Pathophysiology
Clinical meaning
Migraine pharmacotherapy targets specific nodes in the trigeminovascular cascade. Acute treatments act on the activated trigeminal system: triptans (5-HT1B/1D receptor agonists) constrict dilated meningeal vessels via 5-HT1B receptors and inhibit CGRP release from trigeminal nerve terminals via presynaptic 5-HT1D receptors, aborting the neurogenic inflammatory cascade. Triptans are most effective when administered early before central sensitization develops (before allodynia onset). Gepants (CGRP receptor antagonists such as ubrogepant, rimegepant) block CGRP signaling at the trigeminal ganglion and central trigeminocervical complex without causing vasoconstriction, making them safe in patients with cardiovascular disease. Ditans (lasmiditan) selectively activate 5-HT1F receptors to inhibit trigeminal nociceptive transmission centrally without vasoconstriction. NSAIDs inhibit cyclooxygenase-mediated prostaglandin synthesis, reducing meningeal inflammation and peripheral sensitization. Preventive therapies modify the underlying excitability of the trigeminovascular system: beta-blockers (propranolol, metoprolol) reduce central noradrenergic tone and may inhibit cortical spreading depression. Topiramate modulates voltage-gated sodium channels, enhances GABAergic inhibition, and blocks AMPA/kainate glutamate receptors, raising the cortical excitability threshold. Valproate enhances GABA transmission and blocks sodium channels. CGRP monoclonal antibodies (erenumab targets the CGRP receptor; fremanezumab and galcanezumab target the CGRP ligand) provide sustained...