16 November 2009

Does methadone cause QT problems or is it often viral?

HIV and Long QT syndrome - Cause or coincidence? Puri R, Roberts-Thomson KC, Young GD. International Journal of Cardiology 2009 133;1:e9-e10

Dear Colleagues,

This may be the first article to formally describe the link between HIV and torsade de pointes tachycardia and at the same time to question the role of methadone. Their single case report has much in common with others in the literature: the 36 year old female with HIV was taking long term methadone for dependency and presented with recurrent syncope. The dose was only 70mg daily at the time of the torsade but importantly, had been 190mg daily 18 months previously – at which time ECG showed the QTc to be normal - and there were no cardiac symptoms. The authors proposed that their patient did not have methadone induced QT changes, but HIV-induced long QT (LQT) syndrome. The QTc was 540ms around the time of the torsade.

These authors go on to discuss the effects of HIV on the heart. Up to 60% apparently have positive cardiac findings at autopsy and 30% of cases may have asymptomatic prolonged QTc, largely in the absence of ‘culprit’ medications (citing Kocheril 1997). “Minor repolarisation abnormalities in HIV infecteds may therefore become clinically overt in the setting of concomitant predisposing drug therapies.”

The authors state in their introduction: “Methadone use has been associated with prolongation of the QTc and an increased risk of sudden cardiac death.” In fact after 40 years of widespread use there has been no such association with sudden cardiac deaths. Yet this statement well exemplifies the current popular mythology around the subject. Since Krantz and colleagues wrote the original case series (but not the first case) in 2002, there have been no confirmed or strongly suspected deaths due to torsade tachycardia from my reading. The only 2 or 3 deaths were either remote from the period of the torsade and/or else were due to another reported cause such as myocardial infarction. French reports from over 30 years ago quote a mortality from ‘torsade de pointes’ of around 16%. Since this was before modern mobile resuscitation and pacing technologies were widespread, the survival rate of 84% might have increased to something over 95%.

It is now clear that ‘torsade de pointes’ tachycardia rarely if ever occurs in new entrants to methadone treatment. The 103 reports in the literature and Justo’s excellent summary of the field in the Addiction journal inform us that simple clinical features can highlight risk and indicate the need for ECG monitoring where appropriate. Almost 50% of the ~100 reported cases in the literature had HIV infection. The author of the original FDA report, Ellen Pearson, has postulated that QT prolongation and torsade are ‘threshold events’ with numerous contributors based on the known risk factors.

The risk factors (not in order) are:

(1) long term methadone maintenance for addiction
(2) female sex
(3) age over 40
(4) doses over 150mg daily
(5) HIV infection
(6) concomitant use of drugs which either increase methadone levels and/or prolong QT interval
(7) metabolic disturbance
(8) structural heart disease
(9) alcohol

When used with supervision and adequate supports methadone treatment for heroin addiction reduces mortality substantially. It should be used with confidence as the benefits far outweigh even the most pessimistic views of the possible side effects.

Comments by Andrew Byrne ..

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

Kocheril AG, Bokhari SAJ, Batsford WP, et al. Long QTc and torsades de pointes in human immunodeficiency virus disease. Pacing Clin Electrophysiol 1997 20:2810-6

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

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

Pearson EC, Woosley RL. QT prolongation and torsades de pointes among methadone users: reports to the FDA spontaneous reporting system. Pharmcoepidemiol Drug Safety. 2005 14;11:747-753

Methadone safe in cancer patients - minor QT problems went away after 4-8 weeks methadone

The Effect of Oral Methadone on the QTc Interval in Advanced Cancer Patients: A Prospective Pilot Study. Reddy S, Hui D, El Osta B, de la Cruz M, Walker M, Palmer JL, Bruera E. Journal of Palliative Medicine, October 13, 2009 E-pub ahead.

