2 December 2013

Poor retention buprenorphine/nxn vs. methadone. Also NYT article on bupe.

Hser YI, Saxon AJ … Ling W. Treatment Retention among Patients Randomized to Buprenorphine/Naloxone Compared to Methadone in A Multi-site Trial. Addiction. 2013 Aug 20
Dear Colleagues,
Over 1000 opiate dependent patients were randomised to methadone or Suboxone and then followed for 24 weeks.  Retention in the methadone group was 74% compared with 46% (p<.01) for those taking buprenorphine with naloxone.  The buprenorphine retention was so poor, more than half dropping out, that they had to recruit more subjects to allow a meaningful comparison of liver function tests, the primary purpose of this Phase IV study (see ref 1 for original report).  There were 24 cases of extreme elevations of liver enzymes but reassuringly, no difference between the groups.  There was no discussion of harm reduction measures since American doctors are banned from such interventions so that harm maximisation can co-exist with an ‘ethical’ trial.  Seroconversions among treated individuals in the community should be exceptional even with the most rudimentary public health services.  Men did better on buprenorphine for some reason. 
While the authors say that the retention rates are ‘in the range’ of other studies, the low buprenorphine retention rate would seem to be well out of step with the several RCTs comparing pure buprenorphine with methadone, each finding either no difference or a modest difference between the groups (see Cochrane summary on the subject - ref 2, also refs 3, 4 and 5).  To my reading none found such a substantial difference in retention.  The present authors make the rather hopeful speculation that doses higher than 32mg daily might improve the poor retention rates, despite the basic pharmacology being against this (not to mention the undignified dosing and enormous cost, as well as the fact that most had dropped out long before such doses were achieved).  Inadequate induction protocols might also apply to methadone.  And without routine supervised doses in America, induction in community treatment with buprenorphine in America is hard to determine. 
Another possible explanation for the poor results on combination buprenorphine might be that the added naloxone reduced the efficacy of buprenorphine, something which has not been formally tested to my knowledge.  Most RCT have involved pure buprenorphine, including the recent MOTHER study (with all its faults).  There is still no cogent evidence for the thesis that the combination reduces abuse, despite the attractiveness of the concept empirically (ref 6 and see Wiki quote at ref 8). 
The possibility that adding naloxone changes the characteristics of buprenorphine is supported by a small but well conducted pilot study from Sydney, funded by the NSW Health Department.  Bell et al. transferred 17 stable (pure) buprenorphine patients to the combination formulation, finding that most needed a higher dose with a mean of just over 50% of the original dose (ref 7). 
This present trial was not blinded and we are not informed how patients attending clinics were consented and randomised.  It is possible that incentives such as free treatment might have induced previously successful methadone patients to take a chance on buprenorphine, causing a falsely high drop-out rate for buprenorphine.  However, until there is a valid comparison of pure buprenorphine with the combination product we are forced to rely on indirect evidence and imperfect studies, few if any of which support the use of combination buprenorphine.  Today’s New York Times quotes of the US FDA: “Early this year, it [FDA] approved generic tablets and asked the Federal Trade Commission to investigate potentially anticompetitive business practices by the company.” See link below for very wide-ranging article on buprenorphine. 
I still find no cogent reason to use combination buprenorphine.  It is possible that large numbers of opiate dependent patients in Australia and elsewhere are taking naloxone for reasons which are more related to good marketing than good medicine.  I remain a fervent supporter of (pure) buprenorphine as a maintenance treatment and would recommend it as an excellent alternative to methadone with some major benefits as well as some shortcomings. 
Written by Andrew Byrne ..
STOP PRESS – I highly recommend this detailed front page item in the New York Times http://www.nytimes.com/2013/11/17/health/in-demand-in-clinics-and-on-the-street-bupe-can-be-savior-or-menace.html?partner=rss&emc=rss&_r=0  They still omit the ‘elephant in the room’ which is clinic-type treatment.  Monthly dispensed pills without some structure (counselling, urine testing and/or supervised doses etc) have never been shown to be safe or effective yet that is exactly what many French and American patients receive.  
1. Saxon AJ, Ling W, Hillhouse M, Thomas C, Hasson A, Ang A, Doraimani G, Tasissa G, Lokhnygina Y, Leimberger J, Bruce RD, McCarthy J, Wiest K, McLaughlin P, Bilangi R, Cohen A, Woody G, Jacobs P. Buprenorphine/Naloxone and methadone effects on laboratory indices of liver health: A randomized trial. Drug Alcohol Depend 2013;128:71-76
2. Mattick RP, Kimber J, Breen C, Davoli M. Buprenorphine maintenance versus placebo or methadone maintenance for opioid dependence. Cochrane Database Syst Rev. 2008 Apr 16;(2):CD002207
3. Schottenfeld RS, Pakes JR, Olivento A, Kosten TR, Zeidonis D. Buprenorphine vs Methadone Maintenance Treatment for Concurrent Opioid Dependence and Cocaine Abuse. Arch Gen Psychiatry. 1997 54:713-720
4. Schottenfeld RS, Pakes JR, Kosten TR. Prognostic factors in Buprenorphine- versus methadone-maintained patients. J Nerv Ment Dis. 1998 186;1:35-43
5. Pani PP, Maremmani I, Pirastu R, Tagliamonte A, Gessa GL. Buprenorphine: a controlled clinical trial in the treatment of opioid dependence. Drug Alcohol Depend. 2000 60;1:39-50
6. Bruce RD, Govindasamy S, Sylla L, Kamarulzaman A, Altice FL. Lack of Reduction in Buprenorphine Injection After Introduction of Co-Formulated Buprenorphine/Naloxone to the Malaysian Market. Am J Drug Alcohol Abuse 2009 Feb 12:1
7. 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

