Carbamazepine versus phenobarbitone monotherapy (single drug treatment) for epilepsy

This is an updated version of the Cochrane Review previously published in Issue 12, 2016 of the Cochrane Database of Systematic Reviews.

Background

Epilepsy is a common neurological disorder in which abnormal electrical discharges from the brain cause recurrent seizures. We studied two types of epileptic seizures in this review: generalised onset seizures, in which electrical discharges begin in one part of the brain and move throughout the brain; and focal onset seizures, in which the seizure is generated in and affects one part of the brain (the whole hemisphere of the brain or part of a lobe of the brain). Focal seizures may become generalised (secondary generalisation), and move from one part of the brain throughout the brain. For around 70% of people with epilepsy, a single antiepileptic medication can control generalised onset or focal onset seizures.

This review applies to people with focal seizures (with or without secondary generalisation) and people with generalised tonic-clonic seizures, a specific generalised seizure type. This review does not apply to people with other generalised seizure types such as absence seizures or myoclonic seizures, as the recommended treatments for these seizure types are different.

Worldwide, phenobarbitone and carbamazepine are commonly used antiepileptic drugs, however, carbamazepine is used more commonly in the USA and Europe because of concerns over side-effects associated with phenobarbitone, particularly concerns over behavioural changes in children treated with phenobarbitone. Phenobarbitone is still commonly used in low- and middle-income countries in Africa, Asia, and South America because of the low cost of the drug.

Objective

The aim of this review was to compare how effective these drugs are at controlling seizures, to find out if they are associated with side effects that may result in individuals stopping the medication, and to inform a choice between these medications.

Methods

The last search for trials was in May 2018. We assessed the evidence from 13 clinical trials in which people received either carbamazepine or phenobarbitone and their treatment was decided randomly. We were able to combine data for 836 people from six of the 13 trials; for the remaining 619 people from seven trials, data were not available to use in this review.

Key results

Results of the review suggest that people are likely to stop taking phenobarbitone treatment earlier than carbamazepine treatment, because of seizure recurrence, side-effects of the drug, or both. Results also suggest that recurrence of seizures after starting treatment with phenobarbitone may happen later than treatment with carbamazepine (and therefore a seizure free period of 6 months or 12 months may occur earlier with phenobarbitone than with carbamazepine) for people with focal onset seizures, and vice-versa for people with generalised onset seizures.

Some side effects reported by people taking carbamazepine and people taking phenobarbitone were abdominal pain, nausea, vomiting, tiredness, motor problems (such as poor co-ordination), cognitive problems (poor memory), rashes and other skin problems. Behavioural side effects such as aggression were reported on both drugs in three trials in children.

Quality of the evidence

Some of the trials contributing data to the review had methodological problems, which may have introduced bias and inconsistent results into this review, and some individuals over the age of 30 with newly diagnosed generalised onset seizures may have had their seizure type wrongly diagnosed. These problems may have affected the results of this review and we judged the quality of the evidence provided by this review to be moderate to low quality. We do not suggest using the results of this review alone for making a choice between carbamazepine or phenobarbitone for the treatment of epilepsy. We recommend that all future trials comparing these drugs or any other antiepileptic drugs should be designed using high-quality methods to ensure results are also of high quality.

Authors' conclusions: 

Moderate-quality evidence from this review suggests that carbamazepine is likely to be a more effective drug than phenobarbitone in terms of treatment retention (treatment failures due to lack of efficacy or adverse events or both). Moderate- to low-quality evidence from this review also suggests an association between treatment efficacy and seizure type in terms of seizure recurrence and seizure remission, with an advantage for phenobarbitone for focal onset seizures and an advantage for carbamazepine for generalised onset seizures.

However, some of the trials contributing to the analyses had methodological inadequacies and inconsistencies that may have impacted upon the results of this review. Therefore, we do not suggest that results of this review alone should form the basis of a treatment choice for a patient with newly onset seizures. We recommend that future trials should be designed to the highest quality possible with consideration of masking, choice of population, classification of seizure type, duration of follow-up, choice of outcomes and analysis, and presentation of results.

Read the full abstract...
Background: 

This is an updated version of the Cochrane Review previously published in 2016. This review is one in a series of Cochrane Reviews investigating pair-wise monotherapy comparisons.

Epilepsy is a common neurological condition in which abnormal electrical discharges from the brain cause recurrent unprovoked seizures. It is believed that with effective drug treatment, up to 70% of individuals with active epilepsy have the potential to become seizure-free and go into long-term remission shortly after starting drug therapy with a single antiepileptic drug in monotherapy.