Dear Colleagues,

These authors have done a great service by following serial ECGs prospectively on 100 patients who were being considered for methadone treatment for advanced cancer pain. ECG was ordered at baseline, 2, 4 and 8 weeks. Due to altered medication, hospice transfers, community discharges and one death (non-cardiac) in this palliative patient population the follow up results were available for 64, 41, and 27 patients at 2, 4 and 8 weeks.

Perhaps the most interesting and unexpected findings of this study were that even before starting the medication, over a quarter of patients (28%) had QT prolongation (>430 ms in males; >450 ms in females) and this dropped. The proportion of subjects was *lower* at each of the follow-up periods with only 8-11% of patients having QT prolongation.

At two weeks 11 patients (17%) had QTc>10% above baseline. However, by 4 and 8 weeks this had dropped to one single patient (3%). There was only one ECG in one single patient where QTc increased beyond 500ms (1.6%). This was asymptomatic and not associated with any tachycardia episode. Furthermore, that patient’s prolonged QT resolved spontaneously in subsequent ECG tracings. The authors express their surprise at these unexpected findings which they ascribed partly to the high baseline occurrence of QT prolongation and/or possibly a reduction in other drugs prescribed or improvements in electrolyte disturbances.

The doses of methadone were relatively low compared to the dose levels used for addiction (median at 2 weeks 23mg daily and maximum was 90mg daily).

The authors conclude: “clinically significant QTc prolongation rarely occurred … our preliminary findings are encouraging. … we believe that methadone should be prescribed without reservations … . For patients with significant risk factors … monitoring with ECGs at baseline and at subsequent intervals may be reasonable.”

This should give doctors and patients confidence that methadone is still a safe and effective analgesic and that concerns regarding cardiac side effects may have been exaggerated out of keeping with the literature. When I contacted the study’s author I was told that they had seen no cases of torsade tachycardia in relation to methadone treatment at the MD Anderson Cancer Center to date.

Comments by Andrew Byrne ..

1 November 2009

Safe and effective opioid prescribing in addiction treatment. Article written for UK psychiatry journal.

Commissioned by editor of 'Advances in Psychiatric Treatment', accepted, paid for but never published for reasons quoted as relating to 'legal matters'. 

Safe and effective opioid prescribing in addiction treatment.

Author Dr Andrew Byrne


A large body of research supports the prescribing of maintenance opioids for heroin addiction yet poor quality treatment in the UK has limited the potential benefits. This in turn has caused many to become disillusioned about addiction treatment generally. Inadequate dose levels without the necessary supervision and psychosocial supports have both contributed to this state of affairs in the UK. By failing to address this situation, the National Addiction Centre in London has actually perpetuated it. While some progress has been made in recent years, psychiatry trainees in the UK are ideally placed to help improve the quality of pharmacotherapies in line with other European countries in moving towards an evidence base.


The principles linking opioid maintenance treatment and behavioural therapies were defined in Dole and Nyswander’s classic paper which is now one of the most quoted in the medical literature [ref 1]. Psychiatrist Marie Nyswander had noted limited success treating heroin addicts in New York using psychoanalytic techniques alone. With Dr Dole, she reported a cohort of ‘hopeless’ New York street addicts responding favourably to a trial of strictly supervised, ‘high-dose’ methadone treatment (mean 100mg/d, range 15-180) with intensive psychosocial supports. They found dramatic reductions in illicit drugs use, excellent retention in treatment along with vocational, social and other demographic improvements. The trial was radical at the time as it placed social functioning as its primary goal, rather than abstinence from all opiates. Patients received daily supervised medication and their drug use was monitored by regular urine tests as part of treatment. Many rigorous studies since have further refined ‘best practice’ and also documented safety data. These were especially important in long-term patients, pregnancy and in those with coexisting mental illness.

