Exploring the Role of Early Add-On Cenobamate in Uncontrolled Focal Epilepsy: A Critical Appraisal of the Evidence

Cenobamate is a third-generation antiseizure medication (ASM) for the treatment of uncontrolled focal seizures. As evidence accumulated across randomized clinical trials and real-world studies, clinically relevant questions have emerged regarding its comparative efficacy, optimal timing of introduction, safety and interaction profile, long-term retention, and outcomes beyond seizure control.

This structured expert narrative review addressed four predefined domains-efficacy, safety and retention, pharmacological interactions, and patient-centered outcomes-using PICO-formulated questions. PubMed searches identified randomized controlled trials, network meta-analyses, and observational studies of adjunctive cenobamate in adults with focal epilepsy. Given heterogeneity in design and reporting, evidence was synthesized narratively and interpreted through multidisciplinary expert discussion.

Across diverse study types, cenobamate consistently demonstrated high efficacy, including clinically relevant rates of seizure freedom and ≥ 50% response. Several real-world analyses suggested that earlier introduction-typically after failure of two prior ASMs-may be associated with higher seizure-freedom rates than early use of other ASMs; these signals derived from non-randomized comparisons and may reflect residual confounding. Safety was dominated by predictable, dose-related central nervous system events, with tolerability strongly dependent on titration and proactive adjustment of interacting ASMs (notably clobazam, phenytoin, phenobarbital, and high-dose sodium-channel blockers). Long-term retention remained high across cohorts. Cognitive performance was generally stable and psychiatric symptoms stable or improved, with quality-of-life gains reported, including in patients who had previously failed resective surgery or neuromodulation, albeit from uncontrolled data.

Cenobamate may offer substantial benefit in adults with uncontrolled focal epilepsy, with a favorable efficacy-tolerability balance, high retention, and possible advantages when introduced earlier (after two ASMs). Its interaction profile underscores the importance of careful management of concomitant ASMs. Because the comparative signals derive largely from non-randomized data, prospective controlled research is needed to confirm any benefit of early use and to better characterize long-term cognitive and psychiatric effects.