Clonazepam monotherapy for treating people with newly diagnosed epilepsy

Background: Epilepsy is one of the most common neurological disorders worldwide, with an age-adjusted prevalence of 4 to 8 per 1000 population and an age-adjusted incidence of 44 per 100,000 person-years in developed countries. Monotherapy represents the best therapeutic option in people with newly diagnosed epilepsy. This is an updated version of the original Cochrane Review published in 2019, Issue 11. Objectives: To assess the efficacy and tolerability of oral clonazepam used as monotherapy for newly diagnosed epilepsy, compared with placebo or a different anti-seizure medication. Search methods: For the latest update of this review we searched the following databases on 14 September 2021: the Cochrane Register of Studies (CRS Web) and MEDLINE (Ovid) (1946 to 13 September 2021). CRS Web includes randomized controlled trials (RCTs) or quasi-RCTs from PubMed, Embase, ClinicalTrials.gov, the World Health Organization International Clinical Trials Registry Platform (ICTRP), the Cochrane Central Register of Controlled Trials (CENTRAL), and the Specialized Registers of Cochrane Review Groups, including Epilepsy. Selection criteria: We included RCTs or quasi-RCTs comparing oral clonazepam used as monotherapy treatment versus placebo or a different anti-seizure medication (active comparator) in people of any age with newly diagnosed epilepsy, defined according to the clinical practical definition proposed by the International League Against Epilepsy (ILAE). Data collection and analysis: The following outcomes were considered: proportion of participants seizure-free at one, three, six, 12, and 24 months after randomization; proportion of responders (those with at least a 50% reduction in seizure frequency from baseline to end of treatment); proportion of participants with treatment-emergent adverse events (TEAEs) during the treatment period or leading to discontinuation during the treatment period; proportion of dropouts/withdrawals due to side effects, lack of efficacy or other reasons; and improvement in quality of life, as assessed by validated and reliable rating scales. Two review authors independently screened all titles and abstracts to assess the eligibility of publications identified by the searches. We independently extracted data from trial reports and cross-checked them for accuracy. Any disagreements between the two authors regarding data extraction were resolved by discussion and consensus. We scrutinized trials and evaluated the methodological quality of all included studies. We used GRADE assessment criteria to evaluate the certainty of the evidence. Main results: Two randomized controlled trials had already been included in the previous version of the review, with a total of 115 participants. One study compared clonazepam to carbamazepine as monotherapy for participants with newly diagnosed psychomotor epilepsy (a condition corresponding to what is now termed mesial temporal lobe epilepsy). One study (published as an abstract) compared clonazepam to ethosuximide as monotherapy for children with absence seizures. Based on the available data and the details on methodology provided, we judged both studies as being at unclear or high risk of bias for the domains assessed (apart from the selective reporting (reporting bias) domain - we judged one study as being at low risk of bias and the other study at high risk of bias). In the study comparing clonazepam to carbamazepine, no difference was found between the groups regarding the proportion of participants who were seizure-free at one month after randomization (risk ratio (RR) 1.97, 95% confidence interval (CI) 0.99 to 3.94; 30 participants; very low-certainty evidence), three months after randomization (RR 1.19, 95% CI 0.62 to 2.29; 26 participants; very low-certainty evidence), and six months after randomization (RR 0.50, 95% CI 0.09 to 2.73; 9 participants; very low-certainty evidence). No statistical difference was found between clonazepam and carbamazepine in terms of proportion of participants with TEAEs leading to discontinuation (RR 2.61, 95% CI 0.80 to 8.52; 36 participants; very low-certainty evidence) and in terms of dropouts/withdrawals due to side effects, lack of efficacy or other reasons (RR 1.56, 95% CI 0.61 to 4.02; 36 participants; very low-certainty evidence). The study did not provide any information on our other prespecified outcomes of interest. The study comparing clonazepam to ethosuximide did not provide any data on efficacy. The proportion of dropouts/withdrawal was higher in the group receiving clonazepam compared to the group receiving ethosuximide (RR 3.63, 95% CI 1.12 to 11.74; 79 participants; very low-certainty evidence). No information on other outcomes of interest was provided in this study. Authors' conclusions: We did not find any new studies since the last version of this review. There is only limited and very low-certainty evidence from randomized controlled trials on the efficacy and tolerability of clonazepam used in monotherapy for the treatment of epilepsy. No difference in efficacy and tolerability was found in a small trial comparing clonazepam to carbamazepine for the treatment of mesial temporal lobe epilepsy. Clonazepam was less well tolerated than ethosuximide in a trial of children with absence seizures, however no comparative data on efficacy were provided. There is currently insufficient evidence to support the use of clonazepam as monotherapy treatment for epilepsy.