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:
http://www.ncbi.nlm.nih.gov/pubmed/19047020
http://www.tripdatabase.com/spider.html?itemid=801110
Comments by Andrew Byrne ..
Clinic web page: http://www.redfernclinic.com/#news
References:
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 ..
References:
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
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 ..
References:
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
6 December 2008
APSAD Annual Scientific Conference 2008 [part I]
APSAD Annual Scientific Conference 2008
Australasian Professional Society on Alcohol and other Drugs.
November 23 - 26, 2008 Part I (Sunday 23 Nov).
Dear Colleagues,
This year's APSAD conference was a fine affair. I must have been to 15 or more of these in most State capitals, Cairns and Canberra. I missed last year’s Fest in Auckland but those who attended said it was excellent. Like national leaders’ meetings with their funny hats, shirts and coats, each APSAD conference is characterised by its own conference attaché bag. This natural-inspired over-the-shoulder model was one of the few I could imagine using in the future.
The venue was splendid, Darling Harbour being just an 8 minutes (downhill) walk from Town Hall station which made me into a commuter again. With medical practice responsibilities I was a part-time conference goer. Thus these notes are incomplete and (as usual) opinionated.
The Sunday afternoon pre-conference session had been booked by the only drug company with a major stake in our field. Reckitt-Benckiser is manufacturer of buprenorphine which is the only registered alternative to methadone, the latter being a generic drug with small bread-and-butter profit lines in comparison. The sponsors began with the topics of pharmaceutical abuse and innovations in addiction management, then ending with two presentations on the potential cardiac complications of methadone before a panel discussion to which I had been invited (and generously funded).
Adrian Dunlop spoke eloquently about the past, present and future of addiction treatments.
Dr Eric Strain covered some historical details of non-medical use of pharmaceuticals in the US, giving some results on prevalence and consequences from household surveys over 25 years. Apparently most users obtained their supplies from one doctor; many from friends or relatives with less only ~1% or less from the internet. Australian figures may be quite different as people are entitled to attend more than one doctor on Medicare. Another speaker quipped that if Australia had a Bill of Rights, it would include being able to attend “as many doctors as you like”. Dr Strain touched on the gap between occasional use and dependent use, something some of us may still forget because of the selected referrals we receive. The other major differences between American street heroin users and those abusing pain killers is that the latter are more likely to be employed, white race and non-injectors. Dr Strain was too modest to mention his own research on buprenorphine abuse and perhaps too polite to mention the reported non-medical use of buprenorphine, including a naloxone combination product which became the drug of choice (mostly injected) by more than half those presenting for treatment in Wellington, New Zealand (see Robinson 1993).
Dr Nick Lintzeris gave some pointers about pharmaceutical abuse in Australia. His talk ending with a plea to put methadone treatment, including side effects, into context both globally, as well as for individual patients. In his rather frequent exposure during the conference, he reminded us that there are much more relevant issues for opioid therapy as patients get older such as testosterone levels, calcium leaching, osteoporosis, dental, viral and bowel problems.
Jason White detailed the rather sparse literature on cardiac complications in methadone recipients. He seemed persuaded that the connection between methadone and torsade is significant and that methadone treatment could be restricted or further regulated as a result. As a demonstration of patients on ‘normal’ methadone treatment coming to torsade, he cited Pearson and Woosley’s report of 59 FDA notifications from 1969 to 2002. While not fully documented, from the limited data 12 could have been on ‘standard’ MMT, 8 of whom were over 40 years of age. This leaves just 4 reported ‘standard’ MMT cases in the USA over a 33 year period in the age group we normally start on MMT. Justo’s more recent literature review found only 6 of 40 cases reported could have been on ‘standard’ MMT cases without other triggering factors (85% had one or more of these known causes of QT prolongation aside from high methadone doses).
QT prolongation on the cardiograph has long been know to occur in about a quarter of methadone patients yet its only serious consequence, ‘torsade de pointes’ tachycardia, hardly ever seems to occur in young patients (<40>40 years of age, electrolyte disturbance, etc.
As our patient population on maintenance treatment gets older so we must be more vigilant about this and other eventualities. As with other related medical issues, close attention should be paid to cardiac status. This may include an ECG in those taking over 150mg, those prescribed other ‘at risk’ medications or those with HIV or personal/family history of unexplained syncope or fainting.
At this session I was delighted to finally learn the origin of the term ‘ether-a-go-go’ which is from the rhythmic dancing induced in the legs of doomed drosophila drones (flies) under the influence of ether in genetic experiments on channel blockers.
We were then shown a 15 minute video ‘interview’ with Colorado cardiologist Dr Mori Krantz detailing blow by blow the now supposedly conclusive case for methadone’s guilt beyond reasonable doubt in causing fatal arrhythmias. The final proof of any medical argument, we are told, involves randomisation of subjects and so the RCT by Wedam is proffered. This trial, a secondary analysis of ECG tracings obtained incidentally in a 1990s RCT, showed very high rates of QT prolongation in the first 4 months of MMT but no cases of torsade. One of the panellists said to me privately that this appears to be rather persuasive of the safety of methadone rather than the opposite.
As above, hardly anyone has ever seen a case except in patients who are already stressed and in highly complex medical circumstances. I note that since his classic description of 17 non-fatal cases in 2002 (8 were pain management cases), Krantz has only reported two other individual cases of torsade, one of which was attributed to cocaine.
In the video, we are told that because one cannot diagnose an electrical disturbance after death, coroners are unable to detect whether the death was due to cardiac arrhythmia or respiratory depression from the drug. In fact many cases are very clear at autopsy as having the classic findings of post mortem sub-acute lung changes and high blood levels as to leave little doubt about the cause of death. So while Krantz’s proposition may be true for a certain minority, with a 20% mortality, there ought to be 4 times as many (80%) torsade survivors. Yet few if any of these ever seem to get to an emergency room (or ambulance) and have their potentially fatal problem diagnosed with a simple cardiograph tracing. Such reports are exceedingly rare or non-existent. I called one of Australia’s busiest casualty departments to be told that their long-time medical director had never seen a case of methadone associated torsade. He also pointed out that for the past several years modern cardiograph machines have given an automated print-out of QTc, making this information much more available than previously. This just might be the single most important cause of the ‘epidemic’ of electrical changes in the absence of actual symptomatic disease.
Further on in the presentation Krantz states the obvious “it’s not to say that there is an epidemic of cardiac events in America”. Yet elsewhere he has written that a large number of patients are at risk of developing torsade. Fanoe’s Copenhagen syncope study was put up as a written question in the video ‘interview’ (there was no interviewer as such) but Krantz failed to comment on it for some reason. Fanoe showed that out of 800 cases (with no torsade reported) that high rates of syncope (over 20% in most dose groups) in methadone patients was at least in part explained by cardiac conduction problems such as torsade. This is hard to understand for a complication known to occur in less than 1% of patients. Krantz then alluded to Chugh’s Portland study suggesting that it lent support to his torsade theory, yet like so many of the other quoted references, this is another report which does not document any torsade cases at all.
Do I belabour the point? If this is a serial killing, Miss Marple, where are the bodies?
[more about lives saved in another conference posting shortly]
Comments by Andrew Byrne ..
~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~
Dr Andrew Byrne MB BS (Syd) FAChAM (RACP)
Dependency Medicine,
75 Redfern Street, Redfern,
New South Wales, 2016, Australia
Email - ajbyrne@ozemail.com.au
Tel (61 - 2) 9319 5524 Fax 9318 0631
~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~
Surgery web page: http://www.redfernclinic.com/#news
References:
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
Strain EC, Stoller K, Walsh SL, Bigelow GE. Effects of buprenorphine versus buprenorphine/naloxone tablets in non-dependent opioid abusers. Psychopharmacology (Berl) 2000 Mar;148(4):374-83
Justo D. Methadone-Induced Long QT Syndrome vs Methadone-Induced Torsades de Pointes. Arch Intern Med 2006 166:2288
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, 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, Rowan SB, Mehler PS. Cocaine-related torsade de pointes in a methadone maintenance patient. J Addict Dis. 2005;24(1):53-60
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
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
Australasian Professional Society on Alcohol and other Drugs.
November 23 - 26, 2008 Part I (Sunday 23 Nov).
Dear Colleagues,
This year's APSAD conference was a fine affair. I must have been to 15 or more of these in most State capitals, Cairns and Canberra. I missed last year’s Fest in Auckland but those who attended said it was excellent. Like national leaders’ meetings with their funny hats, shirts and coats, each APSAD conference is characterised by its own conference attaché bag. This natural-inspired over-the-shoulder model was one of the few I could imagine using in the future.
The venue was splendid, Darling Harbour being just an 8 minutes (downhill) walk from Town Hall station which made me into a commuter again. With medical practice responsibilities I was a part-time conference goer. Thus these notes are incomplete and (as usual) opinionated.
The Sunday afternoon pre-conference session had been booked by the only drug company with a major stake in our field. Reckitt-Benckiser is manufacturer of buprenorphine which is the only registered alternative to methadone, the latter being a generic drug with small bread-and-butter profit lines in comparison. The sponsors began with the topics of pharmaceutical abuse and innovations in addiction management, then ending with two presentations on the potential cardiac complications of methadone before a panel discussion to which I had been invited (and generously funded).
Adrian Dunlop spoke eloquently about the past, present and future of addiction treatments.
