Epilepsy is a common neurological disorder. In approximately 30% of epilepsy cases, seizures are uncontrolled by one antiepileptic drug (AED). These people require treatment with a combination of multiple AEDs and are described as having drug‐resistant epilepsy. Oxcarbazepine is a keto‐analogue of carbamazepine, an established AED, and can be used as an add‐on treatment for drug‐resistant epilepsy.
To assess the efficacy and tolerability of oxcarbazepine as an add‐on treatment for people with drug‐resistant focal epilepsy.
The following databases were searched on 24 September 2018: Cochrane Register of Studies (CRS Web), which includes the Cochrane Epilepsy Group Specialized Register and the Cochrane Central Register of Controlled Trials (CENTRAL); Medline (Ovid) 1946 to 21 September 2018; ClinicalTrials.gov; and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP). Originally, we also searched SCOPUS as a substitute for Embase, but this is no longer necessary, because randomised and quasi‐randomised controlled trials in Embase are now included in CENTRAL.
Randomised controlled trials with parallel‐group or cross‐over design, recruiting people of any age with drug‐resistant focal epilepsy. We accepted any level of blinding and trials could be placebo‐ or active‐controlled.
Data collection and analysis
In accordance with the methodological procedures expected by the Cochrane Collaboration, two review authors independently assessed trial eligibility before extracting data and assessing risk of bias. We assessed the primary outcomes: median percentage seizure reduction per 28 days; 50% or greater reduction in seizure frequency; and adverse effects including ataxia, hyponatraemia, and somnolence. We assessed the secondary outcomes: seizure freedom; treatment withdrawal; cognitive effects; and quality of life. We used an intention‐to‐treat population for all primary analyses. We present results as risk ratios (RR) with 95% confidence intervals (CI), with the exception of adverse effects which we present with 99% CI.
We identified six eligible studies, involving 1593 participants. We judged that three studies were at unclear risk of bias and three were at high risk of bias. Bias mainly arose from lack of methodological details and from high attrition rates. Participants were aged 1 month to 65 years, with a diagnosis of drug‐resistant focal epilepsy. All studies were either placebo‐ or alternative‐dose‐controlled with parallel‐group design. The treatment period varied from 9 days to 26 weeks.
The median percentage seizure reduction per 28 days (3 studies; moderate‐certainty evidence) ranged from 26% to 83.3% for participants randomised to experimental oxcarbazepine compared to 7.6% to 28.7% for participants randomised to control treatment. Oxcarbazepine may increase the responder rate for 50% or greater reduction in seizure frequency compared to control treatment (RR 1.80, 95% CI 1.27 to 2.56; random‐effects model; 6 studies; low‐certainty evidence). For seizure freedom, the RR was 2.86 (95% CI 1.19 to 6.87; random‐effects model; 5 studies; low‐certainty evidence), suggesting an advantageous effectiveness of oxcarbazepine over control treatment. Treatment with oxcarbazepine was associated with an increased treatment withdrawal rate compared to control (RR 1.75, 95% CI 1.44 to 2.13; fixed‐effect model; 6 studies; moderate‐certainty evidence). The largest oxcarbazepine dose used, 2400 mg/d, was associated with a higher treatment withdrawal rate (RR 2.38, 95% CI 1.92 to 2.94; fixed‐effect model; 2 studies) compared to control, than 1200 mg/d (RR 1.54, 95% CI 1.21 to 1.95; fixed‐effect model; 3 studies) or 600 mg/d oxcarbazepine (RR 0.79, 95% CI 0.55 to 1.15; fixed‐effect model; 1 study). Treatment with oxcarbazepine was associated with an increased incidence of multiple adverse effects including: ataxia (RR 2.54, 99% CI 0.86 to 7.54; random‐effects model; 5 studies; moderate‐certainty evidence); and somnolence (RR 2.03, 99% CI 1.17 to 3.54; random‐effects model; 6 studies; low‐certainty evidence). Hyponatraemia occurred more frequently with oxcarbazepine treatment but not significantly so (RR 2.53, 99% CI 0.27 to 23.85; fixed‐effect model; 6 studies; moderate‐certainty evidence).
Oxcarbazepine might be effective at reducing seizure frequency when used as an add‐on for drug‐resistant focal epilepsy. The efficacy outcomes — 50% or greater seizure reduction and seizure freedom — were derived from low‐certainty evidence. We are, therefore, uncertain whether the estimated effect size is representative of the true effect. In contrast, the evidence for median percentage seizure reduction and treatment withdrawal were of moderate certainty: thus, we are fairly certain of the effect estimates’ reliability. Overall, we are unsure of the true efficacy of oxcarbazepine, but have concerns about its tolerability.
Plain language summary
Oxcarbazepine add‐on for drug‐resistant focal epilepsy
Epilepsy is a neurological disorder which causes people to have seizures. Most people can control their epilepsy with a single antiepileptic drug. Some people, however, require multiple antiepileptic drugs to control their epilepsy, and are said to have drug‐resistant epilepsy. Oxcarbazepine is an antiepileptic drug and is similar to an older antiepileptic drug, carbamazepine. Oxcarbazepine can be taken as an add‐on treatment, alongside other antiepileptic medication, to treat drug‐resistant epilepsy.
Aim of the review
This review examined whether oxcarbazepine is tolerable and effective when used alongside other antiepileptic medication by people with drug‐resistant focal epilepsy (epilepsy that originates from one area of the brain).
We included six clinical trials that investigated oxcarbazepine as an add‐on treatment for people with drug‐resistant focal epilepsy. There were 1593 people across the studies and they were aged from 1 month to 65 years.
People who received oxcarbazepine in addition to their normal antiepileptic medication were more likely to have a 50% or greater reduction in the frequency of their seizures compared to people who were on a control treatment, which is believed to have little or no effect. They were also nearly three times more likely to be free from all seizures than those receiving control treatment. Both of these findings suggest that oxcarbazepine is effective at treating drug‐resistant focal epilepsy. These findings are, however, based on evidence that was of low certainty. This means that we are not confident that the findings that we have reported are accurate.
People who received oxcarbazepine add‐on treatment were also more likely to withdraw from the studies and were more likely to experience side effects, including dizziness and drowsiness, than people receiving control add‐on treatment. The evidence for treatment withdrawal was of moderate certainty, and this means that we can be fairly confident that this is a true effect.
As a result of the low‐certainty evidence, we cannot be sure that oxcarbazepine is an effective add‐on treatment for people with drug‐resistant focal epilepsy. Instead, we have concerns about the tolerability of oxcarbazepine because of the increased number of people who withdrew from treatment and who experienced side effects.
The evidence is current to September 2018.