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

Estimates of pituitary adenylate cyclase-activating peptide-38's (PACAP-38) activity in cluster headache are sparse. We investigated whether plasma levels of PACAP-38 differ between disease states (i.e., bout, remission, chronic) and compared to headache-free controls. Secondly, we assessed a possible correlation between plasma levels of PACAP-38 and Calcitonin gene-related peptide (CGRP). In an observational case-control setup, prospectively collected interictal plasma samples from participants in the Danish Cluster Headache Biobank were analyzed for plasma levels of PACAP-38 and CGRP. All participants had blood samples drawn; once if chronic cluster headache or controls, and twice if episodic cluster headache (in bout and in remission phase). Plasma levels were measured with validated immunoassays. Plasma was derived from 205 patients with cluster headache according to ICHD-3 criteria and 101 sex- and age-matched headache-free controls. PACAP-38 plasma levels were significantly higher in all three disease states of cluster headache: compared to controls, they collectively had a 34.3% (95% CI: 20%-49%, p < 0.0001) higher mean PACAP-38 level. Chronic cluster headache showed the greatest difference by 49.8% (95% CI: 26.7-77.2, p < 0.0001) higher PACAP-38 levels, while episodic cluster headache in bout and remission showed respectively 39.5% (95% CI: 18.8-63.8, p < 0.0001) and 34.1% (95% CI: 14.2-57.5, p = 0.0005) higher plasma levels. No correlation between plasma levels of PACAP-38 and CGRP was demonstrated (Spearmans r = 0.08, p = 0.10). This large-scale study demonstrated increased PACAP-38 levels in all disease states of cluster headache compared to headache-free controls, strengthening the hope of a possible effect of PACAP-38 targeting treatments in future trials. The lacking correlation between PACAP-38 and CGRP levels should be interpreted with caution and needs to be investigated in future studies.