Dr Eric Strain covered some historical details of non-medical use of pharmaceuticals in the US, giving some results on prevalence and consequences from household surveys over 25 years. Apparently most users obtained their supplies from one doctor; many from friends or relatives with less only ~1% or less from the internet. Australian figures may be quite different as people are entitled to attend more than one doctor on Medicare. Another speaker quipped that if Australia had a Bill of Rights, it would include being able to attend “as many doctors as you like”. Dr Strain touched on the gap between occasional use and dependent use, something some of us may still forget because of the selected referrals we receive. The other major differences between American street heroin users and those abusing pain killers is that the latter are more likely to be employed, white race and non-injectors. Dr Strain was too modest to mention his own research on buprenorphine abuse and perhaps too polite to mention the reported non-medical use of buprenorphine, including a naloxone combination product which became the drug of choice (mostly injected) by more than half those presenting for treatment in Wellington, New Zealand (see Robinson 1993).
Dr Nick Lintzeris gave some pointers about pharmaceutical abuse in Australia. His talk ending with a plea to put methadone treatment, including side effects, into context both globally, as well as for individual patients. In his rather frequent exposure during the conference, he reminded us that there are much more relevant issues for opioid therapy as patients get older such as testosterone levels, calcium leaching, osteoporosis, dental, viral and bowel problems.
Jason White detailed the rather sparse literature on cardiac complications in methadone recipients. He seemed persuaded that the connection between methadone and torsade is significant and that methadone treatment could be restricted or further regulated as a result. As a demonstration of patients on ‘normal’ methadone treatment coming to torsade, he cited Pearson and Woosley’s report of 59 FDA notifications from 1969 to 2002. While not fully documented, from the limited data 12 could have been on ‘standard’ MMT, 8 of whom were over 40 years of age. This leaves just 4 reported ‘standard’ MMT cases in the USA over a 33 year period in the age group we normally start on MMT. Justo’s more recent literature review found only 6 of 40 cases reported could have been on ‘standard’ MMT cases without other triggering factors (85% had one or more of these known causes of QT prolongation aside from high methadone doses).
QT prolongation on the cardiograph has long been know to occur in about a quarter of methadone patients yet its only serious consequence, ‘torsade de pointes’ tachycardia, hardly ever seems to occur in young patients (<40>40 years of age, electrolyte disturbance, etc.
As our patient population on maintenance treatment gets older so we must be more vigilant about this and other eventualities. As with other related medical issues, close attention should be paid to cardiac status. This may include an ECG in those taking over 150mg, those prescribed other ‘at risk’ medications or those with HIV or personal/family history of unexplained syncope or fainting.
At this session I was delighted to finally learn the origin of the term ‘ether-a-go-go’ which is from the rhythmic dancing induced in the legs of doomed drosophila drones (flies) under the influence of ether in genetic experiments on channel blockers.
We were then shown a 15 minute video ‘interview’ with Colorado cardiologist Dr Mori Krantz detailing blow by blow the now supposedly conclusive case for methadone’s guilt beyond reasonable doubt in causing fatal arrhythmias. The final proof of any medical argument, we are told, involves randomisation of subjects and so the RCT by Wedam is proffered. This trial, a secondary analysis of ECG tracings obtained incidentally in a 1990s RCT, showed very high rates of QT prolongation in the first 4 months of MMT but no cases of torsade. One of the panellists said to me privately that this appears to be rather persuasive of the safety of methadone rather than the opposite.
As above, hardly anyone has ever seen a case except in patients who are already stressed and in highly complex medical circumstances. I note that since his classic description of 17 non-fatal cases in 2002 (8 were pain management cases), Krantz has only reported two other individual cases of torsade, one of which was attributed to cocaine.
In the video, we are told that because one cannot diagnose an electrical disturbance after death, coroners are unable to detect whether the death was due to cardiac arrhythmia or respiratory depression from the drug. In fact many cases are very clear at autopsy as having the classic findings of post mortem sub-acute lung changes and high blood levels as to leave little doubt about the cause of death. So while Krantz’s proposition may be true for a certain minority, with a 20% mortality, there ought to be 4 times as many (80%) torsade survivors. Yet few if any of these ever seem to get to an emergency room (or ambulance) and have their potentially fatal problem diagnosed with a simple cardiograph tracing. Such reports are exceedingly rare or non-existent. I called one of Australia’s busiest casualty departments to be told that their long-time medical director had never seen a case of methadone associated torsade. He also pointed out that for the past several years modern cardiograph machines have given an automated print-out of QTc, making this information much more available than previously. This just might be the single most important cause of the ‘epidemic’ of electrical changes in the absence of actual symptomatic disease.
Further on in the presentation Krantz states the obvious “it’s not to say that there is an epidemic of cardiac events in America”. Yet elsewhere he has written that a large number of patients are at risk of developing torsade. Fanoe’s Copenhagen syncope study was put up as a written question in the video ‘interview’ (there was no interviewer as such) but Krantz failed to comment on it for some reason. Fanoe showed that out of 800 cases (with no torsade reported) that high rates of syncope (over 20% in most dose groups) in methadone patients was at least in part explained by cardiac conduction problems such as torsade. This is hard to understand for a complication known to occur in less than 1% of patients. Krantz then alluded to Chugh’s Portland study suggesting that it lent support to his torsade theory, yet like so many of the other quoted references, this is another report which does not document any torsade cases at all.
Do I belabour the point? If this is a serial killing, Miss Marple, where are the bodies?
[more about lives saved in another conference posting shortly]
Comments by Andrew Byrne ..
~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~
Dr Andrew Byrne MB BS (Syd) FAChAM (RACP)
Dependency Medicine,
75 Redfern Street, Redfern,
New South Wales, 2016, Australia
Email - ajbyrne@ozemail.com.au
Tel (61 - 2) 9319 5524 Fax 9318 0631
~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~
Surgery web page: http://www.redfernclinic.com/#news
References:
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
Strain EC, Stoller K, Walsh SL, Bigelow GE. Effects of buprenorphine versus buprenorphine/naloxone tablets in non-dependent opioid abusers. Psychopharmacology (Berl) 2000 Mar;148(4):374-83
Justo D. Methadone-Induced Long QT Syndrome vs Methadone-Induced Torsades de Pointes. Arch Intern Med 2006 166:2288
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, 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, Rowan SB, Mehler PS. Cocaine-related torsade de pointes in a methadone maintenance patient. J Addict Dis. 2005;24(1):53-60
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
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
5 December 2008
APSAD Annual Scientific Conference 2008 [part II]
APSAD Annual Scientific Conference 2008 [part II]
November 23 - 26, 2008
The plenary sessions on Tuesday were excellent, starting out with an American statistician, Rosalie Liccardo Pacula talking about the new generation RAND drug use modelling. This appears to be an enormously detailed, almost 4-dimensional system of looking longitudinally at multiple individual markers as well as societal/drug changes. Already they are able to predict drug trends with far fewer people than household surveys but there is still more work to be done to hone this new tool. Like all statistical models, it is only as good as the information fed into it. [http://www.apsad2008.com/abstract/300.asp]
Next we heard Prof Ross Homel giving a talk about complex family interventions, often involving three generations, with the emphasis on child safety, development and education. He gave numerous examples of what they are doing in a non-Government organisation associated with Mission Australia. There were vastly diverse interventions from group therapies, vocational referrals to literacy programs. Their main aim was to embed such programs into schools where there was a high proportion of disadvantaged children.
It was most appropriate that Prof Ann Roche gave the Rankin Oration this year. She did a broad overview of our field and her involvement in it looking back and then giving some views about the future using many clever and apposite quotes from Woody Allen, Elenor Roosevelt, the Dalai Lama and others. One memorable quote from the conference was a post-modern concept for the single woman to ask of any man she dates: �Is this really the man I want to look after my children on weekends?�
Greg Dore then revealed just what we all needed to know about hepatitis C. He dealt with the progress of the epidemic since it was first formally recognised in our communities around 1990. With no initial symptomatology in most patients, it is hard to determine the true incidence. However, by looking at the prevalence in young age groups one can determine changes from time to time. This would seem to indicate that although there are still many reported new cases each year, fewer of these appear to be true new infections as the prevalence in younger people is dropping more rapidly than in the overall population. [http://www.apsad2008.com/abstract/294.asp]
The range of treatments was detailed, pointing out the major improvements in recent years. We can now expect up to 80% �cure� rates (absent viral PCR at 6 months) in genotypes 2 and 3 with around 50% for genotypes 1 and 4. With several innovations such as closer viral load monitoring, liver "fibro-scans" and treatments for anti-viral side-effects, better results can be expected in the next few years. It is only by combining all of our resources, including GPs, addiction clinics, pharmacies and liver specialists that we will be able to address this epidemic which has a high proportion of patients on opioid therapies.
A talk was then given by Marina Davoli from Rome about the Cochrane Collaboration and internet library. Australia has had a special contribution to several areas and we have the only free access for internet users. Australian and New Zealand have also contributed much more serious research than other comparable western countries by population. This underlines all the evidence based interventions we use today.
I missed the session chaired by Dr Deborah Zador on opioid overdose but happily the conference abstracts are all available on the internet (see below). Dr Zador wrote some of the most important seminal studies on the subject in the 1990s. Two papers were given about naloxone, both its distribution amongst the drug using population and intriguingly by the intranasal route by paramedics in the overdose situation. The �Good Samaritan� provisions and international developments were detailed by Paul Dietze and Simon Lenton. [http://www.apsad2008.com/session/353.asp]
Bethany Butler reported some more results in an on-going study of several thousand NSW cases starting for the first time on methadone (~2500) or buprenorphine (~3500). There was no significant difference in the overall mortality in the groups (~65 subjects in each) but an excess mortality (~5-fold) in the methadone group in the first 2 weeks of treatment (7 versus 2). As well as direct toxicity, this might also be explained by methadone patients being in a higher risk group to start with. Even so, only a randomised trial can scientifically compare the two treatments and this is probably no longer ethical as most patients know which drug they want (see Pinto). It is certainly gratifying that when used in the normal course of practice that patients on each of these drugs have a marked drop in mortality. This study found those who remained in treatment were about three times less likely to die.
