Characterization of trigeminal C-fiber reactivity through capsaicin-induced release of calcitonin gene-related peptide.

OBJECTIVE: We hypothesized that the response of trigeminal dermal blood flow (DBF) in the trigeminal system and consecutive expansion of flare response to capsaicin would differ from the somatosensory system (arm). We also investigated whether there are differences between patients with migraine and healthy controls (HC). BACKGROUND: Functional differences between the trigeminal and extracephalic somatosensory systems may partly explain the susceptibility for headaches in patients with migraine. Capsaicin-induced activation of nociceptive C-fibers in the skin is mainly mediated by calcitonin gene-related peptide (CGRP) and induces cutaneous vessel dilatation and flare response. METHODS: Female patients with migraine (n = 38) and age-matched HC (n = 35) underwent DBF measurement at baseline and after topical capsaicin administration using laser speckle imaging. DBF before and after capsaicin stimulation was analyzed over ophthalmic nerve/maxillary nerve/mandibular nerve (V1/V2/V3) dermatomes and the forearm as an extracephalic control. RESULTS: Capsaicin-induced DBF increased more in the trigeminal dermatomes than on the forearm. The V1 dermatome showed a smaller increase of DBF in patients with migraine compared to HC. CONCLUSION: Our results suggest that the trigeminovascular system reacts differently from extracephalic areas, which may explain the trigeminal susceptibility to CGRP-mediated pain attacks. By demonstrating a different reactivity of the V1 dermatome in patients with migraine, our finding suggests that the first trigeminal branch is functionally different from the second and third branches; however, only in patients with migraine.

Galcanezumab modulates Capsaicin-induced C-fiber reactivity.

BACKGROUND: The vasodilatory calcitonin-gene related peptide (CGRP) is understood as pivotal mediator in migraine pathophysiology. Blocking CGRP with small molecules or monoclonal antibodies (CGRP-mAb) reduces migraine frequency. However, prescription of CGRP-mAbs is still regulated and possible predictive measures of therapeutic success would be useful. METHODS: Using standardized capsaicin-induced dermal blood flow model, 29 migraine patients underwent a laser speckle imaging measurement before and after administration of galcanezumab. At both sessions dermal blood flow before and after capsaicin stimulation as well as flare size were analyzed over all three trigeminal branches and the volar forearm for extracranial control. Long-term measures were repeated in 14 patients after continuous treatment ranging from 6 to 12 months. RESULTS: Resting dermal blood flow remained unchanged after administration of galcanezumab. Capsaicin-induced dermal blood flow decreased significantly after CGRP-mAb in all tested areas compared to baseline and this was consistent even after 12 months of treatment. However, following galcanezumab administration, the flare size decreased only in the three trigeminal dermatomes, not the arm and was therefore specific for the trigemino-vascular system. None of these two markers distinguished between responders and non-responders. CONCLUSION: CGRP-mAb changed blood flow response to capsaicin stimulation profoundly and this effect did not change over a 12-month application. Neither capsaicin-induced flare nor dermal blood flow can be used as a predictor for treatment efficacy. These data suggest that the mechanism of headache development in migraine is not entirely CGRP-mediated.

Trigeminal sensory modulatory effects of galcanezumab and clinical response prediction.

ABSTRACT: Galcanezumab, a monoclonal antibody against calcitonin gene-related peptide, is an emerging migraine preventative. We hypothesized that the preventive effects are conveyed via the modulation of somatosensory processing and that certain sensory profiles may hence be associated with different clinical responses. We recruited migraine patients (n = 26), who underwent quantitative sensory tests over the right V1 dermatome and forearm at baseline (T0), 2 to 3 weeks (T1) and 1 year (T12) after monthly galcanezumab treatment. The clinical response was defined as a reduction of ≥30% in headache frequency based on the headache diary. Predictors for clinical response were calculated using binary logistical regression models. After galcanezumab (T1 vs T0), the heat pain threshold (°C, 44.9 ± 3.4 vs 43.0 ± 3.3, P = 0.013) and mechanical pain threshold (log mN, 1.60 ± 0.31 vs 1.45 ± 0.26, P = 0.042) were increased exclusively in the V1 dermatome but not the forearm. These changes were immediate, did not differ between responders and nonresponders, and did not last in 1 year of follow-up (T12 vs T0). However, baseline heat pain threshold (OR: 2.13, 95% CI: 1.08-4.19, P = 0.029) on the forearm was a robust predictor for a clinical response 3 months later. In summary, our data demonstrated that galcanezumab modulates pain thresholds specifically in the V1 dermatome, but this modulation is short-lasting and irrelevant to clinical response. Instead, the clinical response may be determined by individual sensibility even before the administration of medication.