Latest News

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

Dear Colleagues,

This instructive case history which pre-dates Krantz’s report by several months, describes a long term methadone patient aged 39 developing ‘torsade de pointes’ a few days after starting triple therapy for HIV in the context of opioid withdrawal symptoms/signs and low blood levels. The patient also had chronic hepatitis C and epilepsy. As well as valproic acid for the latter, benzodiazepines, cannabis and alcohol were also involved in this seminal case.

The patient presented to the emergency room in opioid withdrawal. There was no electrolyte disturbance but methadone level was found to be ‘sub-therapeutic’ despite daily doses of 115mg administered by suppository (this is routinely used by some doctors in Switzerland). The QTc interval was available from a month before the episode at 480ms (normal less than 450mg).That cardiograph may have been ordered as part of a ‘work-up’ prior to starting anti-retroviral therapy but this is not detailed in the text.

While in hospital, 15 minutes following the daily rectal methadone dose the patient developed bradycardia, bigeminy and then torsade tachycardia. He was successfully resuscitated despite major seizures occurring simultaneously. The methadone was replaced by morphine 200mg twice daily which was associated with QTc interval reduction from 480 to 430ms.

Subsequent challenge a few days later with just 40mg methadone saw the QTc interval increase to 520ms and so the trial was abandoned due to the perceived risk. A cardiograph two weeks later showed the QTc interval to be still slightly elevated at 460ms despite the methadone having been long ceased. These observations are consistent with other evidence that methadone causes some modest prolongation of the QT interval and that this effect alone is generally of little clinical significance.

This patient took methadone, valproic acid, alcohol, cocaine and cannabis for at least 7 years without reported cardiac problems and so the onset of torsade during a period when the methadone level was low is hard to ascribe as a direct and dose-related effect. Rather, a combination of factors including possibly some myocardial ‘priming’ may be occurring.

This appears to be the very first of over 100 case reports in the literature of torsade de pointes in patients taking methadone maintenance for addiction. In nearly every case where details are available there were other drugs, extremely high dose, overdose, HIV and/or electrolyte disturbance reported. Pearson has called this a ‘threshold’ effect. Since methadone levels are sometimes in the low range it is possible that the drug is sometimes a ‘bystander’ while other drugs and/or the HIV virus itself might be responsible for the electrical instability in the heart.

Like others, these authors give some details of the management given to the patient. Even 7 years later, there still appears to be little agreement about an approach to treatment as cardiologists, intensivists and emergency physicians describe quite diverse approaches. These have included (1) efforts to maintain heart rate, (2) restoring electrolyte balance, (3) removal of triggering factors and (4) supportive measures. Magnesium and potassium infusions, administration of isoprenaline, atenalol, quinidine, lignocaine, amiodarone (!), glucoheptonate; implantable cardioverter-defibrillator (ICD); reducing methadone; continuing methadone; changing to morphine or buprenorphine. A review of such clinical manoeuvres by a cardiologist would be highly desirable in my view.

Instead of this logical step, Krantz and his panel have advised ‘discussions of risk’ (which are still largely unknown), pre-treatment ECG and continued QT interval monitoring. This is in the context of a lack of evidence for the effectiveness of such a strategy to prevent arrhythmias. Krantz’s group, in their extensive literature review of almost 100 papers left out numerous seemingly relevant articles (eg. Justo, Athanasos, Krook and Cruciani). It is hard to understand how the CSAT panel of experts could have completely overlooked these crucial papers, each of which is available on a simple internet search.

Further, despite the clear association with HIV infection (40% according to Justo), HIV is not even mentioned in the entire Annals paper from March 2009. The drugs gabapentin and ciprofloxacin come up in numerous reports, including 5 of Krantz’s original series of 9 pain management cases. Likewise, the issue of targeting strategies to those taking such medication is not emphasised by the CSAT panel report.

This early report from Switzerland contains some vital but conflicting evidence concerning causation. Like others, these authors find evidence of multifactorial causes for their patient’s torsade tachycardia. Yet there seems to be QT prolongation in relation to methadone dose levels, despite torsade occurring only very rarely in such cases. The cautious trial to reintroduce methadone caused QT prolongation but no arrhythmia. At the same time, it is questionable that a purported side effect of methadone would occur when the blood level was low and the patient was in a drug-induced withdrawal state.