Next Louisa Degenhardt gave a paper on her group�s investigations of all deaths in NSW opioid maintenance cases since 1985, showing some differences over time. Overall 0.9% of subjects died each year of follow-up: 0.6% for those in treatment compared with 1.2% for those who had left. There was with a much higher chance of dying in the first two weeks of treatment when rate was 4.2%. This latter has dropped significantly since the early 1990s and does not apply at all to buprenorphine cases. The authors state that the treatments have the same mortality rates since those on buprenorphine have a lower retention rate, consistent with the comparative literature.
Finally, the session was given information about significant reductions in local ambulance attendances during the opening hours of the Sydney injecting centre (MSIC) as well as comparisons with the 2 years prior to its opening.
On the Wednesday morning we heard a plenary talk by Nicholas Lintzeris on the directions of treatment in the 21st century. He alluded to the shortage of doctors working in the field, the use of new medications requiring less supervision and models of treatment from elsewhere such as France. His subtext seemed to be individualising treatments rather than having rules and one-size-fits-all. He quoted the average age of methadone prescribers approaching the average daily dose! [Which is now about 75mg!] The speaker also did a study with Adam Winstock regarding attitudes towards withdrawal from treatment.
Next, those of us nursing a headache from the previous night�s dinner at L�Aqua Restaurant were given a fascinating talk by Sharon Walsh who is working in Kentucky on the effects of non-medical use of pharmaceuticals. She reminded us that in some areas there is now as much or more such abuse as for heroin. [This was also reported recently from inner Sydney in an ABC radio story which was nominated for a Walkley Award.] The emergence of prescription drug abuse may mean that we need to alter our approach and will increase the need for treatment services. Despite street and prescription drug use having essentially the same dependency diagnosis, these occur in quite different demographics (see Dr Strain�s talk from Sunday). The new RACP Policy on Prescription Opioids and Chronic Non-malignant Pain was introduced in another session, mapping out a plan for problematic use of prescription opioids in Australia and New Zealand [http://www.apsad2008.com/session/374.asp].
Dr Walsh reported on her results in human laboratory studies on oxycodone (Oxycontin; Prolodone), hydromorphone (Dilaudid) and hydrocodone. The latter is not available in Australia but is a constituent of Vicodin, a commonly abused drug in America. While hydromorphone is thought to be about 7 times stronger than morphine for its analgesic effects, in experiments on recreational users the differences between these three drugs were only marginal. [http://www.apsad2008.com/session/380.asp]
Despite running short of time, the next speaker Mark Tyndall spent some minute or two giving a hilarious description of the harm reduction aspects of pedestrians running red �WALK� signs. Next the hapless visiting Canadian described his shock at being taken to a surf beach where crashing waves buffeting swimmers who risked life and limb against the elements which were anything but �pacific� of late. His implication, I think, was that life savers are the equivalent of harm reduction services for drug users.
Returning to his subject, a square kilometre of western urban Canada, there were an estimated 6000 drug users, mostly injectors, of whom 25% had already contracted HIV and 90% hepatitis C. Services were and are grossly inadequate despite statistics which show disastrous rates of just aboot everything one would not want in one�s neighbourhood (crime, public injecting, overdose, deaths, hospital admissions, HIV cases, infections, etc). The Vancouver injecting centre is slightly larger in scale and opening hours, but shares all the essential characteristics of the Sydney injecting centre at Kings Cross (on which some say it was modelled). It has registered over 10,000 Canadian drug users (not all injectors as in Sydney). There are moves to close down this centre despite a wealth of public health research showing benefits to drug users and the community generally at modest cost (or even a net saving to the health system). Its closure would be a most pointed and poignant natural experiments in public health, comparable perhaps with the Broad Street pump exposure in London in the 1800s.
Next I attended a break-out session in which Carla Treloar spoke about the impressions people had about hepatitis C (http://www.apsad2008.com/session/388.asp). The myths were myriad. Defeatist misconceptions abounded. Some of her quotes were classics. Clearly our first job with hepatitis C is to inform people about the truth. Yes, the disease is still difficult and poorly understood. But we now have simple ways of determining the stage of the disease (�fibroscans�, risk criteria, etc) and we have reasonable and tolerable treatments with success rates up to 80%.
Nick Lintzeris reported some findings of an excellent intervention started some years ago in western Sydney in which OTP patients were offered a rapid vaccination program for hepatitis B. The results and a literature review showed that people at risk should probably be given a booster just about any time they are prepared to take one when it is available, even in quite short succession or as a booster down the line. Strict and appointment based regimens are perhaps not best suited to our patient group and so haphazard inoculations are probably more effective than no inoculations at all.
Some 9 cases of bacterial endocarditis in Newcastle area were reported next by Andrew Taylor. These formed a small minority of the total number of such cases in the region. Candida and staphylococcus aureus were common pathogens. The costs of such treatment to the health care system were high and the savings in prevention substantial.
The final segment of the conference for me at least was our own pet topic, hepatitis C outcomes. Carolyn Day, Paul Haber and colleagues reported on the barriers to addressing this public health priority (http://www.apsad2008.com/abstract/263.asp). From the low rates of assessment and treatment, even some prominent and well run clinics seem not to have effective strategies for testing and referring their patients. Some have no idea what proportion of their patients have been tested. Where resources allow, this can be pro-active, �on-site� and direct to hepatology services. Alternatively, referral to the individual patient�s GPs may be the best way to handle such matters in some situations. It is no longer acceptable to do nothing as advocated by some, claiming that �the treatment is worse than the disease�(!!). Some clinic practices seem so calcified that they have not even managed the change from methadone syrup (containing alcohol, caramel, sorbitol, gum, etc) to the safer �pink� methadone, despite majority patient support where the transfer was done some years ago (eg. NSW prisons; Rankin Court, Langton Centre, Clinic 36, Regent House, etc). At a recent health department forum at North Sydney some senior salaried clinicians described every barrier to improved treatment except themselves!
Next I moved to the session on intervention outcomes where Richard Hallinan reported our own 6 year experience prioritising hepatitis C assessments in OTP cases in Redfern (http://www.apsad2008.com/abstract/270.asp). We used some simple criteria devised by Greg Dore to indicate the likelihood of disease progression with liver fibrosis or cirrhosis. Some findings were given from 315 consecutive assessments with follow-up results for 30 cases having anti-viral treatment. Pegylated interferon alpha plus ribavirin were monitored in a shared care model with specialist hepatology services, with encouraging results thus far showing an overall 74% sustained viral response.
Comments by Andrew Byrne ..
Surgery web page: http://www.redfernclinic.com/#news
Opera blog: http://www.redfernclinic.com/opera/critique/blog/
New York in 2008: http://ajbtravels.blogspot.com/
New York diaries 1922: http://bpresent.com/harry/code/10b_bowery.php
Travel log: http://www.redfernclinic.com/c/2007/10/lord-howe-island-naturalists.php4
Vincent Dole in Nepal Diary: http://vincentdolehimalaya.blogspot.com/
Old photos of Sand Souci: http://sanssouciphotos.blogspot.com/
Reference:
Pinto H, Rumball D, Maskrey V, Holland R. A pilot study for a randomized controlled and patient preference trial of buprenorphine versus methadone maintenance treatment in the management of opiate dependent patients. Journal of Substance Use 2008 13;2:73-82
�Current policy puts too much emphasis on protecting society from methadone, and not enough on protecting society from the epidemic of addiction, violence and infections that methadone can help reduce.�
Institute of Medicine 1995
November 23 - 26, 2008
The plenary sessions on Tuesday were excellent, starting out with an American statistician, Rosalie Liccardo Pacula talking about the new generation RAND drug use modelling. This appears to be an enormously detailed, almost 4-dimensional system of looking longitudinally at multiple individual markers as well as societal/drug changes. Already they are able to predict drug trends with far fewer people than household surveys but there is still more work to be done to hone this new tool. Like all statistical models, it is only as good as the information fed into it. [http://www.apsad2008.com/abstract/300.asp]
Next we heard Prof Ross Homel giving a talk about complex family interventions, often involving three generations, with the emphasis on child safety, development and education. He gave numerous examples of what they are doing in a non-Government organisation associated with Mission Australia. There were vastly diverse interventions from group therapies, vocational referrals to literacy programs. Their main aim was to embed such programs into schools where there was a high proportion of disadvantaged children.
It was most appropriate that Prof Ann Roche gave the Rankin Oration this year. She did a broad overview of our field and her involvement in it looking back and then giving some views about the future using many clever and apposite quotes from Woody Allen, Elenor Roosevelt, the Dalai Lama and others. One memorable quote from the conference was a post-modern concept for the single woman to ask of any man she dates: �Is this really the man I want to look after my children on weekends?�
Greg Dore then revealed just what we all needed to know about hepatitis C. He dealt with the progress of the epidemic since it was first formally recognised in our communities around 1990. With no initial symptomatology in most patients, it is hard to determine the true incidence. However, by looking at the prevalence in young age groups one can determine changes from time to time. This would seem to indicate that although there are still many reported new cases each year, fewer of these appear to be true new infections as the prevalence in younger people is dropping more rapidly than in the overall population. [http://www.apsad2008.com/abstract/294.asp]
The range of treatments was detailed, pointing out the major improvements in recent years. We can now expect up to 80% �cure� rates (absent viral PCR at 6 months) in genotypes 2 and 3 with around 50% for genotypes 1 and 4. With several innovations such as closer viral load monitoring, liver "fibro-scans" and treatments for anti-viral side-effects, better results can be expected in the next few years. It is only by combining all of our resources, including GPs, addiction clinics, pharmacies and liver specialists that we will be able to address this epidemic which has a high proportion of patients on opioid therapies.