Over four succeeding decades, methadone and other maintenance treatments have become just one component of a more complex therapeutic repertoire for addiction including the anti-craving drugs, mood altering medications, detoxification, brief interventions, CBT, formal psychotherapy and other strategies. These are all aimed primarily at reducing the harms from drug addiction while also encouraging engagement in normal social activities. Contrary to popular opinion, the natural history of opiate use, like smoking and alcoholism, in fact moves towards abstinence, with or without treatment [ref 2].

British perspective – historical background of opioid treatment in the UK.

Due to an unwillingness of the dependency establishment to accept methadone as a valid maintenance treatment, a majority of heroin users in treatment in the UK have been subjected to a ‘culture of abstinence’. This is akin to Nancy Reagan’s retort of “just say no to drugs!” Like smokers, drug addicts are generally well aware of the dangers they are taking. Even by 1989 when methadone maintenance was being introduced into many other countries, UK treatment practise was only for short term reduction prescribing. We knew then as now that this leads to relapse in over 90% of cases.

At a time when needle sharing was still common, this caused many otherwise preventable cases of HIV. To this day, many doctors in the UK will only condone short-term, low dose methadone. Others continue to implement a punitive policy of enforced dose reductions when drug use, even non-opiate drug use, is found on urine testing. Some NHS clinics refuse to readmit their own old discharged patients for arbitrary periods, raising further barriers for those most needing assistance.

In the 1980s two forward thinking doctors introduced a more evidence based type of maintenance treatment into Scotland using GP ‘shared care’. Pharmacists were instructed (and paid) to witness the administration of liquid doses and an emphasis on rehabilitation replaced a priority of dose reductions to abstinence [ref 3]. High quality, clinic-based services were also developed in some centres in England (eg. Sheffield, Portsmouth, Manchester). Nevertheless, a large proportion of methadone in the UK was still prescribed ‘on demand’ in general practice using doses which were often inadequate and ineffective, and in settings where there was no dose supervision, little urine testing and no check on compliance. The poor outcomes led predictably to a cycle of negative attitudes towards methadone treatment which persists to the present day [ref 4]. With the unrealistic goal of short term abstinence, it is not surprising that many informed citizens, parents, police and even health workers held little confidence in methadone treatment, despite its glowing record in public health circles when properly implemented.

Uniquely in the UK, methadone and other opioid prescriptions are at least theoretically available to all addicts through the NHS. This would utilise GPs and/or specialist clinics with other health workers giving counselling and psycho-social supports which are known to improve outcomes [ref 5]. Pharmacists or clinic nurses would administer (supervised doses) and dispense (give out medication for later consumption) the medication. Guidelines were finally introduced in 1999 which incorporated what Dole in New York and others around the world had been doing for decades [ref 6]. These advised maintenance treatment and also the use of supervised dosing for new and unstable patients as well as adequate dose schedules. Yet even four years later Strang et al report that most methadone is given without supervision and in doses which are still inadequate for most to curtail injecting behaviour [ref 7].

Some jurisdictions which introduced methadone maintenance propitiously have avoided the HIV epidemic almost completely in their injecting population (Hong Kong, Australia, New Zealand). Unfortunately, for reasons which are still being elucidated, this did not extend to hepatitis C which continues to spread even where new HIV cases had almost ceased.

What is opioid maintenance treatment? What can it do? What can’t it do?

Who needs treatment? When do they need it? The first dose.

Who is best placed to provide such treatments?

So what is needed for the future?

What is opioid maintenance treatment? What can it do? What can’t it do?

Opioid maintenance treatment involves the legal prescribing of a drug of dependence to an addicted patient within a defined therapeutic framework, involving goals, support, supervision and regular review. Short term opioid abstinence is usually considered secondary to other goals such as reduced risk taking behaviour, better general health, work, education and family responsibilities.