8. Wiki page on buprenorphine excerpt: http://en.wikipedia.org/wiki/Buprenorphine
"There is a common misconception that naloxone, a potent opioid antagonist included in the Suboxone formulation, is active and responsible for this blockade effect. This is not true. Instead, Buprenorphine alone is responsible for the blockade effect due to its high binding affinity at the brains opioid receptors, a higher affinity than that of naloxone. The naloxone is in effect not active regardless of the route of administration."


2 August 2013

Should drug companies try to 'tamper-proof' their products? Tactics, profits and ethics may clash.

Summary: Andrew Byrne argues that doctors should not change prescribing practices unless there is substantial evidence regarding safety and effectiveness.  He gives numerous examples where drug companies have got it wrong in the past, sometimes grievously.  He finds that evidence is still lacking for combined buprenorphine preparations over their highly effective and safe (pure) predecessors. 
Dear Colleagues,
A recent New York Times report states that the FDA has rejected a petition by the original manufacturer of a so-called ‘tamper resistant’ version of oxymorphone analgesic to stop generic competitors being licensed because they were alleged to be less safe than the original product.  The claim by the originators to have a ‘tamper-resistant’ product was rejected by the FDA as the tablets were found to be able to be ‘misused by cutting, grinding, chewing or injecting’.  For yet another long acting opioid a similar recent FDA petition was accepted since the drug, OxyContin “appeared to be less prone to abuse”.  This report was in the NYT ‘business’ section rather than under ‘health’ … and it ends with stock movements following the FDA decisions. http://www.nytimes.com/2013/05/11/business/endo-loses-bid-to-block-sales-of-generic-painkiller.html?src=rechp&_r=0 ). 
In another recent ruling, the FDA refused a petition by Reckitt Benckiser, Inc to prevent the approval of generic buprenorphine tablets combined with naloxone due to their alleged dangers to children.  The determination also stated: “The timing of Reckitt’s September 2012 announcement that it would discontinue marketing of the tablet product because of pediatric exposure issues, given its close alignment with the period in which generic competition for this product was expected to begin, cannot be ignored.” (page 15; http://www.regulations.gov/#!documentDetail;D=FDA-2012-P-1028-0011).  
These complex stories raise the question of whether drug companies and regulatory authorities are capable of regulating the use of a drug beyond its recommended indication and route of administration.  Preventing the inappropriate use of medication is indeed a difficult field and some might say impossible.  The introduction of long acting forms of opioid, including morphine, which are supposedly safer, also coincided with the onset of the present enormous epidemic of analgesic opioid abuse in America and elsewhere. 
Certain supposed safety innovations have ended up being more harmful than the original (eg. the altered gel-caps of triazolam (ref 1) which caused serious embolic disease among injectors - one theory was that heating the gel allowed it to dissolve, only to re-precipitate in the body, causing embolic disease).  Drug companies have a potential conflict of interest in that alterations in the formulation of a drug may allow a new patent to be issued, ensuring more profits and locking out competition.  This occurs whether the changes prove effective or not (see above).  Such patents may be perfectly in order yet examples are few in my experience and with each benefit there may be a corresponding ‘sense of security’, ensuing increased prescribing and potentially more harms overall.  Extending patents also raises prices so that many legitimate recipients, even in advanced western countries, may be denied appropriate treatment  (eg. buprenorphine in some parts of the UK).  Another conundrum is that in many advanced countries injectable opioids, including heroin, are now made available for addiction treatment in certain cases. 
One early attempt to avoid codeine addiction in Australia employed over-the-counter mixed analgesics such as Vincent’s, ‘Bex’ and APC powders.  They were marketed widely to the public, causing a creeping epidemic of kidney failure, largely in women, 10 to 20 years later.  These mixed analgesics were advertised prominently to the public and large profits were made as people unknowingly suffered slow and irreversible renal damage. 
In the case of mixed analgesics, each of the constituents, aspirin, phenacetin, codeine and/or caffeine were arguably in the patients’ medical interests.  In recent times, we find drug companies adding compounds which are of no therapeutic benefit to the individual patient, but are alleged to prevent third-party or unsanctioned abuse (eg. injecting). 
Can we be certain that naloxone and buprenorphine is a safe combination?  We were told by the company representatives and senior professional colleagues that the naloxone was not absorbed significantly.  Yet good quality research available long before the drug’s approval would seem to contradict this (ref 2). 
We were also told, mostly by senior medical colleagues, that the two approved versions of the drug (pure and combination) were clinically equivalent yet there are no formal comparative trials to my knowledge (and the company now emphasises absorption differences between some of their formulations).  One comparative pilot study with a chronological control indicated the need for substantially higher doses (~50%) when naloxone was added to patients who had been stabilised using pure buprenorphine (ref 3).  Such a finding, if confirmed, would imply substantially increased cost per patient to government, insurance companies and/or the individual patients while at the same time more sales and profits for the manufacturer.  It also implies the consumption of enormous quantities of naloxone by patients who have no requirement for the drug. 
