Advances in Sodium Channel Modulation in Epilepsy Therapy: Focus on Eslicarbazepine, Lacosamide and Cenobamate

Background/Objectives: Voltage-gated sodium channels (VGSCs) are among the most important molecular targets in epilepsy therapy. Unlike classical antiseizure medications (ASMs), newer sodium channel modulators selectively affect slow inactivation or persistent sodium currents, potentially improving seizure control while preserving physiological neuronal activity. This review summarizes the pharmacology, mechanisms of action, clinical efficacy, and therapeutic potential of eslicarbazepine acetate, lacosamide, and cenobamate. Methods: A narrative review of published clinical trials, meta-analyses, and real-world evidence was conducted. The analysis focused on sodium channel modulation, pharmacokinetic properties, efficacy in monotherapy and adjunctive therapy, and safety profiles in focal epilepsy. Main findings of the review: Eslicarbazepine acetate and lacosamide primarily enhance slow inactivation of VGSCs, suppressing pathological repetitive neuronal firing with limited effects on normal neuronal signaling. Both agents demonstrated efficacy in monotherapy and add-on therapy, with favorable pharmacokinetic properties and a relatively low potential for drug–drug interactions. Cenobamate represents a novel therapeutic approach through preferential inhibition of persistent sodium currents combined with positive allosteric modulation of GABAA receptors. Clinical trials and real-world studies demonstrated high responder and seizure freedom rates, particularly in patients with drug-resistant focal epilepsy. The most common adverse effects across these agents included dizziness, somnolence, fatigue, and gastrointestinal symptoms, while notable safety concerns included hyponatremia with eslicarbazepine acetate and drug interactions or dose-dependent adverse effects with cenobamate. Conclusions: Recent advances in sodium channel modulation have expanded therapeutic options for focal epilepsy and support the development of more selective, mechanism-based ASM therapies. Eslicarbazepine acetate, lacosamide, and cenobamate demonstrate favorable efficacy and tolerability profiles and may improve seizure control in patients with drug-resistant epilepsy.