Many things change in an addict’s life when starting opioid maintenance treatment. Studies have shown mortality declines from over 2% per years to less than 0.5% [refs 8,9]. Since there is less injecting, viral disease is less likely to be passed on by those who are already infected. As well as less injecting, employment, legal and financial matters have all been shown to improve substantially for those in treatment (Ref 9b). And the longer treatment lasts, the greater these improvements. This is not to say that everyone needs treatment indefinitely and a large proportion do successfully withdraw from maintenance opioids [refs 2, 12].

Only a very small proportion of patients will successfully withdraw from the opioid treatment in the short term and still remain opiate abstinent [ref 9b]. This is probably less than 10% of the total, even though many more express a desire for such an outcome. Hence all opioid dependent patients should have access to continuing prescribed opioids and those who discontinue should be encouraged to seek supports which seem appropriate for the individual.

Who needs treatment? When do they need it? The first dose.

A careful assessment is essential in any patient presenting with drug or alcohol problems. This involves a thorough history, physical examination (pupils, mental state and injecting sites as a minimum) and usually a supervised urine test and blood tests including liver function, hepatitis B/C, HIV status, etc. As for other medical prescribing, the necessary minimum includes both a clear diagnosis and, usually, the failure of non-drug treatments. In practice, the need for opioid maintenance is relatively easy to establish, except in the very young or in those with concurrent medical or psychiatric illness. The diagnostic criteria for opiate dependence involve compulsive self administration, escalating doses, withdrawal effects and usually, documented adverse health and social consequences. It is important to document all of these clearly in the patient record before prescribing any medication. In addition, the patient’s identity and some aspects of their past treatment history needs to be confirmed.

To make our job easier, patients may have ‘self-selected’ by seeking out a doctor or clinic where dependency services are available. Some may not want methadone but seek other medications to assist with detoxification. Such patients should be informed of the benefits of maintenance therapies in case their detox episode is unsuccessful. All patients should be informed about self help groups including AA, NA and the new SMART Recovery movement [ref 10].

Most patients will have a substantial history of heroin or other opioid use, often by injection and with documented complications, end-organ damage, legal, financial and social consequences. Venous scarring is the most obvious sign of long term history. The drug use may take the form of injected heroin, black market methadone, codeine, morphine, opium or even poppy seeds in rare cases. As long as the use is consistent and compulsive with tolerance and withdrawal symptoms/signs the criteria of dependency are fulfilled. It is helpful to use the DSM-IV definition although it must be remembered that this was devised for use by private American psychiatrists and there may be occasional deviations in ‘normal’ countries.

In patients who are very young (under 18 years) or who have unstable mental illness, it is important to ascertain that opiate opioid maintenance therapy is indeed the most suitable option at the time. Some such patients may develop a mistaken notion that they need prescribed opiates opioids. They may also give a credible history of dependence. This always needs to be carefully corroborated with physical examination and urine testing. This is especially so if there are no venipunctures, no history of hepatitis C, overdose, financial, legal or other consequences of opiate dependence. In such sensitive cases it is prudent to seek a written opinion from a colleague to ensure that other forms of treatment may not be more appropriate. This may be the patient’s own GP or consultant who has been involved. In some jurisdictions parental permission may be required at this age. Health authorities or family services may also have to be involved in under-age cases, with details varying between jurisdictions.

As with other major treatment decisions, the patient should fully informed about its nature. This essential information should be given verbally, allowing for questions, as well as in writing. Various documents are available on the internet for patient education. Some documentation of consent should also be obtained in the patient records. Patients need to know that both methadone and buprenorphine have benefits and also certain side effects such as headache, constipation and sweating. The issue of cardiac conduction defects has never been shown to be a problem in patients being treated under dependency guidelines. However, for those taking higher doses (>150mg daily) or with other risk factors a cardiograph is a prudent step [ref 11].

Although many patients do attain opiate abstinence, methadone and buprenorphine treatments are not ‘cures’ for addiction. Patients should be aware that this is a treatment which requires regular attendance for medication, medical reviews, counselling and urine testing. They should also be informed that this treatment often lasts for months and sometimes for years. The myth of methadone being “for life” has been disproved by longitudinal studies with acronyms NTORS, ATOS, etc [ref 12]. Gossop points out that because clinics see successful patients less often than others, staff may develop the incorrect impression that few ever successfully withdraw from treatment.