Even after decades of experience with the combination products, I can still find no consistent evidence showing any net benefits to balance these increased costs.  There is legion evidence that the combination product can be injected with impunity and gusto by patients and others, despite the good intentions of the manufacturer, prescribers, authorities, etc.  A modest reduction in injecting in New Zealand after national substitution of the pure drug with a combination product in 1992 was cancelled out to some extent by a reported increase in the use of injected morphine (ref 4). 
Analgesic buprenorphine was reportedly the leading drug of abuse in several western countries for some years in the 1990s (eg. Spain and New Zealand).  While the financial incentives are obvious, from a public health viewpoint this is a largely uncharted nexus between illicit drug markets and pharmaceuticals for non-medical purposes.  It is hard to believe that the manufacturers were unaware that they were underwriting a large heroin substitution enterprise in those days. 
On no less than two occasions, when nearing the end of its patent (or exclusive marketing) period, existing and familiar forms of buprenorphine were suddenly found to have serious problems, ‘requiring’ us to change our prescribing habits to the new versions … and this despite apparently satisfactory results in community practice with pure buprenorphine tablets, and a very low level of adverse events.  So the major advance of the introduction of buprenorphine for opioid dependency was marred by two major disruptions for questionable reasons.  From the patients’ point of view, even when changing brands of a drug, colours or flavours of existing medications, some may experience major torment and even drop out of treatment (ref 5). 
After lavish drug launches in Sydney and other capitals in 2006 and 2011 (see my only two food reviews on the research web site) and high profile professional and government support, our colleagues changed their prescribing habits promptly en masse.  In France, where buprenorphine (pure) has been used widely since 1995, moves to combination product were stayed as generic versions of the pure buprenorphine had made major inroads into the market years ago (apparently an Australian company, Sigma-Arrow, was a major player). 
Two claims by the manufacturer would seem to be little more than ruses, a contention which is supported by delightfully restrained language in the FDA findings and from abundant anecdotal reports available on the internet plus clinical experience.  We were told by company representatives in Australia that the Suboxone tablets are being withdrawn due to paediatric exposure … something which has only been reported on any scale in America and where tablets are inexplicably sold in bottles of loose pills rather than child resistant blister packs.  The FDA finding reported that by the time of this Reckitt announcement (1) the number of exposures was already dropping in response to existing measures, and (2) in the only quantitated report (n=131), the great majority of exposures were of one tablet or less (2mg to 8mg).  The FDA report did not mention any morbidity or mortality from childhood exposure to buprenorphine despite the theoretical possibility of respiratory depression and death, even from these modest doses (hopefully not combined with alcohol or other drugs). 
Another claim was that the new ‘films’ or ‘strips’ would be substantially faster to administer yet this is hard to demonstrate in practice.  Furthermore it is less relevant in America where dose supervision is not used to any degree.  Australian pharmacists and nurses I have spoken to say that the films take longer to give out than the previous tablet forms, and this may not be made up in less time for dissolution of the medication.  In my experience only a proportion of drug administration episodes involve full inspection from buccal insertion to dissolution, with exceptions in the prison system and some well staffed specialist clinics.  The highly soluble films may be easier to abuse but this seems not to have been tested (except by some of our more enterprising patients). 
Further to these changes, and without any notice or discussion, in early 2013 the company introduced new packaging for the pure form, Subutex.  It is hard to find any logical reason for this except to make it more difficult to use in replacing a perfectly satisfactory and familiar blister pack.  Subutex is the form which should be used in pregnancy or in those likely to become pregnant.  It is also the only form which is available in 0.4mg increment, a size we find essential in reductions for about a third of our patients, especially on their final reductions to abstinence (a sceptic might think that the company was not interested in abstinence).  The new Subutex packets are very cumbersome, requiring a new skill as well as sharp finger-nails and/or implements to separate the tablet compartments and then extract their contents, a two-step process.  And this in a country with few if any reports of paediatric exposure as far as I am aware.  On behalf of our nurses and pharmacists I have asked the company representative to reconsider and return to the old ‘friendly’ blister packs (to no avail to date). 
For those who still feel confident with all the information they receive from drug companies I would remind:
(a) Heroin was invented by the Bayer company and marketed as a ‘calmative’ for babies and a non-addictive treatment for morphine addiction [sic]. 
(b) Thalidomide was reportedly not withdrawn directly in all countries in which it was marketed, even after the publication in Lancet of Dr William McBride’s seemingly unanswerable report in December 1961 (ref 6). 
