CGRP-Targeted Therapies for Migraine
Overview of CGRP Treatment Options
CGRP-targeted therapies represent the first migraine-specific treatments and include two main classes: monoclonal antibodies (mAbs) for prevention and small-molecule receptor antagonists (gepants) for both acute and preventive treatment. 1, 2
Acute Migraine Treatment with Gepants
When to Use Gepants
- Gepants are third-line options for acute migraine treatment, reserved for patients who fail first-line NSAIDs plus antiemetics or second-line triptans (including triptan-NSAID combinations). 1, 3
- Consider gepants when triptans provide insufficient pain relief after three consecutive attacks without treatment success. 1
Available Acute Gepants
- Ubrogepant and rimegepant are FDA-approved for acute migraine treatment. 4
- Zavegepant (intranasal formulation) is also available. 2
Efficacy Considerations
- Gepants may have lower likelihood of achieving pain freedom and relief at 2 hours compared to triptan-NSAID combinations (low-certainty evidence). 2
Preventive Treatment with CGRP Monoclonal Antibodies
Treatment Positioning
CGRP monoclonal antibodies are third-line preventive medications, used after failure of first-line agents (beta blockers, topiramate, candesartan) and second-line agents (flunarizine, amitriptyline, valproate in men). 1, 3
FDA-Approved CGRP mAbs
Four monoclonal antibodies are available: 1, 5
- Erenumab (targets CGRP receptor) 6
- Galcanezumab (targets CGRP ligand) - also approved for episodic cluster headache 6
- Fremanezumab (targets CGRP ligand) 7
- Eptinezumab (targets CGRP ligand) 1, 5
Efficacy Data
- CGRP mAbs reduce migraine frequency by 0.76-0.80 fewer days per month compared to other preventive treatments like valproate or topiramate. 2
- Effective for both episodic and chronic migraine. 5
- Efficacy should be assessed only after 3-6 months of treatment (unlike oral preventives which are assessed at 2-3 months). 1, 3
Dosing Specifics
Galcanezumab (Emgality): 6
- Migraine prevention: 240 mg loading dose (two consecutive 120 mg subcutaneous injections), then 120 mg monthly
- Episodic cluster headache: 300 mg (three consecutive 100 mg injections) at cluster onset, then monthly until cluster period ends
Gepants for Migraine Prevention
Rimegepant and atogepant are approved for migraine prevention and represent an alternative to mAbs, particularly when injectable therapy is not preferred. 5
Safety Profile
Tolerability Advantages
- CGRP antagonists have significantly fewer discontinuations due to adverse events compared to traditional preventives - 162 fewer events per 1000 people compared to topiramate. 2
- Most common side effects are injection-site reactions (for mAbs) and upper respiratory tract infections. 2, 6
Important Safety Concerns
- Erenumab has been associated with development or worsening of hypertension in post-marketing surveillance - monitor blood pressure regularly. 2
- Hypersensitivity reactions can occur days after administration and may be prolonged - discontinue immediately if serious hypersensitivity occurs. 6
- Contraindicated in patients with serious hypersensitivity to the drug or excipients. 6
Clinical Decision-Making
When to Initiate Preventive CGRP Therapy
Consider preventive treatment in patients adversely affected by migraine on ≥2 days per month despite optimized acute treatment. 1, 3
Additional factors warranting prevention: 1
- Severity and duration of attacks
- Migraine-related disability
- Medication overuse
Switching Between CGRP mAbs
Switching from one CGRP mAb to another may benefit a fraction of patients who don't respond to the first agent. 8
Combination Therapy
Currently insufficient evidence exists to support or reject combining CGRP mAbs or gepants with oral preventive agents or botulinum toxin A, though this approach may be considered in difficult-to-treat cases. 8
Treatment Duration
- When treatment has been successful for 6-12 months, consider pausing to determine if preventive treatment can be stopped. 1
- This minimizes unnecessary drug exposure and allows some patients to manage with acute medications only. 1
Critical Cost Considerations
CGRP antagonists are substantially more expensive than traditional migraine medications, which is a major limitation. 2
Annual costs: 2
- Oral gepants: $4,959-$5,994
- Intranasal zavegepant: $8,800
- CGRP mAbs: $7,071-$22,790
Prescribe less costly medications when appropriate - use CGRP therapies after failure of traditional first- and second-line agents. 2
Common Pitfalls to Avoid
- Do not use CGRP therapies as first-line treatment - they are third-line options after failure of traditional preventives. 1
- Do not assess efficacy too early - wait 3-6 months for mAbs (not the 2-3 months used for oral preventives). 1, 3
- Do not overlook hypertension monitoring with erenumab. 2
- Do not assume all CGRP mAbs are identical - while mechanistically similar, individual patient response may vary, justifying switching attempts. 8