A talk was then given by Marina Davoli from Rome about the Cochrane Collaboration and internet library. Australia has had a special contribution to several areas and we have the only free access for internet users. Australian and New Zealand have also contributed much more serious research than other comparable western countries by population. This underlines all the evidence based interventions we use today.
I missed the session chaired by Dr Deborah Zador on opioid overdose but happily the conference abstracts are all available on the internet (see below). Dr Zador wrote some of the most important seminal studies on the subject in the 1990s. Two papers were given about naloxone, both its distribution amongst the drug using population and intriguingly by the intranasal route by paramedics in the overdose situation. The �Good Samaritan� provisions and international developments were detailed by Paul Dietze and Simon Lenton. [http://www.apsad2008.com/session/353.asp]
Bethany Butler reported some more results in an on-going study of several thousand NSW cases starting for the first time on methadone (~2500) or buprenorphine (~3500). There was no significant difference in the overall mortality in the groups (~65 subjects in each) but an excess mortality (~5-fold) in the methadone group in the first 2 weeks of treatment (7 versus 2). As well as direct toxicity, this might also be explained by methadone patients being in a higher risk group to start with. Even so, only a randomised trial can scientifically compare the two treatments and this is probably no longer ethical as most patients know which drug they want (see Pinto). It is certainly gratifying that when used in the normal course of practice that patients on each of these drugs have a marked drop in mortality. This study found those who remained in treatment were about three times less likely to die.
Next Louisa Degenhardt gave a paper on her group�s investigations of all deaths in NSW opioid maintenance cases since 1985, showing some differences over time. Overall 0.9% of subjects died each year of follow-up: 0.6% for those in treatment compared with 1.2% for those who had left. There was with a much higher chance of dying in the first two weeks of treatment when rate was 4.2%. This latter has dropped significantly since the early 1990s and does not apply at all to buprenorphine cases. The authors state that the treatments have the same mortality rates since those on buprenorphine have a lower retention rate, consistent with the comparative literature.
Finally, the session was given information about significant reductions in local ambulance attendances during the opening hours of the Sydney injecting centre (MSIC) as well as comparisons with the 2 years prior to its opening.
On the Wednesday morning we heard a plenary talk by Nicholas Lintzeris on the directions of treatment in the 21st century. He alluded to the shortage of doctors working in the field, the use of new medications requiring less supervision and models of treatment from elsewhere such as France. His subtext seemed to be individualising treatments rather than having rules and one-size-fits-all. He quoted the average age of methadone prescribers approaching the average daily dose! [Which is now about 75mg!] The speaker also did a study with Adam Winstock regarding attitudes towards withdrawal from treatment.
Next, those of us nursing a headache from the previous night�s dinner at L�Aqua Restaurant were given a fascinating talk by Sharon Walsh who is working in Kentucky on the effects of non-medical use of pharmaceuticals. She reminded us that in some areas there is now as much or more such abuse as for heroin. [This was also reported recently from inner Sydney in an ABC radio story which was nominated for a Walkley Award.] The emergence of prescription drug abuse may mean that we need to alter our approach and will increase the need for treatment services. Despite street and prescription drug use having essentially the same dependency diagnosis, these occur in quite different demographics (see Dr Strain�s talk from Sunday). The new RACP Policy on Prescription Opioids and Chronic Non-malignant Pain was introduced in another session, mapping out a plan for problematic use of prescription opioids in Australia and New Zealand [http://www.apsad2008.com/session/374.asp].
Dr Walsh reported on her results in human laboratory studies on oxycodone (Oxycontin; Prolodone), hydromorphone (Dilaudid) and hydrocodone. The latter is not available in Australia but is a constituent of Vicodin, a commonly abused drug in America. While hydromorphone is thought to be about 7 times stronger than morphine for its analgesic effects, in experiments on recreational users the differences between these three drugs were only marginal. [http://www.apsad2008.com/session/380.asp]
Despite running short of time, the next speaker Mark Tyndall spent some minute or two giving a hilarious description of the harm reduction aspects of pedestrians running red �WALK� signs. Next the hapless visiting Canadian described his shock at being taken to a surf beach where crashing waves buffeting swimmers who risked life and limb against the elements which were anything but �pacific� of late. His implication, I think, was that life savers are the equivalent of harm reduction services for drug users.
Returning to his subject, a square kilometre of western urban Canada, there were an estimated 6000 drug users, mostly injectors, of whom 25% had already contracted HIV and 90% hepatitis C. Services were and are grossly inadequate despite statistics which show disastrous rates of just aboot everything one would not want in one�s neighbourhood (crime, public injecting, overdose, deaths, hospital admissions, HIV cases, infections, etc). The Vancouver injecting centre is slightly larger in scale and opening hours, but shares all the essential characteristics of the Sydney injecting centre at Kings Cross (on which some say it was modelled). It has registered over 10,000 Canadian drug users (not all injectors as in Sydney). There are moves to close down this centre despite a wealth of public health research showing benefits to drug users and the community generally at modest cost (or even a net saving to the health system). Its closure would be a most pointed and poignant natural experiments in public health, comparable perhaps with the Broad Street pump exposure in London in the 1800s.
Next I attended a break-out session in which Carla Treloar spoke about the impressions people had about hepatitis C (http://www.apsad2008.com/session/388.asp). The myths were myriad. Defeatist misconceptions abounded. Some of her quotes were classics. Clearly our first job with hepatitis C is to inform people about the truth. Yes, the disease is still difficult and poorly understood. But we now have simple ways of determining the stage of the disease (�fibroscans�, risk criteria, etc) and we have reasonable and tolerable treatments with success rates up to 80%.
Nick Lintzeris reported some findings of an excellent intervention started some years ago in western Sydney in which OTP patients were offered a rapid vaccination program for hepatitis B. The results and a literature review showed that people at risk should probably be given a booster just about any time they are prepared to take one when it is available, even in quite short succession or as a booster down the line. Strict and appointment based regimens are perhaps not best suited to our patient group and so haphazard inoculations are probably more effective than no inoculations at all.
Some 9 cases of bacterial endocarditis in Newcastle area were reported next by Andrew Taylor. These formed a small minority of the total number of such cases in the region. Candida and staphylococcus aureus were common pathogens. The costs of such treatment to the health care system were high and the savings in prevention substantial.
The final segment of the conference for me at least was our own pet topic, hepatitis C outcomes. Carolyn Day, Paul Haber and colleagues reported on the barriers to addressing this public health priority (http://www.apsad2008.com/abstract/263.asp). From the low rates of assessment and treatment, even some prominent and well run clinics seem not to have effective strategies for testing and referring their patients. Some have no idea what proportion of their patients have been tested. Where resources allow, this can be pro-active, �on-site� and direct to hepatology services. Alternatively, referral to the individual patient�s GPs may be the best way to handle such matters in some situations. It is no longer acceptable to do nothing as advocated by some, claiming that �the treatment is worse than the disease�(!!). Some clinic practices seem so calcified that they have not even managed the change from methadone syrup (containing alcohol, caramel, sorbitol, gum, etc) to the safer �pink� methadone, despite majority patient support where the transfer was done some years ago (eg. NSW prisons; Rankin Court, Langton Centre, Clinic 36, Regent House, etc). At a recent health department forum at North Sydney some senior salaried clinicians described every barrier to improved treatment except themselves!
Next I moved to the session on intervention outcomes where Richard Hallinan reported our own 6 year experience prioritising hepatitis C assessments in OTP cases in Redfern (http://www.apsad2008.com/abstract/270.asp). We used some simple criteria devised by Greg Dore to indicate the likelihood of disease progression with liver fibrosis or cirrhosis. Some findings were given from 315 consecutive assessments with follow-up results for 30 cases having anti-viral treatment. Pegylated interferon alpha plus ribavirin were monitored in a shared care model with specialist hepatology services, with encouraging results thus far showing an overall 74% sustained viral response.
Comments by Andrew Byrne ..
Surgery web page: http://www.redfernclinic.com/#news
Opera blog: http://www.redfernclinic.com/opera/critique/blog/
New York in 2008: http://ajbtravels.blogspot.com/
New York diaries 1922: http://bpresent.com/harry/code/10b_bowery.php
Travel log: http://www.redfernclinic.com/c/2007/10/lord-howe-island-naturalists.php4
Vincent Dole in Nepal Diary: http://vincentdolehimalaya.blogspot.com/
Old photos of Sand Souci: http://sanssouciphotos.blogspot.com/
Reference:
Pinto H, Rumball D, Maskrey V, Holland R. A pilot study for a randomized controlled and patient preference trial of buprenorphine versus methadone maintenance treatment in the management of opiate dependent patients. Journal of Substance Use 2008 13;2:73-82
�Current policy puts too much emphasis on protecting society from methadone, and not enough on protecting society from the epidemic of addiction, violence and infections that methadone can help reduce.�
Institute of Medicine 1995
Tiny tobacco "tea-bags" commonly used in USA, unregulated!
http://www.nytimes.com/aponline/health/AP-Reinventing-Tobacco.html
Dear Readers,
This contains some information which is quite interesting. In some American states there are currently significant numbers of tobacco �suckers� compared with traditional smokers (eg. West Virginia 16% vs. 27%). Apparently these products have not been formally approved yet they were never banned and thus are legal and marketable. We await some good research on their use but most believe that they are probably safer than smoking.