(c) The early lipid lowering agent Clofibrate (“Atromid-S”) was supposed to prevent heart attacks but was reportedly found to cause an increase in strokes.  This was only detected after the company marketed the product for a substantial period during which many patients had received little or no net benefit from the medication. 
(d) Reserpine was an early treatment for hypertension which was used less and less due to side effects such as depression (despite the drug at one stage, like benzodiazepines, being used as a depression treatment). 
(e) “Halcion” (triazolem), once a big selling sleeping medication in the UK, is quoted as follows: “Clinical trials which Upjohn had withheld from publishing showed a very unfavourable risk benefit ratio with 9.9% of patients dropping out of one triazolam study versus 1.9% of trial subjects taking a comparison benzodiazepine, flurazepam. Another study not published by Upjohn found 12.2% of triazolam patients dropped out, again due to psychiatric adverse effects compared against 4.1% for flurazepam. A further study found that after only 3 weeks use of triazolam patients typically became markedly anxious. As a result of these studies, both published and unpublished, coming to light showing frequent severe psychiatric disturbances the United Kingdom and Brazil decided to ban triazolam.” (Wikipedia).  The company’s choice of name says a lot about their tactics/antics. 
The list goes on. 
In my view doctors should beware of getting all their information about new drugs from drug company sources but seek independent information on all therapeutic matters, even knowing that medical journals, universities and even Royal Colleges take funding from drug companies.  It is my view that we should be very wary of sample packs (not available for controlled drugs!).  These are so often provided only for preparations which are new, expensive treatments, and which conservative doctors might consider second-line.  In my view, short of a major breakthrough, these should generally be reserved for those who do not do well with existing standard, safe treatments.  If this rule were followed by more doctors some of the disasters of the past might have been avoided. 
Despite the above serious reservations about marketing, I respect the pharmaceutical industry as being there to make profits for its shareholders in devising new drugs and bringing them to market.  We all benefit from the great advances of such endeavours. 
Written by Andrew Byrne ..
Ref 1: Ruben S, Morrison CL. Temazepam misuse in a group of injecting drug users. Br J Addict 1992 87:1387–92
Ref 2: Preston KL, Bigelow GE, Liebson IA. Effects of sublingually given naloxone in opioid-dependent human volunteers. Drug and Alcohol Dependence (1990) 25:27-34
Ref 2: 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
Ref 4: 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
Ref 5: Byrne A, Hallinan R, Love A. Administration of a lighter-coloured methadone liquid. D&A Review (2002) 21;4:405
Ref 6: McBride WG. Thalidomide and Congenital Abnormalities. Lancet 1961 2:1358
These are a few items which relate to this theme.  Some are rigorous studies, others just anecdotal or opinion pieces which I leave the reader to judge. 
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
Big Pharma Company Jacks Up Price of Overdose Life Saver by 1100%: Now, More People Will Die.             http://www.alternet.org/big-pharma-company-jacks-price-overdose-life-saver-1100-now-more-people-will-die?akid=10303.1120210.FX4JwZ&rd=1&src=newsletter821675&t=5&paging=off
Anaphylaxis After the Injection of Buprenorphine. Boggs CL, Ripple MG, Ali Z, Brassell M, Levine B, Jufer-Phipps R, Doyon S, Fowler DR. J Forensic Sci. 2013 Mar 29
Britain Accuses Glaxo of Paying Rivals for Delay of Generic Antidepressant Stephen Castle.  New York Times 20 April
Making medicines evergreen. Another loophole exploited by the drug industry. Brunet MD. BMJ 2013; 346 doi: http://dx.doi.org/10.1136/bmj.f354 (Published 22 January 2013)
Acute hepatitis and renal failure related to intranasal buprenorphine misuse: case report and literature analysis. Eiden C, Ripault M-P, Peyriere H, Larrey D. Conference presentation. Société Française de Pharmacologie et de Thérapeutique. 8th Congress Angers April 2013
Suboxone Misuse Along the Opiate Maintenance Treatment Pathway. Furst RT. J Addict Disease 2012 32;1:53-67
Hansen H, Roberts SK. Emerald Book Chapter: Two Tiers of Biomedicalization: Methadone, Buprenorphine, and the Racial Politics of Addiction Treatment. Advances in Medical Sociology 2012 14:79-102
Hansen H, Skinner ME. From white bullets to black markets and greened medicine: The neuroeconomics and neuroracial politics of opioid pharmaceuticals. Annals of Anthropological Practice 36.1 167-182
Hitchings AW, Baker EH, Khong TK. Making medicines evergreen. BMJ 2012 345:e7941 http://www.bmj.com/content/345/bmj.e7941
Peles E, Schreiber S, Adelson M. Opiate-Dependent Patients on a Waiting List for Methadone Maintenance Treatment Are at High Risk for Mortality Until Treatment Entry. J Addict Med 2013 Mar 20. [Epub ahead of print]
Reindeerspotting. A Finnish documentary film. The film focuses on a drug addict whose drug of choice is Subutex taken intravenously. He is unemployed and he finances his addiction through thefts, burglaries, and welfare payments.
Schwartz RP et al.  Opioid Agonist Treatments and Heroin Overdose Deaths in Baltimore, Maryland, 1995–2009.  March 14, 2013 American Journal of Public Health
Winstock AR, Lea T, Sheridan J. Prevalence of diversion and injection of methadone and buprenorphine among clients receiving opioid treatment at community pharmacies in New South Wales, Australia. International Journal of Drug Policy 2008 19:450–458
Launch of Suboxone Film - Sydney Olympic Site - August 2011
Suboxone Sydney launch 2006
Lenzer J. Why we cant trust clinical guidelines. BMJ 2013;346: f3830

