PACAP38- and VIP-induced cluster headache attacks are not associated with changes of plasma CGRP or markers of mast cell activation

Background Pituitary adenylate cyclase-activating polypeptide-38 (PACAP38) and vasoactive intestinal polypeptide can provoke cluster headache attacks in up to half of cluster headache patients in their active phase. At present, it is unknown whether provoked attacks are mediated via calcitonin gene-related peptide or mast cell activation. Methods All enrolled patients with cluster headache were randomly allocated to receive a continuous infusion of either PACAP38 (10 pmol/kg/min) or vasoactive intestinal polypeptide (8 pmol/kg/min) over 20 min. We collected clinical data and measured plasma levels of calcitonin gene-related peptide and markers of mast cell activation (tryptase and histamine) at fixed time points: at baseline (T0), at the end of the infusion (T20), 10 min after the infusion (T30), and 70 min after the infusion (T90). Results Blood was collected from episodic cluster headache patients in active phase (n = 14), episodic cluster headache patients in remission (n = 15), and chronic cluster headache patients (n = 15). At baseline, plasma levels of calcitonin gene-related peptide, tryptase, and histamine were not different among the three study groups. Plasma levels of calcitonin gene-related peptide ( p = 0.7074), tryptase ( p = 0.6673), or histamine ( p = 0.4792) remained unchanged during provoked attacks compared to attack-free patients. Conclusion Cluster headache attacks provoked by either PACAP38 or vasoactive intestinal polypeptide were not accompanied by alterations of plasma calcitonin gene-related peptide, tryptase or histamine. The provoked attacks may not be mediated by calcitonin gene-related peptide or mast cell activation. Trial Registration: The study is registered at ClinicalTrials.gov (NCT03814226).

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Calcitonin gene-related peptide and disease activity in cluster headache

Cephalalgia ◽

10.1177/0333102419837154 ◽

2019 ◽

Vol 39 (5) ◽

pp. 575-584 ◽

Cited By ~ 15

Author(s):

Agneta Snoer ◽

Anne Luise H Vollesen ◽

Rasmus P Beske ◽

Song Guo ◽

Jan Hoffmann ◽

...

Keyword(s):

Cluster Headache ◽

Vasoactive Intestinal Polypeptide ◽

Active Phase ◽

Calcitonin Gene Related Peptide ◽

Chronic Cluster Headache ◽

Related Peptide ◽

Episodic Cluster Headache ◽

Calcitonin Gene ◽

Headache Patients ◽

Intestinal Polypeptide

Objective To investigate the role of calcitonin gene-related peptide, pituitary adenylate cyclase-activating polypeptide-38 (PACAP38) and vasoactive intestinal polypeptide in cluster headache, we measured these vasoactive peptides interictally and during experimentally induced cluster headache attacks. Methods We included patients with episodic cluster headache in an active phase (n = 9), episodic cluster headache patients in remission (n = 9) and patients with chronic cluster headache (n = 13). Cluster headache attacks were induced by infusion of calcitonin gene-related peptide (1.5 µg/min) in a randomized, double-blind, placebo controlled, two-way cross-over study. At baseline, we collected interictal blood samples from all patients and during 11 calcitonin gene-related peptide-induced cluster headache attacks. Results At baseline, episodic cluster headache patients in remission had higher plasma levels of calcitonin gene-related peptide, 100.6 ± 36.3 pmol/l, compared to chronic cluster headache patients, 65.9 ± 30.5 pmol/l, ( p = 0.011). Episodic cluster headache patients in active phase had higher PACAP38 levels, 4.0 ± 0.8 pmol/l, compared to chronic cluster headache patients, 3.3 ± 0.7 pmol/l, ( p = 0.033). Baseline levels of vasoactive intestinal polypeptide did not differ between cluster headache groups. We found no attack-related increase in calcitonin gene-related peptide, PACAP38 or vasoactive intestinal polypeptide levels during calcitonin gene-related peptide-induced cluster headache attacks. Conclusions This study suggests that cluster headache disease activity is associated with alterations of calcitonin gene-related peptide expression. Future studies should investigate the potential of using calcitonin gene-related peptide measurements in monitoring of disease state and predicting response to preventive treatments, including response to anti-calcitonin gene-related peptide monoclonal antibodies.

