Levels of calcitonin gene-related peptide (CGRP) are higher in patients with migraine in the interictal period and change over the course of a migraine.1 As CGRP can be measured in saliva, it may be a useful biomarker for migraine and for predicting response to anti-CGRP monoclonal antibody (mAb) treatment. At IHC 2023, Cephalalgia Award recipient Professor Patricia Pozo-Rosich discussed the research her team carried out investigating salivary levels of CGRP in people with episodic or chronic migraine. Although similar work has been carried out before, this was one of the only studies to measure such levels longitudinally (over 30 days) and before and after 3 months administration of an anti-CGRP mAb. These studies confirmed that basal salivary CGRP levels are higher in people with migraine, and showed that levels correlate with migraine frequency. Results also showed that while typically levels vary across the migraine cycle, around 20% of migraine attacks were ‘non-CGRP dependent.’ Having a better response to anti-CGRP mAb treatment was associated with higher basal CGRP levels. For people with depressive symptoms, CGRP levels increased more and differentiated episodic and chronic migraine patients. Salivary CGRP was shown to be a feasible and reproducible means to measure levels of this neuropeptide in people with migraine.
Calcitonin gene-related peptide (CGRP) and migraine
CGRP, a potent vasodilator, is a neuropeptide found widely in the central and peripheral nervous systems.2 CGRP levels can differ over the course of a migraine attack3,4 but are often increased even in the interictal period.5,6 CGRP levels may be predictive of treatment response, for example, higher basal CGRP levels correspond with better response to onabotulinumtoxinA treatment.7
Basal CGRP levels may be predictive of response to preventive migraine treatment7,9
Professor Pozo-Rosich discussed her team’s work at the Headache Unit, Vall d’Hebron University Hospital, Barcelona, Spain, as detailed in two recent papers first authored by Dr Alicia Alpuente (named Study 1 and Study 2 here).8,9 The studies included preventive treatment naïve females aged 18−35 with episodic migraine (EM; n=22 Study 1, n=27 Study 2)8,9 or chronic migraine (CM; n=16 Study 2),9 compared to healthy controls (HCs; n=22 Study 1, n=27 Study 2). Demographics were similar between the groups.8,9
Saliva was chosen as the means to analyse CGRP levels due to proximity of salivary glands to the trigeminal nerve and studies showing measurable levels of CGRP in this fluid.4,10
The primary objective of Study 1 was to, over 30 days, monitor the temporal profile of salivary CGRP during ictal and interictal migraine phases by collecting samples daily, and during and after the headache period.7 Secondary objectives were to assess salivary CGRP as a migraine diagnostic biomarker8,9 and a biofluid to measure CGRP;8 to analyse changes in salivary CGRP levels before and after anti-CGRP monoclonal antibody (mAb) treatment; and to evaluate basal salivary CGRP levels as a predictor of anti-CGRP mAb response.9
Study 1 results
In the migraine group, reported Professor Pozo-Rosich, interictal mean CGRP salivary levels were significantly higher compared to HCs. Using pairwise comparisons, CGRP levels were shown to rise significantly from baseline at headache onset (p≤0.001), decrease significantly at 2 hours compared to headache onset (p≤0.01), and returned to interictal levels at 8 hours after headache onset. Of note though, absolute mean levels of CGRP overlapped between the different time periods.8 However, highlighted Professor Pozo-Rosich, in around 20% of migraine attacks, there was no significant increase in CGRP. Incidences of photophobia (p=0.024), phonophobia (p=0.036), and dizziness (p=0.047) were significantly lower in the non-CGRP-dependent attacks.8
Migraine symptoms may be CGRP-dependent or -independent
Use of either a non-steroidal anti-inflammatory drug or a triptan mostly led to similar CGRP patterns; however, at the 8 hour timepoint, CGRP levels increased, to, with triptan especially, a similar level as headache onset.8
Study 2 results
Overall, both migraine groups had mean basal CGRP levels significantly higher than HCs (p<0.05). Results showed that 72.1% of migraine patients but only 7.4% of HCs had a baseline salivary CGRP level above 104 pg/mL, indicating, said Professor Pozo-Rosich, that this cut-off could be a potential biomarker for migraine. Following anti-CGRP mAb administration, 41.7% of patients were stratified as treatment responders [≥50% reduction in monthly headache days (RR)] and 58.3% as non-responders (<50% RR). For people with EM, but not CM, treatment response was predicted by baseline salivary CGRP and the interaction of this and baseline headache frequency.9
Salivary CGRP levels differ in people with migraine and concomitant depressive symptoms
Patients with depressive symptoms were included in Study 2 as it has been shown that depressive symptom occurrence increases when migraine frequency increases.11 Additionally, CGRP levels are altered in animal models of depression.12 Analysis of the high-frequency EM and CM participants showed that higher mean basal CGRP salivary levels were associated with occurrence of depressive symptoms (p=0.030), as well as age (p<0.001), greater headache frequency (p=0.002), or both headache frequency and depressive symptoms (p=0.007).9 For patients with depressive symptoms, the CM group had significantly higher CGRP levels than the EM and HC group.9 Findings of differences in CGRP levels following treatment in the depressive symptoms group9 led Professor Pozo-Rosich to propose that “if you have depressive symptoms, you may need more months of treatment to converge CGRP levels.”
Conclusions
While changes in CGRP levels over the course of a migraine have been shown before,3,4 Professor Pozo-Rosich highlighted that these studies also show this longitudinally.8;9 “Maybe,” she postulated “CGRP salivary levels can help us to perform personalised medicine in migraine.” Overall, the collection and analysis methods used for these studies proved, according to Professor Pozo-Rosich to be “an easy and non-invasive way of monitoring CGRP.”8,9
CGRP: Calcitonin gene-related peptide
mAb: monoclonal antibody
IHC: INternational Headache Congress
EM: Episodic migraine
CM: Chronic migraine
HCs: Healthy controls
BE-NOTPR-0355
Approved:10-2023
