Salivary calcitonin gene-related peptide as a potential biomarker for migraine

Calcitonin gene-related peptide (CGRP) and migraine

CGRP, a potent vasodilator, is a neuropeptide found widely in the central and peripheral nervous systems.¹ CGRP levels can differ over the course of a migraine attack^2,3 but are often increased even in the interictal period.^4,5 CGRP levels may be predictive of treatment response, for example, higher basal CGRP levels correspond with better response to onabotulinumtoxinA treatment.⁶

Basal CGRP levels may be predictive of response to preventive migraine treatment^6,8

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).^7,8 The studies included preventive treatment naïve females aged 18−35 with episodic migraine (EM; n=22 Study 1, n=27 Study 2)^7,8 or chronic migraine (CM; n=16 Study 2),⁸ compared to healthy controls (HCs; n=22 Study 1, n=27 Study 2). Demographics were similar between the groups.^7,8

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.^3,9,10

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 biomarker^7,8 and a biofluid to measure CGRP;⁷ 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.⁸

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.⁷ 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.⁷

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.⁷

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.⁸

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).⁸ For patients with depressive symptoms, the CM group had significantly higher CGRP levels than the EM and HC group.⁸ Findings of differences in CGRP levels following treatment in the depressive symptoms group⁸ 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,^2,3 Professor Pozo-Rosich highlighted that these studies also show this longitudinally.^7,8 “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.”^7,8