Comments by Andrew Byrne ..

Clinic web page: http://www.redfernclinic.com/c/

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

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

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

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

Greenwald G. Drug Decriminalization in Portugal: Lessons for Creating Fair and Successful Drug Policies. Cato Institute. 2009

Dear Colleagues,

It has taken a long time, but finally we have convincing evidence, even proof, that decriminalising drugs helps drug users and society in practice. Like alcohol before it, the banning of drugs with criminal sanctions against users is a counter-productive and dangerous ‘experiment’ which should be abandoned in favour of more logical and effective ways to control drugs in society.

As a response to burgeoning drug use, the Portuguese government decriminalised all personal drug use, possession and cultivation from July 2001. The history of this goes back to at least 1996 and involved support from two successive Prime Ministers, a popular Portuguese media personality and some key legal figures at Lisbon University. There were also apparently New York and Californian connections in the lead-up to decriminalisation.

The approach taken by the Lisbon government removes legal sanctions for any adult detected with up to ‘ten days average use’ for any drug, psychoactive plant or ‘preparation’. Rather than a court, drug users who come to attention can still be dealt with by a ‘drug dissuasion commission’ (an imperfect translation I suspect). Set up in each health region, these are boards of three members including a health professional. They take into account whether the person is addicted or not and how much drug/drugs were involved. They can theoretically mandate treatment but in fact they have no power to enforce their advice, rather like medical advice for voluntary mental health cases.

Despite my best efforts to be informed, little solid evidence had emerged in the years following the removal of criminal sanctions for drug use and observers have speculated on the outcomes. Now Dr Greenwald and the Cato Institute have put together a comprehensive review which demonstrates from every aspect they examined, the exercise was beneficial. Dire predictions of mayhem from some quarters simply failed to occur. It appears that even in staunchly Catholic Portugal there is strong support for the policy and only a fringe group of activists opposes the current law.

Rather than a surge in drug use predicted by some, there were significant reductions in most types of drug use in Portugal each year following decriminalisation. While the UK topped most of the statistics for the periods covered by the report, by 2006 Portugal had some of the lowest drug use, HIV, overdose and other statistics in the entire EU. They reported no ‘drug tourism’ which some had predicted.

Holland and the state of South Australia both decriminalised cannabis use about 30 years ago and the results have been reportedly positive with few serious moves to reverse the decision. Two neighbouring jurisdictions, Belgium and Northern Territory have apparently done the same thing some years later.

Substantial resources have been redeployed from policing to treatment. I know from experience of patients who have visited that Portugal has an efficient system of well run opiate addiction clinics, for example, something which cannot be said of the UK a country which recently reclassified cannabis as being the equivalent of a dangerous narcotic and has some of the worst statistics in Europe regarding drug use and related viral infections.

Governments of all persuasions need to reduce the reliance on prohibitions or else drug related harms will continue to increase. Society generally is now sceptical of the effects of policing and is ready for change, either incrementally as done in Adelaide, but preferably ‘across the board’ as in Portugal. This very policy was proposed for Mexico but was cancelled at the last minute, probably after lobbying from an influential northern neighbour.

I would strongly recommend readers look over this 34 page report.

Comments by Andrew Byrne ..

http://cato.org/pub_display.php?pub_id=10080

http://www.cato.org/pubs/wtpapers/greenwald_whitepaper.pdf

AATOD meeting, Hilton Hotel, New York City. 26-28 April 2009
American Association for the Treatment of Opioid Dependence.
Brief and selected commentary on this talk-fest, especially cardiac matters.

Dear Colleagues,

I was privileged to attend this conference which is the successor to the long-standing National Methadone Conferences which started in the 1970s. It is essentially the meeting for the American ‘methadone clinic’ sector held every 18 months but it now draws in patient advocates, scientific community, policy makers and even an international connection with ‘EUROPAD’ and occasional delegates from the wide world (I noted several other Australians attending). I had been asked to speak at the session on cardiac consequences of methadone - see below.

