Cluster headache is a chronic
headache disorder with a prevalence of 0.5 to 1.0 out of the population of
1000.
The study concluded that the calcitonin
gene-related peptide provokes cluster headache attacks in active-phase episodic
cluster headache and chronic cluster headache but not in remission-phase
episodic cluster headache. These results suggest anti-CGRP drugs may be useful
in cluster headache management.
Cluster headache is a chronic headache disorder with a prevalence of 0.5 to 1.0 out of the population of 1000. Cluster headache attacks are characterised by prominent ipsilateral cephalic autonomic symptoms (CAS), such as tearing, conjunctival redness, rhinorrhea or nasal congestion, ptosis, as well as the sense of agitation or restlessness. Most of the patients experiencing episodic cluster headache with month-long attack periods separated by remission periods. The remaining 10% to 15% of patients experience chronic cluster headache. Extended cluster headache periods dramatically hinder individuals with increased health care expenses. The initiating pathways for the cluster periods and individual attacks are still unknown. There is no doubt that treatment options are limited, and no disease-specific preventive medication exists. The number of studies suggested the role of CGRP in the inducing the migraine. Furthermore, the literature indicated that CGRP antagonism with receptor antagonists or monoclonal antibodies stops and prevents migraine. Although phenotypically different, migraine and cluster headache showed the elevated plasma level of CGRP. The results of the previous studies confirmed the role of CGRP in the induction cluster headache attack and provided a novel target for the researchers to overcome the lack of drugs. The findings from previous studies indicate that intravenous infusion of CGRP would stimulate the cluster headache attacks in patients with chronic cluster headache. To confirm these findings, Anne Luise H. et al. conducted a randomised, double-blind, placebo-controlled, 2-way crossover study.
Rationale behind research
The number of previous studies reported the role of CGRP in the pathogenesis of cluster headache, but none of them evaluated the effect of CGRP on the induction of cluster headache.
Therefore, in the current study, the authors used a CGRP infusion to test its role in the provoking the cluster headache.
Objective
The study was aimed to determine whether CGRP induces cluster headache attacks in episodic cluster headache in active phase, episodic cluster headache in the remission phase, and chronic cluster headache.
Study outcomes:
Time period: NA
Outcomes
In the 30 days before study day 1, the 7 patients who did report a cluster like attack after CGRP reported a median attack frequency of 33. The 7 patients who did not report attack after CGRP had a median attack frequency of 7.5 (Figure 2). The mean AUC from 0 to 90 minutes for CGRP was 1.214 (95% CI, 0.395-2.033), and the mean AUC from 0 to 90 minutes for placebo was 0.036 (95% CI, 0-0.114) (P = .01).
In conclusion, it was demonstrated that CGRP provokes
cluster headache attacks during the active phase in patients with cluster
headache. The results also guardedly suggest the efficacy of CGRP antagonism in
the treatment of cluster headache.
The results of the current study suggested that CGRP
provoked cluster headache attacks only in the active phase and not in patients
in remission. Overall, the findings propose that (1) CGRP plays a crucial role
in the initiation of a single cluster headache attack and (2) suggested a
possible clinical efficacy of anti-CGRP (e.g., specific monoclonal antibodies).
The previous studies reported elevated ictal plasma levels
of CGRP in patients with cluster headache. This elevated CGRP reached to normal
after oxygen inhalation and subcutaneous sumatriptan injection. CGRP is known
as one of the most potent vasodilators, and it innervates human cranial
arteries. Cyclic adenosine mono-phosphate mediates the intracellular signalling
cascade after CGRP receptor activation. CGRP also regulates the activity of
nociceptive trigeminal neurons as well as central structures that process
trigeminal pain. Neurons in the trigeminal and sphenopalatine ganglia express
CGRP, and CGRP is released on the thermocoagulation of the trigeminal ganglion.
This recommends that CGRP is optimally located to play a role at both the
nociceptive and parasympathetic end of the trigeminal-autonomic reflex. CGRP
could exert its cluster headache–inducing abilities in 3 distinguishing ways.
First, this may occur via vascular effects of CGRP, likely involving neurogenic
inflammation. Second, CGRP receptor components are also found in the human
trigeminal ganglion, which has been suggested as the possible target for the
CGRP receptor antagonists. Third, neurons in the sphenopalatine ganglion
express CGRP and its receptor components. The efferent outflow of CGRP from
sphenopalatine ganglia reported as the initiating
mechanism of cluster headache attacks. Interestingly, in the present study, the
median time to onset of parasympathetic symptoms preceded the median onset of
head pain. These data indicate that CGRP may induce parasympathetic outflow and
trigger cluster headache attacks.
Previous studies revealed that glyceryl trinitrate induced
cluster headache during the active phase. Glyceryl trinitrate produced attacks
in 20 to 78% of patients of chronic cluster headache. The results of the
current study extend these findings showing that CGRP did not provoke cluster
headache attacks during remission. These data suggest peripheral mechanisms
alone cannot explain CGRP-induced attacks and central mechanisms altering the
provocability threshold by CGRP should be considered. The remarkable
circadian/circannual periodicity in cluster headache, as well as neuroendocrine
changes, hint to the hypothalamus as responsible for altering the provocability
threshold. Brain imaging studies have generated strong support for this
hypothesis. Activation of the posterior hypothalamus was seen during cluster
headache attacks.
Additionally, structural deformities in the same region were
detected using voxel-based morphometry magnetic resonance imaging in patients
with cluster headache. However, later more extensive studies were unable to
reproduce this. These controversies were notwithstanding, deep brain
stimulation studies showed that continuous posterior hypothalamus stimulation
aborts clusters. This suggests that direct neuronal inhibition in the
hypothalamus is not responsible for the success of deep brain stimulation.
Preferably, the hypothalamus may modulate the system lowering the provocability
threshold down to allowing a peripheral trigger to set off attacks.
The present study revealed that CGRP plays an essential role
in the induction of cluster headache attacks in both the active-phase episodic
cluster headache and chronic cluster headache but not inremission-phase. The
findings of the study also provoke the researchers to target the new molecule
by using anti-CGRP drugs in cluster headache management.
JAMA neurology. 2018 Jul 9.
Effect of Infusion of Calcitonin Gene-Related Peptide on Cluster Headache Attacks: A Randomized Clinical Trial
Anne Luise H. Vollesen et al.
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