28 August 2012

RPAH Grand Rounds were indeed GRAND!

Grand Rounds at Prince Alfred circa 1975. An institution within an institution.

Recently I chanced to meet two senior medical colleagues who had participated in the Grand Rounds at Royal Prince Alfred Hospital for the years that I was a student and resident there in the late 70s. These were Friday afternoon sessions in which two cases were presented plus one or two follow-up cases from the senior registrars involved. The two regular attenders were Dr John Hallinan, chief radiologist and Dr John Emder, a senior local GP and probably one of the last GPs ever to be allowed in the doors of the hospital in the great age of the specialist.

Medical Grand Rounds was a long standing venerable tradition at the hospital according to my father who had been a resident there around 1950. The Scot Skirving lecture theatre was a windowless Victorian conclave between A2 medical ward and the small veranda ward used for peritoneal dialysis. There was an element of anticipation each Friday afternoon as hurried last minute pathology results or research papers were incorporated into the presentations, some of which were so notable (or notorious) that some of the audience already met the patient(s) involved in our own ‘rounds’.

Some of the more exotic diagnoses included myasthenia gravis, osteogenesis imperfecta (the only time in my experience that an actual patient was wheeled into the hall), lacunar stroke, dissecting aneurysm, carotid sinus syndrome, hairy cell leukaemia, cerebral lymphoma, mononeuritis multiplex, small bowel leiomyosarcoma, splanchnic claudication, ‘HHH syndrome’ (later called AIDS), methicillin resistant staphylococcus infection, cardiac tamponade, mixed connective tissue disease, idiopathic thrombocytopaenic purpura, systemic lupus erythematosus and narcolepsy/cataplexy.

Dramatis personae: The main characters of this high academic drama included the following: Prof Ruthven Bickerton Blackburn (lord high physician and usual chair person), Prof Tony Basten (immunology), Prof Martin Tattersall (oncology: “I do not treat the relatives”), Prof Anne Woolcock (respiratory medicine … and in real life, wife to Prof Blackburn), John Greenaway (possibly the last physician in Macquarie Street), David Tiller (who could derive a social profile from a biochemical one), John Hassall (rheumatology).

Less often, and sometimes on special occasions, there would be guest appearances from Prof Jim McLeod (neurology and dean of faculty), Harry Kronenberg (haematology), John Allsop (neuro), John Turtle (endocrine), Richard Benn (bacto), Geoff Duggin (renal), Warwick Selby (gastro), John York (rheumatology), Dick Richards (cardio), Lou Bernstein (cardio staff), Rodney Shearman (gynae), John Sands (of the games fame), Frank Harding Burns (notionally drug and alcohol and an advocate for God and moderation), Geoff McDonald (another of the few Catholics), and perhaps a dozen others.

The senior registrars at the time were amongst the most gifted young doctors in the country, including Michael Field, Michael Halmagi, Roger Tuck, Ian Caterson, Bill Bye, Stephen Lee, Sheryl Van Nunen, Geraldine Room, Paul Russell, Ben Friedman and many others.

Classic statements:

“Myaesthenia gravis is called gravis because it IS ‘gravis’”.

“Sjogren’s syndrome does not require the existence of a rash”. Response from up-start registrar: “When I worked with Dr Sjogren in Stockholm he used to say otherwise”.

‘The only five medical causes of abdominal patient are myocardial infarction, diabetes, familial Mediterranean fever, porphyria and tabes dorsalis.’

After a long and tedious discussion about a patient with auto-immune cold agglutinins, cryoprecipitins and acute renal failure Dr Jonathan Leicester, who was not associated with the case, commented in his slow, measured way: “I wonder if the patient just had a chill on the kidney?” (huge laughter from the audience).

Dr John Greenaway (leaning over the wooden railing, frowning sternly): “Mr Chairman, I would take to task the treating team over all these investigations!”

Mr Bruce Leckie (thoracic surgeon invited concerning a chest lump, possibly parathyroid): “Look, Mr Chairman I have been sitting here for 30 minutes listening to all these differential diagnoses, fancy test results, nuclear scans and other learned speculation. In that time, I could have made a small incision in the patient’s side, exposed the lesion and in all probability, cured it. I’m afraid I have to go back to work!”

I have always enjoyed being a fly on the wall but after three years of passive attendance I was finally asked to present a case when working for the neurology team in C1 ward under HMOs McLeod and Allsop. It may have been posterior inferior cerebellar artery (PICA) syndrome and I did not do the case justice.

I had the misfortune to speak French better than John Allsop which put me on the back foot as he looked after the private patients from Noumea who would be brought from the airport by ambulance once weekly for triage. They would have all manner of interesting diseases, mostly strokes, but also myopathies, epilepsy, neuritis, tumours and other differential exotica. John’s speciality was demonstrating gait disturbances, sure to trigger the funny-bone of each new cohort of students as he looked like Quasimodo lurching large.

