Trigeminovascular Activation in Preventive Treatment of Headache Disorders

Headache disorders such as migraine and cluster headache are highly disabling
for patients and have a large impact on their environment and society.
The pathophysiology of migraine is not fully understood and is probably
multifactorial. In migraine, a crucial role in the development of an attack is
attributed to the activation of the trigeminovascular system.
This system consists of sensory neurons of the trigeminal nerve and the cranial
blood vessels they innervate. Upon stimulation of the trigeminal nerve, the
neuropeptide CGRP (calcitonin gene-related peptide) is released from the nerve
endings surrounding the meningeal blood vessels.
Cluster headache is one of the trigeminal autonomic cephalalgias. A
trigeminal-autonomic reflex is assumed to play an important role in the
pathophysiology of an attack.
A number of pharmacological treatment options are currently being used as
preventive treatment for migraine and cluster headache.
Efficacy rates of preventive treatment are mediocre and unpredictable and side
effects often occur.
Because CGRP is attributed an important role in the pathogenesis of headache
attacks in migraine and in cluster headache, drugs aimed at reducing the
function of CGRP or the CGRP receptor have been developed.
When looking at responder rates, there seems to be a subset of patients that
respond very well to CGRP (receptor) blocking therapy, while others do not.

Candesartan is the most frequently prescribed migraine prophylactic drug in the
LUMC. How this anti-migraine effect is achieved, is unknown. Previously, we
have demonstrated that trigeminovascular CGRP release is inhibited by the
acutely acting antimigraine drug sumatriptan(5-HT1B/1D receptor agonist), as
well as by the prophylactic antimigraine drug propranolol (ß-adrenoceptor
antagonist). Thus, it may well be that the trigeminovascular pathway, involving
CGRP release, is a common pathway that can be triggered via different
pharmacological mechanisms,

CGRP can be released from the trigeminal nerve endings by external electrical,
mechanical, chemical or thermal stimuli. Capsaicin, the pungent ingredient of
red hot chili peppers, activates the TRPV1 channel (transient receptor
potential cation channel subfamily V member 1) in the trigeminal nerve, causing
vasodilation, which most likely is a CGRP-mediated process, resulting in an
increase in blood flow. The change in dermal blood flow after application of
capsaicin to the skin can be measured with laser Doppler perfusion imaging.
Electrical stimulation can directly stimulate the trigeminal nerve, causing an
increase in blood flow, without involving the TRPV1 release pathway. The
increase in dermal blood flow in response to electrical stimulation is probably
not (completely) mediated by CGRP. It is also not influenced by the menstrual
cycle, while stimulation with capsaicin is. This trigeminovascular model has
been used as a biomarker for changes in trigeminovascular activation by acute
antimigraine drugs.
The effect of preventive pharmacological treatment on the trigeminovascular
activation has so far not been studied. Knowledge of how trigeminovascular
activity changes due to reduced CGRP pathway function and whether
trigeminovascular (de)activation is correlated to the clinical response to
treatment with anti-CGRP (receptor) antibodies could give us more insight in
how this treatment works. Being able to predict the clinical response to
preventive treatment would be a major advance for clinical practise.

We hypothesise that capsaicin induced trigeminovascular activation is reduced
by treatment with antibodies directed against CGRP or its receptor.
We hypothesise that the reduction in trigeminovascular activation is predictive
for the clinical response.
We hypothesise that the trigeminovascular model is indicative for
trigeminovascular activation exclusively mediated by CGRP.

This study aims to evaluate the effect of preventive treatment with monoclonal
antibodies targeting CGRP or the CGRP receptor and of treatment with
candesartan on trigeminovascular activation in migraine and cluster headache
patients. We want to explore the predictive value of trigeminovascular
activation for the clinical response to this treatment.
Objectives are:
I. To explore the predictive value of trigeminovascular activation for the
clinical response to treatment with anti-CGRP (receptor) antibodies and to
treatment with candesartan
II. To quantify the effect of treatment with anti-CGRP (receptor) antibodies
and with candesartan on trigeminovascular activation in patients with migraine
and cluster headache.
III. To establish whether the trigeminovascular model is an indicator for
exclusively CGRP mediated trigeminovascular activation.

This is an exploratory longitudinal study, during which the trigeminovascular
activation will be measured twice.

Subjects must come to the hospital twice for a 45 minute measurement. Subjects
are asked to refrain from eating heavy meals <2 hours before the measurement.
Data are recorded about drug use, diet and any comorbidity. During the
measurement, subjects should be silent and applied capsaicin solution to the
skin, applied electrical stimulation and measured blood pressure.
All products and equipment used during this investigation are used within the
registered indication. Theoretical risks arise from the use of capsaicin
solution and by the use of the laser dimming device. The eyes are shielded to
prevent them from coming into contact with capsaicin or the laser.
There is no benifit for individual subjects.