Comment by Andrew Byrne .. (see excerpt below). http://www.redfernclinic.com/#news
MORGANTOWN, W.Va. (AP) -- They're discreet, flavorful and come in cute tin boxes with names like ''frost'' and ''spice.'' And the folks who created Joe Camel are hoping Camel Snus will become a hit with tobacco lovers tired of being forced outside for a smoke.
But convincing health officials and smokers like Ethan Flint that they're worth a try may take some work.
Snus -- Swedish for tobacco, rhymes with ''noose'' -- is a tiny, tea bag-like pouch of steam-pasteurized, smokeless tobacco to tuck between the cheek and gum. Aromatic to the user and undetectable to anyone else, it promises a hit of nicotine without the messy spitting associated with chewing tobacco. Just swallow the juice.
Dear Readers,
This contains some information which is quite interesting. In some American states there are currently significant numbers of tobacco �suckers� compared with traditional smokers (eg. West Virginia 16% vs. 27%). Apparently these products have not been formally approved yet they were never banned and thus are legal and marketable. We await some good research on their use but most believe that they are probably safer than smoking.
Comment by Andrew Byrne .. (see excerpt below). http://www.redfernclinic.com/#news
MORGANTOWN, W.Va. (AP) -- They're discreet, flavorful and come in cute tin boxes with names like ''frost'' and ''spice.'' And the folks who created Joe Camel are hoping Camel Snus will become a hit with tobacco lovers tired of being forced outside for a smoke.
But convincing health officials and smokers like Ethan Flint that they're worth a try may take some work.
Snus -- Swedish for tobacco, rhymes with ''noose'' -- is a tiny, tea bag-like pouch of steam-pasteurized, smokeless tobacco to tuck between the cheek and gum. Aromatic to the user and undetectable to anyone else, it promises a hit of nicotine without the messy spitting associated with chewing tobacco. Just swallow the juice.
21 November 2008
Publications from Byrne Surgery in Redfern, New South Wales.
Byrne A, Hallinan R. HIV seroconversion. [letter] ANZ J Pub Health 2002 26;2:182
Byrne A, Hallinan R, Love A. Administration of a lighter-coloured methadone liquid. D&A Review 2002 21;4:405
Byrne A, Hallinan R. The introduction of buprenorphine into a medical practice treating addiction. Monograph Byrne Surgery March 03
Hallinan R, Byrne A, Amin J, Dore GJ. Hepatitis C virus incidence among injecting drug users on opioid replacement therapy. ANZ Journal Public Health 2004 28;6:576-578
Byrne A, Hallinan R. Evaluation of accreditation of methadone clinics in NSW - Survey of clinics. Poster presentation 29;112 APSAD conference November 2004, Perth WA.
Hallinan R, Byrne A, Amin J, Dore GJ. Hepatitis C virus prevalence and outcomes among injecting drug users on opioid replacement therapy. J Gastro Hepatology 2005 20;7:1082-1086
Hallinan R, Ray J, Byrne A, Agho K, Attia J. Therapeutic thresholds in methadone maintenance treatment: A receiver operating characteristic analysis. Drug Alc Dep 2006 81:129-136
Byrne A, Graham G, Hallinan R, Murnion B. Naltrexone implants as treatment for heroin dependence: Part I. Addiction Biology 2005 10:201
Hallinan R, Ray J, Byrne A, Agho K, Attia J. Therapeutic thresholds in methadone maintenance treatment: A receiver operating characteristic analysis. Drug and Alcohol Dependence 2006 81;2:129-136
Byrne A, Hallinan R. Methadone is still needed in addiction treatments. BMJ 2006;332:53
http://www.bmj.com/cgi/content/extract/332/7532/53-a
Hallinan R, Byrne A, Dore G. Harm reduction, hepatitis C and opioid pharmacotherapy: an opportunity for integrated HCV-specific harm reduction. Drug Alc Rev 2007 26:437-443
http://www.redfernclinic.com/c/2007/06/harm-reduction-hepatitis-c-and-opioid_9756.php4
Byrne A. Safe and effective opioid prescribing in addiction treatment. Monograph of article commissioned, accepted and rejected by Advances in Psychiatric Treatment journal 2008
http://www.redfernclinic.com/c/2009/11/safe-and-effective-opioid-prescribing.php4
Hallinan R, Byrne A, Agho K, Dore GJ. Referral for chronic hepatitis C treatment from a drug dependency treatment setting, D&A Dependence 2007 88;1:49-53
http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6T63-4M69JK7-1&_user=10&_coverDate=04%2F17%2F2007&_rdoc=1&_fmt=high&_orig=browse&_sort=d&view=c&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=d58ea170adbb9c060472366c8f9fc696
Byrne A, Hallinan R, Love A. Administration of a lighter-coloured methadone liquid. D&A Review 2002 21;4:405
Byrne A, Hallinan R. The introduction of buprenorphine into a medical practice treating addiction. Monograph Byrne Surgery March 03
Hallinan R, Byrne A, Amin J, Dore GJ. Hepatitis C virus incidence among injecting drug users on opioid replacement therapy. ANZ Journal Public Health 2004 28;6:576-578
Byrne A, Hallinan R. Evaluation of accreditation of methadone clinics in NSW - Survey of clinics. Poster presentation 29;112 APSAD conference November 2004, Perth WA.
Hallinan R, Byrne A, Amin J, Dore GJ. Hepatitis C virus prevalence and outcomes among injecting drug users on opioid replacement therapy. J Gastro Hepatology 2005 20;7:1082-1086
Hallinan R, Ray J, Byrne A, Agho K, Attia J. Therapeutic thresholds in methadone maintenance treatment: A receiver operating characteristic analysis. Drug Alc Dep 2006 81:129-136
Byrne A, Graham G, Hallinan R, Murnion B. Naltrexone implants as treatment for heroin dependence: Part I. Addiction Biology 2005 10:201
Hallinan R, Ray J, Byrne A, Agho K, Attia J. Therapeutic thresholds in methadone maintenance treatment: A receiver operating characteristic analysis. Drug and Alcohol Dependence 2006 81;2:129-136
Byrne A, Hallinan R. Methadone is still needed in addiction treatments. BMJ 2006;332:53
http://www.bmj.com/cgi/content/extract/332/7532/53-a
Hallinan R, Byrne A, Dore G. Harm reduction, hepatitis C and opioid pharmacotherapy: an opportunity for integrated HCV-specific harm reduction. Drug Alc Rev 2007 26:437-443
http://www.redfernclinic.com/c/2007/06/harm-reduction-hepatitis-c-and-opioid_9756.php4
Byrne A. Safe and effective opioid prescribing in addiction treatment. Monograph of article commissioned, accepted and rejected by Advances in Psychiatric Treatment journal 2008
http://www.redfernclinic.com/c/2009/11/safe-and-effective-opioid-prescribing.php4
Hallinan R, Byrne A, Agho K, Dore GJ. Referral for chronic hepatitis C treatment from a drug dependency treatment setting, D&A Dependence 2007 88;1:49-53
http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6T63-4M69JK7-1&_user=10&_coverDate=04%2F17%2F2007&_rdoc=1&_fmt=high&_orig=browse&_sort=d&view=c&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=d58ea170adbb9c060472366c8f9fc696
12 November 2008
Methadone safe in young uncomplicated patients; check QT in older folk and those taking other drugs or alcohol, or with HIV.
Electrocardiogram characteristics of methadone and buprenorphine maintained subjects. Athanasos P, Farquharson AL, Compton P, Psaltis P, Hay J. Journal of Addictive Diseases 2008 27;3:31-35
Dear Colleagues,
These authors from Adelaide, South Australia report a relevant and reassuring ECG study from a 'normal' addiction clinic setting.
We are presented with a comparison of 35 methadone maintained patients, 19 on buprenorphine and 17 controls. Methadone doses varied from 15-145mg daily, being in the common range used clinically around the world. Most subjects were in their 30s and 28 of 71 subjects (39%) were female.
They report no significant difference between the mean corrected QT interval (QTc) of the three groups (407, 407 and 397 milliseconds). There was also no correlation found between methadone dose and QT interval. The QTc in those taking more than 60mg daily were slightly longer (405ms or 6.3%) than for those taking less than 60mg (381ms) (p=0.02). There were also some 'U' waves reported in the methadone patients. Two methadone patients and one control had prolonged QTc when defined as 430ms or longer for males (450 for females). No result was over 475ms. The threshold above which risk of torsade rises significantly is believed to be 500ms.
These findings are all consistent with the report of Lipsky et al. 35 years ago linking methadone prescription with QT prolongation and U waves. The clinical significance of these findings is still uncertain. These authors report no cases of torsade arrhythmia.
They conclude: 'Although an association is thought to exist between high methadone doses and elongated QTc, methadone and buprenorphine, at commonly used daily doses, remain safe agents for opioid substitution therapy.'
As a further exercise I contacted two prominent addiction experts in Adelaide (pop 1.2 million) on this subject. One had seen no cases and the other was aware of one possible case some years before. This is on a long background of good quality methadone treatment, both private and public, in that city.
