20 March 2009

Does adding an antagonist reduce injecting?

Lack of Reduction in Buprenorphine Injection After Introduction of Co-Formulated Buprenorphine/Naloxone to the Malaysian Market. Bruce RD, Govindasamy S, Sylla L, Kamarulzaman A, Altice FL. Am J Drug Alcohol Abuse 2009 Feb 12:1

Dear Colleagues,

In this important paper Dr Bruce from Yale University finds no reduction in quantities injected after the widespread change from pure to combination product (Suboxone). Even more worrying is a finding of increased needle sharing in the high proportion who reported withdrawal symptoms following the change.

In a group of 41 recruited illicit buprenorphine injectors in Kuala Lumpur, Bruce and co-workers posed questions about injection of both the pure and combination products after a change in Government policy aimed at discouraging injecting. Pure buprenorphine was banned due to widespread abuse (as it was in New Zealand in 1991) and replaced with a combination product containing naloxone. As in previous experiences, (Robinson 1993), a change to the combination product was not associated with elimination or substantial reduction in abuse.

Half the sample (20) reported experiencing withdrawal symptoms after the change yet this had apparently not discouraged them from injecting. Average daily use increased 30% (from 1.9 to 2.5mg per day). Reported needle sharing was much more prevalent in those who also reported withdrawal symptoms (15 out of 20 or 75% of the ‘withdrawal’ subgroup).

The 41 used other drugs such as methadone (4), ketamine (10), amphetamine (6) or benzodiazepines (13). The authors speculate that this may have been to medicate withdrawals in some cases. They state that none of the subjects appeared to be using the buprenorphine as a recreational drug but to maintain a functional level of opiates in the body.

This paper is not consistent with claims that Suboxone reduces injecting behaviour. While the manufacturer has always been modest in its claims, others have made extravagant statements about the alleged property of combination buprenorphine to prevent diversion. It appears that the drug was approved by the American FDA and marketed without rigorous comparative studies. Combination agonist/antagonists may sound persuasive in theory but this has never been demonstrated in the field despite a long pedigree (methadone and naloxone were first tried together over 30 years ago). Now, 15 years apart and in very different settings, two naturalistic studies on buprenorphine make comparable and consistent findings.

Like Bruce in Malaysia, Robinson in New Zealand took advantage of a similar scenario in which buprenorphine was being widely abused in the community. The government and manufacturer changed to the naloxone-containing product, so Robinson was able to interview patients enrolling in his opioid treatment program in Wellington, NZ. He reported numerous demographic and drug use characteristics before and after, finding that the drug was still widely abused. Indeed, for 59% it was still the drug of choice - and mostly injected.

Interestingly, the Malaysian figures are remarkably close to a published comparison of pure buprenorphine with the combination product. In a small pilot study, Bell and colleagues found that substantial increases (average 50%) in doses were needed by nearly all 17 stable subjects after changing from Subutex to Suboxone. Another factor I learned in my research was that apparently the main driver for injecting in Malaysia was financial since sublingual administration requires a far higher dose due to lower bio-availability and all doses must be paid for by the patient in that country.

Comments by Andrew Byrne ..

Clinic web page: http://www.redfernclinic.com/#news


Robinson GM, Dukes PD, Robinson BJ, Cooke RR, Mahoney GN. The misuse of buprenorphine and a buprenorphine-naloxone combination in Wellington, New Zealand. Drug Alcohol Dependence (1993) 33;1:81-6
Bell J, Byron G, Gibson A, Morris A. A pilot study of buprenorphine-naloxone combination tablet (Suboxone®) in treatment of opioid dependence. Drug Alcohol Rev (2004) 23;3:311-318

7 March 2009

Torsade rare in guideline-treated cases: routine ECG not appropriate.

First Do No Harm ... Reduction? Annals of Internal Medicine 2009 150;6 (Annals on line, pre-publication March 17) Gourevitch MN. http://www.annals.org/cgi/content/full/0000605-200903170-00111v1

Dear Colleagues,

With this stentorian editorial Annals of Internal Medicine finally puts the cardiac health of methadone treatment into its correct perspective. Dr Marc Gourevitch questions the utility of routine ECGs to detect or prevent such side effects, countering Krantz and colleagues (Ref 1) who have an article in this issue recommending routine electrocardiography before and during treatment - claiming some sort of professional consensus. In 2006 Krantz had written: “Although QT prolongation associated with higher doses of methadone is an important safety concern, we do not believe that routine ECG screening is warranted for heroin addicts entering treatment” (Ref 2). As Gourevitch points out, no new evidence is presented in this paper to justify a reversal of this widely held view - in fact four important papers are simply omitted by Krantz et al (Ref 3-6). Each of these is reassuring in that torsade is rare and largely occurs in extraordinary clinical circumstances.

