Glucagon-like Peptide-1 Receptor Agonists and Chronic Pain: Preclinical Antinociceptive Mechanisms, Indirect Metabolic-Functional Effects, and Clinical Considerations-A Narrative Review.

Epilepsy is one of the most prevalent neurological disorders, affecting approximately 50 million people worldwide [,]. Conceptually, an epileptic seizure is defined as a transient occurrence of signs and/or symptoms due to abnormal, excessive, or synchronous neuronal activity in the brain, whereas epilepsy denotes an enduring predisposition to generate such seizures, including their neurobiological, cognitive, psychological, and social consequences []. This enduring predisposition, in turn, can be conceptualized as a pathologically lowered seizure threshold—a state in which multiple causal factors converge to increase the probability of recurrent seizures []. Most currently available antiseizure medications (ASMs) address this predisposition at the level of neural excitability, reducing seizure probability by modulating ion channels and neurotransmitter systems [,]. Current diagnostic framework in epilepsy explicitly acknowledges the multifactorial nature of the disease. The International League Against Epilepsy (ILAE) recommends a stepwise classification proceeding from seizure type through epilepsy type to syndromic diagnosis [,], with parallel etiologic assignment across structural, genetic, infectious, metabolic, immune, and unknown categories. Etiology is explicitly recognized as predictive of prognosis, comorbidities, and the likely relevance of non-neuronal mechanisms such as immune signaling, blood–brain barrier (BBB) dysfunction, or metabolic factors []. Yet in routine clinical practice, in most cases, the etiologic category shapes the choice of ASM rather than lead to questioning whether the use of ASM is the right therapeutic strategy. ASM monotherapy remains the cornerstone of initial management, achieving seizure freedom in approximately 50% of newly diagnosed patients with the first agent and an additional 11% to 12% with the second regimen [,]. However, approximately one-third of patients develop drug-resistant epilepsy (DRE) despite multiple therapeutic trials [,]. The ILAE defines DRE as “failure of adequate trials of two tolerated and appropriately chosen and used ASM schedules (whether as monotherapies or in combination) to achieve sustained seizure freedom” []. Despite the introduction of more than a dozen new ASMs with diverse mechanisms of action over the past three decades, long-term treatment outcomes have changed little at the population level []. Moreover, drug-induced seizure exacerbation further complicates ASM management, as certain agents may paradoxically worsen seizure control in susceptible individuals [,], suggesting that continued ASM development focused only on stronger seizure suppression is unlikely to fully meet the needs of the substantial proportion of patients whose epilepsy remains uncontrolled.