During a migraine attack, several substances that are related to pain are released. One of these is calcitonin gene-related peptide (CGRP), which is a commonly used therapeutic target for the treatment of migraine by blocking drugs. This therapy, however, is not effective in all cases. Now, the Headache and Neurological Pain group at Vall d'Hebron Research Institute (VHIR) has measured the levels of this protein in saliva during migraine attacks and has observed that there are two types of attacks: those in which CGRP increases and those in which it does not. Describing migraine at the molecular level and understanding the differences between individuals may help to establish a classification between types of migraine and move towards personalized medicine. The results of the work have been published in the journal Cephalalgia.

Migraine is a very prevalent disease, most frequently affecting women, for which there are no biomarkers that can be used to diagnose the disease or to predict the efficacy of treatment. With the aim of understanding its biological mechanisms and searching for biomarkers, the Vall d'Hebron work has studied the levels of the CGRP protein. "They have been analyzed in saliva samples, since they are non-invasive and can be obtained repeatedly and easily. It therefore allows monitoring over time, unlike, for example, a blood sample," explains Dr. Patricia Pozo Rosich, head of the Neurology Department at Vall d'Hebron University Hospital, head of the Headache and Neurological Pain group at VHIR and head of the Migraine Adaptive Brain Center at Vall d'Hebron. Until now, it was usual to measure it in blood, but it is more difficult to obtain and the results were not very conclusive.

The study involved 22 women with sporadic migraine and 22 without headache, aged between 18 and 65 years. All of them were followed for 30 days. On the first day, a blood sample was taken and, for the rest of the month, the participants had to take saliva samples every morning. In case of a migraine attack, they also had to take saliva samples at three points in time: at the beginning of the attack, 2 hours later and 8 hours later. In total, 49 migraine attacks could be studied.

Higher CGRP levels in women with migraine

First, CGRP levels were compared between control women and women with sporadic migraine. Specifically, CGRP measurements on headache-free days were taken into account. The results showed that, despite large differences between individuals, on average, protein levels were almost twice as high in migraine sufferers.

These differences were not observed in plasma, which reinforces the use of saliva to measure CGRP. The researchers in the paper argue that saliva levels are a sign of trigeminovascular system activation and local inflammation in the head region. It seems, therefore, that measurement in saliva, near the region where CGRP is released during migraine, would be more effective than in blood.

The increase of CGRP during migraine attacks: towards molecular classification of the disease

In addition to the differences between individuals, the study focused on analyzing the change in CGRP levels in the same person during a migraine attack. It was found that CGRP levels increase during the attack and decrease again after the attack. "This is the first study to show a gradual change in CGRP levels during the attack and gives us more information about the molecular mechanisms of migraine, which until now is only diagnosed on the basis of symptom-based clinical criteria. It could, therefore, be a molecular biomarker for monitoring migraine," explains Dr. Alicia Alpuente, a specialist in the Neurology Service of Vall d'Hebron University Hospital and a researcher in the Headache and Neurological Pain group at VHIR. The work is part of her doctoral thesis and the research is expected to be continued with a larger sample of patients. 

But these changes in CGRP levels during the migraine attack were not clearly seen in all attacks. The researchers identified that this happened in 79.6% of attacks, which are considered to be CGRP-dependent. In contrast, 20.4% were not CGRP-dependent. Considering the attacks in the same patient, 13 of the 22 patients had only CGRP-dependent attacks, 3 had only non-CGRP-dependent attacks, and 6 of them had both types of attacks.

Furthermore, depending on whether the attack was CGRP-dependent or non-CGRP-dependent, certain associated symptoms tended to appear. In addition to pain, CGRP-dependent patients had more classic migraine symptoms, such as photophobia and phonophobia. On the other hand, those not dependent on CGRP were more associated with symptoms such as dizziness. 

"This study allows us to begin to describe migraine at the molecular level and understand the differences between individuals, which can help establish a classification based on molecular biology and bring us closer to a future of precision medicine. If we understand the pathophysiology of migraine, in the future, we could offer an appropriate personalized treatment based on the characteristics of each patient," concludes Dr. Alpuente.