E-DRUG: Revisiting phenobarbital for epilepsy
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[Essential in Africa, hardly used in the UK!?; copied as fair use; WB]
http://bmj.bmjjournals.com/cgi/content/full/329/7476/1199
BMJ 2004;329:1199-1200 (20 November), doi:10.1136/bmj.329.7476.1199
Revisiting phenobarbital for epilepsy
Large gaps in knowledge still exist, but we may be underestimating its
clinical value
A recent review of phenobarbital for the treatment of epilepsy draws
attention to an ethical dilemma and to the many gaps in our knowledge
about a drug that has been in use since 1912.1 Phenobarbital is commonly
prescribed in the developing world, but in most developed countries it
has fallen into disrepute. The World Health Organization (WHO)
recommends it as a first line drug for partial and generalised
tonic-clonic seizures in developing countries.2 Its antiepileptic
efficacy is undisputed, but concerns remain about its side effects.1 If
people with epilepsy in Britain are not prescribed phenobarbital because
of its toxicity, is it ethical to recommend its use in developing
countries? And if the drug is not as toxic as it is believed to be,
might it not be used more in the developed world?
Phenobarbital has many favourable features: broad spectrum efficacy
against all seizure types other than absences; a starting dose within
the clinically effective range; seizure freedom rates comparable to
those associated with modern drugs; a very low risk of life threatening
adverse effects; linear pharmacokinetics; long half life compatible with
once daily dosing; low propensity to be a target for drug interactions
(except for the inhibition of its metabolism by valproate); availability
of a parenteral formulation, and low cost.3 The perception that
phenobarbital is more commonly associated with withdrawal seizures is
not supported by the best available evidence.4 Documented disadvantages
include enzyme induction, which may alter response to co-administered
drugs such as oral contraceptives, and adverse cognitive and behavioural
effects, particularly in children.1 3
Most of the evidence on phenobarbital comes from observational studies,
and controlled trials are scarce and mostly of modest quality. In
randomised trials in developed countries, phenobarbital was associated
with higher discontinuation rates than carbamazepine and phenytoin,5 6
but the difference was not huge and was mostly seen in open label trials
where management could have been affected by doctor or patient bias.1
Even in children, in whom phenobarbital is considered to be least well
tolerated, evidence for a negative impact on cognition and behaviour is
less compelling than generally thought. Although phenobarbital has been
repeatedly reported to affect adversely intelligence scores and
behaviour in children with febrile seizures (no longer an acceptable
indication), results from studies in adults and children with epilepsy
did not yield univocal evidence for significant cognitive and
behavioural impairment.1 Most importantly, studies in developing
countries did not usually show excess neuropsychological toxicity in
comparison with modern antiepileptic drugs.1 7-10 Admittedly, many of
these studies had methodological weaknesses, but their more favourable
results might also be related to the use of lower effective doses than
in trials conducted in developed countries.1
What conclusions can we draw from this evidence? The first is that low
cost is not just phenobarbital's greatest asset but also its greatest
liability, having led the drug into commercial neglect. Eadie pointed
out appropriately that phenobarbital "may be allowed to fade from use,
at least in affluent societies, not so much because of its limitations,
but because its virtues are no longer promoted," and one cannot avoid
wondering what we would be saying about phenobarbital today if it had
been licensed in the last decade.11 Phenobarbital probably does have an
inferior tolerability (including subtle neurotoxic effects and, in
children, overt behavioural disturbances) compared with some other
antiepileptic drugs, but the size of the difference may have been
overstated and may not necessarily apply to dosages at the lower end of
the effective range.
In affluent societies, phenobarbital is unlikely to represent the best
choice for most people with newly diagnosed epilepsy.1 In the developing
world, when the choice is between the cheapest treatment or no treatment
at all, phenobarbital should be used, particularly in adults. However,
local doctors should not present phenobarbital to patients as the best
drug but should inform them about its advantages and disadvantages (and
deficiencies in knowledge) compared with alternative treatments. After
all, cost is an important consideration in drug selection in developed
countries too, and prioritising allocation of health resources is never
unethical when done in a fair and transparent way. We also need to
remember that making a drug available in a remote part of a developing
country involves much more than the price of tablets, and includes the
costs of a reliable and uninterrupted transport service and of
facilities for storage and dispensing. Such added costs would be similar
for all drugs.
Although phenobarbital may be less toxic than generally thought, and
might be considered more often to treat patients in developed countries
(particularly as second line treatment), gaps in knowledge about this
drug (and other antiepileptic agents) remain a major concern. Can
dose-response relationships for its efficacy and neurotoxicity be better
defined? Do pharmacogenetic differences exist in its tolerability
between people from diverse ethnic backgrounds? Are we sure that
patients in the developing world are not just tolerating a greater
degree of side effects because they are offered little choice in their
treatment? Doing high quality research will be expensive and, given the
lack of interest of pharmaceutical companies in phenobarbital, difficult
to fund.
The International League Against Epilepsy and WHO, which have a series
of demonstration projects for epilepsy, have the responsibility of
addressing these issues, particularly as they continue to endorse the
use of phenobarbital in poor countries. Simply doing more observational
studies or non-randomised open trials cannot solve the problem. Only
robust evidence will address the gaps in our knowledge and the ethical
dilemma of recommending a drug for the developing world but shunning it
in the developed world.
Rajendra Kale, assistant editor
BMJ (rkale@bmj.com)
Emilio Perucca, professor
Institute of Neurology IRCCS C. Mondino Foundation, University of
Pavia, Via Mondino 2, I-27100 Pavia, Italy
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Competing interests: Both RK and EP do not recall ever having been
funded by the manufacturers of phenobarbital.
RK has been a member of the executive committee of the International
Bureau for Epilepsy and chaired the Commission for the Developing World
of the International League Against Epilepsy. Several of the epilepsy
and neurology meetings, especially those organised by these
organisations, which RK participated in and gave talks at have been held
all over the world and have been funded directly or indirectly by
pharmaceutical companies (including Novartis, SmithKlineBeecham, E
Merck, Cipla, Sanofi, Pfizer, and others). For more information please
see http://bmj.bmjjournals.com/aboutsite/comp_editorial.shtml
EP has received research grants and fees from the manufacturers of
carbamazepine and oxcarbazepine (Novartis), gabapentin and phenytoin
(Pfizer), lamotrigine (GSK), levetiracetam (UCB Pharma), topiramate
(Johnson and Johnson), valproate and vigabatrin (Sanofi-Aventis).
References
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the 21st century: a critical review. Epilepsia 2004;45: 1141-9.
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WHO/MNH/MND/90.3).
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eds. Antiepileptic drugs. 5th ed. Philadelphia: Lippincott, Williams and
Wilkins, 2002: 514-21.
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