In attending RPAH Medical Grand Rounds I was immensely privileged to be witness to this magnificent piece of medical history the likes of which have probably not been seen before or since in this country. Who in their right mind would expect a high-powered group of people to muster at 5pm on a Friday these days unless it was for a keg of beer and a music box? In fact the latter occurred slight later on a Friday at the Gross Farm Hotel nearby in Missenden Road.

Written by Andrew Byrne MB BS FAChAM (RACP)
Dependency Physician
75 Redfern St
Redfern 2016
9319 5524

[with thanks to John Byrne, Richard Benn, Martin Tattersall, John Hallinan, John Hassall and John Emder.] 

  This item was 'politely declined' by MJA as being too Sydney-centric for their Christmas edition.  Such is life!

Rare non-fatal cardiac risk should not discourage the use of adequate supervised methadone doses which save lives.

Increased incidence of QT interval prolongation in a population receiving lower doses of methadone maintenance therapy. Roy A, McCarthy C, Kiernan G, McGorrian C, Keenan E, Mahon N, Sweeney B. Addiction 2012 107;6:1132-9

Dear Readers,

These Irish researchers examine QT intervals in relation to methadone dose, cocaine, opiates and benzodiazepine use in 180 stable maintenance patients (total clinic population 376). They find that 9-11% have ‘drug induced’ QT prolongation despite finding no relation to daily methadone dose (which was a healthy mean of 80mg, SD 27mg) and no control group. Nor was there any relation between QT interval and the presence of cocaine in toxicology tests.

The article’s title makes an implication about the relevance of high versus low dose methadone in relation to QT prolongation. Yet the very first report of nine dependency cases had six taking less than 130mg daily and four taking less than 100mg (ref 1 - but see below why this cannot be gleaned from the paper directly).

QT prolongation has been reported in a high proportion of potential methadone recipients, but who were not actually taking methadone at the time. In hospice patients being considered for methadone treatment Reddy found QT prolongation in 28%. Lipski and her colleagues in 1973 reported 19% of street heroin users had QT prolongation before starting methadone treatment.

It is clear that a population of patients taking a variety of medications and with certain underlying illnesses such as HIV and hepatitis C are at risk of having QT prolongation, quite apart from any methadone treatment. Alcohol is also believed to be a risk factor [ref 4]. With a lack of any reported cases of this arrhythmia in 37 years, one might reasonably infer that this issue was not a major clinical problem in methadone prescribed patients.

Yet in the past decade there have been just over 100 reported cases of torsade in methadone patients. So, as our patients have survived their addiction, viral infections (and especially treatment for those infections), a small proportion have reached an age at which they have become susceptible to a rare clinical entity which most large centres have now seen at least once. Torsade de pointes was so rare amongst methadone recipients in 2002 that it was thought to be a new entity [see ref 13 for an earlier report]. Yet torsade de pointes was delineated and re-branded in the 1960s by a French group (no relation to methadone which was not used in that country at the time) [ref 11]. In 1985 another French group also provided a systematic approach to torsade treatment such that for eight years they had a mortality of zero [ref 12].

One may ask why we do not see more torsade de pointes since QT prolongation has a high prevalence in out treatment population. In a RCT Wedam [ref 8] found ~10% of new methadone recipients in Baltimore had QTc > 500mg (but no torsade cases), yet contrary-wise nearly all of the reports of torsade are in longer-term patients [ref 5 and pers comm].

So QT prolongation, even at the level of greater than 500ms in this population of methadone recipients does not appear to confer a measurable risk of torsade de pointes tachycardia (and numerous torsade cases had normal ECG away from the arrhythmia episode).

While torsade is symptomatically a distressing and unpleasant condition, it is rarely if ever fatal and is “controllable 100% of the time” with modern treatment, according to US cardiologist Phibbs [ref 6].

Suggestions from some quarters that there may be large numbers of unrecognised deaths due to torsade are not credible for two reasons: (1) deaths of patients on methadone programs are reportedly very rare and (2) such deaths are usually rigorously investigated by coroners and positive findings are the rule with only very occasional ‘unknown causes’ which might include a fatal arrhythmia [Anchesen; Perrin-Terrin, refs 9 and 10].

It is regrettable that in his seminal article on the subject Krantz did not delineate pain from addiction subjects [1]. This appears to have caused a decade of confusion about the supposed effect of extremely high doses of methadone (see Annals Editorial comments relating to “very-high-dose methadone”). When the cases were separated for the reader in a follow-up paper [7], it became clear that torsade may occur in those taking average doses as well as with the supra-therapeutic doses cited by Krantz’s group (up to 1000mg daily in the pain cases). Yet only two of nine addiction cases were taking such doses when developing torsade de pointes. Six of the nine were prescribed between 65mg and 125mg (mean 96mg), which are dose levels found commonly in methadone maintenance treatment reports. There were no deaths among these nine MMT patients. Indeed there are no documented torsade deaths in MMT as far as I can find in the entire literature (one suspected death in France has been reported).

