What are CGRP Antagonists?
CGRP antagonists are medications that block the calcitonin gene-related peptide (CGRP) receptor or ligand, representing a newer class of migraine-specific treatments that include small-molecule oral agents called "gepants" and monoclonal antibodies (CGRP-mAbs). 1
Mechanism of Action
CGRP antagonists work by blocking the CGRP receptor, which plays a central role in migraine pathophysiology. 2, 3 The neuropeptide CGRP is known to be critically involved in the underlying mechanisms of migraine attacks. 4 Unlike triptans, CGRP antagonists do not cause vasoconstriction, making them safer for patients with cardiovascular concerns. 5
Types of CGRP Antagonists
Small-Molecule Gepants (Oral Agents)
The gepants are small molecules that can be taken orally and include: 1
- Rimegepant - approved for both acute and preventive treatment 6
- Ubrogepant - approved for acute treatment 7
- Zavegepant - third-generation gepant available as intranasal spray 2
- Atogepant - approved for preventive treatment 3
These agents have the advantage of oral or intranasal administration and can partially cross the blood-brain barrier. 5
Monoclonal Antibodies (Injectable Agents)
CGRP-mAbs are large molecules administered via subcutaneous injection, typically monthly or quarterly, used primarily for migraine prevention. 8 These antibodies target either the CGRP ligand or its receptor and have limited ability to cross the blood-brain barrier, suggesting their primary site of action is in peripheral structures like intracranial vessels, dural mast cells, and the trigeminal system. 5
Clinical Applications
Acute Treatment
For acute episodic migraine, gepants are considered alternative options when patients fail first-line combination therapy of a triptan plus NSAID or acetaminophen. 1 The American College of Physicians notes that CGRP antagonist-gepants may have lower likelihood of pain freedom and relief at 2 hours compared to triptan-NSAID combinations (low-certainty evidence). 1
Preventive Treatment
For migraine prevention, CGRP-mAbs may reduce migraine frequency by 0.76-0.80 fewer days per month compared to other preventive treatments like valproate or topiramate. 8 They also significantly reduce discontinuations due to adverse events compared to topiramate (162 fewer events per 1000 treated people). 8
Safety Profile
CGRP antagonists have a superior safety profile compared to many traditional migraine medications, with generally mild adverse events. 3, 9
- Most common side effects include injection-site pain (for mAbs) and upper respiratory tract infection 8
- Critical caveat: Erenumab specifically has been associated with development or worsening of hypertension in post-marketing surveillance 8
- Gepants do not cause the hepatotoxicity seen with first-generation CGRP antagonists 3
- No vasoconstriction occurs, unlike triptans, making them safer for patients with cardiovascular disease 5
- Discontinuation rates due to adverse events are generally low 8
Cost Considerations
A major limitation is cost: CGRP antagonists are substantially more expensive than traditional migraine medications. 1 Annual costs range from $4,959 to $5,994 for oral gepant formulations, $8,800 for intranasal zavegepant, and $7,071 to $22,790 for CGRP-mAbs. 1, 8 The American College of Physicians recommends prescribing less costly medications when appropriate. 1
Unique Characteristics
Gepants can be used concomitantly with CGRP monoclonal antibodies for refractory migraine cases. 10 This represents a unique treatment strategy where both a small-molecule receptor antagonist and an antibody targeting the CGRP pathway can be combined safely and effectively. 10
The site of action differs between gepants and antibodies: gepants can partially cross the blood-brain barrier and may have central effects, while antibodies act primarily on peripheral structures not protected by the blood-brain barrier. 5