6 May 2008

Manhattan in April - drug matters - cherry blossoms a bonus!

Dear Colleagues,

Like the Pope I found myself in Manhattan in April. Because of the prevailing official attitude of government, funding agencies and health authorities generally, medical matters are rarely predictable in America. Yet it is always instructive to compare and contrast matters from an Australian perspective.

My first day 'on the hustings' found me at a drug policy institution learning serendipitously about 'snus', so-called Swedish 'chewing' tobacco. In fact it is not 'chewed' at all but placed in the gums as a miniature, stringless 'tea-bag' which delivers substantial amounts of nicotine without polluting the lungs with soot, carbon monoxide, tar and other pollutants. In America there appears to be no licensing system for 'snus' but it is openly sold with attached large-letter warnings: "This product is not a safe alternative to cigarettes" (this is probably incorrect); "This product may cause gum disease and tooth loss"; "This product may cause mouth cancer" (warnings which are probably reasonable, up to a point).

I was referred to a well known city tobacconist near Grand Central Station where I purchased 4 packs of different brands and flavours for about $20 total. I was told that they send mail-orders around the world, including Australia, and as long as it is for personal use this was considered 'legal'. When I asked if they also sold nicotine patches I was told: "Sir! Nicotine patches go against everything we stand for!" [web site on request] My interview with a single snus user was glowingly positive.

It is my belief that this 'snus' product should be studied urgently to see if it is a viable intervention in stemming the huge toll from tobacco. The evidence from Sweden, where about half the tobacco is consumed in this way, is apparently mostly good with far less lung cancer. However, there is a down-side which needs elucidating (an increased rate of mouth cancers and tooth decay).

Other matters dealt with on my American visit included Hep A, B and C in injectors (up to 85%), buprenorphine treatment with and without supervision, transfers between methadone and buprenorphine, cocaine trials using disulfiram (Antabuse), the elusive but much publicised cardiac complications of methadone, addictions in patients with disabilities, publishing in the internet age, amongst other things.

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

Does QT tachycardia occur in methadone maintenance patients?

A Community-Based Evaluation of Sudden Death Associated with Therapeutic Levels of Methadone. Chugh SS, Socoteanu C, Reinier K, Waltz J, Jui J, Gunson K. American Journal of Medicine 2008 121, 66-71

Dear Colleagues,

In my view this study draws a long pseudo-scientific bow, implicating methadone treatment in cardiac effects without as much as one confirmed case description of an arrhythmia in a methadone maintenance subject in the catchment area.

The study selected all 183 subjects who died of sudden death in Portland, Oregon over a 4 year period, grouping them according to whether they had �therapeutic� levels of methadone (up to 1.0mg/L) or not. They excluded cases of proven poisoning from methadone (11 cases) or other recreational drugs (32 cases - all apparently in the methadone group). They also excluded those who did not have a full autopsy 7/29 in study group and 5/111 in the �control� group (a rather large difference). The authors found that there was identifiable structural heart disease in 23% of the methadone group and 60% of the �control� group. This was mostly coronary artery disease and/or ventricular hypertrophy.

Of the 22 cases with therapeutic levels of methadone, 55% were prescribed the drug for pain, 14% took it �recreationally�, 18% unknown and 14% for �opioid withdrawal� - note that none were reported to be on methadone maintenance treatment (although 3 patients, 14%, were apparently prescribed the drug for addiction purposes). We are not informed of the quality and availability of addiction services in the area but I understand there are a number of large licensed methadone clinics in Portland. We are not told the details of the 3 addiction cases who died.

The authors claim their data show an association between methadone at �therapeutic� levels and sudden death. They speculate about cardiac conduction, prolonged QT interval and ventricular tachycardia despite no reported cardiographic evidence pre-mortem. The world literature they cite only appears to contain 28 cases of methadone related tachycardia, mostly non-fatal (see below). A more likely cause of death from methadone than arrhythmia is respiratory depression, even at �normal� blood levels. The authors note this in their discussion but still maintain that their study provides evidence, albeit indirect, for arrhythmias.

I find the methodology of this paper bewildering. If this study were duplicated for any other drug, eg. insulin, thiazides, aspirin, fluoxetine or lipid lowering drugs, such conclusions on the cause of death would be considered laughable in my view.

