Pregabalin for pain: exploiting regulatory weaknesses
Geoff Kirwood, GDip Clinical Research
‘The bad news is that you will need to take this medication everyday for the rest of your days. The
worse news is that you won’t need many scripts.’ - palliative care joke.
Medicine is focused on Therapeutic Goods
Administration (TGA) or FDA approval of
treatments, in order to enhance the doctor’s
armamentarium. On the other hand, cost
benefit is vitally important to the patient.
Advocacy groups lobbying for Pharmaceutical
Benefit Scheme (PBS) approval of subsidy is
often at a sponsor’s behest. Efficacy is also
paramount to health consumers but
Prescriber Information from the TGA doesn’t
reveal risk benefit metrics of Number Needed
to Treat (NNT) versus Number Needed to
Harm (NNH), relying instead on an exhaustive
list of possible albeit unlikely side-effects.
In Victoria for the six years to 2015,
prescription medications caused 40.2% of
fatal overdoses, illegal drugs 13.8%, and a
combination was responsible for 22% of the
deaths – more than triple roadtoll fatalities.
Coroner Jamieson included this data in her
report on one case, finding: “…immediate need
for a real-time prescription monitoring system
to assist doctors in their clinical decision-
making around drug prescribing” (1). There
have been 21 such calls over four years, and a
tentative step will soon be taken. The majority
of the dangers, including non-fatal but
nonetheless debilitating side-effects, are not
being addressed. The Australian state of
Victoria is examined, and is typical of
pharmacotoxicology crises internationally.
Advocacy for regulatory control of
The announced proposal in April 2016 from
Victorian Health Minister Jill Hennessy to fund
Dept Health & Human Services (DHHS) for
Real-Time Prescription Monitoring to check
on high risk medication, at a minimum
morphine and oxycodone (2), falls short of
tackling the enormity of this problem.
Oxycodone contributed to 53 of 420 overdose
deaths in the year preceding the funding
announcement, and another 7 were
attributed to morphine. The Press Release
stated no more than future intent to address
drugs such as diazepam, which was found in
176 cases (1).
Even if the scope of controls was expanded
sufficiently to reduce fatalities, over-
prescribing of sedatives is rife. Pain
medications have had substantial industry
investment, owing to palliative need and
resultant longterm dependency, often
entailing easier repeat scripts (3). This has
diverted attention and resource from
addressing the conditions causing pain,
according to the Director of Hunter Hospital
Integrated Pain Service (4). The current trend
to de-prescribe opioids is reversing their
popularity a decade ago with doctors, but
harmful alternatives taking their place are
detailed below. Greater diligence needs to be
applied to the approvals given to subsidised
analgesia, and priority transferred onto
supporting specialist pain clinics.
The discourse that follows was submitted to
Minister Hennessy, who referred the concern
to DHHS Chief Officer Drugs and Poisons
Regulation, Dr Anna Peatt. The response
letter is supplementary to this article, and
states that "While I can understand your
concerns about fraud in research, my area has
responsibility for reducing the likelihood of
harm by certain medicines by regulating their
supply, manufacture and use. This drugs and
poisons regulation area does not oversee
research carried out by chemical
manufacturers." The manufacturer’s
deception of PBS Advisory Committee is
noted, but criticism in statistical reviews by
PBS Drug Utilisation Sub-Committee does not
trigger further investigations of extant
approvals. Federal Health Minister Greg
Hunt’s office did not reply to this advocacy.
Background: Profile of the Chronic Pain
Nociceptive pain is resultant from either
traumatic insult or acute illness, and is
defined as chronic if unresolved for three
months. Other pain is often neuropathic,
arising due to either damaged nerves or
sensory perception, where no primary cause
could be treated affects 8.5% of the
population (5). Poor prevalence data is
available – the 2014 National Health survey
lacks detail but 29.9% reported suffering from
musculoskeletal conditions (6) with inherent
chronic joint pain. Lying between these
figures is the commonly used estimate of 1 in
5 Australians, and the average result of two
similar studies done in SA and NSW shows
that 16.6% suffer chronic pain (7). Only 0.7%
of Chronic Pain Australia members suffer from
cancer pain (8).
In a Dutch purposive sample of older persons
surveyed to determine the condition most
impacting Quality of Life (QoL), as measured
by SF-36, those 24% suffering musculoskeletal
conditions reported the greatest impairment
(9). Insurer MBF commissioned a report into
Australia’s financial burden of pain, estimating
$34.3bn (10) of which one third was lost
productivity, and one fifth health costs.
Among seven strategic concerns the study
highlighted the absence of information on
pain in children, only aggregated data on
society’s most vulnerable being available with
1% of pre-teens afflicted by musculoskeletal
disease (6). Another seven recommendations
included more attention to be paid to the
association of chronic pain with
socioeconomic status (10). Pain sufferers
were 3.9 times more likely to be receiving
disability benefits (11). One twelfth of those
who’d retired early (after 45) due to back pain
had no assets, and the remainder had asset
values eleven twelfths below that of those
who’d worked to 64 (12). Twice as many of
Chronic Pain Aust members complained of
pain’s impact upon ability to work, than on
their family life (8).
