Carbamazepine versus phenobarbitone monotherapy for epilepsy: an individual participant data review

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.

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).

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.

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

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.

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.

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.