Sumatriptan Causes Parallel Decrease in Plasma CGRP Concentration and Migraine Headache During Nitroglycerin-Induced Migraine Attack: Reply

Dear Sir The letter of Vanmolkot and colleges is an interesting contribution to the discussion about the role of calcitonin gene-related peptide (CGRP) in migraine headache. Our recent article (1) and the accompanying editorial (2) concluded that antimigraine effects of triptans may be induced by a mechanism related to normalization of cranial venous CGRP levels. Vanmolkot and colleges express their doubts in their letter as to whether and how triptans affect CGRP plasma concentrations during an acute migraine attack in humans.

Experimental findings suggest at least three sites of action for the antimigraine effect of the triptans. They may act as vasoconstrictors in the cranial vasculature—a postjunctional effect. They may block trigeminal-induced dural plasma-protein extravasation—a prejunctional effect, or inhibit release of CGRP. Finally, they may inhibit transmission in the trigeminal nucleus caudalis, thus blocking afferent traffic to the second-order neurons, probably again by blocking the action of CGRP (3). Furthermore, 5-HT_1B/1D receptor activation in the ventrolateral periaqueductal grey activates descending pain-modulating pathways that inhibit dural nociceptive input (3). Interestingly, triptans also influence the CGRP promoter and regulate CGRP secretion from neurons in culture (4).

We agree that the previous observations showed a gradual decrease in the plasma CGRP concentrations after a peak in the first hour of the migraine attacks (5–7). However, the decrease between the first and second hour of the migraine attacks is marginal and not significant (7). Furthermore, all previous studies have confirmed that the CGRP concentrations were continuously well above the CGRP level measured in the headache-free period, during the whole migraine attack (5–7). In addition, the changes in plasma CGRP concentration preceded and thus predicted the migraine headache intensity, suggesting a causal relationship (1, 7, 8). In our recent study, first blood samples were obtained 120 min after the onset of the migraine, immediately before the application of sumatriptan nasal spray (1). At this time, plasma CGRP concentrations were significantly elevated compared with the headache-free period (unpublished data). Furthermore, in those subjects whose headache improved significantly after sumatriptan administration (Group I), the plasma CGRP concentration decreased markedly, close to the basal, headache-free value (unpublished data). Furthermore, three of the Group I patients experienced a rebound headache 3–4 h after sumatriptan, which contradicts the assumption that they were in a spontaneous remission phase.

In summary, based on previous animal and human studies, it would not be surprising if a placebo-controlled, double-blind study provided us with definitive proof that 5-HT_1B/1D receptor agonist triptans are able to decrease the CGRP concentration in parallel with migraine pain during an acute attack (1, 9, 10). However, it would be interesting to study why triptans are ineffective in some patients (1, 11). In our study, there were no significant changes in plasma CGRP concentrations in those subjects whose headache did not improve after sumatriptan administration (Group II). Furthermore, these non-responder patients had significantly higher basal plasma CGRP concentrations compared with the responders (unpublished data). These observations highlight a permanent dysregulation in CGRP metabolism in non-responders that might be relevant to the lack of effectiveness of triptans in a subgroup of patients. In addition, these data suggest that the potent CGRP receptor antagonist BIBN-4096BS, which has been shown to be effective in the treatment of acute migraine (12–14), holds great promise for these patients.

In conclusion, we agree with Vanmolkot and colleges that the exact mechanism of development and cessation of migraine pain is still obscure and that to examine the magnitude of neuronal and vascular components separately is very difficult in human studies. However, our recent data apparently further emphasize the role of CGRP in the antimigraine effect of the sumatriptan.