Discussion
migraine
MIGRAINE, RECRUITMENT
A novel finding of our study is that migraine attacks induced by upregulation of intracellular cAMP levels are not affected by blocking the CGRP receptor. Our work provides clinical evidence that cAMP-evoked migraine attacks do not require CGRP receptor activation. We want to highlight three important observations in this context: (i) patients who were pretreated with erenumab still experienced migraine attacks when cilostazol was administered; (ii) patients who were susceptible to migraine attacks following CGRP administration also had migraine attacks induced by cilostazol; and (iii) most participants who did not experience migraine attacks after receiving CGRP did have migraine attacks when cilostazol was administered.Cilostazol, a PDE-3-inhibitor, blocks both isoforms of PDE3, which is responsible for metabolizing cAMP.Cilostazol primarily inhibits the isoform PDE3A, which is predominantly found in vascular smooth muscle cells.We found that CGRP receptor blockade did not completely prevent CGRP-induced migraine attacks. One-quarter of patients in the erenumab group still experienced a migraine attack following administration of CGRP, which exceeds the expected rate of a nocebo response [8.1% (95% CI, 2.5–15.5%)].Although we applied rigorous criteria during recruitment and standardized experimental procedures, we could not rule out various environmental factors (e.g. stress, food intake) after discharge from the laboratory and the subsequent outpatient 12-h observation phase. However, alternative 12-h inpatient monitoring would have limited the feasibility of the study. In addition, the migraine attack induction rates for CGRP and cilostazol in the placebo arm were comparable to previously reported studies with these substances.