Immediate-release versus controlled-release carbamazepine in the treatment of epilepsy

Background Epilepsy is defined as the tendency to spontaneous, excessive neuronal discharge manifesting as seizures. It is a common disorder with an incidence of 50 per 100,000 per year and a prevalence of 0.5% to 1% in the developed world (Hauser 1993). Carbamazepine (CBZ) is a widely used antiepileptic drug that is associated with a number of troublesome adverse events including dizziness, double vision and unsteadiness. These often occur during peaks in drug plasma concentration. The occurrence of such adverse events may limit the daily dose that can be tolerated and reduce the chances of seizure control for patients requiring higher doses ( Vojvodic 2002). A controlled-release formulation of carbamazepine delivers the same dose over a longer period of time when compared to a standard formulation, thereby reducing post-dose peaks and potentially reducing adverse events associated with peak plasma levels. Objectives To determine the efficacy of immediate-release CBZ (IR CBZ) versus controlled-release CBZ (CR CBZ) in patients diagnosed with epilepsy. The following review questions were investigated. (1) For newly diagnosed patients commencing CBZ, how do IR and CR formulations compare for efficacy and tolerability? (2) For patients on established treatment with IR CBZ but experiencing unacceptable adverse events, what is the effect on seizure control and the tolerability of a switch to a CR formulation versus remaining on the IR formulation? Search methods We searched the Cochrane Epilepsy Group Specialized Register (10 November 2014), Cochrane Central Register of Controlled Trials (CENTRAL) via the Cochrane Register of Studies Online (CRSO) 11 November 2014, and MEDLINE (Ovid, 1946 to 11 November 2014). Selection criteria Randomised controlled trials comparing IR CBZ to CR CBZ in patients commencing monotherapy and patients presently treated with IR CBZ but experiencing unacceptable adverse events. Primary outcome measures include seizure frequency, incidence of adverse events, proportion of patients with treatment failure and quality of life measures. Data collection and analysis The methodological quality of each study was assessed with respect to study design, type of control, method and concealment of allocation, blinding and completeness of follow up, and the presence of blinding for assessment of non-fatal outcomes. We did not make use of an overall quality score. Two review authors (GP, MS) independently extracted the data and recorded relevant information on a standardised data extraction form. The trials were assessed for inclusion. The heterogeneity of the included trials resulted in only a narrative, descriptive analysis being possible for both the categorical and time-to-event data. Main results Ten trials fulfilled the criteria for inclusion in this review. One trial included patients with newly diagnosed epilepsy and nine included patients on treatment with IR CBZ. Eight trials reported heterogeneous measures of seizure frequency with conflicting results. A statistically significant difference was observed in only one trial, with patients prescribed CR CBZ experiencing fewer seizures than patients prescribed IR CBZ. Nine trials reported measures of adverse events. There was a trend in favour of CR CBZ with four trials reporting a statistically significant reduction in adverse events compared to IR CBZ. A further two trials reported fewer adverse events with CR CBZ but the reduction was not statistically significant. One trial found no difference, with a further trial reporting increased adverse events in the CR CBZ group although the increase was not statistically significant. Authors' conclusions At present, data from trials do not confirm or refute an advantage for CR CBZ over IR CBZ for seizure frequency or adverse events in patients with newly diagnosed epilepsy. For trials involving epilepsy patients already prescribed IR CBZ, no conclusions can be drawn concerning the superiority of CR CBZ with respect to seizure frequency. There is a trend for CR CBZ to be associated with fewer adverse events when compared to IR CBZ. A change to CR CBZ may therefore be a worthwhile strategy in patients with acceptable seizure control on IR CBZ but experiencing unacceptable adverse events. The included trials were of small size, had poor methodological quality and possessed a high risk of bias, limiting the validity of this conclusion. Randomised controlled trials comparing CR CBZ to IR CBZ and using clinically relevant outcomes are required to inform the choice of CBZ preparation for patients with newly diagnosed epilepsy.