Episodic migraine affects approximately 12% of the world population and represents the second leading cause of disability in years lived with disability, according to the World Health Organization. The arrival of anti-CGRP (calcitonin gene-related peptide) monoclonal antibodies represented a revolution in prophylaxis — but the absence of head-to-head studies between the three approved agents made individualized therapeutic choice difficult. A network meta-analysis published in European Journal of Clinical Pharmacology filled this gap, systematically analyzing galcanezumab, fremanezumab, and erenumab from 16 randomized clinical trials and 9,123 participants.
The main conclusion is that, although the three agents are superior to placebo, there are relevant differences in efficacy and safety profile: fremanezumab 225 mg offers the best balance between efficacy and tolerability, galcanezumab 240 mg presents the largest gross effect magnitude, and erenumab 28 mg stands out for the most favorable safety profile.
The anti-CGRP mechanism: modulating the trigeminal pain pathway
CGRP is a vasoactive neuropeptide released from trigeminal nerve endings during a migraine attack. It promotes meningeal vasodilation, neurogenic inflammation, and peripheral sensitization of perivascular nociceptive fibers. Anti-CGRP monoclonal antibodies block this signal in two ways: galcanezumab and fremanezumab bind directly to the CGRP ligand, while erenumabblocks the CGRP-R receptor. Both approaches interrupt the trigeminal inflammatory cascade without the systemic effects of older oral preventives (topiramate, valproate, propranolol).
Methodology: 16 trials, three molecules, 9,123 patients
The review by Shakir I et al. (2026) included 16 double-blind, placebo-controlled randomized clinical trials, totaling 9,123 participants with episodic migraine (4 to 14 migraine days per month). The primary outcomes were:
Outcomes evaluated in the network meta-analysis
- Reduction in the number of monthly migraine days — continuous measure (SMD)
- Response rate ≥ 50% in the reduction of migraine days per month — dichotomous measure (OR)
- Safety profile: any-grade adverse events vs. placebo (OR)
- Comparisons by specific dose: galcanezumab 120 mg and 240 mg, fremanezumab 225 mg and 675 mg, erenumab 28 mg and 70 mg and 140 mg
ANTI-CGRP FOR EPISODIC MIGRAINE — MAIN DATA
Comparison among the three agents
GALCANEZUMAB VS. FREMANEZUMAB VS. ERENUMAB
| AGENT / DOSE | EFFICACY AND SAFETY PROFILE |
|---|---|
| Galcanezumab 240 mg (monthly) | Highest absolute efficacy (SMD = 0.50) · Monthly subcutaneous administration · autoinjection available |
| Fremanezumab 225 mg (monthly) or 675 mg (quarterly) | Best efficacy-safety balance · OR = 3.17 for response ≥ 50% · only one with quarterly option |
| Erenumab 70-140 mg (monthly) | Best safety profile (OR = 0.68) · blocks receptor (not the ligand) · may increase constipation |
The authors conclude that fremanezumab offers the best balance between efficacy and safety, considering simultaneously the clinical response rate and tolerability. For patients in whom maximizing efficacy is a priority, galcanezumab 240 mg demonstrated the largest effect magnitude. For those with a history of adverse events or tolerability concerns, erenumab presented the most favorable profile.
Frequently Asked Questions
All three are humanized monoclonal antibodies that block the CGRP pathway, but in distinct ways. Galcanezumab and fremanezumab bind directly to the CGRP peptide, preventing it from acting on its receptors. Erenumab, in contrast, blocks the CGRP-R receptor — therefore, it does not interfere with CGRP function in other tissues where it is released in response to physical activity or stress, which may explain the differentiated safety profile. In practice, the three molecules have comparable efficacy, with the quantitative differences revealed by this network meta-analysis.
International guidelines (AHS, EAN) and approvals from major drug regulatory agencies (FDA, EMA, and others) indicate anti-CGRP antibodies for adults with episodic migraine (≥ 4 days/month) or chronic migraine (≥ 15 days/month with migraine features) who have presented failure or intolerance to at least two conventional oral preventives (topiramate, valproate, propranolol, amitriptyline, venlafaxine).
Coverage varies by country and program. In many jurisdictions, anti-CGRP antibodies are not on essential-medicines lists and are accessed through specialty pharmacies with significant monthly cost. In countries where they are covered, access often requires prior authorization with documented failure of conventional oral preventives.
Yes. There is no known contraindication to the combination. Medical acupuncture has independent evidence for episodic migraine prophylaxis — recent meta-analyses (including a study published in JAMA Neurology) demonstrate significant reduction in attack frequency. In patients in whom the cost or availability of anti-CGRP is limiting, acupuncture constitutes a non-pharmacologic first-line alternative. In patients already on anti-CGRP, acupuncture can be used as adjunctive therapy to optimize control.
Guidelines suggest a minimum of 6 to 12 months of treatment before considering discontinuation, with periodic assessment of response. Extension studies show that a significant portion of responders maintain benefit after suspension, possibly due to modification of the central sensitization state. The decision to continue or stop should be individualized, considering clinical response, cost, and patient preferences.
Sources consulted
- Shakir I, Shahzad F, Shabbir A, et al. Efficacy and safety of CGRP monoclonal antibodies for migraine prevention in episodic migraine: a network meta-analysis. Eur J Clin Pharmacol. 2026;82(2):27. DOI: 10.1007/s00228-025-03934-3.
- Edvinsson L, Haanes KA, Warfvinge K, Krause DN. CGRP as the target of new migraine therapies — successful translation from bench to clinic. Nat Rev Neurol. 2018.
- Diener HC, Tassorelli C, Dodick DW, et al. Guidelines of the International Headache Society for controlled trials of preventive treatment of migraine. Cephalalgia. 2020.
- Zhao L, Chen J, Li Y, et al. The long-term effectiveness and safety of acupuncture for migraine prevention. JAMA Intern Med. 2017.
- FDA labels for Emgality (galcanezumab), Ajovy (fremanezumab), and Aimovig (erenumab). U.S. Food and Drug Administration, 2018-2024.
Fonte Original
European Journal of Clinical Pharmacology(em inglês)Estudo Científico
DOI: 10.1007/s00228-025-03934-3Founded in 1989 by physicians trained at the University of São Paulo (USP) and specialized in China, CEIMEC is a Brazilian national reference in the teaching and practice of medical acupuncture. With more than 3,000 physicians trained over 35 years, it collaborates with HC-FMUSP and is recognized by the Brazilian Medical College of Acupuncture (CMBA/AMB).