Patients often arrive in distress and dismay, wanting to get into treatment urgently. It is still essential to ascertain who needs opioids and who may be more appropriate for detoxification services. Just because a patient says that they are in withdrawals does not mean that a doctor must write a prescription for opioids, although this should always be seriously considered as an option. Prescribing always has more predictable outcomes than detoxification. The doctor takes responsibility for the former and the patient the latter. Vincent Dole, the co-inventor of methadone treatment, said that “detoxification is an experiment in the life of the patient”
Who is best to provide such treatments? How is it done?

The delivery of methadone can occur in either the specialised clinic setting or in existing community facilities. There are advantages and disadvantages to both types, but ideally, new and unstable addiction cases would be treated in a specialised clinic. This allows close supervision for a period, after which stable and longer term patients could be referred back to GPs and pharmacists for community treatment. In practice there are usually more patients than services available so any treatment opportunity will have immediate applicants, most of whom are assessed as appropriate for maintenance treatment.

As with other acute presentations, one cannot do everything in the first consultation. However the basics need to be organized and a decision taken promptly as to whether or not the patient is to be prescribed opioids in a treatment ‘program’. At that point, one can afford to put off certain other matters until the patient feels better and has more confidence and familiarity with the staff and treatment setting. Another essential detail at this point is whether the patient has adequate housing considering they may be dispensed bottles of strong medicine. Also one needs to find out if there are children in the house and stress the importance of safe drug storage out of their reach.

The first dose.

The patient should usually be given a starting dose of 30mg with small increases in subsequent days up to the usual effective dose of 60 – 120mg. If given too quickly, drug accumulation can cause fatal toxicity so vigilance is needed in the first two weeks when this can occur. An additional 5 to 10mg every 2 to 3 days is usually a safe increase. On the other hand, if doses are kept too low, some patients will drop out while others may continue to use street drugs and/or alcohol. In some clinical settings it may be possible to give supplementary doses later the same day but only if the prescribing doctor has examined the patient 2 to 4 hours after the first dose. Where supplements are given, the second day’s dose should normally be the sum of the first day’s doses as long as there is no sign of toxicity.

Inductions onto buprenorphine are not as critical since early overdose is not a problem owing to the “ceiling effect” for respiratory depression. Most start with 4 to 8mg as a supervised sublingual dose, increasing only after 3 to 4 days when steady-state levels are achieved in this very long acting drug. Supplements may also be given, but these should be considered ‘loading doses’ and may only be needed in the first few days. The usual effective dose is 6 to 16mg daily with only a small proportion requiring more or less than this level. 32mg is the maximum daily dose.

Patients often know from previous experience how much they need and which drug suits them best. About a third of heroin addicts treated with buprenorphine will continue to feel drug cravings even when doses have been raised to the maximum of 32mg daily [ref 13]. Such patients usually do well on methadone using standard doses. For this and other reasons, methadone is probably still the best first line drug. A smaller proportion of methadone patients report unacceptable side effects such as sedation, sexual dysfunction, constipation or sweating and a transfer to buprenorphine can be very rewarding. However this can only be done ideally when the methadone dose has been reduced below 40mg daily due to the potential for a precipitated withdrawal episode as the partial opioid agonist buprenorphine replaces the full agonist methadone. This can be very unpleasant although it is usually short lived, in most cases less than one hour.

The first month of treatment is crucial to long term success. Hence it is essential to engage with the patient and establish a confident and professional relationship. This will involve all health care workers from reception staff to nursing, medical and pharmacists.