After pre-conference sessions on the weekend, the official opening was an address by Karen Carpenter-Palumbo, the Commissioner for the Office of Alcoholism and Substance Abuse Services of New York State. She spoke ‘loud, brash and somewhat arrogant’, as she put it, to emphasise the scope of the problem in her state but also the contribution New York has made to policy, research and funding of drug issues over the years. She answers directly to Governor Patterson who, we were told, had just signed away some of the worst elements of the Rockefeller laws … or ‘dropped the Rock’ as she put it. Further, the Governor had stated publicly that drug users should be ‘treated and not incarcerated’ in New York State. She used many catch-phrases, sounding rather like a campaigning politician, receiving a standing ovation at the end based on her stirring the crowd. “Ladies and gentlemen, methadone IS recovery!!” She spoke so close to her microphone that it was almost painful to the ears.

The Commissioner reminded us that 44% of those entering opiate maintenance treatment now were using prescription drugs and that 33% of entrants had self-injected. To emphasise the shortage of treatment availability, we were told that 15% of Americans in methadone treatment crossed state lines to do so. There are car pools of people travelling long distances, sometimes daily, to access treatment. Some even crossed two state lines to receive medication (and probably a few taking treatment in Canada). A Detroit addiction doctor told me that many of his addicted patients had outstanding legal matters and risked immediate arrest at the border. Hence despite good treatments in Canada, this was not an option for many addicted individuals in America, even those few who might reside close to the border.

There were too many break-out sessions for me to document here but all presentations were put onto a CD which was given to every delegate. I tried to keep abreast of several of the sessions but recommend looking at the program for your own area of interest. Conference abstracts and power point presentations were contained on a CD ROM given to every delegate on registration.

Maternal and neonatal outcomes were discussed in detail by Jack McCarthy, Hendree Jones and Karol Kaltenbach in a well-attended break-out session on the Monday morning. It was pointed out repeatedly that heroin, cocaine and alcohol are all very dangerous for both mother and unborn baby. Methadone treatment can reverse many of the worst consequences of such drug use. Detoxification is still requested by some women and a number of studies were quoted, each showing high rates of relapse (40 - 96%). It was agreed by most that reductions in methadone doses could be affected safely in the middle trimester of pregnancy but that this should be gradual and ONLY if the woman was not using other drugs and/or alcohol at the time. We were reminded that there was a stronger motivation to cease tobacco, alcohol and drugs as in this important period during which so much can be accomplished with adequate support rather than coercion. Of course on the other hand, great damage can also occur when a pregnant woman with drug/alcohol problems has no access to treatment which is still the case in much of America where there are still some areas which might be mistaken for a third world country, so scarce and/or expensive are these services.

Prison systems in Philadelphia have had an experimental pharmacotherapy intervention involving over 500 inmates over a number of years and results are positive, according to John Carroll and Roland Lamb. Similarly, reports from Rhode Island at a previous AATOD meeting had also been positive. However, such reports need to be contrasted with the country’s oldest custodial methadone delivery system at Riker’s Island in New York City which has recently been threatened with de-funding of the ‘KEEP’ program by New York State. Methadone has been available for pre-existing patients prior to sentencing but not in up-state regular jails where most sentences are served. As might be expected, the experience of methadone treatment in the custodial system report positive results. The main benefit to the community we were told were the dramatically lower recidivism rates in those receiving treatment when compared to addicted folk in jail who did not receive treatment (see power point presentations for exact figures). The lack of treatment in jails is yet another American tragedy where careful research has been ignored to the detriment of the entire society.

Many of these prisoners were victims of unfair and discriminatory laws and should not have been in jail at all. The severity of sentences was discussed at another forum later that week on the Upper West Side. The Voluntary Committee of Lawyers (VCL) honoured Federal District Judge Robert W Sweet for his stance in refusing to hear drug cases in his New York District court 20 years ago. In his acceptance speech he said that he had found that 80% of the work in his jurisdiction was related to minor or personal drug use/possession which he found completely unproductive. We were reminded of the cruel sentences still handed out in some states. In Alabama, for example, it was mandatory for the third cannabis offence to receive a virtual life sentence. Fortunately many states are now coming to terms with the enormous cost of all of this futile ‘war on drugs’ due to the economic crisis forcing every aspect of state expenditure to be reviewed. There are now many instances of early release of low-security prisoners to save money. Some optimistic commentators at the AATOD conference were now saying that “the stars are lining up” for change to the punitive American approach to drug/alcohol use.

