Carbamazepine versus phenytoin (given as a single drug treatment) for epilepsy

This is an updated version of the Cochrane Review previously published in Issue 2, 2017 of the Cochrane Database of Systematic Reviews

Background

Epilepsy is a common neurological disorder in which recurrent seizures are caused by abnormal electrical discharges from the brain. 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 only one part of the brain (the whole hemisphere of the brain or part of a lobe of the brain). For around 70% of people with epilepsy, generalised onset or focal onset seizures can be controlled by a single antiepileptic drug. Worldwide, phenytoin and carbamazepine are commonly used antiepileptic drugs, although carbamazepine is used more often in the USA and Europe due to concerns over side effects associated with phenytoin. Phenytoin 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

For this updated review, we looked at the evidence from 11 randomised controlled clinical trials comparing phenytoin and carbamazepine, based on how effective the drugs were at controlling seizures (i.e. whether people went back to having seizures or had long periods of freedom from seizures (remission)), and how tolerable any related side effects of the drugs were.

Methods

We were able to combine data for 595 people from four of the 11 trials; for the remaining 507 people from seven trials, information was not available to use in this review. The evidence is current to August 2018.

Key results

This review of trials found no difference between these two drugs for the seizure types studied for the outcomes of treatment failure (withdrawal from treatment for any reason and also withdrawal from treatment due to continuing seizures or due to side effects) and controlling seizures (recurrence of seizures or achievement of a seizure-free period (remission) of six months or 12 months). Three-quarters of the people recruited in the four trials had focal onset seizures and only one quarter of the people recruited in the four trials had generalised onset seizures, so the results of this review mainly apply to people with focal onset seizures and the results are very limited for people with generalised onset seizures. More information is needed for people with generalised onset seizures.

Some side effects reported by people taking carbamazepine and people taking phenytoin were abdominal pain, nausea, vomiting, tiredness, motor problems (such as poor co-ordination), cognitive problems (poor memory), rashes and other skin problems.

Certainty of the evidence

We judged the certainty of the evidence as moderate to low for the evidence of treatment failure, moderate for remission outcomes and low for seizure outcomes, as it is likely that misclassification of seizure type influenced the results of the review. Within two of the trials providing data for this review, the design of the trial meant that the people and treating clinicians knew which medication they were taking. This design may have influenced the results.

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 certainty of the evidence provided by this review as moderate for people with focal onset seizures and of low certainty for people with generalised onset seizures. We do not suggest using the results of this review alone for making a choice between carbamazepine or phenytoin for the treatment of epilepsy.

We suggest that all future trials comparing these drugs or any other antiepileptic drugs should be designed using high-quality methods, and that the seizure types of people included in trials should be classified very carefully to ensure results are also of high quality.

Authors' conclusions: 

Moderate-certainty evidence provided by this systematic review does not show any differences between carbamazepine and phenytoin in terms of effectiveness (retention) or efficacy (seizure recurrence and seizure remission) for individuals with focal onset or generalised onset seizures.

However, some of the trials contributing to the analyses had methodological inadequacies and inconsistencies, which may have had an impact on the results of this review. We therefore do not suggest that results of this review alone should form the basis of a treatment choice for a person with newly-onset seizures. We did not find any evidence to support or refute current treatment policies. We implore that future trials 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 update of a Cochrane Review first published in 2002 and last updated in 2017. 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 phenytoin are commonly-used broad spectrum antiepileptic drugs, suitable for most epileptic seizure types. Carbamazepine is a current first-line treatment for focal onset seizures in the USA and Europe. Phenytoin is no longer considered a first-line treatment, due to concerns over adverse events associated with its use, but the drug is still commonly used in low- to middle-income countries because of its low cost. No consistent differences in efficacy have been found between carbamazepine and phenytoin 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 phenytoin 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 13 August 2018: the Cochrane Register of Studies (CRS Web), which includes the Cochrane Epilepsy's Specialised 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 phenytoin 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: 

IPD were available for 595 participants out of 1102 eligible individuals, from four out of 11 trials (i.e. 54% of the potential data). For remission outcomes, a HR greater than 1 indicates an advantage for phenytoin; and for first seizure and withdrawal outcomes, a HR greater than 1 indicates an advantage for carbamazepine. Most participants included in analysis (78%) were classified as experiencing focal onset seizures at baseline and only 22% were classified as experiencing generalised onset seizures; the results of this review are therefore mainly applicable to individuals with focal onset seizures.

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 546 participants: 0.94, 95% CI 0.70 to 1.26, moderate-certainty evidence); time to treatment failure due to lack of efficacy (pooled HR adjusted for seizure type for 546 participants: 0.99, 95% CI 0.69 to 1.41, moderate-certainty evidence); both showing no clear difference between the drugs and time to treatment failure due to adverse events (pooled HR adjusted for seizure type for 546 participants: 1.27, 95% CI 0.87 to 1.86, moderate-certainty evidence), showing that treatment failure due to adverse events may occur earlier on carbamazepine than phenytoin, but we cannot rule out a slight advantage to carbamazepine or no difference between the drugs.

For our secondary outcomes (pooled HRs adjusted for seizure type), we did not find any clear differences between carbamazepine and phenytoin: time to first seizure post-randomisation (582 participants): 1.15, 95% CI 0.94 to 1.40, moderate-certainty evidence); time to 12-month remission (551 participants): 1.00, 95% CI 0.79 to 1.26, moderate-certainty evidence); and time to six-month remission (551 participants): 0.90, 95% CI 0.73 to 1.12, moderate-certainty evidence).

For all outcomes, results for individuals with focal onset seizures were similar to overall results (moderate-certainty evidence), and results for the small subgroup of individuals with generalised onset seizures were imprecise, so we cannot rule out an advantage to either drug, or no difference between drugs (low-certainty evidence). There was also evidence that misclassification of seizure type may have confounded the results of this review, particularly for the outcome 'time to treatment failure'. Heterogeneity was present in analysis of 'time to first seizure' for individuals with generalised onset seizures, which could not be explained by subgroup analysis or sensitivity analyses.

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

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