As with other conditions, management involves educating our patients, prescribing medications judiciously and supervising and monitoring progress. As with diabetes, depression or blood pressure, there is wide variation in views about how frequently patients may need to see a doctor, counsellor, pathology service or pharmacist. But the general principle is that new and unstable patients need more frequent and intensive involvement than long-term stable patients. Where there are psychologists, counsellors and other staff medical visits may be less frequent after the first month of treatment. There should be a formal interview each week until the patient shows signs of stability, then 2 to 4 weekly consultations should suffice for a year. Even very long term patients should probably see their prescriber every two months at a minimum.

Urine testing.

All patients who have come to the attention of dependency services should probably have urine testing at some frequency. This is essential at the initial assessment and twice yearly urine toxicology is probably a minimum for any person prescribed take-home doses of opioids, probably including pain management cases. Tests should be ‘supervised’ to some degree. The most useful tests for research or legal purposes will be directly witnessed and done at random. This is not always practical, nor is it necessary in most cases in clinical practice, unless the patient needs to prove their status for legal, family, sporting or sensitive employment matters. It is usually sufficient to ask for a urine test on a particular consultation day and have the staff test the temperature of the specimen. This may be done manually or using adherent temperature sensitive strips.

The interpretation of urine testing involves distinguishing non-specific ‘opiate’ positive tests from ‘morphine’ which is the breakdown product of heroin. One must take into account the half-lives of the cannabinoids, benzodiazepines, cocaine, amphetamine, etcetera. There should be no punitive outcomes from urine tests and these should only be used as a clinical indicator.

Dose supervision.

For new and unstable patients, as with other areas of medical practice, outcomes are directly related to compliance. The treatment of malaria, TB and HIV have each been shown to improve with directly observed treatment [refs 14,15]. Likewise with opioid therapies, witnessed doses improve outcomes and reduce the scope for diversion. In practice, most patients can be successfully treated by attending one to three times weekly depending on time in treatment, stability and dose level. The uniquely British practice of attendance at the pharmacy every one of two days to take bottles of medicine home is not based on any research and should be abandoned.

Cardinal rules for methadone:

The effective dose is generally 60-120mg daily with a small proportion needing more or less that this range due to unusual metabolism or tolerance. No more than 30mg should be given as a starting dose with increases of 5-10mg every 2-3 days, more rapidly only where close medical supervision is possible. Methadone should be avoided with fluvoxamine (inhibits metabolism), phenytoin or carbamazepine (induce metabolism) or pentazocine (may precipitate withdrawal, like buprenorphine). Special precautions are also necessary with various anti-HIV and TB drugs which may increase or decrease blood levels of methadone. Even grapefruit juice, with its effect on the cytochrome P450 enzymes can reduce methadone metabolism and raise levels. The principle is to carefully monitor any patient who is prescribed other drugs and be prepared to raise or lower the dose as appropriate – an examination 3-4 hours post-dose for signs of intoxication, and 24 hours afterwards for signs of withdrawal is generally more useful than measuring methadone blood levels [ref 16]. Patients should be warned not to drive, operate machinery or look after children until they are stable.

So what is needed for the future?

Treating addictions can be enormously rewarding and one does not have to wait for years to see the fruits of interventions. Many of these patients are ‘survivors’ who have enormous energy and resources which they often use to turn their lives around while in treatment. A ‘lapse’ back to drug use does not imply failure, but may mean that more attention needs to be paid to treatment. In cases of ‘relapse’, a second attempt at treatment is more likely to be successful than the first, especially if depression and anxiety are correctly dealt with.

All psychiatrists should be comfortable with treating dependency problems. There are some parallels between the management of nicotine, alcohol, opiate and stimulant addictions. Each has a behavioural and a chemical component. We should be aware of the differences and the similarities, each requiring appropriate interventions when required. Addictions are still inadequately covered in most undergraduate and family medicine training. Indeed, there was a time when some considered substance dependency not to be an area for doctors, nurses and pharmacists at all!