A lunch meeting was held for about 200 clinic managers, researchers and policy makers on the Monday. This was addressed by ex-marine and now Washington DC Senior Public Health Advisor - Substance Abuse, Office of Public Health, Gregory Goldstein MPH. He spoke about the competing areas and priorities for his office in Washington, starting with a briefing on the latest issue, the influenza H1N1 outbreak.

In questions from the audience Dr Mary Jeanne Kreek made a brief tribute and commentary in response to the address reminding us of her 44½ years in the field and her work on opiate receptors. She stated that we now had two ‘marvellous’ drugs for opiate addiction but that current work may well turn up other medications for amphetamine, cocaine and other addictions. She sounded more hopeful than others in the room. One wonders whether stimulant users would care to take a pill which made their stimulants inactive. Equally would those who enjoy coffee, tobacco or alcohol take an experimental vaccine to negate the effects of their drug of choice?

The final question/comment was from the conference chair Ira Marion which was to ask if President Obama might be persuaded to make a visit to a ‘methadone clinic’ [sic] to show his administration supports such services. This was taken on notice by Mr Goldstein. In response, AATOD president Mark Parrino mentioned an anecdote about such a request under a previous administration in which the person making the request was simply told that they would only ask such a question if they did not value their present job!

I was one of four speakers in a workshop and panel discussion on cardiological status of methadone patients. Dr Mori Krantz gave his case for methadone being the causative agent for QT interval prolongation and torsade tachycardia which is potentially fatal. He has stated that methadone safety is a ‘national priority’. One by one he re-quoted the numerous studies which he believes conclude that, despite no actual cases, methadone may be a cause of torsade tachycardia. Chugh, Fanoe, Martell, Peles, Lipsky and Wedam were all studies without, as far as I can gather, any documented cases of torsade de pointes tachycardia. Krantz makes it clear that the Wedam randomised trial takes away doubts about subject selection and thus increases the significance of the findings. Yet this reports relatively high rates of substantial QT prolongation in a group of relatively young, otherwise healthy ‘street heroin addicts’ (some with chronic or mental illnesses were excluded). Yet this is the very group which appears to be almost immune from ‘torsade de pointes’ judging by their absence from the detailed reported cases. Krantz was careful to point out that without actual cases of torsade de pointes, some of these studies had limitations regarding causation.

I pointed out that with so few documented torsade cases in so many cited studies, one interpretation might be that in methadone treated patients, QT prolongation does not seem to induce torsade at all (cardiologists often cite amiodarone as being in this same category). It is surprising that Dr Krantz did not cite the only literature review of torsade in addiction cases. Justo, in the Addiction journal, reported several risk factors affecting virtually all 40 documented cases he identified in the literature up to 2006. These included high dose, co-medication, HIV, electrolyte disturbance, cirrhosis and structural heart disease.

Dr Krantz and Dr Barry Stimmel described the processes of their expert panel and its decision to publish recommendations, including cardiograph tracings before treatment, at three months and annually thereafter … with additional ECGs in those taking 100mg or more daily or with positive medical histories. Neither speaker explained why their advice was contrary to that given by Krantz consistently since 2002 that routine ECG was not necessary in MMT patients. The first three speakers, Stimmel, Martin and Krantz, were all co-authors on the Annals article proposing mandatory ECGs.

Dr Krantz contends that torsade will prove to be a major contributor to the death toll of those taking methadone, despite only one report in the literature in over 40 years. He stated that deaths were increasing significantly in both addiction treatment programs and the pain management field. This is not consistent with the reference he has quoted (Ballesteros) which shows 96% of such deaths in one state were treated for pain rather than addiction. Despite Krantz’s contention, I have read no evidence suggesting increased sudden deaths in the clinic treated population.

San Francisco doctor Judy Martin said that she has been performing ECGs in all her patients for over a year. Despite this precaution, she still reported two of her patients developed torsade in the twelve month period, both apparently complex medical cases. It was hard to understand her continued staunch support for routine cardiographs for all new and continuing patients on methadone (I had a long talk with her afterwards). She stated that in her own clinic it was simple and cheap to get these tests organised. It is fortunate that her employers in California are so accommodating. In many American clinics it is still difficult to obtain even simple hepatitis C, HIV and other testing.