Losing all hope makes life-saving a priority.
Suicide can be seen as a rational solution to
inescapable pain, for which palliative relief
destroys QoL. Back pain alone elevates this
risk by 13% (13), after adjusting for comorbid
mental illness. Support groups are vital, yet
the majority of carers are dissatisfied with
their involvement by health professionals (8)
and 20% report no inclusion. Focusing on
wellbeing has the potential to restore vitality,
as shown in its significant association with
foot pain improvers over three years (14). A
bias is apparent in this report, in that poor
mental health is falsely attributed to non-
responders (statistically insignificant p=0.08),
reflecting an industry agenda in the
researchers subsequent grant to trial an
antidepressant in this population.
There has been much discussion of marijuana.
The safe, non-psychotropic extract
cannabidiol is in trial in Australia for treating
mood disorders, intractable juvenile epilepsy,
and chemotherapy-induced nausea. Distrust
of naturally produced drugs has been pivotal
to the 36 year wait since positive studies (15).
Regardless of the merit of using instead the
psychotropic THC-rich marijuana for pain
relief, there is comfort in the knowledge that
road safety risk is routinely monitored by
police already. Both illicit dope and sedatives
limit social engagement, thus introducing
isolation as a determinant of poor health.
Policy changes sought
Governance improvements are required
across the board, from drug approvals
through to dispensing controls. To exemplify
pregabalin/Lyrica®, it being of questionable
efficacy against pain when NNT/NNH is
considered. Yet heavily promoted (16), and in
the six months to Sept 2015 Pfizer Australia
sponsored four pain practitioner Education
Events per week (20). It’s prescribed in 25, 75,
150, and 300mg dosages, whereas Oxycodone
is upped incrementally from 5, 10, 15, 20, 30,
40 to 80mg. Titration by doubling is likely to
create sudden onset of side-effects such as
blackout, given that somnolence is a listed
Top of the list of prescription volume
increases in the last annual PBS statistics
released (17), pregabalin was number eight in
annual cost of $AUD171.5m in third year of
listing - which is considerably more than the
year five $100m envisaged in the re-
application for PBS listing (18). The second
year usage was 58% above projections,
leading to speculation of excessive off-label
prescribing (19). In the top 20 ranked by cost
of government subsidy, it’s the only palliative
medication. All others address disease
Governance concerns are raised due to PBS
approval of pregabalin for neuropathic pain
after Pfizer’s application was refused the
previous year, when the only new published
study was a negative (21) finding of no
improvement over amitriptyline for diabetic
neuralgia but worsened side-effects.
Unpublished study 1107 conducted by the
manufacturer Pfizer was also submitted, but
authors’ identities are confidential: “There IS
an agreement between Principal Investigators
and the Sponsor (or its agents) that restricts
the PI’s rights to discuss or publish trial
results”, per trial NCT00407745 registration
with NIH. Regardless of this lack of
transparency, newly appointed PBS Advisory
Committee chair Dr Suzanne Hill endorses
trials conducted by the pharmaceutical
industry for their methodological rigour (22).
Pregabalin was blamed in 31 fatalities in 2015
(1) and overseas forensic toxicology reports
similar. Incidence in German cases trebled
between 2010 and 2011 (23), and a
retrospective analysis of Scottish heroin
overdoses found pregabalin and its weaker
predecessor gabapentin in 35% of cases (24).
It is dispensed five times as often as
oxycodone, with substantial loss of QoL
through impaired functionality such as
inability to drive. It is overlooked in the
VicRoads ‘Impaired Driving’ pamphlet
currently provided for doctor’s surgeries,
however Valium® is noted. That
benzodiazepine family increases risk of crash
leading to hospitalisation fivefold, whereas for
opioids it’s a non-significant difference (25)
against casualties determined to be
The standard pregabalin starting dose, 75mg
administered twice daily, resulted in a 50%
increase in steering wheel error rate on a
simulator in a small trial (26). This is one
quarter of the maximum recommended dose.
Pfizer reports on the ‘Likeability’ of pregabalin
in a small number of recreational drug users,
and the “high” from 450mg was equated to
that from 30mg of diazepam/Valium® (27),
the current leading cause of overdose
fatalities. This rough formulae can be applied
to the past quarter of dispensing data, where
prescriptions for 1,234 5mg tabs of diazepam
were written, compared to an adjusted
equivalent of 848 for pregabalin (28). Usage
of the former is on the wane, but the latter’s
popularity is rapidly rising.
