dose methadone in relation to QT prolongation. Yet the very first report of nine dependency cases had six taking less than 130mg daily and four taking less than 100mg (ref 1 - but see below why this cannot be gleaned from the paper directly).

QT prolongation has been reported in a high proportion of potential methadone recipients, but who were not actually taking methadone at the time. In hospice patients being considered for methadone treatment Reddy found QT prolongation in 28%. Lipski and her colleagues in 1973 reported 19% of street heroin users had QT prolongation before starting methadone treatment.

It is clear that a population of patients taking a variety of medications and with certain underlying illnesses such as HIV and hepatitis C are at risk of having QT prolongation, quite apart from any methadone treatment. Alcohol is also believed to be a risk factor [ref 4]. With a lack of any reported cases of this arrhythmia in 37 years, one might reasonably infer that this issue was not a major clinical problem in methadone prescribed patients.

Yet in the past decade there have been just over 100 reported cases of torsade in methadone patients. So, as our patients have survived their addiction, viral infections (and especially treatment for those infections), a small proportion have reached an age at which they have become susceptible to a rare clinical entity which most large centres have now seen at least once. Torsade de pointes was so rare amongst methadone recipients in 2002 that it was thought to be a new entity [see ref 13 for an earlier report]. Yet torsade de pointes was delineated and re-branded in the 1960s by a French group (no relation to methadone which was not used in that country at the time) [ref 11]. In 1985 another French group also provided a systematic approach to torsade treatment such that for eight years they had a mortality of zero [ref 12].

One may ask why we do not see more torsade de pointes since QT prolongation has a high prevalence in out treatment population. In a RCT Wedam [ref 8] found ~10% of new methadone recipients in Baltimore had QTc > 500mg (but no torsade cases), yet contrary-wise nearly all of the reports of torsade are in longer-term patients [ref 5 and pers comm].

So QT prolongation, even at the level of greater than 500ms in this population of methadone recipients does not appear to confer a measurable risk of torsade de pointes tachycardia (and numerous torsade cases had normal ECG away from the arrhythmia episode).

While torsade is symptomatically a distressing and unpleasant condition, it is rarely if ever fatal and is “controllable 100% of the time” with modern treatment, according to US cardiologist Phibbs [ref 6].

Suggestions from some quarters that there may be large numbers of unrecognised deaths due to torsade are not credible for two reasons: (1) deaths of patients on methadone programs are reportedly very rare and (2) such deaths are usually rigorously investigated by coroners and positive findings are the rule with only very occasional ‘unknown causes’ which might include a fatal arrhythmia [Anchesen; Perrin-Terrin, refs 9 and 10].

It is regrettable that in his seminal article on the subject Krantz did not delineate pain from addiction subjects [1]. This appears to have caused a decade of confusion about the supposed effect of extremely high doses of methadone (see Annals Editorial comments relating to “very-high-dose methadone”). When the cases were separated for the reader in a follow-up paper [7], it became clear that torsade may occur in those taking average doses as well as with the supra-therapeutic doses cited by Krantz’s group (up to 1000mg daily in the pain cases). Yet only two of nine addiction cases were taking such doses when developing torsade de pointes. Six of the nine were prescribed between 65mg and 125mg (mean 96mg), which are dose levels found commonly in methadone maintenance treatment reports. There were no deaths among these nine MMT patients. Indeed there are no documented torsade deaths in MMT as far as I can find in the entire literature (one suspected death in France has been reported).

Krantz’s finding of nine cases of torsade in a small catchment over a relatively short period remains to be explained as it has never been duplicated anywhere else in the world to my best knowledge. Most reports have been of one or two cases. One wonders if there were other factors at play such as a viral induced cluster, the high altitude in Denver or some other factor unique to Krantz’s area.

It is often instructive to go back to the original sources and while most cite Lipski et al., few seem to have actually read the paper which is elegantly written. Even some major authors on the subject apparently believed that Lipski and colleagues were examining the effect of methadone on the QT interval. They were in fact examining why so many heroin users in New York died of apparent overdose but with relatively low levels of morphine at post-mortem examination, proposing arrhythmia in some such cases (from heroin or other street drugs). As they had no way of testing QT effects from heroin, ECG changes were examined in new entrants to treatment at their methadone program (which closed down recently, to the shame of the otherwise venerable Mt Sinai Medical Center in northern Manhattan).

In short, these early researchers performed 12-lead cardiographs on 75 patients new to methadone treatment. About half had not yet started treatment and had used heroin in the previous 24 hours. The rest were already taking methadone and a range of other drugs as shown by urine testing. The first group had prolonged QT intervals in 19% of subjects while the new patients who had started treatment had a rate of 34%. The latter were reportedly using combinations of heroin, cocaine, methadone and other drugs. So their theory was not confirmed yet their findings indicated a possibility that methadone extended the QT interval despite this being asymptomatic in all cases. Further, there were no reports of arrhythmias in MMT patients for the next 29 years.

This leaves us asking why one would spend time and money highlighting, emphasising and investigating the torsade issue while ignoring the vastly more important issue of standards of treatment. Drop-outs, deaths, overdose, viral infection, unemployment, etc, are all well documented consequences of deficient doses, inadequate supervision and a lack of psychosocial supports which are still sadly common. Each of these factors was clearly delineated in Dole’s first report in 1965 - and which modern prescribers ignore to their patients’ eternal cost.

Notes by Andrew Byrne .. Clinic web page: http://methadone-research.blogspot.com/


1. 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

2. Reddy S, Fisch M, Bruera E. Oral methadone for cancer pain: no indication of Q-T interval prolongation or torsades de pointes. Journal of Pain and Symptom Management 2004 28;4:301-303

3. Lipski J, Stimmel B, Donoso E. The effect of heroin and multiple drug abuse on the electrocardiogram. American Heart J 1973 86:663-8

4. Hyslop B. Prolongation of the QT interval on methadone: how important is methadone dose? New Zealand Medical Student Journal 2007 6 Aug

5. 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

6. Phibbs B. Advanced ECG: boards and beyond. 2006 Elsevier

7. Krantz MJ, Kutinsky IB, Robertson AD, Mehler PS. Dose-related effects of methadone on QT prolongation in a series of patients with torsade de pointes. Pharmacotherapy. 2003;23:802-805

8. 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

9. 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

10. Perrin-Terrin A, Pathak A, Lapeyre-Mestre M. QT interval prolongation: prevalence, risk factors and pharmacovigilance data among methadone-treated patients in France. Fundam Clin Pharmacol. 2010 Sep 6

11. Dessertenne PF. La tachycardie ventriculaire a deux foyers opposes variables. Arch Mal Coeur 1966 59:263-72

12. Salle P, Rey JL, Bernasconi P, et al. Torsades de pointe. Apropos of 60 cases. Ann Cardiol Angeiol (Paris). Jun 1985;34(6):381-8

13. Bittar P, Piguet V, Kondo-Oestreicher J et al. Methadone induced long QTc and "torsade de pointe". Swiss Medical Forum 2002 S4;P244:36S

Roy A, McCarthy C, Kiernan G, McGorrian C, Keenan E, Mahon N, Sweeney B. Increased incidence of QT interval prolongation in a population receiving lower doses of methadone maintenance therapy. Addiction. 2012 107;6:1132-9