CGRP Migraine Drugs May Increase Risk of Raynaud's Phenomenon — Analysis of FDA Adverse Event Reports | Research

The takeaway

Analysis of 149 FDA adverse event reports identified a potential link between CGRP antagonist migraine drugs and Raynaud's phenomenon, with the PI3K/AKT pathway as the likely mechanism for small molecule drugs.

149 RP adverse event reports
Across 7 CGRP antagonists in the FDA database, with fremanezumab showing the strongest statistical signal and PI3K/AKT identified as the underlying mechanism

What the researchers found

From the FAERS database (Q2 2018 to Q1 2025), 149 adverse event reports linked CGRP antagonists to Raynaud's phenomenon across 7 drugs:

- Erenumab had the most reports

- Fremanezumab showed the strongest adverse event signal across all four statistical methods

- Drug-gene network analysis identified key molecular nodes: AKT1, EGFR, ERBB2 for rimegepant

- KEGG pathway analysis revealed PI3K signaling as the most likely mechanism for small molecule CGRP antagonists (rimegepant, atogepant, ubrogepant) inducing Raynaud's

- The PI3K/AKT pathway connects CGRP blockade to vascular dysfunction

The authors recommend regular monitoring for Raynaud's in patients receiving CGRP antagonists, particularly those with underlying vascular dysfunction.

Why it matters

CGRP is a potent vasodilator — blocking it to treat migraines could theoretically cause blood vessel constriction elsewhere. This study provides the first systematic evidence that CGRP antagonists may trigger Raynaud's phenomenon, an important safety consideration for the millions of patients now taking these drugs for migraine prevention and treatment.

How the study worked

Disproportionality analysis of the FAERS database using four established signal detection methods. Gene targets of CGRP antagonists and Raynaud's were predicted using multiple databases. Protein-protein interaction (PPI) networks were built using STRING. KEGG pathway enrichment analysis identified potential mechanisms. Analysis covered Q2 2018 through Q1 2025.

What this study cannot tell us

FAERS data is based on voluntary reporting and cannot establish causation — only a statistical signal. Reporting biases may affect which drugs appear more frequently. The 149 reports represent a small fraction of total CGRP antagonist users. The drug-gene network analysis is computational and requires experimental validation. Pre-existing vascular conditions in reported patients were not always documented.

How to read the evidence

This is a pharmacovigilance study using real-world adverse event data with computational network analysis. FAERS-based studies can identify potential safety signals but cannot establish causation — they generate hypotheses requiring clinical validation.

When this study was published

Published in 2025 with data through early 2025, this study provides the most current safety signal analysis for CGRP antagonists and vascular adverse events.

The bigger picture

CGRP plays essential roles beyond migraine — including maintaining blood vessel dilation and protecting against hypertension. As CGRP-targeting therapies become blockbuster drugs prescribed to millions, understanding their vascular side effects becomes critical. This study highlights the need to monitor the long-term cardiovascular safety of chronic CGRP blockade.

Questions still open

Should patients with Raynaud's or other vascular conditions avoid CGRP antagonists?
Do antibody-based CGRP blockers (erenumab, fremanezumab) carry different Raynaud's risk than small molecule gepants?
Does the duration of CGRP antagonist use correlate with Raynaud's risk?

Common questions

What is Raynaud's phenomenon and why might CGRP drugs cause it?

Raynaud's phenomenon causes episodes where blood flow to fingers and toes is temporarily reduced, turning them white or blue and causing pain. CGRP is a powerful blood vessel dilator — blocking it with migraine drugs could theoretically cause blood vessels to constrict excessively, especially in the extremities. This study found evidence supporting this concern in FDA reports.

Should I stop my CGRP migraine medication if I get cold fingers?

Don't stop any medication without consulting your doctor. If you notice new episodes of cold, painful, or discolored fingers or toes after starting a CGRP antagonist, report it to your prescribing physician. They can evaluate whether it's Raynaud's and decide whether to continue, switch medications, or add monitoring. Patients with pre-existing vascular conditions may need closer observation.

Read the original research

Calcitonin gene-related peptide antagonists in Raynaud's phenomenon: a disproportionality study based on real data and drug-gene network analysis.

Naunyn-Schmiedeberg's archives of pharmacology

View on PubMed ↗Publisher’s paper ↗

Citation

Zhu, Haibin; Ma, Minghua; Tian, Weiwei; Wu, Tingting; Wang, Yan; Huo, Yan; Liao, Xiaolan. (2025). Calcitonin gene-related peptide antagonists in Raynaud's phenomenon: a disproportionality study based on real data and drug-gene network analysis.. Naunyn-Schmiedeberg's archives of pharmacology. https://doi.org/10.1007/s00210-025-04877-3