Pregabalin and diazepam work the same way
in suppressing neuron activity that alcohol
does, by respectively: enhanced GABA
transport; GABA receptor agonist ie stronger
effect of GABA; and longer effect of GABA on
receptors. This commonality explains the
major side-effect warning of dizziness and
somnolence. Perception is inhibited, including
nociceptive and proprioceptive – hence lost
In systematic reviews of trials for either the
archetypal chronic pain of fibromyalgia or the
commonest pain disability stemming from
lower back, pregabalin doesn’t reduce pain
per se (29, 30). These meta-analyses
contradict that undertaken by the Cochrane
group responsible for Palliative Pain Support
(31), however team member Dawn Carroll’s
employment by Pfizer before publishing casts
doubt on the independence of this evidence.
The report’s Principal Investigator Prof
Andrew Moore was keynote speaker at the
Pfizer sponsored Australian Pain Society 2014
conference, alongside past President and
recipient of the 2006 ‘Pfizer international
visiting professorship in pain medicine’
psychologist Stephen Gibson (32) who teaches
that: “gabapentinoids [pregabalin and
gabapentin] stabilise nerves” (33). Prof Moore
has contracted to Pfizer but declared such
under pseudonym (34), and further
undeclared conflict of interest is apparent in
positive Cochrane review CD011790 for the
anti-depressant Cymbalta® despite journal
correspondence revealing contract to the
Unwitting patients are being put onto this
product due to dichotomous specialisations
for their conditions, being anaesthetists for
pain relief, and either rheumatologists for
musculoskeletal or oncologists for cancer.
Interest in the analgesic and latest party drug,
ketamine shows desire for a stoned trance is
commonplace, but not so in the pain
community (8). Consolidated effort is required
to instead provide a transparent pathway of
care and rehabilitation. Medication costs will
rise exponentially with approvals underway
for newer expensive bio-agents (10), already
comprising two of the three highest grossing
drugs for 2016 - each at a cost of over
$USD2000 per month (36). Policy is urgently
needed so as to improve governance.
Resultant health sector objectives
Canada recognises the cycle of disability and
worsened illness (38) revealed by differential
outcomes as being a socioeconomic health
determinant, with escalating costs to carers
and inordinate workload burden on
practitioners. Over-reliance on medications
leads to worsened consequence such as
substance abuse risk, whereas behavioural
approaches such as physiotherapy focus on
improved functionality (10). There is an
urgent requirement to determine cost-
effectiveness of care (39), so as to enable
more universal access to affordable
treatments. It has been proposed that
multidisciplinary pain clinics offer best value
for the health dollar (40), whereas over
prescription of opioids reflects a cheaper
interim answer (41).
Encouragement of activity would immediately
improve the ambulatory proportion of back
pain patients, addressing the exponential
increase in transport cost of 129% for a
condition whose prevalence increased 29%
over the same period (42). The question of
weight gain resultant from medication is of
concern. Initially developed as an
anticonvulsant, pregabalin in an epileptic
population increased BMI 0.9 on an average
dose of 300mg and, after up-titration for
seizure control, a 1.4 increase on 380mg (43).
This will detrimentally impact activity. A
Patient Reported Outcome site shows that
18% of users complained of weight gain, and
the majority suffered side-effects severe to
Meta-analysis of back pain guidelines recently
published argue that the rate of imaging is
currently overused at one in eight back pain
cases (45), unless cancer or an infection is
suspected. Physical therapy should precede
costly CTs or MRIs. The UK consensus
guidance is to offer medication foremost, and
referral to Pain Clinic only if severely affected
(46). However, the limitation of
pharmacotherapy is shown by systematic
review determining a Number Needed to
Treat of > 6 for the halving of neuropathic
pain (47), that is to say at least five leave the
physician without substantial benefit for each
Pregabalin’s cost-effectiveness study has been
provided by Pfizer, but the conclusion only
offers comparisons against their other
product gabapentin/Neurontin® and the
competitor’s Cymbalta® (48). The hindering
complexity of a multiplicity of measures
including Quality Adjusted Life Years, lost
work days, and direct costs indicates the need
for homogeneity in pharmacoeconomic
reports. An optimal protocol for a community
pain clinic is described (49) but financial
modelling of longterm outcomes will take
In accordance with preceding arguments, the
following are sought:
1. That Health Minister Hennessy
expand the scope of the imminent
DHHS prescription monitoring scheme
to include all analgesia previously
shown to have potential for fatal
2. That Federal Health Minister Hunt
establish a review into the extant
approval for subsidy of pregabalin on
3. That NHMRC funding be made
available for a study to be undertaken
into sedative doses and equivalent
blood-alcohol levels w.r.t. driving
ability impairment for the purposes of
4. That a working group comprising
representatives of ANZCA, RACGP and
RACP, and patients be established for
audit of existing Pain Clinics, with
aims of capturing tracking &
performance data and improving
carer collaboration through best
Affiliation declaration: The author is a
member of Chronic Pain Australia, but does
not act in any official capacity.
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