Worldwide, carbamazepine and phenobarbitone are commonly used broad-spectrum antiepileptic drugs, suitable for most epileptic seizure types. Carbamazepine is a current first-line treatment for focal onset seizures, and is used in the USA and Europe. Phenobarbitone is no longer considered a first-line treatment because of concerns over associated adverse events, particularly documented behavioural adverse events in children treated with the drug. However, phenobarbitone is still commonly used in low- and middle-income countries because of its low cost. No consistent differences in efficacy have been found between carbamazepine and phenobarbitone in individual trials; however, the confidence intervals generated by these trials are wide, and therefore, synthesising the data of the individual trials may show differences in efficacy.

Objectives: 

To review the time to treatment failure, remission and first seizure with carbamazepine compared with phenobarbitone when used as monotherapy in people with focal onset seizures (simple or complex focal and secondarily generalised), or generalised onset tonic-clonic seizures (with or without other generalised seizure types).

Search strategy: 

For the latest update, we searched the following databases on 24 May 2018: the Cochrane Register of Studies (CRS Web), which includes Cochrane Epilepsy's Specialized Register and CENTRAL; MEDLINE; the US National Institutes of Health Ongoing Trials Register (ClinicalTrials.gov); and the World Health Organization International Clinical Trials Registry Platform (ICTRP). We handsearched relevant journals and contacted pharmaceutical companies, original trial investigators, and experts in the field.

Selection criteria: 

Randomised controlled trials comparing monotherapy with either carbamazepine or phenobarbitone in children or adults with focal onset seizures or generalised onset tonic-clonic seizures.

Data collection and analysis: 

This was an individual participant data (IPD), review. Our primary outcome was time to treatment failure. Our secondary outcomes were time to first seizure post-randomisation, time to six-month remission, time to 12-month remission, and incidence of adverse events. We used Cox proportional hazards regression models to obtain trial-specific estimates of hazard ratios (HRs), with 95% confidence intervals (CIs), using the generic inverse variance method to obtain the overall pooled HR and 95% CI.

Main results: 

We included 13 trials in this review and IPD were available for 836 individuals out of 1455 eligible individuals from six trials, 57% of the potential data. For remission outcomes, a HR of less than 1 indicates an advantage for phenobarbitone and for first seizure and treatment failure outcomes a HR of less than 1 indicates an advantage for carbamazepine.

Results for the primary outcome of the review were: time to treatment failure for any reason related to treatment (pooled HR adjusted for seizure type for 676 participants: 0.66, 95% CI 0.50 to 0.86, moderate-quality evidence), time to treatment failure due to adverse events (pooled HR adjusted for seizure type for 619 participants: 0.69, 95% CI 0.49 to 0.97, low-quality evidence), time to treatment failure due to lack of efficacy (pooled HR adjusted for seizure type for 487 participants: 0.54, 95% CI 0.38 to 0.78, moderate-quality evidence), showing a statistically significant advantage for carbamazepine compared to phenobarbitone.

For our secondary outcomes, we did not find any statistically significant differences between carbamazepine and phenobarbitone: time to first seizure post-randomisation (pooled HR adjusted for seizure type for 822 participants: 1.13, 95% CI 0.93 to 1.38, moderate-quality evidence), time to 12-month remission (pooled HR adjusted for seizure type for 683 participants: 1.09, 95% CI 0.84 to 1.40, low-quality evidence), and time to six-month remission pooled HR adjusted for seizure type for 683 participants: 1.01, 95% CI 0.81 to 1.24, low-quality evidence).

Results of these secondary outcomes suggest that there may be an association between treatment effect in terms of efficacy and seizure type; that is, that participants with focal onset seizures experience seizure recurrence later and hence remission of seizures earlier on phenobarbitone than carbamazepine, and vice versa for individuals with generalised seizures. It is likely that the analyses of these outcomes were confounded by several methodological issues and misclassification of seizure type, which could have introduced the heterogeneity and bias into the results of this review.

Limited information was available regarding adverse events in the trials and we could not compare the rates of adverse events between carbamazepine and phenobarbitone. Some adverse events reported on both drugs were abdominal pain, nausea, and vomiting, drowsiness, motor and cognitive disturbances, dysmorphic side effects (such as rash), and behavioural side effects in three paediatric trials.

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