It is essential that consultant psychiatrists know how to set up and run a dependency unit within a community hospital setting. These will have the ability to take referrals with a view to assessments and a range of treatments, both medicated and non-medicated, based on rational, practical and cost-effective principles. As with general psychiatry, the great majority of such cases can be handled as out-patients but a small sub-set will need hospital admission. As with alcoholism, needs may vary from just brief respite care to acute care and intensive treatment. All the same principles of good medical practice should apply just as in every other medical specialty. While in treatment special attention needs to be paid to other areas of risk such as hepatitis C and other communicable diseases [ref 17].

Opioid maintenance treatment should be considered for all those who are addicted to either street heroin or pharmaceutical opioids and who are unable or unwilling to cease using such drugs. The same could be said for nicotine or, indeed, many medical situations where prescribing is only appropriate when non-drug approaches have failed or are inappropriate (eg. diabetes, hypertension, hyperlipidaemia).

For reasons which would be unacceptable in other fields, deficiencies in dependency treatments in the UK have undoubtedly contributed to the epidemics of HIV, hepatitis C, overdose and other consequences of addiction. It may take many years to turn these deficiencies around. Conceding them would be a great starting point. Methadone treatment has long been treated with great suspicion by the addiction ‘establishment’ in the UK. Indeed, Professor John Strang of the Maudsley Hospital has revealed his own misgivings about methadone by claiming that, despite its known benefits, it may have a ‘bitter final pathological twist’ (ref 18). Such personal reservations stand in stark contrast to 40 years of positive research findings, much published in the high rating journal, Addiction, of which he is an assistant editor.

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Declaration of interest:
Dr Byrne’s addiction clinic charges a fee for dispensing methadone and buprenorphine.

8 September 2009

Torsade rarity: Annals responses argue ECG ineffective and unnecessary before MMT.

Krantz et al, Annals of Internal Medicine March 17: letters in reply, Aug 4 2009.


Dear Readers,

Each of four responses to this item was strongly critical of the position or Krantz et al. regarding cardiac safety in methadone patients. Apart from my own small contribution, there were considered responses from physicians and alumni of Johns Hopkins, Harvard and Rockefeller University as well as the medical director of a network of private addiction clinics treating 5000 methadone patients in California. There was no letter in support of Krantz et al and their “guidelines”.

Despite my written requests to Drs Krantz, Stimmel, Haigney and Martin, there is still no indication from these authors on the proposed means whereby regular ECG tracings would or could prevent torsade tachycardia from occurring in MMT patients. It would seem incumbent on Dr Krantz and colleagues to explain just how they anticipate the published recommendations might reduce cardiac side effects, and further, what might be the downside of the recommendation in terms of barriers to methadone treatment for those who want and need it both in developed and developing countries.

Krantz has written that cardiac safety in methadone treatment is a ‘national priority’ and that torsade is ‘potentially fatal’. Yet in 40 years there has still not been one confirmed death due to this complication in a methadone patient I can find in the literature. Out of ~100 case reports the great majority had complex medical scenarios including HIV, existing heart disease, metabolic disturbance and/or taking exceedingly high doses (mean 400mg daily in Krantz’s original report). These would only represent a small minority of those being assessed in addiction clinics around the world.

It is difficult to accept these guidelines in their present form when the main authors simply deflect criticism from senior colleagues rather than responding to it - see their response to the four letters.

Two original panel members declined to be associated with the publication and its recommendations. Their names were on the original internet version published around 1 Dec 2008 and now withdrawn. To my knowledge their dissenting views have not been published although the Annals editors took the rather unusual step of writing their own rapid response pointing out some of the facts following my initial communications: http://www.annals.org/cgi/eletters/0000605-200903170-00103v1 (‘Putting the cart before the horse’). They also published a balanced and well considered editorial in the same hard-copy edition by Gourevitch.

