PACAP vs. CGRP in Migraine: Comparing Two Key Neuropeptide Targets | Research

The takeaway

PACAP emerges as a complementary migraine target to CGRP, with distinct roles in autonomic symptoms and potentially different patient populations.

2 targets
CGRP and PACAP serve complementary roles in migraine with distinct anatomical distributions

What the researchers found

CGRP and PACAP play complementary but distinct roles in migraine — CGRP drives trigeminal pain while PACAP primarily influences autonomic symptoms.

Why it matters

For patients who don't respond to CGRP-targeted drugs, PACAP may represent an alternative therapeutic pathway.

The numbers in context

Both peptides elevate cAMP via PKA. PACAP more effective at activating certain pathways. CGRP more abundant in trigeminal system. PACAP more prominent in parasympathetic ganglia.

How the study worked

Review comparing preclinical mouse model data and clinical evidence on PACAP and CGRP in migraine pathophysiology.

Who was studied

Not applicable (migraine pathophysiology review)

What this study cannot tell us

Review relies heavily on preclinical data — PACAP-targeted therapies are earlier in clinical development than CGRP drugs.

How to read the evidence

Review of preclinical and translational evidence — strong scientific rationale but PACAP-targeted drugs are not yet clinically validated.

When this study was published

Published in 2025, reflecting the cutting edge of migraine neuroscience.

The bigger picture

Expanding migraine treatment beyond CGRP could help the significant proportion of patients who don't respond adequately to current anti-CGRP therapies.

Questions still open

Would combining CGRP and PACAP-targeted therapies provide superior migraine relief?
Which patient subgroups would benefit most from PACAP-targeted treatment?

Common questions

What is PACAP and how does it relate to migraine?

PACAP is a neuropeptide involved in migraine, particularly in autonomic symptoms like tearing and nasal congestion. It may be a target for new treatments.

Are there drugs targeting PACAP for migraine?

PACAP-targeted therapies are in early development. Current approved migraine drugs target CGRP, but PACAP could help patients who don't respond to those.

Read the original research

PACAP versus CGRP in migraine: From mouse models to clinical translation.

Cephalalgia : an international journal of headache, 45(9), 3331024251364242

View on PubMed ↗Publisher’s paper ↗

Citation

Pietra, Adriana Della; Kuburas, Adisa; Russo, Andrew F. (2025). PACAP versus CGRP in migraine: From mouse models to clinical translation.. Cephalalgia : an international journal of headache, 45(9), 3331024251364242. https://doi.org/10.1177/03331024251364242