19 July 2013

Adverse Event reports should inform clinical medicine but this is cardiac alarmism at its worst.

QTc interval screening for cardiac risk in methadone treatment of opioid dependence. Pani PP et al. Cochrane Database CD008939
Trends in reporting methadone-associated cardiac arrhythmia, 1997-2011: an analysis of registry data. Kao D et al. Ann Intern Med 2013
Opioid addiction agonist therapy and the QT prolongation phenomenon: state of the science and evolving research questions. Wedam EF, Haigney MC. Addiction 2013
False sense of safety by daily QTc interval monitoring during methadone IVPCA titration in a patient with chronic pain. Miranda-Grajales H et al. J Pain Res 2013 [full citations below]
Dear Reader,
Before commenting on these four recent items, here is my summary of the state of play: While distressing and serious, torsade de pointes tachycardia is a very rare event in methadone patients.  This arrhythmia is highly treatable with a low or zero mortality rate judging from the cases reported in the literature since 2002 (n~100).  Torsade de pointes appears to affect the older patient population (>40 years), is more common in women and generally when higher doses of methadone (>120mg daily) are combined with other drugs such as certain antibiotics and anti-virals. 
These four recent items related to cardiac complications in patients prescribed methadone.  While the Cochrane review finds insufficient evidence to advise any interventions on this subject, the other three papers are disappointingly thin on facts and high on the fog factor despite the clarity now appearing after a decade of clinical experience since Krantzs seminal report of 17 cases in 2002.  [Cochrane abstract: http://www.ncbi.nlm.nih.gov/pubmed/23787716?dopt=Abstract ]
Kao, Krantz (senior and corresponding author) and colleagues purport to present an analysis of FDA adverse event reports.  Their torsade figures include reports which were not primarily due to methadone (43% not primary suspect) and further, it also comprises reports of QT prolongation without a break-down of these two very different syndromes.  Hence to arrive at the actual number of torsade reports where methadone was the primary suspect one needs to discount 361 by 43% and then take account of the proportion of torsade cases (figure not given here but was about 70% in Pearsons paper).  This makes about 2 reports of torsade tachycardia per month in America.  About half would have been dependency cases (FDA information).  See my own more detailed description and conclusions [ http://methadone-research.blogspot.com.au/2013/07/can-adverse-event-reports-inform.html ].  [Abstract can be accessed here: http://www.ncbi.nlm.nih.gov/pubmed/23689766?dopt=Abstract ]
In an Addiction editorial Wedam and Haigney write discomforting and confusing words about the so-called QT prolongation phenomenon.  Why call it a phenomenon any more than a fever in an infant with an infection?  But it serves to spice up the mystery which scientific discourse is meant to dispel.  Many commentators and public health authorities have called for more substantial research on this subject, preferably national surveys.  Yet now that such research it to hand from Norway and France (sudden deaths in Norway and torsade reports in France, all very reassuring and consistent) many writers seem to ignore its outcomes.  Wedam and Haigney cite the Norway article by Anchersen but then states that Americans must be different to Europeans!!  Their citations do not (and cannot) justify such a position, making the contention no more than a ruse to confuse. 
This Addiction editorial continues a long history of apparent antagonism to methadone treatment.  Their titles would seem to support this while few of the items would appear to be productive issues aimed at improving patient care or public health goals.  Topics included cravings from additional methadone, memory problems, injecting of methadone, benzodiazepine abuse, deaths, and more. [full Addiction article available on line: http://onlinelibrary.wiley.com/doi/10.1111/add.12123/full ]
The third item is a chronic pain case report of such an extraordinary nature that it can have little or no relevance to regular clinical practice.  Veteran author Dr Cruciani (senior and corresponding author) and colleagues surprisingly publish a detailed day-to-day report of a complex pain patient who was clinically overdosed with methadone given parenterally along with pethidine and other opioids.  The most telling features relative to cardiac safety would include: the lowest QTc values (317, 416ms) were found on the days after the highest methadone doses (334, 363mg).  One slightly prolonged reading (451ms) occurred two days after methadone was ceased altogether.  These findings are consistent with the literature in which normal QTc levels were commonly found in patients who had torsade de pointes away from the tachycardia episode (and also large diurnal variations in QTc values).  A single ECG tracing is almost certainly a waste of time for routine purposes in low or perhaps even high-risk patients.  And despite all the prolonged QT levels this patient still did NOT develop any arrhythmia. 
While torsade de pointes is extremely uncommon, it will still be seen occasionally in dependency and pain practice.  The arrhythmia needs to be considered in someone with fainting, fitting, palpitations, shortness of breath or occasionally, chest pain.  Treatment involves the use of urgent paramedic treatment and transfer to cardiac intensive care for monitoring.  Some patients will need intravenous magnesium, temporary pacemaker and/or cardioversion.  Withdrawal or replacement of the suspected drugs and/or reduction in doses may be useful.  There is no single agreed protocol for this condition but its treatment should be directed by cardiac experts, just as dependency should be directed by dependency experts and pain by pain management experts. It is crucial not to avoid appropriate doses of methadone as the risk of inadequate doses is very substantial, including death, whereas there he never been a reported confirmed death due to torsade de pointes.
As Pani et al. point out there is no proven preventive strategy but it would seem prudent to order a cardiograph on patients who are prescribed high dose methadone (>150mg), especially if there are any other risk factors.   
Comments by Andrew Byrne ..
Full citations for these articles:
Pani PP, Trogu E, Maremmani I, Pacini M. QTc interval screening for cardiac risk in methadone treatment of opioid dependence. Cochrane Database Syst Rev. 2013 Jun 20;6:CD008939
Kao D, Bucher Bartelson B, Khatri V, Dart R, Mehler PS, Katz D, Krantz MJ. Trends in reporting methadone-associated cardiac arrhythmia, 1997-2011: an analysis of registry data. Ann Intern Med. 2013 21;158(10):735-40
Wedam EF, Haigney MC. Opioid addiction agonist therapy and the QT prolongation phenomenon: state of the science and evolving research questions. Addiction 2013 108;6:1015-1017
False sense of safety by daily QTc interval monitoring during methadone IVPCA titration in a patient with chronic pain. Miranda-Grajales H, Hao J, Cruciani RA. J Pain Res 2013 6:375-8