In the formal Q&A afterwards some simpler alternatives were raised such as ‘two finger’ tracings and automated versus manual calculations. One audience member pointed out the difficulties obtaining an accurate QTc measurement and asked whether the timing of cardiographs mattered in relation to methadone dose, meals, diurnal variation, lead placement, posture and other factors. It would seem that Dr Stimmel’s contention of “why not just do a cardiograph to define the risk?” could create a mine field for the unwary (and we now know that a cardiograph does not ‘define’ the risk of torsade to any useful degree. See Viskin et al 2005 below. Dr Martin’s final slide summarised her own clinic’s experience although did not bode well: “Doing the ECG is the least of it: evaluating and addressing contributing factors took the most time.”

In my own presentation I was at pains to point out that there were now over 70 cases of torsade in the literature and we can learn from them who is at risk (and perhaps even what to do to prevent such cases). There is no evidence that wholesale ECG tracings will prevent this complication since QTc is often normal before and after the precipitating event(s). There are many similarities in the reported cases, including very high doses (Krantz reported a mean dose of 400mg daily; Pearson 410mg), concomitant drug/alcohol use, older age groups (Krantz’s series had mean age of 49; Pearson 46) and co-existing viral infections (Justo found 16 of 40 (40%) cases were HIV positive). I could not find any cases reported from standard methadone treatment programs and there was only one single death, despite Dr Krantz’s slide stating that 8% died in Pearson’s series of 43 cases of torsade related to MMT. By my reading it was 1 of 43 (2%), not 5 of 59 (8%). Many of the latter had QT prolongation but no torsade and thus cannot be deemed ‘torsade’ deaths as Krantz has apparently done here.

I pointed out that in different ways, each of the case reports lent support to the contention, first proposed by Ellen Pearson after her FDA report, that there is a ‘threshold effect’ of methadone blood levels in which age, sex, electrolyte aberrations, structural heart disease, viral infections and alcohol can, when combined, can together cause torsade de pointes to occur.

Dr Stimmel indicated that one of the patients from 1973 with long QT had died. However, he failed to mention or include on his slide that his original report stated that the patient in question had an ‘impressive barbiturate habit as well as a sporadic history of parenteral cocaine use’ and further, that the coroner had found a fresh injection site (Lipsky). While discussing torsade and QT prolongation, Dr Krantz also put up another slide which may have been misinterpreted. It stated that Peles et al. reported 3 patients with long QT and that two of them died. Fortunately the author was actually present in the room, so Dr Peles herself was able to clarify to the audience (and the speaker) that neither of these two patients died from cardiac causes (both had confirmed non-cardiac causes of death) and hence should not be considered in the discussion on torsade de pointes.

None of the speakers alluded to the possibility that lengthened QT, high dose methadone and medical illnesses may just be ‘fellow travellers’ rather than a direct causative effect. It is clear that even significantly prolonged QTc in some groups appears to yield little or no risk of torsade in the absence of other factors, as with amiodarone, a drug which is apparently still used by cardiologists despite its propensity to cause significant QT prolongation.

Dr Gourevitch, who wrote the Annals editorial dealing with Krantz et al (2009) also addressed the workshop in question time with some clarifications. He had stated that the ‘expert panel’ had gone well beyond the research evidence in their recommendations. He emphasises that the issue is not as clear cut as the proponents had been saying in the session.

The remainder of the conference had many interesting sessions, workshops, plenaries and discussion groups on every aspect of addictions except the elephant in the room, decriminalisation of drugs for personal use which seems off limits. Medical cannabis (called “medicinal marijuana” by Americans) was mentioned frequently, as were drug courts and other moves away from law enforcement towards treatment.

Comments by Andrew Byrne ..

