PACAP-38 peptide is elevated in all stages of cluster headache, suggesting a new therapeutic target | Research

The takeaway

In 205 cluster headache patients vs 101 controls, PACAP-38 was elevated 34-50% across all disease states (bout, remission, chronic), with no correlation to CGRP levels, positioning PACAP-38 as an independent treatment target.

+50% PACAP-38 in chronic CH
PACAP-38 is elevated in all cluster headache states and does not correlate with CGRP—supporting development of anti-PACAP therapies as an independent treatment approach

What the researchers found

PACAP-38 elevated vs controls: overall +34.3% (p<0.0001), chronic +49.8% (p<0.0001), bout +39.5% (p<0.0001), remission +34.1% (p=0.0005). No PACAP-38/CGRP correlation (r=0.08, p=0.10). 205 patients, 101 controls.

Why it matters

Cluster headache is one of the most painful conditions known. While CGRP-targeting drugs help some patients, the lack of PACAP-38/CGRP correlation suggests anti-PACAP therapies could help patients who do not respond to CGRP treatments.

How the study worked

Prospective case-control study. Danish Cluster Headache Biobank. 205 CH patients (ICHD-3 criteria), 101 matched controls. Interictal plasma PACAP-38 and CGRP by validated immunoassays.

What this study cannot tell us

Cross-sectional measurement—does not prove causation. Interictal measurements may not reflect attack-phase dynamics. Plasma levels may not reflect brain tissue levels. PACAP-38 elevation during remission complicates interpretation.

How to read the evidence

Large prospective case-control study with validated immunoassays from a national biobank. Strong observational evidence.

When this study was published

Published in 2025.

The bigger picture

PACAP-38 joins CGRP as a validated neuropeptide target in headache disorders. Anti-PACAP therapies are in development, and this study provides the strongest human evidence yet supporting their use in cluster headache.

Questions still open

Will anti-PACAP therapies be effective for cluster headache?
Why is PACAP-38 elevated even during remission?
Could PACAP-38 serve as a diagnostic biomarker for cluster headache?

Common questions

What is PACAP-38?

PACAP-38 (pituitary adenylate cyclase-activating peptide) is a 38-amino acid neuropeptide involved in pain signaling. This study found it is significantly elevated in cluster headache patients regardless of whether they are currently having attacks or in remission, suggesting it plays a persistent role in the disease.

Could blocking PACAP-38 treat cluster headache?

Yes—this is a major finding because PACAP-38 appears to be elevated independently of CGRP (the target of current migraine drugs). This means patients who do not respond to CGRP treatments might benefit from anti-PACAP therapies, which are currently being developed in clinical trials.

Read the original research

PACAP-38 in Cluster Headache: A Prospective, Case-Control Study of a Potential Treatment Target.

European journal of neurology, 32(9), e70341

View on PubMed ↗Publisher’s paper ↗

Citation

Søborg, Marie-Louise K; Lund, Nunu; Snoer, Agneta; Barloese, Mads; Jensen, Rigmor Højland; Petersen, Anja Sofie. (2025). PACAP-38 in Cluster Headache: A Prospective, Case-Control Study of a Potential Treatment Target.. European journal of neurology, 32(9), e70341. https://doi.org/10.1111/ene.70341