25 June 2013

Finally some research support for continuing MMT/BMT peri-operatively.

Dear Colleagues,
Some researchers in Adelaide have collaborated with an elegant retrospective analysis on the needs for post operative analgesia in maintenance patients using PCA.  In addition to supporting the safety of continuing methadone, they conclude: “These results confirm that continuation of buprenorphine perioperatively is appropriate.”
Pain relief and opioid requirements in the first 24 hours after surgery in patients taking buprenorphine and methadone opioid substitution therapy. Macintyre PE, Russell RA, Usher KA, Gaughwin M, Huxtable CA. Anaesth Intensive Care 2013 41;2:222-30                                               

19 June 2013

Bad Pharma - quotes from Ben Goldacre's book on Wiki ...

Bad Pharma (2012)

Ben Goldacre's second book, Bad Pharma: How Drug Companies Mislead Doctors and Harm Patients, was published in the UK in September 2012 and will be published in the United States and Canada in January 2013. In the book he argues that:
Drugs are tested by the people who manufacture them, in poorly designed trials, on hopelessly small numbers of weird, unrepresentative patients, and analysed using techniques which are flawed by design, in such a way that they exaggerate the benefits of treatments. Unsurprisingly, these trials tend to produce results that favour the manufacturer. When trials throw up results that companies don't like, they are perfectly entitled to hide them from doctors and patients, so we only ever see a distorted picture of any drug's true effects. Regulators see most of the trial data, but only from early on in a drug's life, and even then they don't give this data to doctors or patients, or even to other parts of government. This distorted evidence is then communicated and applied in a distorted fashion. In their forty years of practice after leaving medical school, doctors hear about what works through ad hoc oral traditions, from sales reps, colleagues or journals. But those colleagues can be in the pay of drug companies – often undisclosed – and the journals are too. And so are the patient groups. And finally, academic papers, which everyone thinks of as objective, are often covertly planned and written by people who work directly for the companies, without disclosure.