After initial pre-publication on Annals-on-line in December 2008, the article by Krantz et al was withdrawn, only to reappear without CSAT endorsement in its title. After originally declaring: “Potential financial conflicts of interest: None declared” fully three primary authors and one panel member subsequently made specific declarations including funding from Reckitt Benckiser, the manufacturer of buprenorphine. All of this should be of some embarrassment to Krantz et al, the Annals editors (they even wrote a rapid response themselves!) and members of an expert panel convened by CSAT, chaired by veteran Dr Barry Stimmel of Mt Sinai Medical School in Manhattan. Two of the panel members declined to be acknowledged in the final version of the paper. It is gratifying that the controversial recommendations in this paper have been countered by an expert editorial by Dr Gourevitch from NYU.

Some major flaws in Krantz’s paper are pointed out. Regarding routine cardiographs before and during treatment, Gourevitch writes: “Unfortunately, this suggested guideline ventures well beyond the evidence presented.” He examines each aspect of Krantz’s ‘case’ for the dangers of QT prolongation and torsade de pointes and the panel’s ‘consensus’ strategy for prevention. We are even told that mandated cardiographs may cause more harm than good, like many other well-intentioned guidelines (ref 7).

Some of the questions raised by Gourevitch are so fundamental that they should have been asked long before in the peer review process or the ‘expert panel’ deliberations. He seems surprised that the panel members were able to (1) discuss 95 detailed references, (2) confer about torsade risk and (3) develop a 5 point plan to address this purported risk in only 2 days at a ‘consensus’ meeting.

Dr Gourevitch implies that ECG testing should be done on those at high risk since overall the rate of torsade is low and cardiac dangers “typically occur in those who receive exceptionally high doses of methadone or who have other risk factors.” [Krantz writes 'relatively high doses' describing an average of 397mg daily.] He also points out that the time frame of ECGs in the article’s recommendations is arbitrary, and there equally seems no rationale behind the 100mg dose level above which the authors say more frequent supervision is needed.

The author points out that the delays involved in getting pre-treatment testing done in this brittle population will inevitably cause some early drop-outs. Further, since torasde is so rare, this could never be balanced by benefits for those remaining in treatment.

The subject of supposed cardiac toxicity from methadone maintenance treatment has taken on a life of its own well beyond the evidence. The contention by Krantz that cardiac safety in methadone maintenance patients is a ‘national priority’ is an overstatement (Ref 8). Those suggesting this have not even determined an approximate incidence (and it may be zero in addiction clinic patients). Amongst ~70 reported cases of torsade, nearly all in older or complex addiction cases, I could only find one which was fatal (a 47 year old female who reportedly also had a myocardial infarction).

This discussion should not allow clinicians to be distracted from the major problems facing our field, notably the hepatitis C epidemic. The overwhelming statistics on this subject put the above minutiae into stark perspective.

Comments by Andrew Byrne ..

Clinic web page: http://www.redfernclinic.com/#news


1. Krantz MJ, Martin J, Stimmel B, Mehta D, Haigney MCP. QTc Interval Screening in Methadone Treatment. Ann Intern Med 2009 150;6: (March 17 issue) http://www.annals.org/cgi/content/full/0000605-200903170-00103v1
2. Krantz MJ, Mehler PS. QTc prolongation: methadone's efficacy-safety paradox. Lancet 2006 368:556-557
3. 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
4. Krook AL, Waal H, Hansteen V. Routine ECG in methadone-assisted rehabilitation is wrong prioritization. Tidsskr Nor Laegeforen 2004 124;22:2940-1
5. Athanasos P, Farquharson AL, Compton P, Psaltis P, Hay J. Electrocardiogram characteristics of methadone and buprenorphine maintained subjects. J Addict Dis. 2008 27(3):31-5
6. Cruciani R. Methadone: To ECG or Not to ECG…That Is Still the Question. Journal of Pain and Symptom Management 2008 36;5:545-552
7. Grimes DA, Schulz KF. Uses and abuses of screening tests. Lancet. 2002 359:881-4
8. Krantz MJ. Heterogeneous Impact of Methadone on the QTc Interval: What Are the Practical Implications? Journal of Addictive Diseases 2008 27;4:5-9

6 March 2009

Close examination finds flaws with Annals article on QT effects from methadone.

Krantz MJ, Martin J, Stimmel B, Mehta D, Haigney MCP. QTc Interval Screening in Methadone Treatment. Ann Intern Med 2009 (March 17 issue)

Dear Reader,

The title of this article has changed since its original publication and the connection with CSAT has been omitted. I found problems with the methods, processes of ‘consensus’, deductions, conclusions and references.

