Role of Substance P and Its Receptor Neurokinin 1 in Chronic Prurigo: A Randomized, Proof-of-Concept, Controlled Trial with Topical Aprepitant

Abstract

Substance P (SP) and its receptor neurokinin 1 (NK1R) are thought to be involved in the pathogenesis of chronic prurigo. Here, we assessed SP serum levels, cutaneous NK1R expression, and the effects of topical aprepitant, an NK1R antagonist, in patients with chronic prurigo. SP and NK1R were increased, compared with controls, in the serum and in lesional vs. non-lesional skin of the patients, respectively. Aprepitant, in a randomized, placebo-controlled, split-sided, doubleblind trial, reduced the intensity of pruritus as assessed by visual analogue scale by >50% from baseline to day 28 (-35.2), but so did placebo vehicle (-38.1, p= 0.76). Overall clinical scores improved significantly by day 28 in both treatment groups, with no significant difference between the 2 groups (p=0.32). Our findings imply that both SP and NK1R are involved in the pathogenesis of chronic prurigo. Parallel groupdesigned trials are needed to assess the efficacy of topical aprepitant treatment in this condition.

Neurokinin 1 receptor antagonists exhibit peripheral effects in prurigo nodularis including reduced ERK1/2 activation

“…Interestingly, we found that the NK1R is up‐regulated in PN even before the therapy compared to healthy controls. This is in line with published data were chronic pruritus patients show higher NK1R expression compared to healthy controls in peripheral blood but has not yet been shown to be relevant in the skin of these patient, too. On the one hand, this supports the important role of the receptor in pruritic diseases such as PN but, on the other hand, does not explain the antipruritic effect by itself.…”

“…Aprepitant was frequently supposed to mediate effects in the skin . But, both, topical and systemic application, have been also reported to be insufficient for successful treatment in other studies …”

Role of mast cells and basophils in pruritus

“…Neurokinin 1 receptor antagonism with aprepitant can lead to a reduction of itch intensity in patients suffering from chronic pruritus . Whether the effect of the drug is central, peripheral or both, remains to be determined as the effect of topical aprepitant was matched by the vehicle . Additional NK 1 R antagonists are now being evaluated and early clinical reports from industry, although not peer‐reviewed, are promising.…”

“…The effectiveness of NK1 antagonists for the treatment of chronic itch is under intense investigation. Promising data have been generated but the failure of topical aprepitant relative to vehicle suggests that therapeutic benefit may arise from targeting central NK1. Moreover, NK1 mutant mice still scratched when injected with SP.…”

“…77 Whether the effect of the drug is central, peripheral or both, remains to be determined as the effect of topical aprepitant was matched by the vehicle. 78 hanced association of mast cells with neural projections. 11 Finally, the classical "mast cell disorder" chronic spontaneous urticaria is associated with increased accumulation of SP/NK 1 R + basophils.…”