Monday, September 15, 2008


From our colleague, Andrew Byrne, MD in Australia, the following observations regarding QT-wave prolongation:

QTC Interval Prolongation and Opioid Addiction Therapy. Baker WA, Krantz MJ. Archives Internal Medicine (letter) 2008 168;14:1502

Dear Colleagues,

In this letter Baker and Krantz applaud Wedam et al’s ‘commendable’ “addition to the medical literature” which found QT prolongation in 23% of methadone subjects. In fact these researchers found much the same as Janet Lipski’s report from 1973 (34%). Thus it is clear that a substantial minority of methadone patients have modest prolongation of QT intervals of uncertain significance.

Baker and Krantz then express the unsurprising deduction that if a lower cut-off for QT prolongation were used, a correspondingly higher proportion of prolongation subjects will result (up to 50%). The clinical significance of these observations, if any, is not detailed. Indeed, not a single subject in the entire study had a QT interval (corrected) of 500ms or more which is considered by some authorities to be the clinically significant cut-off for risk of tachycardia. And none developed tachycardia.

Krantz has wrongly cited Lipski’s study as being (at least in part) to investigate sudden deaths in methadone patients. In fact, Lipski and colleagues were concerned about heroin deaths and the QT findings in methadone patients were incidental. When this mistake was pointed out in Lancet, Krantz in reply ignored the matter and turned to increasing deaths of non-addiction treatment (pain) cases in America more recently (Mehler 2007).

Specifically, Krantz writes that Lipski’s study was aimed at investigating “a perceived increase in the risk of sudden death in heroin addicts, even in those successfully treated with methadone” in 1973 in New York (Krantz MJ 2006). From the title and opening lines it is clear that Lipski and colleagues were actually concerned over deaths in heroin users where sometimes blood levels were not particularly high, an issue raised by long time city coroner Dr Milton Helpern (see ref). They performed cardiographs in new methadone applicants who had used street heroin in the previous hours or day(s) to see if there were any electrical disturbances which might explain the sudden deaths in heroin users.

Unlike in his first paper on this subject, Krantz now treats QT prolongation in isolation as if it were a complication in itself, avoiding discussion of torsades or other cardiac events. And like most of the other studies, Wedam and colleagues report no symptomatic heart disease whatever and, most importantly, no sudden deaths. Over a period of 30 years of intensive, supervised prescription of methadone only one single case of arrhythmia was reported to the FDA (Pearson). So while torsades or ventricular fibrillation occur in methadone patients, the prevalence must be very low and possibly near to the rate in the general population (estimated to be 1 in 2000 - see Smith W).

This laudatory letter is just another ‘weak link’ in the case put by Krantz that due to potential cardiac complications, methadone treatment needs to be reviewed, especially when used in high doses. He recently noted ‘with consternation’ (hardly a scientific term) that higher doses were being used in addiction clinics in his own state, something most public health specialists would have applauded (D’Aunno). Many rigorous studies indicate that higher doses protect dependency patients from significant and measurable events (overdose, viral disease, criminal behaviour, depression, etc). Dole’s seminal study of methadone treatment reported up to 180mg daily with excellent results and no serious side effects.

To my knowledge there have still been no reported series of confirmed case reports of cardiac complications (eg. torsades-de-pointes) in patients receiving methadone treatment for addiction under existing guidelines. Krantz emphasises the proven benefits of MMT yet at the same time questions this established, evidence-based practice, emphasising a difficult therapeutic “trade-off”. Yet this is before there is documented evidence of a problem existing and despite 30 years of careful research showing safety and effectiveness. Further, there has been no analysis of the costs and benefits of any suggested alternative strategies such as low dose methadone or transfer to buprenorphine. Krantz has also apparently had minimal input from dependency specialists. Few non-cardiologists would be so bold regarding advice on heart treatments.

