Effect of fasting-induced headache on calcitonin gene related peptide (CGRP) and other clinical biomarkers on the first day of Ramadan: Sub-analysis from a randomized open label clinical trial.

Background: Fasting-induced headaches (FIHs) have been shown to occur on the first day of Ramadan and clearly decline thereafter. Despite the wealth of knowledge about different types of headaches (e.g., migraine-, cluster-, and tension-type headaches), research on the mechanism underlying FIHs, as well as their treatment, remains scarce. Our study aimed to investigate any association between FIHs during the first day of Ramadan and potential headache-related biomarkers, including fasting blood glucose (FBG), C-reactive protein (CRP), magnesium, vitamin B9, vitamin B12, homocysteine, and calcitonin gene related peptide (CGRP), and to assess whether a prophylactic use of paracetamol may influence these biomarkers.

Methods: As part of a randomized, open-label clinical trial that evaluated the effect of paracetamol as a prophylactic therapy for FIH, blood samples from stratified subjects in the prophylaxis and control groups were withdrawn while fasting after the 1st dose of paracetamol (in the prophylaxis group) and prior to reporting headache occurrence.

Results: Plasma and serum were separated for 61 subjects; 31 and 30 subjects from the prophylaxis and control groups, respectively. Overall, no significant differences were found in the levels of FBG, CRP, magnesium, vitamin B9, and vitamin B12 in headache-suffering subjects compared to those without headache despite the use of paracetamol for prophylaxis. Homocysteine, however, was significantly reduced in all subjects who experienced FIH compared to those without headache (median 6.9 [1.6] vs. 7.7 [2.7] umol/L; p = 0.041). On the contrary, when the CGRP was measured using immunoassay, it was found to be significantly elevated in all headache-suffering subjects compared to those without headache (median 126.1 [17.7] vs. 105.8 [19.6] pg/mL; p ≤ 0.0001). This difference was maintained upon comparing the headache to non-headache subjects in both the prophylaxis (median 121.5 [15.4] vs. 105.8 [9.4] pg/mL; p < 0.01) and control groups (median 128.5 [28.3] vs. 105.8 [23.8] pg/mL; p < 0.01). Additionally, an elevated CGRP level was found to increase the odds of having a FIH [OR = 1.32; 95%CI 1.06-1.22].

Conclusions: Our findings revealed the role of CGRP in FIHs for the first time and suggest further investigation in signaling pathways downstream CGRP receptors. Furthermore, the modulation CGRP or CGRP receptors could have a clinical application in the prevention of FIHs.

Trial registration: This study was registered with the Saudi Food and Drug Authority in the Saudi Clinical Trials Registry (SCTR; No. 22122102).