PharmacologyTier 1Medical Sciences concept

CGRP pathway drugs in migraine (CGRP mAbs, gepants)

Core concept

CGRP is released from trigeminal sensory nerve terminals during a migraine attack
- Potent vasodilatation of meningeal vessels, neurogenic inflammation, mast cell degranulation, and central pain transmission at the trigeminocervical complex
- CGRP infusion provokes migraine in migraineurs; CGRP rises in jugular blood during an attack
Two drug families, both blocking the same axis
- -mab (monoclonal antibodies) - PREVENTION, monthly or quarterly, large molecules that do not cross the BBB (act peripherally on the trigeminal ganglion and dura)
- -gepant (small-molecule receptor antagonists) - ACUTE and preventive, oral, short half-life

Agent	Target	Route / interval	Use
Erenumab	CGRP receptor	SC monthly	Prevention
Fremanezumab	CGRP ligand	SC monthly or quarterly	Prevention
Galcanezumab	CGRP ligand	SC monthly	Prevention
Eptinezumab	CGRP ligand	IV quarterly	Prevention
Rimegepant	CGRP receptor	Oral	Acute and prevention
Ubrogepant, zavegepant	CGRP receptor	Oral / nasal	Acute
Atogepant	CGRP receptor	Oral daily	Prevention

Efficacy: ~50% responder rate, dec ~2-4 migraine days/month over placebo in episodic migraine; effect visible within the first month (unlike topiramate or amitriptyline)
Adverse effects are mild - injection site reaction, constipation (erenumab notably), hypertension (erenumab), nasopharyngitis
- No hepatotoxicity with current gepants; the first-generation gepant telcagepant was withdrawn for that reason
Gepants and ditans do not vasoconstrict - unlike triptans
- Usable in ischaemic heart disease, stroke, uncontrolled hypertension, hemiplegic and basilar migraine, where triptans are contraindicated
Lasmiditan is a different mechanism - a selective 5-HT1F agonist, also non-vasoconstricting; causes driving-impairing dizziness
Gepants do not cause medication overuse headache, a substantial advantage over triptans, opioids and combination analgesics

Prevention is indicated at >=4 migraine days per month, or fewer with severe disability
- Conventional first-line preventives remain propranolol, amitriptyline, candesartan, topiramate, sodium valproate (valproate contraindicated in women of childbearing potential)
- CGRP agents are PBS-restricted in Australia to chronic migraine after failure of multiple conventional preventives - know the failure criteria before promising them
Botulinum toxin A is the other option for chronic migraine (>=15 headache days/month)
Acute treatment ladder: aspirin 900 mg or NSAID + metoclopramide -> triptan -> gepant or lasmiditan if triptans fail or are contraindicated
Medication overuse headache - simple analgesics >=15 days/month, or triptans/opioids/combinations >=10 days/month; withdrawal is the treatment
Check blood pressure on erenumab, and ask about constipation

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