Reproducibility of the capsaicin‐induced dermal blood flow response as assessed by laser Doppler perfusion imaging

Abstract

What is already known about this subject • Capsaicin rapidly produces local neurogenic inflammation (characterized by oedema and erythema) when locally administered to the human skin by binding to the TRPV1 receptor present on dermal sensory nerve endings. • In nonhuman primates, a pharmacodynamic assay has been described and validated using capsaicin‐induced dermal vasodilation measured by laser Doppler perfusion imaging to assess calcitonin gene‐related peptide antagonist activity. • Laser Doppler perfusion imaging has also been shown to be a reliable method for characterizing microvascular changes in the human skin. What this study adds • Capsaicin induces a reproducible within‐subject arm‐to‐arm increase in dermal blood flow (DBF) when applied to the human skin. • This is the first study to describe a non‐invasive pharmacodynamic model in humans using capsaicin‐induced neurogenic inflammation and allowing repeated, reproducible measurements of DBF to be performed. • This model might therefore be utilized in the early clinical evaluation of antagonists of putative mediators involved in capsaicin‐induced dermal vasodilation. Aims Part I: to establish the dose and appropriate application site of capsaicin on the human forearm in order to produce a robust and reproducible dermal blood flow (DBF) response. Part II: to evaluate the within‐subject arm‐to‐arm and period‐to‐period reproducibility. Methods Both parts consisted of two study visits. In part I, placebo and 100, 300 and 1000 µg capsaicin were applied at four predefined sites on the volar surface of both forearms. Placebo and capsaicin doses were randomized and balanced by site between subjects. Changes in DBF were assessed by laser Doppler perfusion imaging up to 60 min after capsaicin application. In part II, only 1000 µg capsaicin was applied on the proximal forearm and changes in DBF assessed up to 30 min (t30). DBF response was expressed as percent change from baseline ± SD and the corresponding AUC0−30. Reproducibility assessment included calculation of the concordance correlation coefficient (CCC). Results Part I (n = 12 subjects): compared with placebo, 300 and 1000 µg capsaicin increased DBF (P < 0.05) at all time points except at 10 min. This increase was reproducible at the two most proximal sites from the 30‐min time point onwards when compared between arms (CCC ≥ 0.8, i.e. substantial to almost perfect reproducibility). In part II (n = 11), t30 averaged 390 ± 120% and arm‐to‐arm reproducibility was almost perfect (CCC = 0.91) for AUC0−30. Conclusions Capsaicin induces a reproducible within‐subject arm‐to‐arm increase in DBF. We provide a non‐invasive pharmacodynamic model in humans to test antagonists of mediators involved in capsaicin‐induced dermal vasodilation, including calcitonin gene‐related peptide antagonists.

Calcitonin Gene-Related Peptide8-37 Antagonizes Capsaicin-Induced Vasodilation in the Skin: Evaluation of a Human in Vivo Pharmacodynamic Model

“…The placebo solution corresponded to the same 3:3:4 mixture of ethanol 100%, Tween 20, and distilled water without capsaicin. We fully described the methodology previously (Van der Schueren et al, 2007b).…”

“…Based on the within-subject standard deviation observed in the reproducibility study and given a type I error probability (␣) of 0.05, a sample size of 11 subjects provides 80% power for detecting a difference in DBF increase after capsaicin application of 20% between arms (Van der Schueren et al, 2007b). The baseline DBF was expressed in arbitrary perfusion units (AU) (Fullerton et al, 2002).…”

“…Supine systolic blood pressure, diastolic blood pressure, and heart rate were measured in the dominant arm with a validated semiautomated oscillometric device (Omron HEM-705CP; Omron Healthcare, Hamburg, Germany). DBF was determined as described previously (Van der Schueren et al, 2007b).…”

“…CGRP, SP, neurokinin A, NO, and prostaglandins are among the mediators thought to play a role in neurogenic inflammation in healthy human skin (Wallengren, 1997). Although dermal vasodilation is only one component of capsaicin-induced neurogenic inflammation, the easy and objective assessment of it by laser Doppler perfusion imaging makes it an attractive parameter for evaluating neurogenic inflammation ( Van der Schueren et al, 2007b). Furthermore, most putative mediators of neurogenic inflammation have vasodilatory properties, which make it reasonable to assume that, if these mediators are major contributors to capsaicin-induced neurogenic inflammation, antagonizing them will affect the dermal blood flow response.…”

“…We previously studied dermal vasodilation elicited by the topical application of capsaicin to the forearm skin of healthy male subjects (Van der Schueren et al, 2007b). Capsaicin is the pungent ingredient in hot chili peppers, and it activates the transient receptor potential vanilloid type 1 receptor on A␦-and C-fiber nociceptors (Caterina et al, 1997).…”