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