Phenobarbital is effective for partial and generalized tonic–clonic seizures; it shows similar efficacy for “time to 12-month remission” or “time to first seizure”: as phenytoin (PHT) and carbamazepine (CBZ) (Taylor et al., 2001; Tudur Smith et al., 2003). All of the important comparative studies in adults and children were undertaken 15 or more years ago (Kwan & Brodie, 2004). More recently 108 children aged 2–15 years in Bangladesh were randomized to phenobarbital or CBZ in a single center (Banu et al., 2007). The focus of the study was on tolerability, particularly on behavioral side effects. However, there were no important differences in efficacy between the drugs over the 12-month follow-up period. In a recent small prospective three-arm parallel-group, case control trial, 95 patients with Alzheimer’s disease and epileptic seizures were randomized to monotherapy with levetiracetam (LEV), lamotrigine (LTG), or phenobarbital (Cumbo & Ligori, 2010). A 4-week dose adjustment was followed by a 12-month evaluation period. There were no statistically significant differences in efficacy between these three AEDs. Four of the patients taking phenobarbital dropped out because of side effects in this nonblinded study.
One interesting recent study involved phenobarbital use in rural China. This was a demonstration project of epilepsy management at primary health level under the auspices of the World Health Organization (WHO) in partnership with the International League Against Epilepsy (ILAE) and the International Bureau for Epilepsy (IBE). The project represents the largest study of phenobarbital, and the results have been published in a series of reports (Wang et al., 2003, 2006, 2008; Kwan et al., 2012). The project started with a door-to-door survey in 2000, estimating a treatment gap (proportion of people with active epilepsy not receiving treatment) of >60% (Wang et al., 2003). In parallel with an educational program, a pragmatic intervention study was then conducted that recruited patients older than 2 years of age, with at least two convulsive seizures in the previous 12 months and not receiving adequate medical treatment (Wang et al., 2006). Trained local primary care physicians made the initial diagnosis using a specially designed questionnaire to screen possible cases of convulsive epilepsy. A supervising neurologist then assessed screen-positive patients to confirm or refute the diagnosis and to establish baseline seizure frequency in those with a confirmed diagnosis. Patients entering the study took phenobarbital monotherapy as the first option. A total of 2,455 patients were treated between December 2000 and June 2004. At 24 months of treatment, 71% of patients showed significant benefit, with 26% free from convulsive seizure during the entire treatment period and another 45% having >50% reduction in seizure frequency (Table 1). A second survey 6 months after the end of the intervention noted that the treatment gap had significantly decreased to 49.8% (Wang et al., 2008). Therefore, the intervention measures were effective and evidently feasible in rural China, contributing to decrease in the treatment gap of epilepsy.
Table 1. Changes in seizure frequency from baseline after 6, 12, and 24 months of phenobarbital monotherapy in rural China
| ||Number of patients (%)|
|6 Months (n = 2,217)||12 Months (n = 1,897)||24 Months (n = 1,324)|
|Seizure-free for the whole period||919 (41)||644 (34)||347 (26)|
|Reduced by >75%||305 (14)||415 (22)||415 (31)|
|Reduced by 51 – 75%||245 (11)||230 (12)||185 (14)|
|Reduced by 26 – 50%||162 (7)||146 (8)||99 (8)|
|≤25% change||217 (10)||156 (8)||91 (7)|
|Increased by at least 25%||369 (17)||306 (16)||187 (14)|
Because epilepsy is a chronic disorder, it is important to determine the long-term impact of any intervention to assess its clinical effectiveness and to inform health care planning. At the study team’s recent revisit of the original study cohort, phenobarbital appeared to have maintained its benefits in the long-term, with an estimated probability of 0.53 for patients remaining on treatment at 6 years (Fig. 1; Kwan et al., 2012). This long-term retention rate compares favorably with newer AEDs used in similar settings. Based on the success of the demonstration project the government has established nationwide epilepsy control programs across rural China (World Health Organization, 2009).
Other observational studies
Over the last decade or so, phenobarbital has been investigated for treating epilepsy in several observational studies, largely undertaken in developing countries. Their conduct was often driven by practical considerations in attempting to establish a feasible clinical service and a constant supply of medication. They tended to include unselected, often untreated, patients with a range of seizure types across all age groups. There have been several published reports, which we shall now consider separately.
To evaluate the availability and accessibility of AEDs in two health districts in Cameroon, Preux et al. (2000) interviewed 33 patients with epilepsy, 26 physicians, 13 private and 8 hospital pharmacists, 8 traditional healers, and 3 drug distributors. They used structured questionnaires to assess knowledge of epilepsy, treatment accessibility, prescription methods, and availability and frequency of delivery of drugs. Only 1 of 33 patients did not take modern treatment; 91% of the patients were followed by a traditional healer, and 78% by a hospital physician. Phenobarbital was the most frequently prescribed drug by 69% of the doctors and was delivered regularly.
The Yelandur study, conducted in rural south India, enrolled only patients with generalized tonic–clonic seizures (Mani et al., 2001). Just 15 (11%) of the 135 recruited patients were lost to follow-up during the 5-year study period. Seventy-five patients (55%) took phenobarbital, and mostly (n = 68) as monotherapy. More than 50% of patients taking phenobarbital were seizure-free at 1 year, but this dropped to 20% over the next 4 years. There were major adverse events in only three patients taking phenobarbital.
In a hospital in urban Nigeria where 90% of 344 children with epilepsy were treated with phenobarbital, 50.6% achieved complete seizure control and only 2 patients stopped the drug because of intolerable side effects (Sykes, 2002). However, 94 (27%) patients were lost to follow-up after one or two visits to the hospital, making it difficult to draw valid conclusions.
In rural Mali, children and adults with epilepsy were treated at home with phenobarbital at dosages ranging from 50 to 200 mg daily (Nimaga et al., 2002). Advice on compliance was provided and an uninterrupted supply of phenobarbital was guaranteed. After a year of treatment, 80.2% had been seizure-free for the previous 5 months. There were improvements in physical and mental health and social status in some patients with few reported side-effects. The authors concluded that low-dose phenobarbital was very effective in this setting with the appropriate patient support.
A 2-year community-based phenobarbital program in rural Laos offered adult patients phenobarbital, 100 mg daily, if they reported two or more generalized seizures during the previous 2 years (Tran et al., 2008). There were limited available data from 46 retained cases (Fig. 2). Twenty percent of the patients were mentally retarded. Some patients dropped out of treatment and few demonstrated optimal compliance. Six patients died of various causes. The 18 people who completed the program deemed it “efficient” and reported an improved working capacity and quality of life. This study illustrates many of the problems in treating epilepsy in a rural environment (Fig. 2). Particular problems occur with compliance (Asawavichienjinda et al., 2003) and in obtaining a constant, high quality supply of phenobarbital (Laroche et al., 2005; Odermatt et al., 2007). There seems little doubt that phenobarbital was effective, well-tolerated, and safe in this setting.
There are few modern data regarding phenobarbital’s efficacy and tolerability in high-income societies. Its everyday use is likely to be largely confined to nonspecialist clinical settings, such as nursing homes (Galimberti et al., 2006). In a recent study of successful combination therapies from Glasgow, United Kingdom, phenobarbital together with phenytoin and carbamazepine were the third and ninth most common successful duotherapy, respectively (Stephen et al., 2012).