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
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
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 can’t trust clinical guidelines. BMJ
2013;346: f3830
