Carbamazepine versus phenobarbitone monotherapy for epilepsy: an individual participant data review
Editorial Group: Cochrane Epilepsy Group
Published Online: 23 JUL 2015
Assessed as up-to-date: 22 SEP 2014
Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
How to Cite
Nolan SJ, Marson AG, Weston J, Tudur Smith C. Carbamazepine versus phenobarbitone monotherapy for epilepsy: an individual participant data review. Cochrane Database of Systematic Reviews 2015, Issue 7. Art. No.: CD001904. DOI: 10.1002/14651858.CD001904.pub2.
- Publication Status: New search for studies and content updated (no change to conclusions)
- Published Online: 23 JUL 2015
This is an updated version of the original Cochrane review published in Issue 1, 2003, of the Cochrane Database of Systematic Reviews.
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 (AED) in monotherapy.
Worldwide, carbamazepine (CBZ) and phenobarbitone (PB) are commonly used broad-spectrum antiepileptic drugs, suitable for most epileptic seizure types. Carbamazepine is a current first-line treatment for partial onset seizures 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, PB is still commonly used in low- and middle-income countries because of its low cost. No consistent differences in efficacy have been found between CBZ and PB in individual trials; however, the confidence intervals generated by these studies are wide, and therefore, synthesising the data of the individual trials may show differences in efficacy.
To review the time to withdrawal, remission, and first seizure of CBZ compared with PB when used as monotherapy in people with partial onset seizures (simple or complex partial and secondarily generalised) or generalised onset tonic-clonic seizures (with or without other generalised seizure types).
We searched the following databases up to September 2014: the Cochrane Epilepsy Group Specialized Register, the Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library (2014, Issue 8), MEDLINE (from 1946), Scopus (from 1823), the US National Institutes of Health Ongoing Trials Register (www.clinicaltrials.gov), and the World Health Organization International Clinical Trials Registry platform (WHO ICTRP). We handsearched relevant journals and contacted pharmaceutical companies, original trial investigators, and experts in the field.
Randomised controlled trials in children or adults with partial onset seizures or generalised onset tonic-clonic seizures with a comparison of CBZ monotherapy versus PB monotherapy.
Data collection and analysis
This was an individual participant data (IPD) review. Our primary outcome was 'Time to withdrawal of allocated treatment', and our secondary outcomes were 'Time to 12-month remission', 'Time to 6-month remission', and 'Time to first seizure postrandomisation'. We used Cox proportional hazards regression models to obtain study-specific estimates of hazard ratios (HRs) with 95% confidence intervals (CIs), with the generic inverse variance method used to obtain the overall pooled HR and 95% CI.
Individual participant data were available for 836 participants out of 1455 eligible individuals from 6 out of 13 trials, 57% of the potential data. For remission outcomes, HR > 1 indicated an advantage for PB, and for first seizure and withdrawal outcomes, HR > 1 indicated an advantage for CBZ.
The main overall results (pooled HR adjusted for seizure type, 95% CI) were HR 1.50 for time to withdrawal of allocated treatment (95% CI 1.15 to 1.95, P = 0.003); HR 0.93 for time to 12-month remission (95% CI 0.72 to 1.20, P = 0.57); HR 0.99 for time to 6-month remission (95% CI 0.80 to 1.23, P = 0.95); and HR 0.87 for time to first seizure (95% CI 0.72 to 1.06, P = 0.18). Results suggest an advantage for CBZ over PB in terms of time to treatment withdrawal and no statistically significant evidence between the drugs for the other outcomes. We found evidence of a statistically significant interaction between treatment effect and seizure type for time to first seizure recurrence (Chi² test for subgroup differences P = 0.03), where PB was favoured for partial onset seizures (HR 0.76, 95% CI 0.60 to 0.96, P = 0.02) and CBZ was favoured for generalised onset seizures (HR 1.23, 95% CI 0.88 to 1.77, P = 0.27). However, methodological quality of the included studies was variable, with 10 out of the 13 included studies (4 out of 6 studies contributing IPD) judged as high risk of bias for at least 1 methodological aspect, leading to variable individual study results and therefore heterogeneity in the analyses of this review. We conducted sensitivity analyses to examine the impact of poor methodological aspects where possible.
Overall, we found evidence suggestive of an advantage for CBZ in terms of drug effectiveness compared with PB (retention of the drug in terms of seizure control and adverse events) and evidence of an association between treatment effect and seizure type for time to first seizure recurrence (PB favoured for partial seizures and CBZ favoured for generalised seizures). Given the varying quality of studies included in this review and the impact of poor methodological quality on individual study results (and therefore variability (heterogeneity) present in the analysis within this review), we recommend caution when interpreting the results of this review and do not recommend that the results of this review alone should be used in choosing between CBZ and PB. We recommend that future trials should be designed to the highest quality possible with considerations for allocation concealment and masking, choice of population, choice of outcomes and analysis, and presentation of results.
Plain language summary
Carbamazepine versus phenobarbitone monotherapy (single drug treatment) for epilepsy
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 partial 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). For around 70% of people with epilepsy, a single antiepileptic drug can control generalised onset or partial onset seizures. Worldwide, phenobarbitone (PB) and carbamazepine (CBZ) are commonly used antiepileptic drugs; however, CBZ is used more commonly in the USA and Europe because of concerns over side-effects associated with PB, particularly concerns over behavioural changes in children treated with PB. Phenobarbitone is still commonly used in developing countries in Africa, Asia, and South America because of the low cost of the drug.
In this review, we evaluated the evidence from 13 randomised controlled clinical trials comparing PB with CBZ based on how effective the drugs were at controlling seizures (i.e., whether people had recurrence of seizures or had long periods of freedom from seizures (remission)) and how tolerable any related side-effects of the drugs were. The date of the last search for trials was 22 September 2014. We were able to combine data for 836 people from 6 of the 13 trials; for the remaining 619 people from 7 trials, data were not available to use in this review.
Results of the review suggest that people are more likely to withdraw from PB treatment earlier than from CBZ treatment, because of to seizure recurrence, side-effects of the drug, or both. Results also suggest that recurrence of seizures after starting treatment with PB may happen earlier than treatment with CBZ for people with generalised seizures, but vice versa for people with partial onset seizures. The opposite is suggested for people with partial onset seizures: Recurrence of seizures may happen earlier after starting treatment with CBZ than PB. We found no difference between CBZ and PB for people achieving long periods of seizure freedom (6- or 12-month remission of seizures). We recommend that the results of this review are interpreted with caution as we were unable to combine the data for all people treated in trials comparing CBZ or PB. Also, for four of the six trials used in our results, we found at least one problem in the design of the trial, which may have impacted upon the quality of the results of the individual trials and therefore our results from combining trial data. We do not recommend using the results of this review alone for making a choice between CBZ or PB 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.