2 October 2017

Large study shows torsade risk remote and ECG non-predictive in methadone maintenance.

Methadone and the QTc Interval: Paucity of Clinically Significant Factors in a Retrospective Cohort. Bart G, Wyman Z, Wang Q, Hodges JS, Karim R, Bart BA. J Addiction Medicine pre-publication 2017. 
Dear Colleagues,
Dr Bart and co-authors have examined the medical records of around 1000 admissions to methadone maintenance nearly all of whom had at least one ECG on or off methadone (or both).  They then compared clinical cardiac events and mortality over 7000 patient years from the major health facility in Minneapolis.  There was an average increase in QTc of 13 milliseconds in those on methadone at the time of the ECG, consistent with other studies.  This was associated with a very low rate of cardiac events of 2.5 per 1000 and QTc intervals were not predictive.  Sudden cardiac death (SCD) rate was lower than age-adjusted community rates (0.4 versus 1.75 per 1000 based on CDC state statistics).  This parallels numerous other reports attesting to the general protective value of being on methadone treatment (see Krantz ref below on cardiac protection).  No case of torsade des pointes was identified by the present authors over 15 years.
This study gives great reassurance in the cardiac safety of methadone maintenance treatment.  The authors also suggest that the requirement for ECG in methadone patients should be reviewed since it does not appear to serve any practical purpose.  A Cochrane review also found no evidence to support QTc screening. 
Concerns over the supposed dangers of QTc prolongation have been over-played, partly by commercial factors favouring the only licensed alternative to methadone maintenance.  Of about 150 torsades cases reported in the literature since 2002 only one was fatal to my best knowledge. 
A paper by Mori Krantz from Denver in 2002 claimed to have found an extraordinary number of tachycardia cases from Colorado methadone clinics and a pain management service in Canada.  Torsade des pointes was reported as a side effect of methadone yet Krantz’s findings have never been replicated elsewhere, even in large samples of closely studied patients over 30 years of research literature.  In the present series by Bart and colleagues not one case was identified in 7000 patient-years.  About 150 anecdotal reports in the literature since 2002 shows this rare event occurs mostly in high-dose, complex methadone patients who were taking other medications, were over 40 years of age and with a higher rate in female patients.  My own practice with approximately 3000 patient-years has identified one single torsade case (non-fatal).  Alcohol and pre-existing heart disease were also associations in this aging population.  Krantz’s claim that methadone was associated with large numbers of otherwise unexplained deaths has also never been supported by the literature (Byrne, Stimmel. Lancet 2009*). 
Notes FYI by Andrew Byrne, Sydney, Australia.  http://methadone-research.blogspot.com/
Krantz on cardiac concerns from the following year (no mention of the balancing protections above): 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 http://www.annals.org/cgi/reprint/137/6/501
*Byrne A, Stimmel B. Methadone and QTc prolongation. Lancet 2007 369:366  http://www.thelancet.com/journals/lancet/article/PIIS0140673607601810/fulltext

