Cite as: Barad M. CGRP targeting treatments: a valuable addition to the migraine armamentarium. ASRA Pain Medicine News 2026;51. https://doi.org/10.52211/asra020126.005.

The trigeminovascular system appears to be a powerful instigator of migraine headaches, triggering a release of neuroinflammatory neuropeptides from trigeminal nociceptors. Calcitonin gene-related peptide (CGRP), a vasodilator, is one of these neuropeptides. CGRP is released from trigeminal sensory afferents and modulates cerebrovascular nociception. CGRP antagonists represent novel acute and preventive options that have revolutionized migraine management. The therapeutic class includes monoclonal antibodies (mAbs) targeting either the CGRP ligand (eptinezumab, galcanezumab, fremanezumab) or the CGRP receptor (erenumab), as well as small-molecule receptor antagonists known as gepants (rimegepant, ubrogepant, atogepant, and zavegepant).^1-3

Monoclonal antibodies are administered subcutaneously or intravenously, typically once monthly or quarterly, and are indicated for migraine prevention (Table 1). All four mAbs are approved by the United States Food and Drug Administration for migraine prevention based on studies in both episodic and chronic migraine. In these studies, around half of the patients achieved a 50% or greater reduction in monthly migraine days (MMDs). The additional advantages of these medications include rapid onset of action, generally within the first week of treatment, and a very mild side effect profile.^4,5 The most commonly reported adverse events include injection site reactions and constipation, and serious safety concerns have not emerged in large studies.¹

Gepants are oral agents used for both acute and preventive treatment. The acute options differ in formulation with rimegepant, an oral dissolving tablet; ubrogepant, an oral tablet; and zavegepant, an intranasal formulation. All are approved for acute migraine attacks, while atogepant (dosed daily) and rimegepant (dosed every other day rather than as needed) are used for prevention. Triptans appear to be more efficacious than gepants in several meta-analyses; however, gepants differ primarily from triptans in that they do not cause vasoconstriction, which makes them a safer option than triptans for patients with cardiovascular risk factors.^6,7

There are three possible sites of action for CGRP antagonists. The trigeminal ganglion is thought to be the primary target as it is the site where CGRP is produced, and its receptor is expressed in Aδ-neurons and C-fiber neurons. CGRP released locally here may also activate satellite glial cells, contributing to peripheral sensitization. The second site of action is in the dura, where CGRP is released from peripheral C-fiber terminals, which act on the vascular smooth muscle cells of meningeal arteries. The final site is the trigeminal nucleus caudalis, where CGRP is released from the central terminals of C-fibers and acts on second-order neurons. Gepants are relatively small molecules (<1 kDa) while CGRP mAbs (∼150 kDa) are considerably larger and thus not able to pass through the brain by the blood–brain barrier. Thus, gepants, but not CGRP mABs, are small enough to cross the blood-brain barrier and modulate CGRP expression at the nucleus caudalis level. However, the central receptor occupancy of CGRP is low in migraine patients on gepants at clinical dosages, suggesting that this third activation site is perhaps not as important as the other two.³

Determination of which medication to initiate typically begins with a discussion of patient preferences. Both CGRP mABs and gepants have demonstrated significant benefit for migraine prevention in both randomized controlled trials (RCTs) and real-world studies. In terms of efficacy and effectiveness, studies are summarized below:

• RCTs consistently show that all four mAbs significantly reduce mean MMD compared to placebo in both episodic and chronic migraine populations. The average reduction ranges from about 3 to 8 days per month, depending on the drug and population.
• RCTs for atogepant and rimegepant show statistically significant reductions in MMD compared to placebo, with cuts of about 3 to4 days per month for episodic migraine and similar efficacy in chronic migraine.
• The responder rate for mAbs (% of patients achieving ≥50% reduction in migraine days) is generally between 40% and 60%, which is significantly higher than that with placebo.
• Responder rates (≥50% reduction in MMD) for gepants are also significantly higher than those for placebo, typically ranging from 41%- 56%, depending on the study and dose.
• Real-world studies confirm these findings, often reporting similar or greater reductions in MMD and higher responder rates with longer follow-up periods (up to 12 months). These studies also support the safety and tolerability of mAbs.^8-13

Direct comparison trials between mAbs and gepants are lacking, and current evidence is based on indirect comparisons. The American Headache Society (AHS) and recent systematic reviews emphasize the need for further comparative studies to determine the best medication of this class definitively.⁸

There are three possible sites of action for CGRP antagonists. The trigeminal ganglion is thought to be the primary target as it is the site where CGRP is produced, and its receptor is expressed in Aδ-neurons and C-fiber neurons. 

