It was already proven 75 years ago that the large arterial and venous blood vessels in the meninges are sensitive to pain - unlike the brain tissue itself. 25 years ago, neuropeptides, i.e. proteins released from nerve fibers, were identified that regulate the width of these blood vessels. One of these substances was CGRP (the calcitonin gene-related peptide ). CGRP is one of the most powerful vasodilators in the body. At the same time, the vasodilation associated with CGRP is accompanied by pain in the experiment.

The crucial importance of CGRP in the development of migraines became apparent when elevated CGRP levels were found in the venous blood of patients during migraine attacks, which returned to normal after the migraine was stopped by administration of sumatriptan. These observations were confirmed when patients were able to induce migraine attacks by infusing CGRP. CGRP is formed, among other things, in nerve fibers of the trigeminal nerve and released when they are activated during a migraine attack (see Figure 1). The released CGRP binds to CGRP receptors in the wall of blood vessels in the meninges. This causes blood vessels to dilate and, at the same time, pain receptors in the blood vessel wall to become sensitized. The pulsation of the dilated blood vessels becomes a pain stimulus, which patients perceive as a pulsating, throbbing migraine pain that intensifies with any physical exertion, usually just by bending over.

Migraine pain mediation through CGRP

Figure 1: Migraine pain mediation by CGRP. During a migraine attack, CGRP (1) is released from fibers of the trigeminal nerve, binds to the CGRP receptor (2), triggers dilation of blood vessels in the meninges (3) and finally leads to sensitization of pain receptors (4). react to the pulsation of the neighboring blood vessels with the sensation of throbbing migraine pain.

 

Triptans bind to certain serotonin receptors located on the endings of the trigeminal fibers and inhibit the release of CGRP during a migraine attack. It still takes some time until the previously released CGRP is broken down, the blood vessels narrow again and the pain receptors have regained their normal (in)sensitivity. Then the migraine is initially interrupted for the patient. This makes it clear that triptans help faster and more strongly the earlier you take them in the attack and the less CGRP has already been released. However, it is also understandable that triptans do not stop migraine attacks. CGRP continues to be formed, just not released temporarily. The CGRP accumulates in the trigeminal fibers and basically just waits for the triptans to be broken down. The then possible and sometimes massive release of CGRP leads to the recurrence of migraine pain in patients, the so-called recurring headache. Taking a triptan again is usually effective again. The whole game is repeated until the migraine attack actually subsides, usually after 4 to 72 hours. As an alternative to triptans, drugs were tested a few years ago that did not block the release of CGRP, but rather the CGRP receptor. The released CGRP therefore found no target in migraine attacks. These CGRP receptor antagonists were similarly effective as the triptans, but unfortunately caused liver damage when taken regularly in higher doses, so they never reached market maturity.

 

Migraine attack treatment with triptans and CGRP receptor antagonists

Figure 2: Migraine attack treatment with triptans and CGRP receptor antagonists. Triptans bind to serotonin receptors on trigeminal nerve endings (5) and thereby inhibit CGRP release (6). The CGRP-mediated migraine symptoms subside. The same effect can be achieved by blocking the CGRP receptor with a CGRP receptor antagonist (8). The problem with triptans is that - even when the migraine seems to have ended - CGRP continues to be formed (7) and is then released after the triptan effect has worn off. A recurring headache occurs.

 

The introduction of triptans was undoubtedly a decisive advance in migraine attack therapy. So far, it has not been possible to achieve similar success in preventing migraines. None of the preventive medications used today were specifically developed . All medications were initially used for other illnesses, such as beta blockers to treat blood pressure, and have a more or less unfavorable benefit-side effect ratio. This is set to change in the future and the CGRP will once again play a crucial role.

Clinical studies are currently being carried out with the participation of the Kiel Pain Clinic, in which monoclonal antibodies are used to prevent migraines, which either destroy the CGRP released in migraine attacks or use the CGRP receptor to destroy its target. The patients are passively vaccinated against migraines. The antibodies are injected under the skin once a month. The initial study results are promising - the substances are significantly more effective than placebo and are well tolerated so far. But what gives particular hope for the future is that in the published phase II studies, a small group of patients became completely free of migraine attacks. It remains to be seen whether the results will be confirmed and, above all, permanent.

Target of monoclonal antibodies for migraine prophylaxis

Figure 3: Target of monoclonal antibodies for migraine prophylaxis. The antibodies are injected under the skin once a month and then destroy either the CGRP released in migraine attacks (9) or the CGRP receptor (10). In theory, migraine attacks should remain painless due to the elimination of the CGRP effect.

Dr. Axel Heinze, Dr. Katja Heinze-Kuhn, Prof. Dr. Hartmut Göbel, Kiel Pain Clinic

Addendum: Many readers ask whether participation in the study is possible. The project provides for defined criteria for participation, which we have to check individually. This is an international study. In order for the results to be comparable worldwide, only a limited number of participants can be selected in the individual centers. This usually requires longer courses of treatment in our outpatient care.