Seventy-five years ago, it was already demonstrated that the large arterial and venous blood vessels in the meninges are sensitive to pain—unlike the brain tissue itself. Twenty-five years ago, neuropeptides, i.e., proteins released from nerve fibers, were identified that regulate the diameter of these blood vessels. One of these substances was CGRP ( calcitonin gene-related peptide). CGRP is among the most potent vasodilators in the body. At the same time, the vasodilation associated with CGRP is accompanied by pain in experiments.

The crucial role of CGRP in the development of migraines became apparent when elevated CGRP levels were found in the venous blood of patients experiencing migraine attacks. These levels normalized after the migraine subsided following administration of sumatriptan. These observations were confirmed when migraine attacks could be induced in patients by infusion of CGRP. CGRP is produced, among other places, in nerve fibers of the trigeminal nerve and released when these are activated during a migraine attack (see Figure 1). The released CGRP binds to CGRP receptors in the walls of blood vessels in the meninges. This leads to vasodilation and simultaneously to the sensitization of pain receptors in the blood vessel walls. The pulsation of the dilated blood vessels becomes the pain stimulus, which patients perceive as a throbbing, pounding migraine pain that intensifies with any physical exertion, often even from simply bending over.

Migraine pain mediation via 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 ultimately leads to sensitization of pain receptors (4) which respond to the pulsation of the adjacent blood vessels with the sensation of throbbing migraine pain.

 

Triptans bind to specific serotonin receptors located on the endings of trigeminal nerve fibers and inhibit the release of CGRP during a migraine attack. It takes some time for the previously released CGRP to be broken down, for the blood vessels to constrict again, and for the pain receptors to regain their normal (in)sensitivity. Then, for the patient, the migraine is temporarily interrupted. This makes it clear that triptans, like any other medication, work faster and more effectively the earlier they are taken during an attack and the less CGRP has already been released. However, it also becomes clear that triptans do not end migraine attacks. CGRP continues to be produced, but its release is temporarily suppressed. The CGRP accumulates in the trigeminal nerve fibers, essentially waiting for the triptans to be metabolized. The subsequent, and sometimes massive, release of CGRP leads to a recurrence of migraine pain in patients, the so-called rebound headache. Taking another triptan is then usually effective again. This cycle repeats itself until the migraine attack finally subsides, usually after 4 to 72 hours. As an alternative to triptans, medications were tested several years ago that did not block the release of CGRP, but rather the CGRP receptor itself. The released CGRP thus found no target in migraine attacks. These CGRP receptor antagonists were similarly effective to triptans, but unfortunately, regular use at higher doses led to liver damage, so they never reached the market.

 

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 appears to have ended—CGRP continues to be produced (7) and is then released after the triptan effect wears off. This leads to recurrent headaches.

 

The introduction of triptans was undoubtedly a crucial advance in migraine attack therapy. So far, similar success in migraine prevention has not been achieved. None of the preventive medications used today were specifically developed for migraine prevention . All of these medications were initially used for other conditions, for example, beta-blockers for treating high blood pressure, and have a more or less unfavorable benefit-risk ratio. This is expected to change in the future, and once again, CGRP plays a decisive role.

Clinical trials are currently underway, involving the Kiel Pain Clinic, monoclonal antibodies for migraine prevention. These antibodies either destroy CGRP, the protein released during migraine attacks, or target the CGRP receptor. Patients are essentially passively vaccinated against migraines. The antibodies are administered subcutaneously once a month. Initial study results are promising – the substances are significantly more effective than a placebo and have so far been well tolerated. What is particularly encouraging for the future, however, is that a small group of patients in the published Phase II trials became completely free of migraine attacks. It remains to be seen whether these results will be confirmed and, more importantly, whether the effects will be sustained.

Target of monoclonal antibodies for migraine prophylaxis

Figure 3: Target of monoclonal antibodies for migraine prophylaxis. The antibodies are injected subcutaneously once a month and then either destroy the CGRP (9) released during migraine attacks or the CGRP receptor (10). In theory, this should prevent migraine attacks from becoming painless due to the elimination of CGRP's effect.

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

Addendum: Many readers have inquired about participation in the study. The project has specific criteria for participation, which we must review individually. It is an international study. To ensure global comparability of the results, each center can only select a limited number of participants. This generally requires longer treatment periods in our outpatient care.