Conventionally, preventive treatment is usually administered for 6-12 months before reassessment. Real-world studies consistently showed an increased headache burden in approximately 3 months after discontinuation of CGRP mAbs in more than half of patients. Unfortunately, there are no discontinuation studies that provide insight into when it is appropriate to stop treatment in patients who have a good long-term response to a CGRP mAb.¹⁴ While there are no trials to guide our decision-making here, it still seems good practice to at least discuss a treatment pause with patients. The European Headache Federation recommends a 12-18-month pause and subsequent reinitiation of treatment for patients who deteriorate.¹⁵ However, AHS does not recommend a routine pause in treatment; the organization advises regular reassessment and discussion.⁸

Several open-label studies have shown that switching from one CGRP mAb to another might be useful; however, no formal guidelines exist. It would seem intuitive that a switch towards a mAb targeting the ligand when erenumab did not work, or vice versa.³ Combination therapy with mAbs and gepants may be considered in partial responders, and ongoing research is exploring their role in menstrual migraine, vestibular migraine, and comorbid pain conditions.³

The challenge in using this drug class is chiefly cost, which remains a barrier to widespread use, but improved quality of life and reduced disability are well documented, and the meds are effective and well-tolerated options for both acute and preventive migraine treatment. AHS recognizes CGRP targeting therapies as first-line options for migraine prevention, and their introduction has transformed migraine management, particularly for patients who are refractory to or intolerant of traditional therapies.⁸

References

1. Arca K, Reynolds J, Sands KA, et. Calcitonin gene-related peptide antagonists for the prevention of migraine: highlights from pivotal studies and the clinical relevance of this new drug class. Ann Pharmacother2020;54(8):795-803. https://doi.org/10.1177/1060028020903417
2. Charles A, Pozo-Rosich P. Targeting calcitonin gene-related peptide: a new era in migraine therapy. Lancet2019 Nov 9;394(10210):1765-74. https://doi.org/10.1016/S0140-6736(19)32504-8
3. Versijpt J, Paemeleire K, Reuter U, et al. Calcitonin gene-related peptide-targeted therapy in migraine: current role and future perspectives. Lancet 2025;405(10483):1014-26. https://doi.org/10.1016/S0140-6736(25)00109-6
4. Schwedt T, Reuter U, Tepper S, et al. Early onset of efficacy with erenumab in patients with episodic and chronic migraine. J Headache Pain 2018;19(1):92. https://doi.org/10.1186/s10194-018-0923-6
5. Detke HC, Millen BA, Zhang Q, et al. Rapid onset of effect of galcanezumab for the prevention of episodic migraine: analysis of the EVOLVE studies. Headache 2020;60(2):348-59. https://doi.org/10.1111/head.13691
6. Karlsson WK, Ostinelli EG, Zhuang ZA, et al. Comparative effects of drug interventions for the acute management of migraine episodes in adults: systematic review and network meta-analysis. BMJ2024;386:e080107. https://doi.org/10.1136/bmj-2024-080107
7. Yang CP, Liang CS, Chang CM, et al. Comparison of new pharmacologic agents with triptans for treatment of migraine: a systematic review and meta-analysis. JAMA Netw Open 2021;4(10):e2128544. https://doi.org/10.1001/jamanetworkopen.2021.28544
8. Charles AC, Digre KB, Goadsby PJ, et al. Calcitonin gene-related peptide-targeting therapies are a first-line option for the prevention of migraine: an American Headache Society position statement update. Headache2024;64(4):333-41. https://doi.org/10.1111/head.14692
9. Haghdoost F, Puledda F, Garcia-Azorin D, et al. Evaluating the efficacy of CGRP mAbs and gepants for the preventive treatment of migraine: a systematic review and network meta-analysis of phase 3 randomised controlled trials. Cephalalgia 2023;43(4):3331024231159366. https://doi.org/10.1177/03331024231159366
10. Messina R, Huessler EM, Puledda F, et al. Safety and tolerability of monoclonal antibodies targeting the CGRP pathway and gepants in migraine prevention: a systematic review and network meta-analysis. Cephalalgia2023;43(3):3331024231152169. https://doi.org/10.1177/03331024231152169
11. Cho S, Kim BK. Update of gepants in the treatment of chronic migraine. Curr Pain Headache Rep2023;27(10):561-9. https://doi.org/10.1007/s11916-023-01167-6
12. Sun W, Cheng H, Xia B, et al. Comparative efficacy and safety of five anti-calcitonin gene-related peptide agents for migraine prevention: a network meta-analysis. Clin J Pain 2023;39(10):560-9. https://doi.org/10.1097/AJP.0000000000001136
13.  Lampl C, MaassenVanDenBrink A, Deligianni CI, et al. The comparative effectiveness of migraine preventive drugs: a systematic review and network meta-analysis. J Headache Pain 2023;24(1):56.https://doi.org/10.1186/s10194-023-01594-1
14. Cho S, Kim BK. Long-term outcome after discontinuation of CGRP-targeting therapy for migraine. Curr Pain Headache Rep 2024;28(8):743-51. https://doi.org/10.1007/s11916-024-01259-x
15. Sacco S, Amin FM, Ashina M. European Headache Federation guideline use monoclonal antibodies targeting calcitonin gene related peptide pathway migraine prevention-2022 update. J Headache Pain 2022;23.https://doi.org/10.1186/s10194-022-01431-x