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Cheap and effective drugs exist but are not accessible to most patients
Of the 35 million people with epilepsy who live in developing countries, around 85% receive no treatment at all.1 2 As a consequence, they experience morbidity related to seizures and the psychosocial consequences of stigma and discrimination. Regrettably, most of these people—many of whom are children—could have their seizures completely controlled and they could return to a normal life by taking a single daily dose of a drug that costs less than $3 (Â£1.50; €2.20) each year.3 In this week's BMJ, a randomised controlled trial in Bangladesh by Banu and colleagues compares the effects of carbamazepine and phenobarbital on seizure control and behavioural side effects in 108 children with epilepsy.4
The World Health Organization recommends phenobarbital as the treatment of choice for partial and tonic clonic seizures in resource restricted countries,5 but this policy has been questioned because phenobarbital is thought to be less well tolerated than other antiepileptic drugs.6 Concerns apply particularly to children, who are especially vulnerable to this drug's adverse cognitive and behavioural effects.7 Differences in tolerability between phenobarbital and other anticonvulsants are probably less prominent than generally thought, however, and they were detected mostly in trials where the assessment of outcomes may have been affected by doctor or patient bias.3 8 Importantly, most studies in developing countries did not show excess neuropsychological toxicity of phenobarbital compared with other anticonvulsants,9 10 11 possibly because dosages in these studies tended to be lower than those used in developed countries, or because lack of options make people less willing to report side effects.
The study by Banu and colleagues found no significant difference in behavioural problems such as restlessness and hyperactivity between phenobarbital and carbamazepine (7% v 11%), and no significant difference in psychological and behavioural assessments after one year.11 Of those children who completed a 12 month follow-up, 47.5% of those on phenobarbital and 60% of those on carbamazepine were seizure-free for the last six months.
Conducting clinical trials in resource restricted countries is difficult. As with previous similar studies, the trial by Banu and colleagues has limitations, including an open label design and low power to detect potentially important differences in seizure outcome and behavioural test scores. More children were lost to follow-up in the phenobarbital group (22%) than in the carbamazepine group (9%). Therefore, on an intention to treat basis, the proportion of children who were seizure free in the last six months was considerably higher in the carbamazepine group than in the phenobarbital group (50% v 35%), which raises questions about potentially lower compliance in children assigned to phenobarbital. Drug concentrations were not reported. The two groups were not well balanced for some characteristics; girls were under-represented in the phenobarbital group, a potentially important factor because behavioural problems were more frequent in girls than in boys.
Despite these limitations, the study shows that most children tolerated phenobarbital well and behaviour even improved in many. This supports other findings in similar settings. In a randomised study of 302 children and adults with epilepsy in rural Kenya, side effects were reported more frequently with phenobarbital than with carbamazepine, but the number of patients with side effects did not differ significantly between drugs; 3% of patients on phenobarbital were withdrawn for adverse effects and 5% on carbamazepine were withdrawn.9 When 73 children with newly diagnosed epilepsy were randomised to phenobarbital, carbamazepine, or valproate in Taiwan, no significant differences in psychometric scores were found between groups.10 Similarly, no treatment related differences in behaviour rating scores were found in 94 children with epilepsy randomised to phenobarbital or phenytoin in rural India.11 Observational studies support the conclusion that phenobarbital is relatively well tolerated in developing countries.2 Apart from its low cost, phenobarbital has other merits such as efficacy against all seizures other than absences, seizure freedom rates comparable to those associated with modern drugs, a starting dose within the effective range, a low risk of life threatening adverse effects, linear pharmacokinetics, once daily dosing, and availability of a parenteral formulation.8
Most controlled trials of phenobarbital in epilepsy have methodological shortcomings, including an open label design, small sample size, and, at times, questionable choice of dosing regimens.3 Although larger double blind randomised studies are needed for a better assessment of the role of phenobarbital in the treatment of epilepsy,8 Banu and colleagues deserve praise for providing more evidence supporting its use in resource restricted settings.
The burden of untreated epilepsy in terms of human suffering and social costs is enormous. Governments and non-governmental organisations in developing countries need to ensure that effective treatment is available for all. Even in these settings, drug choice should be tailored to the individual, and phenobarbital will not be the best option for all. In fact, the price of drugs is a small part of the cost of ensuring a minimum standard of epilepsy care. Dispensing facilities are often unavailable in remote rural areas, and even when available they often fail to provide a continuous supply of drugs,12 which has potentially serious consequences. Seven children in Banu's study discontinued treatment for more than seven days for various reasons; four developed convulsive status epilepticus while not taking their drugs. An efficient epilepsy management programme will work only if fully integrated within a community healthcare delivery system,2 which should provide not only reliable supplies of drugs, with adequate facilities for storage and dispensing, but also educational programmes for health practitioners and the general population.
Competing interests: EP has received speaker's or consultancy fees or research grants from the manufacturers of carbamazepine and oxcarbazepine (Novartis); gabapentin, phenytoin, and pregabalin (Pfizer); lamotrigine (GlaxoSmithKline); levetiracetam (UCB Pharma); tiagabine, valproate, and vigabatrin (Sanofi Aventis); topiramate (Johnson and Johnson); rufinamide and zonisamide (Eisai).