References:

Viskin S, Rosovski U, Sands AJ, Chen E, ... Zeltser D. Inaccurate electrocardiographic interpretation of long QT: The majority of physicians cannot recognize a long QT when they see one. Heart Rhythm 2005;2: 569-574 [Byrne commentary: http://www.redfernclinic.com/c/2009/03/inaccurate-electrocardiographic.php4

Peles E, BodnerG, Kreek M, RadosV, AdelsonM. Corrected-QT intervals as related to methadone dose and serum level in methadone maintenance treatment (MMT) patients: a cross-sectional study. Addiction. February 1 2007;102(2):289-300

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

Ballesteros MF, Budnitz DS, Sanford CP, Gilchrist J, Agyekum GA, Butts J. Increase in Deaths Due to Methadone in North Carolina. JAMA 2003 290:40

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

Gourevitch MN. First Do No Harm ... Reduction? Annals of Internal Medicine 2009 150;417-8

Editor’s response on Krantz et al: http://www.annals.org/cgi/eletters/0000605-200903170-00103v1#112632

Andrew Byrne response to Krantz et al: http://www.annals.org/cgi/eletters/0000605-200903170-00103v1#112623

AATOD conference link: http://www.aatod.org/pdfs/2009/Conference_Glance.pdf

Clinic web page: http://www.redfernclinic.com/c/

Opera blog: http://www.redfernclinic.com/opera/critique/blog/

New York in spring: http://ajbtravels.blogspot.com/

Inaccurate electrocardiographic interpretation of long QT: The majority of physicians cannot recognize a long QT when they see one. Viskin S, Rosovski U, Sands AJ, Chen E, ... Zeltser D. Heart Rhythm 2005 2;6:569-574

Dear Colleagues,

In this well conducted study from Israel 4 cardiograph tracings (2 with long QT syndrome vs. 2 normal controls) were sent to about 1000 doctors in several countries, including Australia for their assessments. Clinicians included QT interval specialists, electro-physiology experts, cardiologists and ‘other physicians’.

Correct classification of all four ECGs was gratifyingly 96% in QT specialists and their results were used as the expected ranges. Only 62% of arrhythmia experts and less than 25% of other physicians (including cardiologists) were correct in all four cases.

More than 80% of arrhythmia experts but less than 50% of regular cardiologists and less than 40% of non-cardiologist physicians calculated the QTc interval correctly in all four trial subject ECGs. Much of the inaccuracy occurred in the correction for rate - clearly many doctors did not know how to do this important step. The most common errors were underestimating the QTc of patients with long QT syndrome and overestimating the QTc of healthy patients.

While there is talk about alleged dangers of heart rhythm disturbances in association with methadone treatment, the QTc interval is often discussed as if it were a constant. Automated calculations are not dealt with in this article but their use is becoming widespread in advanced centres but is apparently rare in the developing world where most dependent individuals live. Even so, abnormal automated results are also subject to certain difficulties, needing the human touch … which from this study would still appear to be far from perfect, even in specialist hands.

This interesting report should remind us that the QT interval issue in methadone treatment needs to be looked at from a practical standpoint related to patient safety and treatment effectiveness. To date few if any young, new or uncomplicated patients treated with standard induction protocols have been reported to develop torsade. And this is despite many such patients being reported to have substantial QT interval prolongation (Wedam found >10% had over 500ms at some stage in the first three months of standard treatment).

In our own practice we have faced numerous challenges in obtaining a confirmed corrected QT (QTc) interval in those who may be at risk of torsade - largely those needing methadone doses in excess of 150mg daily. In New South Wales since 2002 there has been a requirement for a cardiograph with detailed QTc interval before patients are permitted to exceed 200mg daily dose of methadone. Our difficulties have included (1) specified QT request ignored by cardiologist, (2) a bland response: “normal tracing, including QTc”, (3) some approximate figures: eg. “QTc around 0.3ms” and (4) some results which were just wrong when checked by us. We have become reasonably adept at doing these measurements simply because of the variable results we have obtained from cardiology reports.

Of the growing number of torsade reports in the literature, nearly all are of patients with (1) multiple medical illness and/or (2) multiple drug/alcohol use and/or (3) taking very high doses of methadone (>150mg). Fortunately only one death was reported amongst about 80 such cases I found in the literature. See Justo’s review in Addiction for 40 such detailed cases up to 2006: he found virtually all had co-existing contributors over and above standard methadone treatment.