23 May 2017

Medical post-card from New York in April 2017

Butler Library, Columbia University
Dear Colleagues,
New York has had an early spring but all talk is about the new President and his almost daily tweets.  In medical circles, however the opioid overdose crisis across America is top news yet solutions are hard to find and some (like methadone in general practice) are unmentionable.  After three years of investigations I believe I now know why methamphetamine is less of a problem on the US East Coast and it seems to be due to cocaine being so cheap being less than five dollars per cap in some areas.  For the same financial reasons benzodiazepines are less of a problem due to their high price in America.  With national health schemes Valium and other stronger sedatives are relatively easy to obtain at low cost in France, Israel, Australia, etc.  Ergo a larger abuse problem. 
Safer injecting facilities are now being pushed for in public health forums but by few in authority in America.  Naloxone without prescription is now commonplace which is gratifying ... yet by definition it requires the presence of another person at the scene of the overdose to save a life.  Opioid maintenance TREATMENT can ensure a way to stabilize the opioid epidemic yet such treatment is very hard or impossible to access in much of the United States due to the restrictions on methadone programs and the high cost of buprenorphine.  It is a mystery to me why methadone is not available from private American physicians, nor why American pharmacists are banned from administering methadone in addiction programs.  In a meeting at Rockefeller University I was told the reason was the lack of a profit motive as the drug is old and out of patent in its pure form (about 50 cents per dose). I was pleased to be able to get a world authority on buprenorphine, Dr Doug Kramer into the Journal Club of a world authority on methadone, Professor Mary Jeanne Kreek for a lively discussion including the history of FDA approvals and initial dose recommendations. 
A new publication in the British Medical Journal (including an American editorial) attests to the dramatic reduction in mortality, both overdose and all-cause mortality, in those taking opioid maintenance treatment when compared with opioid dependent citizens who are out of treatment.  The metanalysis across several countries shows substantial reductions in deaths, something which has been shown in smaller studies for over 20 years.  See: http://www.bmj.com/content/357/bmj.j1947 (free access for both editorial and article on the subject).  The acute need for action is talked about daily in the US media yet nobody seems to talk about the elephant(s) in the room which are a lack of treatment availability and drug company culpability for pushing profitable opioid analgesics for so long.  As a maintenance treatment, buprenorphine is excellent for those who can afford it and those with lesser habits and the ability to tolerate the induction requirements (being in or near withdrawal before starting).  The lack of a community methadone program is costing America dearly.  One recent report quoted 50,000 deaths in one single year which out-numbers victims or war, cancer, accidents and suicides. 
An interesting side issue is that American states which legalised 'medicinal' cannabis in recent years have significantly lower overdose rates and the initial figures are now being confirmed in longer term statistics.  While one can speculate on the reasons, the 'normalisation' and decriminalisation of cannabis which has been spearheaded by the Drug Policy Alliance, funded by George Soros must now be given credit for saving hundreds or even thousands of lives.  This organisation has been directed by Ethan Nadelmann who stepped down in April after 20 years at the helm.  His send-off was a moving event with supporters, colleagues and friends including Ira Glasser, Stanton Peele, Joyce Lowinson, Ernie Drucker, Clovis Thorn, asha bandele, Chris Soda, Ellen Flenniken, Dr Robert Newman, Tony Newman, Tony Pappa, and many others including Chief Prosecutor from Albany, David Soares and his wife.  I was happy to be able to represent Australia at such an auspicious gathering in Chelsea overlooking the Hudson River. 
Hepatitis C remains a festering issue between outrageous drug prices and limited funding.  The New York based activist group V.O.C.A.L. has long been advocating strongly for State and Federal subsidies for such treatments to be more widely available.  We are very fortunate in Australia that our PBS struck a very favourable deal with the suppliers, allowing universal access to five new direct acting anti-viral (DAA) drugs (the maximum yearly outlay was capped regardless of the number of prescriptions written).  After just over twelve months, an estimated 38,000 patients have been treated ... which is 15% or more of all the cases in Australia.  This makes hepatitis C eradication possible within the next several years.  Only tiny Iceland has done a similar effort, with its reported 1200 HCV cases.
I had very fruitful discussions with senior colleagues at Columbia University and at Rockefeller University regarding the possible safe use of benzodiazepines in stable OTP patients as well as our own recent experience with treating hepatitis C.  It appears that cirrhosis based on viral hepatitis may be partly reversible, contrary to the popular wisdom and I was able to give some examples from Australia.  We have had ~30 viral clearances out of ~30 patients on Direct Acting Antivirals (DAA) over the past 14  months.  This compares with about 45 out of 55 successful treatments on interferon and ribavirin (plus protease inhibitors more recently) over about 9 years (and it was NOT all easy going). 
My last days in Manhattan included some touristy things such as Katz's Deli (a disappointment), Barney Greengrass Deli (a high point), Hello Dolly with Bette Midler ($59 seats in back row sold on day of performance only) and the 50th Anniversary concert at the Metropolitan Opera House.  Details and photos on request (or on my other blogs soon). 
With best regards,
Andrew Byrne ..  

12 February 2017

Lower mortality and better retention in OTP patients prescribed benzos.

