New treatments for migraines: CGRP antagonists

CGRP antagonists: The successors of triptans?

Dr. Axel Heinze, Dr. Katja Heinze-Kuhn and Prof. Dr. Hartmut Göbel

Neurological and Behavioral Medicine Pain Clinic Kiel (https://schmerzklinik.de)

The introduction of sumatriptan in migraine therapy from 1991 onwards not only fundamentally changed migraine treatment, but also spurred an unprecedented expansion of basic research. Currently, seven different triptans are available that can still help patients with severe migraine attacks when all other painkillers fail. Equally important, however, our understanding of migraine has increased immensely over the last 20 years. Medicine not only uses triptans successfully, but also understands their mechanism of action.

And yet, there are patients who have not benefited from the advances in triptans. Basically, there are three possible reasons for this in individual cases:

1. Ineffectiveness of even the most potent triptans

2. Intolerance even to the mildest triptans

3. Presence of contraindications for the use of triptans

a. Justified suspicion or presence of any circulatory disorder

b. Insufficiently controlled high blood pressure.

c. Occurrence of pronounced and long-lasting migraine auras during the headache phase (e.g., in hemiplegic migraine or basilar migraine)

The reason for these restrictions is the vasoconstrictive effect of triptans , which particularly affects the blood vessels in the head. Furthermore, due to insufficient data, the use of triptans during pregnancy or breastfeeding is still not recommended.

This means there remains a need for therapeutic alternatives to triptans for patients with severe migraine attacks. In October 2007, data on the efficacy of a substance called MK-0974 in migraine were published for the first time. MK-0974 belongs to the group of CGRP antagonists, a class of drugs that shows promise as a potential alternative to triptans.

To understand the mechanism of action of CGRP antagonists, one must look at the current understanding of the processes in the brain during a migraine.

Hereditary factors play in the development of migraines . More than 70% of sufferers know first-degree relatives (parents, siblings, or children) who also suffer from migraines. Children of migraine patients have a two- to four-fold increased risk of developing migraines themselves compared to their peers. For a subtype of migraine, familial hemiplegic migraine, underlying genetic defects been identified. These are responsible for the hypersensitivity to a wide range of internal and external stimuli, the so-called trigger factors . These include, among others, disturbances in the sleep-wake cycle, hormonal fluctuations, changes in blood sugar levels or current stress levels, unusual physical exertion, or disturbances caused by smells, noise, or flickering lights. This means that although the genetic predisposition for migraine is passed down through generations, whether a migraine actually occurs in an individual case, and if so, how severe and how frequent, is largely dependent on environmental factors.

The actual migraine headache is caused by a sterile (i.e., not caused by pathogens) inflammation in the blood vessels of the meninges. This inflammation is triggered by the nervous system itself; it is therefore called neurogenic inflammation . The inflammation leads to hypersensitivity of pain receptors in the meninges. The simple pulsation of the blood vessels in the meninges becomes the throbbing, pounding pain of a migraine – any physical exertion, even bending over, leads to a further intensification of the pain.

According to current understanding, a protein released from nerve fibers of the trigeminal nerve, which is activated during a migraine attack, is crucial for the development of inflammation: CGRP ( calcitonin gene-related peptide ). Elevated CGRP levels were already detected in the venous blood of patients during a migraine attack in 1988. After the attack ends or after successful treatment with a triptan, the CGRP level returns to normal. The effect of triptans in migraine is likely due to the inhibition of CGRP release . This desired effect is mediated via a specific serotonin receptor, the 5-HT1D _{receptor .} However, triptans also activate another serotonin receptor, the 5-HT1B _{receptor the} undesired vasoconstrictive effect.

This is where CGRP antagonists into play. Unlike triptans, which affect serotonin receptors (and, for example, constrict blood vessels), they directly block CGRP receptor . As a result, the CGRP released during a migraine attack cannot find a free receptor to bind to and therefore cannot cause any damage. The development or maintenance of inflammation is interrupted, and the migraine symptoms subside.

In the study published by Ho and colleagues in the journal Neurology, it was shown that the CGRP antagonist MK-0974 can interrupt an acute migraine attack just as effectively as the established drug rizatriptan.