It may be timely to examine the evidence for claims that methadone prescription in addiction treatment is accompanied by a significant risk from arrhythmias, including death. Despite there being no body of case reports in such guideline-treated subjects (or perhaps because of it) a number of authors have attempted to assess methadone's role in cardiotoxicity by using indirect and unconventional methods.
For example, Fanoe (ref below) prefers QT/torsade as an explanation for up to 30% of his subjects reporting syncope on MMT in Copenhagen. Since the incidence of torsade is certainly less than 1% annually, this explanation is not credible, especially coming from a country with extremely high alcohol statistics.
Chugh (ref below) used a methodology looking at post mortem structural heart disease in those dying suddenly with or without therapeutic levels of methadone in the blood. Their deduction for QT changes without a single case report seems hard to understand.
Wedam (ref below) wrote 'To compare the effects of [methadone] on the corrected QT (QTc), we conducted a randomized, controlled trial of opioid addicted subjects.' In fact they performed a retrospective re-analysis of old analogue ECG tracings from a 1990s RCT, finding more than 10% had QTc over 500ms. This is not consistent with other reports on the subject. No torsade cases were reported in the study groups.
A review of the world literature by Justo (ref below) found only 40 documented cases, 85% of whom had two or more risk factors. Few of these reported cases bear much similarity to those commencing 'normal' clinic or community addiction treatment. The QT/torsade cases tend to be significantly older, female sex, and to involve co-medications, very high methadone doses (up to 1200mg daily or ten-fold 'normal' doses) as well as certain metabolic (potassium or magnesium deficiencies) and genetic states (familial long QT syndrome).
I believe that it is now possible to restate unequivocally that 'normal', guideline-based methadone treatment is safe and effective. The cardiac arrhythmia issue appears to be based on a combination of factors rather than a consequence of standard methadone treatment. Knowing the other risk factors, most cases could probably be avoided using good clinical practice (see Sticherling). Routine pre-treatment cardiographs would have been unlikely to have detect any of these latter cases.
Even in the face of a dearth of relevant case reports, some have given advice to avoid methadone without due consideration of its benefits and the absence of a suitable alternative in a large proportion of cases, especially high-dose subjects (see Kakko). While methadone-induced torsade clearly can occur, the numbers appear to be exceedingly low and would probably be swamped statistically by reductions in endocarditis cases alone in those taking methadone (these and other benefits are eloquently reported by Krantz in 2001 - ref below).
In practical terms, this means that existing methadone patients needing other strong medications, methadone doses over 200mg or who develop HIV and/or have other risk factors should be recommended a cardiograph, just as they should have electrolytes, liver function tests, etc performed as a matter of clinical course.
We need to ensure that as clinicians we continue to ask the question: what is the evidence?
Comments by Andrew Byrne ..
http://www.redfernclinic.com/#news
References:
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
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
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
Sticherling C, Schaer BA, Ammann P, Maeder M, Osswald S. Methadone-induced Torsade de Pointes tachycardias. Swiss Med Wkly 2005;135:282-285
Kakko J, Gronbladh L, Svanborg KD, von Wachenfeldt J, R�ck C, Rawlings B, Nilsson L-H, Heilig M. A Stepped Care Strategy Using Buprenorphine and Methadone Versus Conventional Methadone Maintenance in Heroin Dependence: A Randomized Controlled Trial. Am J Psychiatry 2007 164;5:797-803
Krantz MJ. Clinical Concepts- Cardiovascular Health in MMT Patients. Addiction Treatment Forum 2001 No 4 http://www.atforum.com/SiteRoot/pages/current_pastissues/fall2001.shtml
Dear Colleagues,
These authors from Adelaide, South Australia report a relevant and reassuring ECG study from a 'normal' addiction clinic setting.
We are presented with a comparison of 35 methadone maintained patients, 19 on buprenorphine and 17 controls. Methadone doses varied from 15-145mg daily, being in the common range used clinically around the world. Most subjects were in their 30s and 28 of 71 subjects (39%) were female.
They report no significant difference between the mean corrected QT interval (QTc) of the three groups (407, 407 and 397 milliseconds). There was also no correlation found between methadone dose and QT interval. The QTc in those taking more than 60mg daily were slightly longer (405ms or 6.3%) than for those taking less than 60mg (381ms) (p=0.02). There were also some 'U' waves reported in the methadone patients. Two methadone patients and one control had prolonged QTc when defined as 430ms or longer for males (450 for females). No result was over 475ms. The threshold above which risk of torsade rises significantly is believed to be 500ms.
These findings are all consistent with the report of Lipsky et al. 35 years ago linking methadone prescription with QT prolongation and U waves. The clinical significance of these findings is still uncertain. These authors report no cases of torsade arrhythmia.
They conclude: 'Although an association is thought to exist between high methadone doses and elongated QTc, methadone and buprenorphine, at commonly used daily doses, remain safe agents for opioid substitution therapy.'
As a further exercise I contacted two prominent addiction experts in Adelaide (pop 1.2 million) on this subject. One had seen no cases and the other was aware of one possible case some years before. This is on a long background of good quality methadone treatment, both private and public, in that city.
It may be timely to examine the evidence for claims that methadone prescription in addiction treatment is accompanied by a significant risk from arrhythmias, including death. Despite there being no body of case reports in such guideline-treated subjects (or perhaps because of it) a number of authors have attempted to assess methadone's role in cardiotoxicity by using indirect and unconventional methods.
For example, Fanoe (ref below) prefers QT/torsade as an explanation for up to 30% of his subjects reporting syncope on MMT in Copenhagen. Since the incidence of torsade is certainly less than 1% annually, this explanation is not credible, especially coming from a country with extremely high alcohol statistics.
Chugh (ref below) used a methodology looking at post mortem structural heart disease in those dying suddenly with or without therapeutic levels of methadone in the blood. Their deduction for QT changes without a single case report seems hard to understand.
Wedam (ref below) wrote 'To compare the effects of [methadone] on the corrected QT (QTc), we conducted a randomized, controlled trial of opioid addicted subjects.' In fact they performed a retrospective re-analysis of old analogue ECG tracings from a 1990s RCT, finding more than 10% had QTc over 500ms. This is not consistent with other reports on the subject. No torsade cases were reported in the study groups.
A review of the world literature by Justo (ref below) found only 40 documented cases, 85% of whom had two or more risk factors. Few of these reported cases bear much similarity to those commencing 'normal' clinic or community addiction treatment. The QT/torsade cases tend to be significantly older, female sex, and to involve co-medications, very high methadone doses (up to 1200mg daily or ten-fold 'normal' doses) as well as certain metabolic (potassium or magnesium deficiencies) and genetic states (familial long QT syndrome).
I believe that it is now possible to restate unequivocally that 'normal', guideline-based methadone treatment is safe and effective. The cardiac arrhythmia issue appears to be based on a combination of factors rather than a consequence of standard methadone treatment. Knowing the other risk factors, most cases could probably be avoided using good clinical practice (see Sticherling). Routine pre-treatment cardiographs would have been unlikely to have detect any of these latter cases.
Even in the face of a dearth of relevant case reports, some have given advice to avoid methadone without due consideration of its benefits and the absence of a suitable alternative in a large proportion of cases, especially high-dose subjects (see Kakko). While methadone-induced torsade clearly can occur, the numbers appear to be exceedingly low and would probably be swamped statistically by reductions in endocarditis cases alone in those taking methadone (these and other benefits are eloquently reported by Krantz in 2001 - ref below).
In practical terms, this means that existing methadone patients needing other strong medications, methadone doses over 200mg or who develop HIV and/or have other risk factors should be recommended a cardiograph, just as they should have electrolytes, liver function tests, etc performed as a matter of clinical course.
We need to ensure that as clinicians we continue to ask the question: what is the evidence?
Comments by Andrew Byrne ..
http://www.redfernclinic.com/#news
References:
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
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
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
Sticherling C, Schaer BA, Ammann P, Maeder M, Osswald S. Methadone-induced Torsade de Pointes tachycardias. Swiss Med Wkly 2005;135:282-285
Kakko J, Gronbladh L, Svanborg KD, von Wachenfeldt J, R�ck C, Rawlings B, Nilsson L-H, Heilig M. A Stepped Care Strategy Using Buprenorphine and Methadone Versus Conventional Methadone Maintenance in Heroin Dependence: A Randomized Controlled Trial. Am J Psychiatry 2007 164;5:797-803
Krantz MJ. Clinical Concepts- Cardiovascular Health in MMT Patients. Addiction Treatment Forum 2001 No 4 http://www.atforum.com/SiteRoot/pages/current_pastissues/fall2001.shtml
8 November 2008
Dr Mori Krantz on cardiac protections in methadone treatment. 2001.
Krantz MJ. Clinical Concepts- Cardiovascular Health in MMT Patients. Addiction Treatment Forum 2001 No 4 http://www.atforum.com/SiteRoot/pages/current_pastissues/fall2001.shtml (Archive accessed on 25/10/08 excerpt herewith)
A.T.F. Volume X #4 Fall 2001
Clinical Concepts- Cardiovascular Health in MMT Patients
By Mori J. Krantz, MD*
According to current estimates nearly 61 million Americans have one or more types of cardiovascular disease, including coronary artery disease (CAD), congestive heart failure, and hypertension.[1] Methadone maintenance treatment (MMT) patients are clearly part of this larger demographic, and there are unique clinical characteristics in this group warranting special attention.
High Risk, Less Access
Patients entering MMT are a very high-risk population from a general health maintenance standpoint. As a rule, patients who use illicit drugs expose themselves to a number of health risks, and are less likely to regularly interface with the healthcare system. An increased reliance on emergency services and a lack of integration into healthcare delivery systems create a backdrop for poor outcomes.