14 June 2013

Kao study: can adverse event reports inform medical practice? Cardiac safety/danger imbalance.

Trends in reporting methadone-associated cardiac arrhythmia, 1997-2011: an analysis of registry data. Kao D, Bucher Bartelson B, Khatri V, Dart R, Mehler PS, Katz D, Krantz MJ. Ann Intern Med. 2013 21;158(10):735-40
Dear Colleagues, 
Following the lead of Pearson and Woosley (see summary below*) in 2005, Kao, Krantz and colleagues have made a search of adverse event reports to the FDA in America regarding methadone and cardiac status. 

From 2003 to 2012 they report a mean of 3.5 cases per week of torsade de pointes or QT prolongation with a mortality of 11% across these two groups.  Mean age was 44 years and 57% were male.  Methadone was the primary suspect in only 57% of reports.  Median daily methadone dose was 150mg.  Table 1 states that the outcome required intervention in 9.5% of cases, making it appear that over 90% of cases were self terminating. 

Consistent with other reports, these authors find that many or most cases are due to more than one factor, lamivudine being the commonest co-prescribed drug (11% of reports).  Other drugs involved were ritonavir and AZT (each at 10%), lorazepam, morphine, apomorphine, tenofovir, lopinavir, ceftriaxone (a cephalosporin antibiotic) and oxazepam (5-7% of reports). 

By failing to separate the groups the reader is denied any real view of the extent of torsade de pointes tachycardia or its mortality (if any).  Torsade is a rare but serious arrhythmia while QT prolongation is a common and usually asymptomatic finding in methadone patients (Stimmel 1973; Wedam 2007; Fareed 2013).  From 2000 to 2002 Pearson reported 8.5% mortality from the combined group (5/59) but no deaths due to torsade itself. 

Clouding matters somewhat, Kao et al. give another combined figure for cardiac arrest and ventricular arrhythmia (1646, 81% mortality, 41% with methadone as the primary suspect).  Neither of these conditions is known to be associated with drug-related QT prolongation and furthermore, both could be terminal events due to overdose or other causes.  About half of the methadone in America is estimated to be used in for cancer and non-cancer pain purposes so many deaths have methadone as a bystander (consistent with 57% where it was not considered the prime suspect). 

If Kao et al. had a similar proportion of torsade cases to Pearson, it would represent approximately 2.5 reports of torsade per month in America.  Considering there are reportedly around 550,000 patients on methadone at any one time in America (FDA 2010) this is not consistent with Kao et al. who contend that the condition is a major factor in methadone deaths.  Furthermore, the figure is consistent with both French adverse reaction reports and a Norwegian mortality survey of methadone patients (Perrin-Terrin 2010, Anchersen 2009). 