Thus we can define a sub-group of methadone patients in whom torsade may be a credible risk and act accordingly. These would include those prescribed the drug in very high dose, those over 40 years of age, female gender, co-prescribed medications, HIV infected, continued use of illicit drugs and/or those with structural heart disease. The most obvious is the co-prescription of drugs known to prolong the QT interval such as erythromycin, droperidol and cisapride.

Just doing an ECG in such cases on its own has limited if any likelihood of avoiding torsade. Most of the reported cases in the literature had a normal ECG before and/or after the torsade episode where one was available. Thus an ECG tracing in such cases is only a starting point or baseline. At best it would detect most cases of familial long QT syndrome (Smith) should this occur in a methadone patient (some may have died during exposure to illicit drugs such as cocaine or amphetamine).

Torsade has also been reported with normal and shortened QT intervals, so this is by no means a yes or no situation - like most other situations in medicine it is a continuum. This is why diagnosis should always be individual and why clinical guidelines should be reserved for particular public health priorities, and only when they are evidence based and known to do more good than harm.

Fortunately, the majority of methadone dependency patients are not in a risk category and do not need cardiography. On the other hand, most should probably be recommended hepatitis testing since this is a major public health issue and a communicable disease.

Thus, despite talk about supposed dangers of high doses, there are in fact far more dangers by using inadequate doses. This is especially so in high risk individuals such as during pregnancy, those with co-existing mental illness and/or continuing drug use. We should be confident to prescribe higher doses for those who need them, based on clinical factors with no arbitrary maximum cut-off. There are major benefits in using adequate doses as shown by many controlled comparative studies. The side effect profile is relatively low as long as patients are properly assessed. Many well run clinics have mean doses around 100mg daily which is about the same as the original report by Dole and Nyswander in 1965. Most well run clinics also have a small number of patients taking over 200mg daily due to rapid metabolism and/or high tolerance to the drug. Not all patients do well on methadone and in some countries there has been considerable experience with buprenorphine which suits a substantial minority of opioid dependent individuals.

Nonetheless, we need to remember that some patients on opioid maintenance treatments are now in the age groups which are subject to other illnesses. These include osteoporosis, hypertension, heart failure, cirrhosis, dementia, etc. These are best addressed by a well co-ordinated “shared care” model utilising family physicians and appropriate specialists.

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

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

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

Recommended audio critique of the subject by Dr Gavin Bart: https://umconnect.umn.edu/methadoneqtcscreening/

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

Dear Colleagues,

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

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

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

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

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

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

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

Comments by Andrew Byrne ..

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

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
Bell J, Byron G, Gibson A, Morris A. A pilot study of buprenorphine-naloxone combination tablet (Suboxone®) in treatment of opioid dependence. Drug Alcohol Rev (2004) 23;3:311-318

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

Dear Colleagues,

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

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

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

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

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

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

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

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

Comments by Andrew Byrne ..

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

References:

1. Krantz MJ, Martin J, Stimmel B, Mehta D, Haigney MCP. QTc Interval Screening in Methadone Treatment. Ann Intern Med 2009 150;6: (March 17 issue) http://www.annals.org/cgi/content/full/0000605-200903170-00103v1
2. Krantz MJ, Mehler PS. QTc prolongation: methadone's efficacy-safety paradox. Lancet 2006 368:556-557
3. Justo D, Gal-Oz A, Paran Y, Goldin Y, Zeltser D. Methadone-associated Torsades de Pointes (polymorphic ventricular tachycardia) in opioid-dependent patients. Addiction. 2006;101:1333-1338
4. Krook AL, Waal H, Hansteen V. Routine ECG in methadone-assisted rehabilitation is wrong prioritization. Tidsskr Nor Laegeforen 2004 124;22:2940-1
5. Athanasos P, Farquharson AL, Compton P, Psaltis P, Hay J. Electrocardiogram characteristics of methadone and buprenorphine maintained subjects. J Addict Dis. 2008 27(3):31-5
6. Cruciani R. Methadone: To ECG or Not to ECG…That Is Still the Question. Journal of Pain and Symptom Management 2008 36;5:545-552
7. Grimes DA, Schulz KF. Uses and abuses of screening tests. Lancet. 2002 359:881-4
8. Krantz MJ. Heterogeneous Impact of Methadone on the QTc Interval: What Are the Practical Implications? Journal of Addictive Diseases 2008 27;4:5-9

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.