The literature confirms that barriers to high quality care for cardiovascular disease are greater in vulnerable patient populations, such as minorities and the poor. A great many MMT patients fall into both of those categories.
For example, African Americans and low-income patients are less likely to receive care by a cardiologist. In contrast, white race, higher income, and college education independently predict care by a cardiologist.[2]
Available data suggest that the gap in cardiovascular disease mortality between the poor and uneducated versus the wealthy and well educated has not lessened and may be widening. The National Conference on Cardiovascular Disease Prevention concluded that to attain the goals set forth by the U.S. Surgeon General�s Healthy People 2010 initiative, we should focus on reducing disparities in health status on the basis of race, ethnicity, and socioeconomic status.[3]
To make matters worse, mainstream physicians often stigmatize MMT patients. This further distances these patients from regular, preventive health care services.
Some Specific Cardiac Risks
Endocarditis
Intravenous drug users (IVDUs) are at high risk for developing infections of their heart valves (infective endocarditis). These infections are a direct result of bacteria entering the bloodstream at the skin site of injection.
Acute infection accounts for the majority of hospital admissions among IVDUs and endocarditis is found in 10% of these episodes.[4] Most of these patients have no pre-existing cardiovascular disease.
The symptoms of this disorder may include persistent fever, chills, sweats, muscle and joint aches, malaise, and back pain.[5] These symptoms are invariably preceded by an episode of intravenous drug use.
Endocarditis has very high morbidity and mortality. It can necessitate extended intravenous antibiotic therapy and in many patients will require complex heart valve surgery or even valve replacement. Other consequences of endocarditis include brain abscess, kidney failure, and death.
MMT offers substantial protection from this deadly disease by eliminating or dramatically reducing the amount of illicit drug use. In our local hospital experience during 2000-2001, practically none of the heroin-abusing patients admitted with endocarditis were in methadone treatment programs.
Furthermore, in my oversight of hundreds of MMT patients during nearly a decade, I have encountered only 3 cases of endocarditis in that population. This evidence is anecdotal and retrospective, but supports the common sense notion that methadone treatment dramatically reduces the risk of endocarditis in IVDUs.
Coronary Artery Disease (CAD)
CAD is the number one cause of death in the Western world [1] and MMT patients are no exception. These patients may be at particularly high risk given that as many as 90% of them smoke tobacco, which is a known risk factor for CAD.[6]
Additionally, cocaine abuse is seen with some frequency in this population. Cocaine use has been linked to the development of arrhythmias, CAD, heart attack, and death.[7]
Despite the uses of tobacco and cocaine in MMT patients there have been no published reports documenting a higher overall incidence of cardiovascular disease in these patients. In my MMT practice, there are very few patients with established CAD. This is remarkable, given the fact that a significant proportion are beyond 50 years of age and many continue to smoke cigarettes.
Is there a possible explanation for this relatively low incidence of CAD in MMT patients?
The evidence is not clear. However, there is some pharmacologic data suggesting that methadone may exert a calcium channel blocking effect.[8] Calcium channel-blocking medications lead to slower heart rates and reduced cardiac work, and these agents are effectively used to treat CAD patients who develop symptoms of angina (chest pain).[9]
Also, opiates, including methadone, are known to reduce blood pressure and slow the heart rate. Morphine, for instance, is a commonly used medication to treat hospitalized patients who experience a heart attack.
Thus, due to these properties, methadone is theoretically protective in preventing or reducing cardiac ischemia (lack of blood supply to the heart).
Cardiac Arrhythmias
There is no compelling evidence in the literature to suggest that methadone treatment is a direct cause of sudden cardiac death or fatal heart rhythm disturbances.
In clinical practice, the risk of cardiac arrhythmias attributable to these treatments currently appears to be quite small. Future research and accurate incidence data will help clarify any contribution of opioid-agonist therapies to arrhythmia risk.
MMT Minimizes Cardiac Risks
Ongoing participation in MMT affords patients many heart health benefits. For one thing, these patients have significantly greater access to preventive cardiac-health services than opioid-dependent persons not in treatment.MMT patients are provided periodic monitoring of their blood pressure and pulse. Vital signs are obtained upon admission, during yearly physical exams, and during dose changes.
In my experience, this has offered a tremendous opportunity to screen patients for hypertension and then provide adequate treatment. Hypertension afflicts 50 million Americans; it is a leading contributor to CAD and the number one cause of stroke.
In my practice, a full lipid panel is obtained annually in all patients to check cholesterol levels. Those with elevated levels can be offered effective treatment with cholesterol-lowering medications, which have clearly been shown to reduce the risk of heart attack and death in patients who are at high risk.[10-12]
Finally, patients in MMT have access to frequent professional counseling, which presents ideal opportunities for discussing the importance of smoking cessation for long term cardiac health. The most common cause of death in smokers is coronary artery disease (CAD).
Stopping smoking dramatically reduces the risk of future heart attack or death. We regularly counsel patients on tobacco risks and many are able to quit or significantly reduce tobacco consumption as part of comprehensive treatment plans.
In conclusion, from a cardiovascular perspective, methadone is a safe medication and MMT program staff can perform vital roles in providing effective cardiac risk-reduction services.
References:
1. American Heart Association. Heart and Stroke Statistical Update; 1999.
2. Auerbach AD, Hamel MB, Califf RM, et al. Patient characteristics associated with care by a cardiologist among adults hospitalized with congestive heart failure. J Am Coll Cardiol. 2000;36:2119-2125.
3. Cooper R, Cutler J, Desvigne-Nickens P, et al. Trends and disparities in coronary heart disease, stroke and other cardiovascular diseases in the United States. Findings of the National Conference on Cardiovascular Disease Prevention. Circulation. 2000;102:3137-3147.
4. Murphy JG. Mayo Clinic Cardiology Review. 2nd ed. Philadelphia: Lippincott Williams & Wilkins; 2000:412.
5. Mandell GL. Principles and Practice of Infectious Diseases. 4th ed. Churchill Livingstone; 1995:748.
6. Practitioner panel: methadone and heart health. Addiction Treatment Forum. 2001;10(3):5.
7. Lange RA, Hillis LD. Cardiovascular complications of cocaine use. N Engl J Med. 2001;345:351-358.
8. Lee CH, Berkowitz BA. Calcium antagonist activity of methadone, l-acetylmethadol and l-pentazocine in the rat aortic strip. J Pharmacol Exper Ther. 1980;215(1):259-265.
9. ACC/AHA/ACP-ASIM guidelines for the management of patients with chronic stable angina. J Am Col Cardiol. 1999;33:2092-2190
10. Long term treatment with pravastatin in ischaemic disease (LIPID) study group. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. N Engl J Med. 1998;339:1349-1357.
11. Scandinavian Simvastatin Survival Study Group. Randomized trial of cholesterol lowering in 4444 patients with coronary heart disease: The 4S trial. Lancet. 1994;344:1383-1389.
12. Sacks FM, Pfeffer MA, Moye LA, et al. Cholesterol and Recurrent Events Trial Investigators. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. N Engl J Med. 1996;335:1001-1009.
*Mori Krantz, MD is Director of the Cardiovascular Risk Reduction Program, Denver Health Medical Center, and Assistant Professor of Medicine and Cardiology, University of Colorado.
A.T.F. Volume X #4 Fall 2001
Clinical Concepts- Cardiovascular Health in MMT Patients
By Mori J. Krantz, MD*
According to current estimates nearly 61 million Americans have one or more types of cardiovascular disease, including coronary artery disease (CAD), congestive heart failure, and hypertension.[1] Methadone maintenance treatment (MMT) patients are clearly part of this larger demographic, and there are unique clinical characteristics in this group warranting special attention.
High Risk, Less Access
Patients entering MMT are a very high-risk population from a general health maintenance standpoint. As a rule, patients who use illicit drugs expose themselves to a number of health risks, and are less likely to regularly interface with the healthcare system. An increased reliance on emergency services and a lack of integration into healthcare delivery systems create a backdrop for poor outcomes.
The literature confirms that barriers to high quality care for cardiovascular disease are greater in vulnerable patient populations, such as minorities and the poor. A great many MMT patients fall into both of those categories.
For example, African Americans and low-income patients are less likely to receive care by a cardiologist. In contrast, white race, higher income, and college education independently predict care by a cardiologist.[2]
Available data suggest that the gap in cardiovascular disease mortality between the poor and uneducated versus the wealthy and well educated has not lessened and may be widening. The National Conference on Cardiovascular Disease Prevention concluded that to attain the goals set forth by the U.S. Surgeon General�s Healthy People 2010 initiative, we should focus on reducing disparities in health status on the basis of race, ethnicity, and socioeconomic status.[3]
To make matters worse, mainstream physicians often stigmatize MMT patients. This further distances these patients from regular, preventive health care services.
Some Specific Cardiac Risks
Endocarditis
Intravenous drug users (IVDUs) are at high risk for developing infections of their heart valves (infective endocarditis). These infections are a direct result of bacteria entering the bloodstream at the skin site of injection.
Acute infection accounts for the majority of hospital admissions among IVDUs and endocarditis is found in 10% of these episodes.[4] Most of these patients have no pre-existing cardiovascular disease.
The symptoms of this disorder may include persistent fever, chills, sweats, muscle and joint aches, malaise, and back pain.[5] These symptoms are invariably preceded by an episode of intravenous drug use.
