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