Dr Krantz's widely publicized views have had the consequence of denigrating methadone as a treatment for both addiction and chronic pain. I can find no evidence suggesting that any cases of cardiac complications resulting from methadone treatment have been avoided as a result. The literature reveals only flimsy and conflicting evidence - most of it retrospective - of an association of methadone and cardiac events. Some have reported a lower cardiac risk (Marmor 2004).

Krantz's articles, letters and personal communications show a clear 'disconnect' between his earlier findings and the sentiments he has expressed more recently. While his earlier findings relate mostly to pain patients, he has strongly targeted an addiction treatment audience for his communications and further research (eg. Krantz 2007). His advice, which has changed over the years, has involved (1) the need (or otherwise) for a cardiograph before starting treatment, (2) the avoidance of methadone where possible and (3) the avoidance of high doses where methadone is used. His other recommendations are purely generic in recommending careful history and physical on each patient and acting on any evidence of cardiac risk. While this is important, it is probably no more important than acting on evidence of infectious disease, overdose risk, liver disease, allergies, mental illness, etc, etc.

The potential risk of cardiac side effects must be balanced against the unequivocal benefits of methadone maintenance to those who need and want it for their condition. There need be no ‘competition’ with buprenorphine which is an excellent alternative with certain benefit and certain disadvantages in the opiate treatment population.

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

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

Mehler PS, Krantz MJ. Authors’ reply. Methadone and QTc prolongation. Lancet 2007 369:366-7

Smith WM. Cardiac repolarisation: the long and short of it. MJA 2008 188;12:688-689

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

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

D'Aunno T, Folz-Murphy N, Lin X. Changes in Methadone Treatment Practices: Results from a Panel Study, 1988 - 1995. American Journal of Drug and Alcohol Abuse 1999 25;4:681-700

Dole VP, Nyswander ME. A medical treatment for diacetylmorphine (heroin) addiction. J Amer Med Assoc 1965;193:646-50 '193(8) 80-84'

Helpern M. Fatalities from narcotic addiction in New York City : incidence, circumstances and pathologic findings. Human Pathology 1972 2:13-21

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

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

Leavitt S. Methadone: facts and fiction


At 8:16 PM, Anonymous Zenith said...

Thanks once again, Bob, for being the "voice of reason" in a sea of hysteria.

At 8:27 AM, Blogger Garrett said...

Bob knows my views on this topic. The hysteria has gone into overdrive here in Dublin where all patients on MMT who are prescribed 100mg or greater have to be referred for EKG. Whilst I believe that an EKG is a worthwhile, simple, cheap and non-invasive test, getting one done routinely because one is prescribed methadone is a pretty lousy indication. The evidence that methadone has any adverse effect on cardiac rhythm is very weak indeed.

Over here the inevitable has happened. Those clinicians who don't like 'big doses' now have a reason not to go over a 100mg. Many patients are being told that unless they have an EKG and its normal they aint getting any more juice. This despite the fact that they are supplementing their crappy doses with illicit opiates. Poor medicine!

Garrett McGovern

At 2:26 PM, Blogger johnson446 said...

The exact impact of of Methadone on QT-wave is
prolongation.Depending upon survey we can confirm that.By the opinion of many patients the impact of QT-wave is more b y keeping this in mind we should move forward.
Addiction Treatment

At 3:03 PM, Anonymous Anonymous said...

I have been in a Methadone Maintainence Program since 1998, with a complete history of absolute
sobriety verified by drug testing.
The dose prescribed to me was increased to 200mg daily over a period of one year and remained at that dose for eight years.
I suffered a sudden cardiac arrest,resulting in a near fatal car accident. After spending 15 days in Intensive Care, 2 of them on life support, I arrested again while in ICU - this time, witnessed on cardiac monitor.

At 3:12 PM, Anonymous Anonymous said...

I was diagnosed with LongQT and had gone into Torsade. I underwent extensive (and expensive) genetic
testing; no markers were identified
(I started this blog on the last comment). My cardiologist and geneticist concluded it was drug-induced, as there were no other predisposing factors. I now have an AICD and am currently tapering off meth. - it is pure hell.

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