Endocarditis has very high morbidity and mortality. It can necessitate extended intravenous antibiotic therapy and in many patients will require complex heart valve surgery or even valve replacement. Other consequences of endocarditis include brain abscess, kidney failure, and death.
MMT offers substantial protection from this deadly disease by eliminating or dramatically reducing the amount of illicit drug use. In our local hospital experience during 2000-2001, practically none of the heroin-abusing patients admitted with endocarditis were in methadone treatment programs.
Furthermore, in my oversight of hundreds of MMT patients during nearly a decade, I have encountered only 3 cases of endocarditis in that population. This evidence is anecdotal and retrospective, but supports the common sense notion that methadone treatment dramatically reduces the risk of endocarditis in IVDUs.
Coronary Artery Disease (CAD)
CAD is the number one cause of death in the Western world [1] and MMT patients are no exception. These patients may be at particularly high risk given that as many as 90% of them smoke tobacco, which is a known risk factor for CAD.[6]
Additionally, cocaine abuse is seen with some frequency in this population. Cocaine use has been linked to the development of arrhythmias, CAD, heart attack, and death.[7]
Despite the uses of tobacco and cocaine in MMT patients there have been no published reports documenting a higher overall incidence of cardiovascular disease in these patients. In my MMT practice, there are very few patients with established CAD. This is remarkable, given the fact that a significant proportion are beyond 50 years of age and many continue to smoke cigarettes.
Is there a possible explanation for this relatively low incidence of CAD in MMT patients?
The evidence is not clear. However, there is some pharmacologic data suggesting that methadone may exert a calcium channel blocking effect.[8] Calcium channel-blocking medications lead to slower heart rates and reduced cardiac work, and these agents are effectively used to treat CAD patients who develop symptoms of angina (chest pain).[9]
Also, opiates, including methadone, are known to reduce blood pressure and slow the heart rate. Morphine, for instance, is a commonly used medication to treat hospitalized patients who experience a heart attack.
Thus, due to these properties, methadone is theoretically protective in preventing or reducing cardiac ischemia (lack of blood supply to the heart).
Cardiac Arrhythmias
There is no compelling evidence in the literature to suggest that methadone treatment is a direct cause of sudden cardiac death or fatal heart rhythm disturbances.
In clinical practice, the risk of cardiac arrhythmias attributable to these treatments currently appears to be quite small. Future research and accurate incidence data will help clarify any contribution of opioid-agonist therapies to arrhythmia risk.
MMT Minimizes Cardiac Risks
Ongoing participation in MMT affords patients many heart health benefits. For one thing, these patients have significantly greater access to preventive cardiac-health services than opioid-dependent persons not in treatment.MMT patients are provided periodic monitoring of their blood pressure and pulse. Vital signs are obtained upon admission, during yearly physical exams, and during dose changes.
In my experience, this has offered a tremendous opportunity to screen patients for hypertension and then provide adequate treatment. Hypertension afflicts 50 million Americans; it is a leading contributor to CAD and the number one cause of stroke.
In my practice, a full lipid panel is obtained annually in all patients to check cholesterol levels. Those with elevated levels can be offered effective treatment with cholesterol-lowering medications, which have clearly been shown to reduce the risk of heart attack and death in patients who are at high risk.[10-12]
Finally, patients in MMT have access to frequent professional counseling, which presents ideal opportunities for discussing the importance of smoking cessation for long term cardiac health. The most common cause of death in smokers is coronary artery disease (CAD).
Stopping smoking dramatically reduces the risk of future heart attack or death. We regularly counsel patients on tobacco risks and many are able to quit or significantly reduce tobacco consumption as part of comprehensive treatment plans.
In conclusion, from a cardiovascular perspective, methadone is a safe medication and MMT program staff can perform vital roles in providing effective cardiac risk-reduction services.
References:
1. American Heart Association. Heart and Stroke Statistical Update; 1999.
2. Auerbach AD, Hamel MB, Califf RM, et al. Patient characteristics associated with care by a cardiologist among adults hospitalized with congestive heart failure. J Am Coll Cardiol. 2000;36:2119-2125.
3. Cooper R, Cutler J, Desvigne-Nickens P, et al. Trends and disparities in coronary heart disease, stroke and other cardiovascular diseases in the United States. Findings of the National Conference on Cardiovascular Disease Prevention. Circulation. 2000;102:3137-3147.
4. Murphy JG. Mayo Clinic Cardiology Review. 2nd ed. Philadelphia: Lippincott Williams & Wilkins; 2000:412.
5. Mandell GL. Principles and Practice of Infectious Diseases. 4th ed. Churchill Livingstone; 1995:748.
6. Practitioner panel: methadone and heart health. Addiction Treatment Forum. 2001;10(3):5.
7. Lange RA, Hillis LD. Cardiovascular complications of cocaine use. N Engl J Med. 2001;345:351-358.
8. Lee CH, Berkowitz BA. Calcium antagonist activity of methadone, l-acetylmethadol and l-pentazocine in the rat aortic strip. J Pharmacol Exper Ther. 1980;215(1):259-265.
9. ACC/AHA/ACP-ASIM guidelines for the management of patients with chronic stable angina. J Am Col Cardiol. 1999;33:2092-2190
10. Long term treatment with pravastatin in ischaemic disease (LIPID) study group. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. N Engl J Med. 1998;339:1349-1357.
11. Scandinavian Simvastatin Survival Study Group. Randomized trial of cholesterol lowering in 4444 patients with coronary heart disease: The 4S trial. Lancet. 1994;344:1383-1389.
12. Sacks FM, Pfeffer MA, Moye LA, et al. Cholesterol and Recurrent Events Trial Investigators. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. N Engl J Med. 1996;335:1001-1009.
*Mori Krantz, MD is Director of the Cardiovascular Risk Reduction Program, Denver Health Medical Center, and Assistant Professor of Medicine and Cardiology, University of Colorado.
6 October 2008
More alarmist speculation on QT 'problems' yet still no incidence of actual complications. Smoke and mirrors.
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. 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.
Comments by Andrew Byrne ..
References:
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 ... http://www.atforum.com/SiteRoot/pages/current_pastissues/2007winter.html
[This summary has been up-dated, omitting an incorrect sentence.]
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. 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.
Comments by Andrew Byrne ..
References:
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 ... http://www.atforum.com/SiteRoot/pages/current_pastissues/2007winter.html
[This summary has been up-dated, omitting an incorrect sentence.]
3 September 2008
Subject: Methadone works in American prisoners who are addicted - no surprise.
A randomized clinical trial of methadone maintenance for prisoners: findings at 6 months post-release. Gordon MS, Kinlock TW, Schwartz RP, O'Grady KE. Addiction 2008 103;8:1333-1342
Dear Colleagues,
These researchers found, predictably, that offering methadone maintenance treatment (MMT) to released prisoners with a history of opiate addiction was feasible, safe and effective, just like it is in the community generally when done according to established guidelines. They compared counselling with/without MMT, finding less heroin use and less criminal activity at 6 months after release in those offered MMT. Treatment retention was also higher.
This is yet another example of American clinical practice which is decades behind other countries. And this is despite heroin addiction has been accepted as a �brain disease� by the White House and methadone/agonist treatments are now approved in every state. However, for those in the US prison system these maxims do not apply for some reason. Note that this study was not published in an American journal.
Almost uniquely, in New South Wales, prisoners have had access to methadone treatment for over 20 years. It was initially introduced in the 1980s as a pre-release measure to address the high rate of overdoses in that group. There is now a copious world literature on the subject, largely very positive. Methadone for prisoners has now been introduced in many other jurisdictions, although rarely �across the board� as occurs in New South Wales.
Thus a trial which gave some subjects no access to such treatment would be unethical, unnecessary and cruel in a �normal� jurisdiction. Yet in America, despite a large drug budget and constitutional protections, denying prisoners appropriate treatment seems to be �business as usual�. These researchers should be commended for trying to buck the trend. They write that there is an �urgent treatment need� and one only hopes that something is done for the sake of the prisoners, their families and the general community where the adverse consequences currently must be enormous.
Comments by Andrew Byrne ..
Surgery web page: http://www.redfernclinic.com/
Dear Colleagues,
These researchers found, predictably, that offering methadone maintenance treatment (MMT) to released prisoners with a history of opiate addiction was feasible, safe and effective, just like it is in the community generally when done according to established guidelines. They compared counselling with/without MMT, finding less heroin use and less criminal activity at 6 months after release in those offered MMT. Treatment retention was also higher.
This is yet another example of American clinical practice which is decades behind other countries. And this is despite heroin addiction has been accepted as a �brain disease� by the White House and methadone/agonist treatments are now approved in every state. However, for those in the US prison system these maxims do not apply for some reason. Note that this study was not published in an American journal.
Almost uniquely, in New South Wales, prisoners have had access to methadone treatment for over 20 years. It was initially introduced in the 1980s as a pre-release measure to address the high rate of overdoses in that group. There is now a copious world literature on the subject, largely very positive. Methadone for prisoners has now been introduced in many other jurisdictions, although rarely �across the board� as occurs in New South Wales.
Thus a trial which gave some subjects no access to such treatment would be unethical, unnecessary and cruel in a �normal� jurisdiction. Yet in America, despite a large drug budget and constitutional protections, denying prisoners appropriate treatment seems to be �business as usual�. These researchers should be commended for trying to buck the trend. They write that there is an �urgent treatment need� and one only hopes that something is done for the sake of the prisoners, their families and the general community where the adverse consequences currently must be enormous.
Comments by Andrew Byrne ..
Surgery web page: http://www.redfernclinic.com/
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