Krantz’s finding of nine cases of torsade in a small catchment over a relatively short period remains to be explained as it has never been duplicated anywhere else in the world to my best knowledge. Most reports have been of one or two cases. One wonders if there were other factors at play such as a viral induced cluster, the high altitude in Denver or some other factor unique to Krantz’s area.

It is often instructive to go back to the original sources and while most cite Lipski et al., few seem to have actually read the paper which is elegantly written. Even some major authors on the subject apparently believed that Lipski and colleagues were examining the effect of methadone on the QT interval. They were in fact examining why so many heroin users in New York died of apparent overdose but with relatively low levels of morphine at post-mortem examination, proposing arrhythmia in some such cases (from heroin or other street drugs). As they had no way of testing QT effects from heroin, ECG changes were examined in new entrants to treatment at their methadone program (which closed down recently, to the shame of the otherwise venerable Mt Sinai Medical Center in northern Manhattan).

In short, these early researchers performed 12-lead cardiographs on 75 patients new to methadone treatment. About half had not yet started treatment and had used heroin in the previous 24 hours. The rest were already taking methadone and a range of other drugs as shown by urine testing. The first group had prolonged QT intervals in 19% of subjects while the new patients who had started treatment had a rate of 34%. The latter were reportedly using combinations of heroin, cocaine, methadone and other drugs. So their theory was not confirmed yet their findings indicated a possibility that methadone extended the QT interval despite this being asymptomatic in all cases. Further, there were no reports of arrhythmias in MMT patients for the next 29 years.

This leaves us asking why one would spend time and money highlighting, emphasising and investigating the torsade issue while ignoring the vastly more important issue of standards of treatment. Drop-outs, deaths, overdose, viral infection, unemployment, etc, are all well documented consequences of deficient doses, inadequate supervision and a lack of psychosocial supports which are still sadly common. Each of these factors was clearly delineated in Dole’s first report in 1965 - and which modern prescribers ignore to their patients’ eternal cost.

Notes by Andrew Byrne .. Clinic web page: http://methadone-research.blogspot.com/


1. 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

2. Reddy S, Fisch M, Bruera E. Oral methadone for cancer pain: no indication of Q-T interval prolongation or torsades de pointes. Journal of Pain and Symptom Management 2004 28;4:301-303

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

4. Hyslop B. Prolongation of the QT interval on methadone: how important is methadone dose? New Zealand Medical Student Journal 2007 6 Aug

5. 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

6. Phibbs B. Advanced ECG: boards and beyond. 2006 Elsevier

7. Krantz MJ, Kutinsky IB, Robertson AD, Mehler PS. Dose-related effects of methadone on QT prolongation in a series of patients with torsade de pointes. Pharmacotherapy. 2003;23:802-805

8. 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

9. Anchersen K, Clausen T, Gossop M, Hansteen V, Waal H. Prevalence and clinical relevance of QTc interval prolongation during methadone and buprenorphine treatment: a mortality assessment study. Addiction 2009 104;6:993-999

10. Perrin-Terrin A, Pathak A, Lapeyre-Mestre M. QT interval prolongation: prevalence, risk factors and pharmacovigilance data among methadone-treated patients in France. Fundam Clin Pharmacol. 2010 Sep 6

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

12. Salle P, Rey JL, Bernasconi P, et al. Torsades de pointe. Apropos of 60 cases. Ann Cardiol Angeiol (Paris). Jun 1985;34(6):381-8

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

Roy A, McCarthy C, Kiernan G, McGorrian C, Keenan E, Mahon N, Sweeney B. Increased incidence of QT interval prolongation in a population receiving lower doses of methadone maintenance therapy. Addiction. 2012 107;6:1132-9

14 August 2012

Pilot RCT points to reduced retention, increase abstinence from illicits and alcohol with more supervision.

A pilot randomised controlled trial of brief versus twice weekly versus standard supervised consumption in patients on opiate maintenance treatment. Holland R, Matheson C, Anthony G, Roberts K, Priyardarshi S, Macrae A, Whitelaw E, Appavoo S, Bond C. D&A Rev 2012 6:483-91

Dear Colleagues,

My old professor held that it was nice to learn of controlled research supporting one’s long-held clinical beliefs. This pilot study by a Scottish group fit’s the bill in my book.

There were 60 stable methadone maintenance patients randomised to daily supervised doses (existing treatment), twice weekly supervised doses and daily unsupervised (dispensed) dosing in community pharmacies with surveys and urine tests over a three month study period. The unsupervised patients were still required to collect their medication bottles at the pharmacy daily (this seems to be a uniquely British practice).