It is evident (but not stated specifically that I could find) that the main issue being addressed is the occurrence of cardiac arrhythmia in patients being prescribed methadone. Yet the title seems to imply that QT prolongation of itself is a problem, despite 40 years of experience showing it is common (up to 40% of subjects) and yet of unknown clinical significance. Torsade tachycardia has very largely been reported in complex medical cases and those taking extremely high doses of methadone rather than those on standard maintenance treatment.

In my view these authors do not make a logical case for their title: “QTc Interval Screening in Methadone Treatment” but ask readers to accept that there is a problem and that their recommendations form a solution to diagnosing and addressing it. Recommendation 1 involves disclosing the cardiac toxicity to all patients; Recommendation 2 advises a history and physical exam. Serial cardiographs are promoted in Recommendation 3. Recommendations 4 and 5 are a cook-book way of dealing with this difficult and largely uncharted clinical territory. Few clinicians have looked after more than one or two such patients and so a rational approach has not yet been arrived at and it is hard to imagine this is the last word on the subject.

Their first paragraph contains a circular argument since they use the existence of a drug black box warning and FDA safety warning on methadone as support for the case for methadone being dangerous. Yet these measures are a result of the same concerns as Krantz claims to be responding to, so as commercial or regulatory decisions, they are not scientific sources, depending as they do on a variety of factors beyond clinical medicine and public health.

Krantz and colleagues are initially at pains to point out the factors which lead to increased risk of torsade de pointes in relation to prolonged QT interval, sex, heart rate and other factors. The rest of the article lacks clarity and the concise scientific discussion that one normally expects in Annals.

Regular practice would start by describing a clinical or public health problem such as a series of case reports, approximate incidence and evidence of the existence of a recognisable syndrome and a possible causation. They appear unwilling or unable to define the problem and its scope. In proposing these clinical recommendations, some of which are ’motherhood statements’ while others appear arbitrary and untested. In this way Krantz and colleagues deny readers a proposed rationale to demonstrate how known reported cases could have been avoided as a result of their newfound wisdom. They circumvent their subject in numerous ways, drawing quite tenuous conclusions from circumstantial reports with no actual cases of torsade arrhythmias despite being cited as important studies demonstrating its importance (eg. Chugh’s study from Portland, Fanoe from Denmark, Wedam from Baltimore).

Despite torsade de pointes being the complication they are addressing, the article spends most text discussing QT prolongation, something we know happens commonly in methadone patients (up to 40%), and which we know, in methadone clinic patients on ‘normal’ doses, is of little if any clinical significance. Torsade can occur in those with normal QT intervals (Ehret) and in those not taking methadone (Smith). While taking pains to be conservative and conceding the many weak links individually in documenting this subject, these authors still conclude that their advice is based on good science.

As above, it is hard to understand how, from a knowledge of the case reports, such a strategy as proposed by Krantz and colleagues would or could prevent torsade cases. The QT interval is regularly normal before and after the triggering events (Sticherling). I have written to Krantz, Haigney, Stimmel and Martin individually to ask how their strategy could apply to the case reports in the literature. I have been sent no attempts to explain this rather large gap in the logic. My understanding is that few if any reported cases would have been prevented by these measures in Annals.

The authors state that of Pearson’s 59 FDA reported cases there was an 8% mortality (Paragraph 14). They omit to say that only one of the 5 deaths was a torsade case (the others QT abnormalities reported but no torsade). Further, the single death was in a 47 year old female patient who also had a myocardial infarction as well as prescription of azithromycin and droperidol. Both the latter drugs are known to be cardio-toxic. The mean dose of the 59 cases was over 400mg daily. None of the other 4 deaths in Pearson’s FDA series had torsade from their prolonged QT intervals and we are not told any further details of the causes of death. Two of the four had been given methadone intravenously (off-label) at extremely high dose levels (360 and 1680mg daily). Another was a 78 year old woman who had been prescribed cisapride, a drug which is no longer available in some countries. The only patient in this group of five deaths who might have been a standard methadone patient also died from un-stated causes, aged 40 on the unusual dose of 29mg daily (and there was no torsade in her case).

By comparison, Krantz’s series of 17 cases had no deaths (0%), Sticherling’s 5 cases all survived (0% deaths) and Justo’s compilations (including some of the above cases) reported no deaths (0%).

Hence the suggestion that any group of methadone patients had a mortality of 8% is almost meaningless without a denominator. Considering the age and other details of reported cases, these would have little relevance to young people with addiction problems who may be started on opioid maintenance therapy. Few if any of those reported torsade cases come from newly started addiction clinic patients, despite the most worrying trial of QT prolongation (Wedam) finding 12% in the high risk group within 4 months of starting treatment. Even if there were a small incidence of significant QT problems, these would still be outweighed by benefits to patients. Krantz himself proposed that putting a drug injector onto methadone had the scope to reduce rates of endocarditis in the community as a “common sense notion” (2001). Endocarditis is probably more common than torsade de pointes arrhythmia.