The main weakness of the study is the attempt to link cases in whom no cause of death could be found with a very rare side effect of methadone, in the face of other possible causes of death. This is especially hard to understand in the majority of cases prescribed the drug for pain relief (55%) as opposed to methadone maintenance patients treated for addiction (~14%). The second weakness of the study related to the 'therapeutic' levels of methadone. They seem to believe (1) that therapeutic levels imply therapeutic doses and (2) that these do not cause respiratory depression and death. Neither of these assumptions is correct and no reference is given to support them, making the paper faulty and its conclusions even more questionable.

Two cited series of prolonged QT interval and/or torsades tachycardia cases (Krantz and Pearson) show a minority of patients treated under addiction program protocols (and in whom there was only one single death). Krantz�s series had an average dose of about four times the usual mean dose in dependency treatment (397mg daily � and none died). Ellen Pearson�s series of 59 FDA reports nationally included only 14 likely dependency patients of whom only one died (a patient on a sub-therapeutic dose of 29mg daily). Ehret�s series was a retrospective study and patients took an average of 4 additional drugs (range 0-14).

Other citations given are single case reports and/or do not involve methadone maintenance patients but are patients with a variety of serious medical conditions for which methadone was used for pain management or else were overdose cases. There are only a few isolated torsades reports in dependency cases over the last 40 years and unexplained sudden death is either unreported or else exceedingly rare. It is certainly not a major public health issue as claimed by Krantz.

In order to be quite certain about all this, having been in New York for several weeks recently I met up with numerous doctors involved in methadone treatment of tens of thousands of patients over a long period. Not one of these could cite a single case of an addiction patient developing torsades in their experience. This is indirect proof to my mind that an easily diagnosed condition (torsades tachycardia) with a mortality of about 15% is no public health problem but a clinical rarity.

Colorado cardiologist Dr Mori Krantz wrote the seminal paper of this subject and while he writes candidly of the various proven benefits of traditional methadone treatment, his clear implication is to avoid methadone treatment if possible and beware of high doses when it is the chosen treatment. Yet most addiction guidelines advise higher dose methadone for better outcomes, with the usual safeguards. Also, most authorities recommend methadone in pregnancy and in those with the most severe dependency and/or co-existing mental illness. Yet Krantz has still not provided a series of detailed individual case studies of this syndrome occurring in regular addiction treatment subjects. And this is despite giving advice about how we should treat such cases.

It is intriguing that Krantz took funding for a large survey of methadone clinic staff awareness, despite the lack of evidence (including his own) of it being a significant problem in such patients when compared to pain management cases. If torsades tachycardia is indeed associated with methadone, it does not appear to occur to any measurable extent in methadone maintenance patients. Most cases have been taking high doses (>300mg daily) and/or were taking multiple drugs with serious medical or metabolic problems. Recent alarming upsurges of methadone-related deaths in America do not involve clinic populations but seem to be associated with the increased popularity of the drug as an analgesic used by doctors and patients who may be unfamiliar with its very long half-life and consequent overdose potential.

Comments by Andrew Byrne ..

Lancet letters: http://www.redfernclinic.com/c/2007/02/methadone-and-qtc-prolongation-letter.php4


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

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

Gr�nbladh L, �hlund LS, Gunne LM. Mortality in heroin addiction: impact of methadone treatment. Acta Psychiatr Scand (1990) 82:223-227

QT cardiographic changes from methadone maintenance treatment. Is it a significant problem?

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

Dear Colleagues,

This is the latest salvo in a cavalcade of papers on the supposed cardiac associations of methadone in addiction treatment. Readers might assume from the title that this is a randomised trial looking at cardiographic changes from a new perspective. In fact it is a re-examination of study performed in the 1990s, this time with old analogue cardiograph traces salvaged and corrected QT estimations attempted. I have repeatedly written to the corresponding author over some apparent discrepancies in the methadone �rescue� group but without any resolution. Some heroin addicted patients received placebo-equivalent (20mg methadone daily) which I believe would be unethical under today�s standards.

These authors report an average corrected QT interval increased of up to 23 milliseconds 4 months into methadone treatment. We are told that 6 of 52 (12%) met clinical criteria for cardiac risk at some stage during the trial (eg. QTc > 500ms).