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Effect of calcitonin gene-related peptide (-receptor) antibodies in chronic cluster headache: Results from a retrospective case series support individual treatment attempts

Cephalalgia ◽

10.1177/0333102420949866 ◽

2020 ◽

Vol 40 (14) ◽

pp. 1574-1584 ◽

Cited By ~ 1

Author(s):

Ruth Ruscheweyh ◽

Gregor Broessner ◽

Gudrun Goßrau ◽

Katja Heinze-Kuhn ◽

Tim P Jürgens ◽

...

Keyword(s):

Cluster Headache ◽

Calcitonin Gene Related Peptide ◽

Chronic Cluster Headache ◽

Individual Treatment ◽

Attack Frequency ◽

Peptide Receptor ◽

Related Peptide ◽

Calcitonin Gene ◽

Receptor Antibodies ◽

Headache Patients

Objective To assess the efficacy of monoclonal antibodies targeting calcitonin gene-related peptide (CGRP) or its receptor in chronic cluster headache (CCH) treatment under real world conditions. Background Calcitonin gene-related peptide has an important pathophysiological role in cluster headache. Although the randomised controlled trial with the calcitonin gene-related peptide antibody galcanezumab was negative, chronic cluster headache patients with insufficient response to other preventive treatments have been receiving individual off-label treatment attempts with calcitonin gene-related peptide-(receptor) antibodies. Methods Data from 22 chronic cluster headache patients who received at least one dose of a calcitonin gene-related peptide(-receptor) antibody and recorded attack frequency in a headache diary were retrospectively collected at eight headache centres. Results The number of previous preventive therapies was 6.5 ± 2.4 (mean ± standard deviation, range: 2–11). The average number of attacks per week was 23.3 ± 16.4 at baseline and significantly decreased by −9.2 ± 9.7 in the first month of treatment with a calcitonin gene-related peptide(-receptor) antibody ( p < 0.001). Fifty-five percent of the patients were 50% responders and 36% were 75% responders with respect to attack frequency. Significant reduction of attack frequency started at week 1 (−6.8 ± 2.8 attacks, p < 0.01). Results were corroborated by significant decreases in weekly uses of acute headache medication (−9.8 ± 7.6, p < 0.001) and pain intensity during attacks (−1.2 ± 2.0, numerical rating scale (NRS) [0–10], p < 0.01) in the first month. In months 2 (n = 14) and 3 (n = 10), reduction of attack frequency from baseline was −8.0 ± 8.4 ( p = 0.004) and −9.1 ± 10.0 ( p = 0.024), respectively. Conclusion Under real-world conditions, individual treatment with calcitonin gene-related peptide(-receptor) antibodies was effective in 55% of our chronic cluster headache patients. This finding supports individual off-label treatment attempts with calcitonin gene-related peptide-(receptor) antibodies in chronic cluster headache patients insufficiently responding to other therapies.

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Baseline tear fluid CGRP is elevated in active cluster headache patients as long as they have not taken attack abortive medication

Cephalalgia ◽

10.1177/0333102420949858 ◽

2020 ◽

pp. 033310242094985

Author(s):

Katharina Kamm ◽

Andreas Straube ◽

Ruth Ruscheweyh

Keyword(s):

