CGRP Antagonists (Small Molecule and Monoclonal Antibodies):
- Small Molecule CGRP Antagonists (Gepants):
- Examples: Rimegepant, Ubrogepant
- Mechanism: Block CGRP receptors, preventing neurogenic inflammation.
- Rationale: Effective for acute and preventive treatment, with fewer GI side effects than triptans.
- Monoclonal Antibodies (CGRP Ligand and Receptor Antagonists):
- Examples: Erenumab, Fremanezumab, Galcanezumab, Eptinezumab
- Mechanism: Bind to CGRP or its receptor, reducing neuronal hypersensitivity.
- Rationale: Longer half-life, allowing for monthly or quarterly dosing; well-tolerated with minimal side effects.
- Ditans (Serotonin 5-HT1F Receptor Agonists):
- Example: Lasmiditan
- Mechanism: Activates 5-HT1F receptors, reducing central pain signaling without vasoconstriction.
- Rationale: Alternative for patients with cardiovascular risk, as it lacks vasoconstrictive effects.
- Botulinum Toxin Type A (OnabotulinumtoxinA):
- Mechanism: Inhibits release of pain mediators (e.g., CGRP, substance P) at the trigeminal nerve.
- Rationale: FDA-approved for chronic migraine prevention; administered every 12 weeks.
- Calcium Channel Blockers (e.g., Verapamil, Flunarizine):
- Mechanism: Block voltage-gated calcium channels, reducing cortical spreading depression.
- Rationale: First-line preventive option; titrate to response (e.g., verapamil 120–240 mg/day).
- Beta-Blockers (e.g., Propranolol, Metoprolol):
- Mechanism: Reduce sympathetic nervous system activity, stabilizing neuronal excitability.
- Rationale: Evidence-based for prevention; start at low doses (e.g., propranolol 40–80 mg/day).
- Antidepressants (e.g., Amitriptyline, Venlafaxine):
- Mechanism: Enhance serotonergic and noradrenergic pathways, modulating pain perception.
- Rationale: Useful for comorbid depression; titrate slowly (e.g., amitriptyline 25–75 mg/day).
- Anticonvulsants (e.g., Topiramate, Valproate):
- Mechanism: Reduce neuronal hyperexcitability via GABAergic or sodium channel modulation.
- Rationale: High efficacy but side effects (e.g., cognitive impairment); topiramate 50–100 mg/day.
Key Considerations:
- Personalized Approach: Tailor therapy based on patient comorbidities (e.g., avoid beta-blockers in asthma).
- Gradual Titration: Start low, increase to maximum tolerated dose (e.g., verapamil 120–240 mg/day).
- Combination Therapy: Consider polytherapy (e.g., CGRP monoclonal + beta-blocker) for refractory cases.
References:
- AHS Guidelines (2021), CGRP Pathway Targets for Migraine (2020), EHF Guidelines (2020).