A randomized, double-blinded, placebo-controlled, crossover study of the HCN channel blocker ivabradine in a capsaicin-induced pain model in healthy volunteers

Figures

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  Figure 1. CONSORT diagram illustrating subject flow during the study.

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  Figure 2. Timeline of the study period. Ivabradine (Iva) or a placebo was orally administered 3 times between the evening of the previous day and the evening of the trial day. Heart rate (HR) was measured before and 30 and 60 min after the first administration of the study drug (Iva or placebo) on the day before the capsaicin trial. HR was measured before and 30 and 60 min after the third administration of the study drug. After the third administration of the study drug, baseline assessment of spontaneous pain (VAS), flare size (Flare), area of dynamic mechanical allodynia using a foam brush (DMA), area of punctate mechanical hyperalgesia using a von Frey filament of 15 g (PMH), mechanical pain threshold (MPT) and heat-pain threshold (HPT) was done. Then a patch of filter paper (circle with a diameter of 2 cm) containing 0.5% capsaicin (100 μl) was placed for 30 min on the skin of the middle volar forearm of the dominant hand. The assessment was repeated up to 180 min after the start of capsaicin application. The bar labeled as “Cap” depicts the onset and duration of capsaicin application.

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  Figure 3. Effects of ivabradine and placebo on capsaicin-induced spontaneous pain assessed by visual analog scale (VAS) score. VAS scores in both groups gradually increased during the 30-min capsaicin application and gradually decreased after the end of capsaicin application. Data are expressed as means ± standard deviation, with n = 20 in each group. There were no significant differences in the VAS score between the groups throughout the study period. Statistical significance from baseline was indicated as #p < 0.05 and ##p < 0.01. Statistical analysis was performed using two-way ANOVA with Scheffe’s multiple comparisons post-hoc test. The bar labeled as “Cap” at the top of the panel depicts the onset and duration of capsaicin application.

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  Figure 4. Effects of ivabradine and placebo on capsaicin-induced changes in heat sensitivity, and areas of punctate mechanical hyperalgesia and dynamic mechanical allodynia. Heat-pain threshold temperature was measured at the primary zone before and after capsaicin application and is presented in the panel (n = 20 in each group) (A). The area of punctate mechanical hyperalgesia was mapped using a von Frey filament of 15 g (n = 10 in each group) (B). The area of dynamic mechanical allodynia was mapped using a foam brush (n = 20 in each group) (C). Data are expressed as means ± standard deviation. Asterisks indicate statistically significant differences between the groups (*p < 0.05 and **p < 0.01). Statistical significance from baseline was indicated as #p < 0.05 and ##p < 0.01. Statistical analysis was performed using two-way ANOVA with Scheffe’s multiple comparisons post-hoc test. The bar labeled as “Cap” at the top of the panel depicts the onset and duration of capsaicin application.

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  Figure 5. Effects of ivabradine and placebo on area of capsaicin-induced flare. Typical examples of laser-Doppler imaging pictures obtained from the same subject after ivabradine (I) and placebo (P) were presented in the panel (A). The increase in flux is indicated by a color code at the right of the panel. Panel (B) shows the time course of changes in flare size in both groups. Data are expressed as means ± standard deviation, with n = 20 in each group. There were no significant differences in flare size between the groups throughout the study period. Statistical significance from baseline was indicated as #p < 0.05 and ##p < 0.01. Statistical analysis was performed using two-way ANOVA with Scheffe’s multiple comparisons post-hoc test. The bar labeled as “Cap” at the top of the panel depicts the onset and duration of capsaicin application.