Cluster Headache ◽

Trigeminal Nerve ◽

Calcitonin Gene Related Peptide ◽

Chronic Cluster Headache ◽

Tear Fluid ◽

Abortive Medication ◽

Related Peptide ◽

Calcitonin Gene ◽

Active Cluster ◽

Headache Patients

Background Calcitonin gene-related peptide plays a key role in cluster headache pathophysiology. It is released from the trigeminal nerve, which also innervates the eye. In this study, we tested if tear fluid calcitonin gene-related peptide measurement detects elevated calcitonin gene-related peptide levels in cluster headache patients compared to controls. Methods Calcitonin gene-related peptide concentration in tear fluid and plasma of 16 active episodic and 11 chronic cluster headache patients (all outside acute attacks) and 60 controls were assessed using ELISA. Results Cluster headache patients without use of attack abortive medication in the last 48 h showed significantly elevated tear fluid calcitonin gene-related peptide levels (1.78 ± 1.57 ng/ml, n = 17) compared to healthy controls (0.79 ± 0.74 ng/ml, p = 0.003) and compared to cluster headache patients who had used attack abortive medication in the last 48 h (0.84 ± 1.40 ng/ml, n = 10, p = 0.022). High calcitonin gene-related peptide levels in cluster headache patients were independent of the occurrence of a cluster headache attack in the last 48 hours (no attack: 1.95 ± 1.65 ng/ml, n = 8; attack: 1.63 ± 1.59 ng/ml, n = 9, p = 0.82) as long as no acute medication was used. No significant difference in tear fluid calcitonin gene-related peptide levels between episodic (1.48 ± 1.34 ng/ml) and chronic cluster headache patients (2.21 ± 1.88 ng/ml, p = 0.364) was detected. In contrast to these results in tear fluid, there were no significant group differences in plasma calcitonin gene-related peptide levels. Conclusion This study shows that active cluster headache patients have increased calcitonin gene-related peptide levels in tear fluid compared to healthy subjects, which are reduced to control levels after intake of attack abortive medication. Calcitonin gene-related peptide measurement in tear fluid is non-invasive, and has the advantage of allowing direct access to calcitonin gene-related peptide released from the trigeminal nerve.

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Sensory Neuropeptides (Substance P, Calcitonin Gene-Related Peptide) and Vasoactive Intestinal Polypeptide in Human Saliva: Their Pattern in Migraine and Cluster Headache

Cephalalgia ◽

10.1046/j.1468-2982.1990.1001039.x ◽

1990 ◽

Vol 10 (1) ◽

pp. 39-50 ◽

Cited By ~ 46

Author(s):

Maria Nicolodi ◽

Elena Del Bianco

Keyword(s):

Substance P ◽

Cluster Headache ◽

Vasoactive Intestinal Polypeptide ◽

Calcitonin Gene Related Peptide ◽

Related Peptide ◽

Control Subjects ◽

Cluster Headache Attack ◽

Calcitonin Gene ◽

Symptomatic Side ◽

Intestinal Polypeptide

Substance P, calcitonin gene-related peptide and vasoactive intestinal polypeptide-like immunoreactivities have been evaluated in the saliva of 15 subjects suffering from migraine without aura and 16 control subjects. All three peptides were also measured in the symptomatic/non-symptomatic side saliva sampled from 10 cluster headache sufferers during the cluster period, 5 cluster headache sufferers out of the cluster period, as well as in the right and left side saliva of 18 control subjects. The most interesting result gives a clear difference in common migraine and cluster headache salivary vasoactive intestinal polypeptide-like immunoreactivity contents. In fact, these are enhanced during cluster headache attack and decreased during migraine attack when compared with the interictal period vasoactive intestinal polypeptide-like immunoreactivity levels. Another remarkable finding concerns the significant increase of substance P-like immunoreactivity and calcitonin gene-related peptide-like immunoreactivity levels, from basal values, in the saliva sampled during both migraine and cluster headache attacks. Control subjects showed a calcitonin gene-related peptide-like immunoreactivity and substance P-like immunoreactivity salivary contents significantly higher than migraine sufferers' saliva sampled in basal conditions. Conversely, calcitonin gene-related peptide-like immunoreactivities levels in controls were lower than in cluster headache sufferers' saliva obtained during intervals. Finally, during cluster headache attacks the enhancement of substance P-like immunoreactivity and vasoactive intestinal polypeptide-like immunoreactivity salivary contents interest the non-symptomatic side, whereas the symptomatic side salivary substance P-like immunoreactivity and vasoactive intestinal poly-peptide-like immunoreactivity contents remain unchanged. These findings do not allow any final conclusion. However, this biochemical evaluation indicates relevant changes of the salivary neuropeptides in diseases, such as migraine and cluster headache, in which pain transmission is surely involved.

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