Bakker A, Streel E. Benzodiazepine maintenance in opiate substitution treatment: Good or bad? A retrospective primary care case-note review. Journal of Psychopharmacology 2016 1-5
Dear Colleagues,
Finally we have some strong evidence that prescribing benzodiazepines for patients on opiate maintenance treatment is not only safe and effective but in some cases may be obligatory, under careful supervision with adequate psychosocial supports. 
Dr Bakker in London has done us the great service of publishing the data he has extracted from his own general practice from over 20 years of caring for drug dependent patients.  His practice is based on sound harm reduction principles, prescribing long acting, low potency benzodiazepines such as diazepam or clonazepam using graduated supervision for dependent patients.  In this he bucked the trend based on what he considered good medical practice, albeit non-evidence based (like much prescribing practice). 
Bakker reports on 278 OTP patients since 1998 (1289 patient/treatment years) comprising a high proportion of socio-economically deprived citizens, two thirds being male.  Regarding prescription for benzodiazepines (bzd) from the practice, patients were classified ‘never prescribed bzd’, ‘occasional prescription bzd’ and ‘maintenance bzd.  Further, he examined those still in treatment against those who had departed (96% still in UK, 4% gone overseas, lost to follow-up).  From comprehensive statistics kept by the British NHS Bakker was able to derive accurate mortality figures for these six groups with surprising results for retention and mortality. 
Never              Occasional       Maintenance
Current pats:   223t/y              301t/y              765t/y  
Mortality:        1.79p100ty      0.33p100ty     1.31p100ty
Retention        34 months       51 months       72 months      
Ex-patients:     267t/y              320t/y              305t/y
Mortality:        2.24 p100t/y    0.63 p100t/y   5.90 p100t/y
Excess mort:    125%               191%               450%
T/y = treatment years
Contrary to some expectations, retention was highest in the group prescribed maintenance benzodiazepines.  Furthermore, mortality was lower than in the group never prescribed sedatives and the lowest mortality was intriguingly in those occasionally prescribed sedatives.  However, the most meaningful, and very worrying statistic is the high mortality in maintenance patients who transferred elsewhere for their treatment (more than 4 fold those remaining in treatment at Dr Bakker’s practice in London).  The authors report that following health authority directives very few maintenance prescribers in the UK allow benzodiazepine prescription in parallel as Dr Bakker’s practice does.  Hence the likely inference that these patients had legal supplies of benzodiazepines curtailed on transferring elsewhere for their OTP treatment. 
Another important finding was that the death rates were lowest, and very significantly lower, in those prescribed benzos occasionally, both in-house patients and in those transferred elsewhere. 
This report is not a randomised controlled trial, nor was it prospective, yet it involves large numbers of patients in a normal medical population over a long period with very few lost to follow-up (4%).  Hence the findings are very meaningful for those involved in comparable practice providing opiate maintenance with methadone and/or buprenorphine in a community setting. 
From this paper is it apparent that withdrawing benzodiazepines may increase mortality substantially.  Hence, official guidelines and clinical recommendations which warn against benzodiazepine prescription may be contributing to excess deaths rather than preventing them.  In my experience most OTP prescribers have a small number of patients who are prescribed benzodiazepines, some long-term.  Yet up to 70% of our patients have had problems with sedatives and so to ignore this and advise: ‘just say no’ may not be the proper approach.  However, prescribing is well beyond the comfort zone for many in our field without formal protocols. 
It is my view that all dependent patients should be able to access benzodiazepines under some clinical framework although this should not be open-ended, just like methadone.  There should be dose supervision initially ranging to normal unsupervised prescription for those who are socially integrated but unable or unwilling to cease sedative use.  Those abusing alcohol should be excluded until they can demonstrate abstinence.  Trial dose reductions should be negotiated periodically, as with methadone.  In our own practice we use diazepam and we aim to a dose of 4-15mg daily which is satisfactory for the great majority after initial reductions. 
Notes by Andrew Byrne ..
Bakker article PDF:
References: Franklyn AM, Eibl JK, Gauthier G, Pellegrini D, Lightfoot NK, Marsh DC. The impact of benzodiazepine use in patients enrolled in opioid agonist therapy in Northern and rural Ontario. Harm Reduction Journal 2017 14:6
Weizman T, Gelkopf M, Melamed Y, Adelson M, Bleich A. 2003 Treatment of benzodiazepine dependence in methadone maintenance treatment patients: A comparison of two therapeutic modalities and the role of psychiatric comorbidity. Aust N Z J Psychiatry 37: 458–463
Lader M. Benzodiazepines revisited—will we ever learn? Addiction 2011 106:2086-2109
Liebrenz M, Boesch L, Stohler R, Caflisch C. Agonist substitution-a treatment alternative for high-dose benzodiazepine-dependent patients? Addiction 2010 105;11:1870–1874