The authors state: “This small study was not statistically powered to estimate the effectiveness of different forms of supervision. Nevertheless, our findings are of interest as results suggest that increasing levels of supervision decreased retention (a negative finding), while reducing illicit heroin and alcohol use (a positive finding). This was not statistically significant (with the exception of the alcohol result) and should be treated with caution.” [alcohol problems were reduced from 47 to 33%, a significant reduction, only in the supervised group - other groups showed the same or worse figures].

In their introduction the authors state: “..there is no evidence base for deciding the optimal period of supervision”. In fact there is some controlled research for observed dosing (ref 1) but in opiate treatment the common practice has been of early supervision and the use of take-away doses later in treatment (as also followed by this service in Scotland). This regimen is used in a large proportion of research reports, virtually all with successful outcomes compared with controls - and with few adverse reports. This is the research basis for all opioid maintenance treatments used around the world today. It also parallels what we do with unstable mental patients or diabetics who are commencing treatment. They are usually given supervised treatment for days, weeks or sometimes months rather than bottles of pills, syringes or other therapies to take home for self administration. This is just sound therapeutics utilising available resources.

Controlled research over days, weeks and a few short months has also been done on dose supervision for patients with malaria, HIV, tuberculosis, HCV and renal tract infections with demonstrated benefits, sometimes dramatic ones. The uncharted territory is in long-term treatment since most formal research is of limited duration. Hence the crucial importance of this type of study in longer-term patients. With the authors’ positive and negative findings above, they appear to be supporting the need for initial supervision with early introduction of take-away doses in appropriate cases.

A substantial black market price for any drug and/or a shortage of the treatment availability (such as HIV meds in the third world or America) can yield a strong incentive to sell or divert medication. New patients and those in difficulties may benefit from on-going observation of their dosing (called ‘DOT’ in some work: Directly Observed Therapy) regardless of what they are being treated for.

In the UK uniquely, addicted patients who are new to treatment are often given doses to consume at home despite no controlled research base for this. Indeed, in some countries this would be considered unethical and dangerous, like the criticism of ‘giving alcohol to alcoholics’ (also debateable - see below Toronto experience ref 3).

New York Mayor Giuliani and Senator John McCain have joined a small number of high profile people with serious attempts to restrict the US methadone program, (which is largely *supervised*). Methadone treatment was called “disgusting and immoral” and “an Orwellian drug swap.” It would be even easier to criticise the UK program which is largely unsupervised. While there are calls for methadone maintenance to be curtailed (Ref 2) there are still UK experts trying to defend the use of unsupervised methadone treatments despite its unproven nature. Such moves to restrict opiate programs have naturally caused disquiet amongst this most vulnerable and stigmatised group.

Supervision using adequate methadone doses and graduated take-home provisions for suitable patients - an approach which is evidence-based and time honoured. And in the UK, even those on official government funded treatment, many receive treatment which is sub-optimal and ineffective (Ref 4). As well as ensuring compliance and protecting the patient/family, dose supervision also protects this treatment from needless controversy. In an exhaustive email exchange with one of the most respected addiction writers in England recently the only concession on this matter I received was: “Andrew, on one thing at least we agree - that supervision may be needed to allay public and political concern. Another is of course that done well it eliminates diversion. And these two facts are of course related.”

I say no more.

Comments by Andrew Byrne ..

Citation: Holland R, Matheson C, Anthony G, Roberts K, Priyardarshi S, Macrae A, Whitelaw E, Appavoo S, Bond C. A pilot randomised controlled trial of brief versus twice weekly versus standard supervised consumption in patients on opiate maintenance treatment. D&A Rev 2012 6:483-91

Ref 1. Rhoades HM, Creson D, Elk R, Schmitz J, Grabowski J. Retention, HIV Risk, and Illicit Drug Use uring Treatment: Methadone Dose and Visit Frequency. 1998 Am J Public Health 88:34-39

Ref 2. Methadone to be dumped in Scotland as treatment for heroin addiction. http://www.news-medical.net/news/2008/05/27/38661.aspx

Ref 3. Podymow T, Turnbull J, Coyle D, Yetisir E, Wells G. Shelter-based managed alcohol administration to chronically homeless people addicted to alcohol. CMAJ 2006 174;1:45-49

Ref 4. The prescribing of methadone and other opioids to addicts: national survey of GPs in England and Wales. Strang J, Sheridan J, Hunt C, Kerr B, Gerada C, Pringle M. Brit J General Practice (2005) 55 (June 2005); 515: 444-451

Disclosure: Dr Byrne owns a clinic which, like addiction clinics in most countries supervises methadone, buprenorphine, diazepam, antabuse and other medications for a fee.