The antihistamine-NSAID combination for cluster headache works by targeting multiple pathophysiological mechanisms, with the NSAID (e.g., ibuprofen) inhibiting cyclooxygenase enzymes to reduce inflammatory prostaglandin synthesis, while the antihistamine (e.g., diphenhydramine) blocks H1 receptors to modulate neurogenic inflammation and provide mild sedative effects. This dual-action approach aims to interrupt pain signaling pathways, reduce vascular inflammation, and potentially mitigate the intense, trigeminal nerve-mediated pain characteristic of cluster headaches.