It appears that no patient developed tachycardia during the trial which is consistent with the literature. Torsades arrhythmia in methadone clinic patients seems to be a very rare event as I could not find a single clinician in New York recently who had ever seen a case out of tens of thousands of MMT subjects. The finding of lengthened QT timings in this trial is consistent with Lipsky�s study from 1973.

The clinical significance in causing arrhythmias is still unclear, but according to Martell, Gourevitch and colleagues: �� an increase in QTc interval of greater than 40 milliseconds [is] the generally accepted threshold for an increase that should prompt clinical concern (4). Similarly, � a QTc interval of more than 500 milliseconds is considered a definite risk for torsade de pointes regardless of sex (5) ��. By these criteria, the findings of Wedam and colleagues are consistent with a substantial theoretical risk of cardiac symptoms in �standard� methadone patients given guideline-based treatment. Yet torsade is almost unknown except for those on extremely high doses (>300mg daily), co-medication (especially alcohol and cocaine), pre-existing heart disease and/or with documented metabolic problems.

Far from conceding this conclusion, the authors find that methadone is far more likely to involve risks which can be avoided by the use of buprenorphine which they state should be considered in its place. This is a most na�ve deduction, and seems to show a lack of insight into the current state of dependency treatment (see Kakko�s trial from Sweden; Ling; Strang and others showing the limitations of buprenorphine in addiction treatment).

Having stated in the first sentence that buprenorphine and methadone are equivalent (which they are not), they state further: �Levomethadyl and methadone each have had reports of notable clinical adverse events, including TdP [refs 9-15 see below].� On closer examination, these references do not generally involve methadone maintenance cases which is what they address in their conclusions, but rather, they are complex medical and overdose cases (see below).

The mean daily dose in Krantz� original study was 397mg (n=17); Walker >600mg (n=3); Sala (n=4) mean 365mg daily; Mokwe � street methadone dose unknown (n=1); de Bels blood levels 3500mg/L and 1740mg/L (n=2) overdose cases (therapeutic range 100-1000mg/L).

Martell: (n=132) doses 30-150mg had �a small QT interval prolongation of uncertain significance� [average 12ms, mostly in males taking 110-150mg daily]. Also not cited is the world�s largest and most authoritative series from FDA reports: Pearson�s mean dose was 410mg (n=56).

The Wedam report concludes: �We know of no published cases of TdP with the use of buprenorphine� [they omit that there are virtually no reports of TdP in uncomplicated methadone maintenance patients either]. Then: �Physicians must use their judgment in choosing the appropriate therapy for opioid dependence; failure of therapy results in considerable mortality. However, given that buprenorphine has previously been proven to be equally efficacious in the treatment of opioid addiction [this is not referenced and is incorrect in my view], buprenorphine may be a safe alternative for treatment of this common and life-threatening problem.� As drug guru Walter Ling has written, finding no significant difference between treatments does NOT prove that they are equivalent.

The paper states: �Financial Disclosure: Dr Johnson is currently an employee of Reckitt-Benckiser Pharmaceuticals Inc, the manufacturer and distributor of buprenorphine. Dr Bigelow has received, or anticipates receiving, research support, through his institution, from Purdue Pharma LP, Biotek Inc, and Titan Pharmaceuticals Inc for studies of other buprenorphine formulations.�

Comments by Andrew Byrne .. http://www.redfernclinic.com/ (who is an enthusiastic prescriber of both buprenorphine and methadone in addiction medicine).


Johnson RE, Chutuape MA, Strain ED, Walsh SL, Stitzer ML, Bigelow GE. A Comparison of Levomethadyl Acetate, Buprenorphine, and Methadone for Opioid Dependence. NEJM (2000) 343;18:1290-1297

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

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, Mehler PS. QTc prolongation: methadone's efficacy-safety paradox. Lancet 2006 368:556-557

Byrne A, Stimmel B. Methadone and QTc prolongation. Lancet 2007 369:366

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

Walker PW, Klein D, Kasze L. High dose methadone and ventricular arrhythimias: a report of three cases. Pain 2003 103:321-4

[This summary has been up-dated with come corrections and clarifications.]