Levels of calcitonin gene-related peptide (CGRP), a neurotransmitter that causes vasodilation, are elevated in the peripheral blood of women with chronic migraine (CM), and to a lesser extent in women with episodic migraine, compared with levels in healthy controls without a history of headache, new research reveals.
The study shows, for the first time, increased CGRP levels in patients with CM outside migraine attacks and in the absence of medication for symptoms.
The results suggest that CGRP levels could be used as a biomarker for permanent trigeminovascular activation and therefore help diagnose chronic migraine. Until now, the diagnosis of primary headache has been based only on clinical grounds.
"It's important to have biomarkers, not only to avoid misdiagnoses but also for treatment follow-up," said study author Julio Pascual, MD, PhD, director, Neuroscience Department, and professor, neurology, University Hospital Central de Asturias, Oviedo, Spain.
"Can you imagine diagnosing and treating diabetes only on clinical grounds? That's what we do now in primary headaches. Chronic migraine is the most frequent type of almost daily headache, and it's very disabling."
The study was published online August 23 in Neurology.
Throbbing Pain
It is well established that during a migraine attack, trigeminal activation leads to release of CGRP from presynaptic nerve terminals. This facilitates a peripheral inflammatory and vasodilatory response and causes activation of neurons involved in pain transmission, the authors note. This explains the typically throbbing pain experienced by people suffering a migraine.
CM is defined at least 15 headache days per month for at least 3 months. Fewer than 15 headache days per month is considered episodic migraine (EM).
Using the right antecubital vein, researchers obtained blood samples from participants who were not experiencing moderate or severe pain and had not taken medication for symptoms in the previous 24 hours. For ethical reasons, participants could continue daily preventive medications, and most with migraine were taking these agents. The investigators determined CGRP levels using a commercial enzyme-linked immunosorbent assay kit.
The study included 103 women with CM (mean age, 43.1 years), 31 matched healthy women with no headache history (mean age, 38.6 years), 43 women with EM (mean age, 44.4 years), and 14 patients with episodic cluster headache (including 13 men; mean age, 45.4 years) matched for age in a pain-free period.
Study participants underwent a general physical and neurologic examination. Those with EM and CM had at least a normal neuroimaging examination.
The analysis showed that CGRP levels were significantly higher in women with CM (74.90 pg/mL) than in control women (33.74 mg/mL; P < .001), women with EM (46.37 pg/mL; P < .001 vs CM and P < .005 vs controls) and to patients with episodic cluster headache (45.87 pg/mL).
"Increased peripheral CGRP levels should be interpreted as a distant sign of activation of the trigeminovascular system; because its molecule is so large, CGRP cannot pass the blood-brain barrier," said the authors.
Thresholds of 43.45 and 58.22 pg/mL optimize the sensitivity and specificity to differentiate patients with CM from healthy controls and patients with EM, respectively, according to the authors.
Migraine With Aura
A total of 46 women with CM had a history of migraine with aura attacks. CGRP levels were significantly higher in these women than in those who had never experienced an aura. However, only 4 patients experienced at least 1 aura per month.
According to the authors, there are several potential explanations for this finding. It could, for example, support the proposal that the pathophysiologic mechanism of the aura, the cortical spreading depression phenomenon, is enough to activate sensory nerve terminals around pial blood vessels.
Among women with EM, CGRP was not significantly elevated in the 21 women with aura compared with the 22 with no aura antecedents.
Among the women with CM, CGRP levels were not significantly different in patients meeting criteria for analgesic overuse. "Even considering that all of the women in our study with CM meeting overuse criteria had tried formal withdrawal of symptomatic medications at least once and for 2 months without success, these results are a further proof that both subtypes of CM, with and without analgesic overuse, would share the same pathophysiologic substrate," the authors write.
Other variables, such as age, depression, fibromyalgia, vascular risk factors, history of triptan use, and type of preventive treatment, also did not influence CGRP levels.
The fact that patients were taking preventive medications could be considered a limitation of the study but could also make the results more relevant because, as the authors point out, these drugs could reduce trigeminovascular system activation, resulting in a decrease in CGRP release.
Although the new study had other potential limitations, such as the use of a select headache clinic population, "it seems that interictal CGRP levels are somewhat specific and sensitive for CM in the context of a patient with daily or almost daily headaches and a history of migraine, which could be of great help on sharpening the diagnosis of the primary headache disorders and supports the proposal of a key role of CGRP of sensitization of pain circuits leading to CM," the authors concluded.
Using CGRP as a biomarker for CM may not be that far off from clinical practice, if the current results are confirmed in other studies using this neuropeptide, perhaps together with other pain-producing peptides, said Dr. Pascual. Such studies, he said, would not be difficult to carry out.
"My prediction is that clinical trials in chronic migraine that include the follow-up of CGRP levels will begin soon after publication of our study," he said.
And, he said, it won't be long before hospitals will start using CGRP levels to routinely follow patients with CM because this testing is neither very expensive nor difficult to perform.
Monitor Status
In an accompanying editorial, Stephen D. Silberstein, MD, Jefferson Headache Center, Jefferson Center for Neuroscience, Philadelphia, Pennsylvania, and Lars Edvinsson, MD, Internal Medicine, Lund University, Sweden, agreed the study demonstrates that peripheral CGRP levels may be a biomarker for CM.
Physicians could use CGRP levels outside migraine attacks, and in the absence of medication for symptoms, to monitor a patent's status and response to preventive treatment, they write.
"Future work on the role of CGRP and its receptor in CNS and intracranial structures will be very interesting," they write. "In particular, we look forward to learning more about the effects of small-molecule CGRP antagonists and antibodies toward CGRP and the CGRP receptor on CGRP levels and clinical outcome."
They noted that until now, CGRP elevations in plasma have not been reproduced in all studies but that technical problems have at times hampered the proper measurements of this neuropeptide.