I am still persuaded by the advice given by Dr Mori Krantz consistently from 2002 up until his Annals article this year that ECG is unnecessary before starting methadone treatment unless there is a specific indication (*see his quotes below). This is parallel with the views of other respected authors such as Krook, Athanasos, Gourevitch, Kreek, Bart and others.

We need a high level of awareness for numerous diseases and complications in older addiction patients. Cardiac conduction disturbance is just one of many such areas that we need to deal with. Although cardiac problems are dwarfed in scope by many other problems such as blood borne infections and hormonal imbalance, they should not be overlooked in known high risk groups.

In our own practice we generally order an electrocardiogram when the methadone dose exceeds 150mg daily and/or when there are other risk factors such as HIV, older age or other drug prescription known to affect methadone metabolism or cardiac conduction.

Comments by Andrew Byrne .. http://www.redfernclinic.com/c/

Original article: http://www.annals.org/cgi/content/full/0000605-200903170-00103v1

Krantz on cardiac health in MMT patients (2001): http://www.atforum.com/SiteRoot/pages/current_pastissues/fall2001.shtml#anchor1222388

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

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

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

*Krantz MJ, Mehler PS. QTc prolongation: methadone's efficacy-safety paradox. Lancet 2006 368;9535:556-557 (quotes herewith from page 557)
“… we do not believe that routine ECG screening is warranted for heroin addicts entering treatment.”
“… we believe that the decision for ECG screening should not only be informed by the patient’s arrhythmia risk factors but also by the dose of methadone received.”

Possibly the last word: 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#anchor1222388

30 June 2009

Cardiac complications in long-term methadone patients seem to be due to diverse factors.

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/


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

22 May 2009

Drug decriminalisation in Portugal successful after 8 years.

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 ..



20 May 2009

New York addiction conference April 2009

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 ..


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/

11 May 2009

Measuring QT interval: more complex than you may think!

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 ..


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/

20 March 2009

Does adding an antagonist reduce injecting?

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

Dear Colleagues,

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

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

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

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

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

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

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

Comments by Andrew Byrne ..

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


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

7 March 2009

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

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

Dear Colleagues,

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

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

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

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

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

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

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

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

Comments by Andrew Byrne ..

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


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

6 March 2009

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

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

Dear Reader,

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Derivative internet summaries:

Comments by Andrew Byrne ..

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


Justo D, Gal-Oz A, Paran Y, Goldin Y, Zeltser D. Methadone-associated Torsades de Pointes (polymorphic ventricular tachycardia) in opioid-dependent patients. Addiction. 2006 101:1333-1338

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

Ehret GB, Voide C, Gex-Fabry M, Chabert J et al. Drug-Induced Long QT Syndrome in Injection Drug Users Receiving Methadone: High Frequency in Hospitalized Patients and Risk Factors. Arch Intern Med 2006 166:1280-1287

Wedam EF, Bigelow GE, Johnson RE, Nuzzo PA, Haigney MCP. QT-Interval Effects of Methadone, Levomethadyl, and Buprenorphine in a Randomized Trial. Arch Intern Med 2007 167;22:2469-2473

Pearson EC, Woosley RL. QT prolongation and torsades de pointes among methadone users: reports to the FDA spontaneous reporting system. Pharmcoepidemiol Drug Saf. 2005 14;11:747-753

Krantz MJ, Lewkowiez L, Hays H, Woodroffe MA, D. Robertson AD, Mehler PS. Torsade de Pointes Associated with Very-High-Dose Methadone. Ann Intern Med. 2002 137:501-504

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

Peles E, Bodner G, Kreek MJ, Rados V, Adelson M. Corrected-QT intervals as related to methadone dose and serum level in methadone maintenance treatment (MMT) patients - a cross-sectional study. Addiction 2007 102;2:289-300

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

Martell BA, Arnsten JH, Krantz MJ, Gourevitch MN. Impact of methadone treatment on cardiac repolarization and conduction in opioid users. Am J Cardiol. 2005;95:915-8

Other references on request.