Krantz and colleagues argue (paragraph 2) in favor of routine cardiographs by taking examples of findings with two antiarrhythmic drugs (sotalol and dovetailed), “highlighting the importance of pretreatment ECG screening for identifying susceptible patients”. One wonders at this comparison when these cases clearly already had heart disease by definition, in contrast to young people attending for addiction treatment. While it would obviously be inappropriate to treat arrhythmias without a baseline and on-going cardiographs, there can be no parallel here with methadone as the authors attempt. A fairer comparison might be prescribing erythromycin, haloperidol or other such agents to young people without cardiac histories.

The 17% mortality of torsade is based on two old references from the French literature relating to hospitalized torsade cases (Paragraph 16). This rate may now be lower in view of better communications, wider availability of ECG and defibrillators as well as improved specialist care. On the other hand, torsades may have become more readily diagnosed, due in part to the advent of automated digital machinery with QTc print-outs.

In paragraph 21 Krantz and colleagues combine 8 references as supporting a correlation between prescribed methadone dose level and QT interval. In fact, Peles’ trial from Israel (which probably had the highest average doses and largest range of any such report) found no significant correlation between their patients’ dose levels and corresponding QT interval. A sub-group of cocaine users were examined separately and a (significant) correlation was found which may or may not support Krantz and colleagues’ thesis. Further, they quote Martell as supporting the correlation but fail to add (as Cruciani states:) “Martell and co-workers studied heroin addicts during the first two months of induction therapy with methadone and observed a higher increment in the duration of the QTc in those patients receiving 110-150 mg/24 h. The clinical significance of this change is questionable, however, because the increment was only 13.2 ms.”

Further, in paragraph 21 these authors state, or rather understate: “Methadone dosages exceeding 100 mg/d have frequently been noted in published cases of torsade de pointes, and some case reports (43, 47, 55) highlight QTc-interval normalization after methadone discontinuation or dose reduction.” In fact methadone dosages exceeding 200mg, 300mg and 400mg have frequently been noted in reports of Pearson and Krantz (2002). Some of the highest were 1100mg, 1680mg, 1000mg in Pearson’s paper. Further, when QTc interval was available after the torsade event and the triggering factor has been removed, QTc intervals nearly always returned to normal or near normal. Krantz omits this common and important finding while stating “some case reports (43, 47, 55) highlight QTc-interval normalization after methadone discontinuation or dose reduction.” To this one should add the several reports where normalisation of the QT interval was reported after addressing triggering factors (eg. all 5 cases of Sticherling, De Bels’ two cases, one reverting to normal while the other’s QT interval dropped from 736ms to 502ms in 4 days).

This style of writing is much closer to advocacy than careful scientific discourse. While there are caveats and alternatives mentioned at various points, the overall feeling is that there is a case already made and this text is there to support it. The choice of references is another example of a lack of balance. Justo’s prominent literature review from the Addiction journal is omitted. Krook’s item which addresses their exact subject is also surprisingly left out (Krook AL, Waal H, Hansteen V. Routine ECG in methadone-assisted rehabilitation is wrong prioritization. Tidsskr Nor Laegeforen 2004 124;22:2940-1).

The authors also unfortunately omitted two highly relevant recent items (i) Athanasos P, Farquharson AL, Compton P, Psaltis P, Hay J. Electrocardiogram characteristics of methadone and buprenorphine maintained subjects. J Addict Dis. 2008 27(3):31-5 (ii) Cruciani R. Methadone: To ECG or Not to ECG…That Is Still the Question. Journal of Pain and Symptom Management 2008 36;5:545-552. These two address Krantz’s issues directly and each makes enlightening and balanced reading, contributing substantially to the field, yet they are ignored by Krantz and colleagues. Cruciani was available in April 2008 while Athanasos on 12th June 2008. Several of the other 95 references were accessed as late as November 12 2008 according to the text.

With almost 100 other references, some of only tenuous relation to the subject, it is a flaw to have missed other such relevant and contributory sources. In this small field, such documents are usually publicised on the internet, professional list-servers and news-wire services long before they reach formal publication date (as in the case of this very item in Annals which appeared in a previous version in early December 2008). The reader may understand cut-off dates for recent references, but to omit Krook and Justo would seem to show a lack of thoroughness unbefitting a panel which proposes to develop guidelines for physicians who work in this important field.

Derivative internet summaries:

Comments by Andrew Byrne ..

Clinic web page: http://www.redfernclinic.com/#news


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

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

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

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

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

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

Krantz MJ. Clinical Concepts- Cardiovascular Health in MMT Patients. Addiction Treatment Forum 2001 No 4

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

Cruciani R. Methadone: To ECG or Not to ECG…That Is Still the Question. Journal of Pain and Symptom Management 2008 36;5:545-552

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

Other references on request.

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