Dr Krantz is the corresponding and senior author of this paper.  His seminal paper on this subject in 2002 failed to separate addiction from pain management cases.  This omission may have contributed to confusion about the dose level at which torsade de pointes may be expected to occur due to the extremely high doses of his pain management cases (which were only revealed in a subsequent paper).  The mean reported dose across the groups was 397mg daily yet their follow-up paper allowed a calculation of very different mean daily dose levels between the two groups (541mg for 8 pain patients and 269mg for 9 dependency cases).  
Kao, Krantz et al. make comparisons with dofetilide and sotalol, antiarrhythmic drugs which can cause QT changes and torsade de pointes.  Yet it can hardly be a useful or valid comparison when one drug is being used in a person already known to have a cardiac problem.  Furthermore there were more than twice as many reported QT/torsade cases with these drugs (478) than with methadone (211) as primary suspects (no indication is given of the total patient years of the former, nor the mortality). 
Despite the conceded limitations of reports of this nature, the authors nevertheless speculate (their word) that there may be an increasing incidence and that the arrhythmia may represent an important but underappreciated contributor to methadone-related morbidity and mortality.  Yet the authors provide no evidence for this and they still cannot cite any group of confirmed deaths (or even one as far as I can find) due to torsade de pointes. 
I am surprised that Krantz allows his colleagues to cite Chugh’s study from Portland, Oregon to justify the claim that arrhythmia contributes to a substantial proportion of methadone deaths.  Close examination of Chugh’s very crude and indirect protocol finds that it is severely flawed and indeed if all his deductions were valid, torsade reports should number in the thousands. 
To try to place this item into some perspective I did a search of the MedWatch web site for torsade de pointes which showed up warnings for citalopram, arsenicals, droperidol, clozapine, azithromycin, LAAM, clarithromycin, thioridazine and ondansetron, on just their first search page.  Further searches for FDA adverse event reports on these drugs from the E-health-me web site reveals 35 reports for citalopram, 33 reports for droperidol, 2 for clozapine, 55 for azithromycin, 82 reports for clarithromycin and none for thioridazine.  There are even torsade reports from alcohol (10 reports), diazepam (41 reports) and salbutamol (14 reports).  When methadone is entered the number of reports is 26 plus another 23 under the trade name for methadone liquid (Methadose) making 49 total over a reporting period of about 15 years.  There may be a simple explanation for what appears to be an inconsistency with Kao’s paper which reports over 300 such cases from the FDA reporting system.
Even allowing for under-reporting, neither is a large number when compared with the number of torsade cases reportedly due to other drugs, nor in view of the very large numbers of patients now taking methadone.  
Pearson and Woosleys report included a detailed table with age, sex, methadone dose, type of report (QT or torsade), outcomes, other contributors, etc.  By contrast, Kao et al. leave the reader in the dark regarding how many actual torsade cases there were and how many, if any, were fatal.  I could find none in the English literature (there may be one from France). 
This Annals paper is one of several recent examples of what one commentator has called “unrepentant fear-mongering” about methadone and cardiac safety.  Despite the deficiencies of the present report, far more important, as the US Center for Disease Control points out, methadone is involved in thousands of overdose deaths every year, with the increasing number of such deaths correlating with the increasing use of methadone for pain in America.  After single-figure reports of torsade and examinations of ‘possible torsade’ (sudden death) from national surveys in France and Norway, it is clear that the increasing deaths are not significantly contributed to by QT prolongation/TdP problems as proposed again by Kao and colleagues.  Indeed, we know that being on supervised methadone treatment reduces deaths dramatically (Caplehorn reported by a factor of four). 
Hence, these patients are less in need of protection from the supposed hazards of QT prolongation or TdP than from irrational alarmism.  Torsade de pointes is an extremely rare adverse event which is complex and multifactorial.  Ignorant speculation needlessly frightens the field about the safety of the methadone treatment and is especially egregious when unproven across-the-board measures are recommended to ‘protect’ against the supposed ‘problem’, even before its scope is defined.  Krantz has still not addressed the anomaly of his large number of cases of torsade (17) in two small catchments in 2002 when compared with large national surveys which have found even fewer cases in far larger populations. 
Concluding comment on cardiac safety in methadone patients:
Torsade de pointes tachycardia is an unpleasant and unusual consequence of a series of events in a person predisposed to QT prolongation (but whose resting QT length is often normal).  Most cases of torsade do not involve methadone but a proportion occur in long term methadone recipients, often involving substantial doses (>100mg daily) with the addition of another drug.  These include common antibiotics, anti-virals, antidepressants and other drugs, each of which can be responsible for torsade in a predisposed individual.  Other factors which contribute to the risk levels are genetic QT prolongation, female sex, older age, pre-existing heart disease, alcohol use, low potassium and HIV infection. 
While torsade de pointes is extremely uncommon, it will still be seen occasionally in dependency and pain practice.  The arrhythmia needs to be considered in someone with fainting, fitting, palpitations, shortness of breath or occasionally, chest pain.  Treatment involves the use of urgent paramedic treatment and transfer to cardiac intensive care for monitoring.  Some patients will need intravenous magnesium, temporary pacemaker and/or cardioversion.  Withdrawal or replacement of the suspected drugs and/or reduction in doses may be useful.  There is no single agreed protocol for this condition but its treatment should be directed by cardiac experts, just as dependency should be directed by dependency experts and pain by pain management experts. 
There is no proven preventive strategy but it would seem prudent to order a cardiograph on patients who are prescribed high dose methadone (>150mg) even in the absence of other risk factors. 
Notes by Andrew Byrne ..
* Pearson found 59 reports in a 7 year period, 43 (73%) had torsade de pointes.  There were five deaths (8.5%), of whom 2 used methadone intravenously (360mg and 1680mg daily), one was 78 years old and took cisapride as well as the methadone, at unknown dosage; the fourth was a 40 year old female who took 29mg methadone daily (none of these had developed torsade but only had QT prolongation); the fifth and only fatal event in a torsade case was a 47 year old female who died from a myocardial infarction in addition to the use of droperidol, azithromycin, and methadone. 
Other references:
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 [see summary below]
Stimmel B, Lipski J, Swartz M, Donoso E. Electrocardiographic changes in heroin, methadone and multiple drug abuse: a postulated mechanism of sudden death in narcotic addicts.  Proceedings of  Fifth National Conference on Methadone Treatment, March 1973
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
Fareed A, Vayalapalli S, Scheinberg K, Gale R, Casarella J, Drexler K. QTc interval prolongation for patients in methadone maintenance treatment: a five years follow-up study. Am J Drug Alcohol Abuse. 2013 Jun 28.
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
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
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
Caplehorn JRM, Dalton MSYN, Cluff MC, Petrenas A. Retention in methadone maintenance and heroin addicts' risk of death. Addiction 1994 89:203-7