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Figure. Individual ratings of pruritus on the aprepitant- vs vehicle-treated sides prior to (A), 30 minutes after (B), and 2 hours after (C) application. VAS indicates visual analog scale score.

Figure. Individual ratings of pruritus on the aprepitant- vs vehicle-treated sides prior to (A), 30 minutes after (B), and 2 hours after (C) application. VAS indicates visual analog scale score.

Table. Summary of Patient Clinical Characteristics
Table. Summary of Patient Clinical Characteristics
1.
Duval A, Dubertret L. Aprepitant as an antipruritic agent?  N Engl J Med. 2009;361(14):1415-1416PubMedArticle
2.
Torres T, Fernandes I, Selores M, Alves R, Lima M. Aprepitant: evidence of its effectiveness in patients with refractory pruritus continues.  J Am Acad Dermatol. 2012;66(1):e14-e15PubMedArticle
3.
Ständer S, Siepmann D, Herrgott I, Sunderkötter C, Luger TA. Targeting the neurokinin receptor 1 with aprepitant: a novel antipruritic strategy.  PLoS One. 2010;5(6):e10968PubMedArticle
4.
Gerber PA, Buhren BA, Homey B. More on aprepitant for erlotinib-induced pruritus.  N Engl J Med. 2011;364(5):486-487PubMedArticle
5.
Wallengren J. Neuroanatomy and neurophysiology of itch.  Dermatol Ther. 2005;18(4):292-303PubMedArticle
6.
Hill R. NK1 (substance P) receptor antagonists—why are they not analgesic in humans?  Trends Pharmacol Sci. 2000;21(7):244-246PubMedArticle
7.
Mantyh PW. Neurobiology of substance P and the NK1 receptor.  J Clin Psychiatry. 2002;63:(suppl 11)  6-10PubMed
Research Letter
Aug 2012

Topical Aprepitant in Clinical and Experimental Pruritus

Author Affiliations

Author Affiliations: Department of Dermatology, Skane University Hospital, Lund, Sweden.

Arch Dermatol. 2012;148(8):957-959. doi:10.1001/archdermatol.2012.1018

Peroral aprepitant is a nonpeptide inhibitor of tachykinin receptor NK1 approved for use as an antiemetic drug for chemotherapy-induced nausea. Duval and Dubertret1 first reported that peroral aprepitant effectively reduced pruritus in 3 patients with Sézary syndrome. Similar results were obtained later for 6 of 7 patients with erythrodermic cutaneous T-cell lymphoma.2 Ständer et al3 reported an open-label study of 20 patients with chronic pruritus treated for a week with peroral aprepitant. It has been suggested that the effects of aprepitant are related to its preventing of mast-cell activation in the skin.4 The aim of the present study was to test this hypothesis with topical aprepitant.

Methods

The experimental protocol for both patients and healthy subjects was designed as a randomized, double-blind, vehicle controlled, right-left study and was approved by the local ethics committee. All participants gave their written informed consent. Aprepitant was blended at a 5% concentration in a lipophilic vehicle in accordance with the European Union Good Manufacturing Practice rules. A visual analog scale (VAS) was used to score pruritus.

Thirteen patients (8 women and 5 men; age range, 33-82 years; median age, 57 years) treating 15 symmetrical skin regions completed the study (Table). The patients received 2 boxes marked “left” and “right,” respectively, each containing 3.5 g of a cream to apply topically on a single occasion. They were asked to evaluate their pruritus before, 30 minutes after, and 2 hours after the treatment.

Seven healthy nonatopic volunteers (6 women and 1 man; age range, 37-56 years; median age, 52 years) were enrolled. Aprepitant and the vehicle were applied to the volar surface of the left and right forearms, respectively, and left on for 30 minutes. The cream was then wiped off, and transepidermal water loss (TEWL) was measured using a closed-chamber device (VapoMeter, Delfin Technologies Ltd) to study the effects of the cream on the skin barrier. Thereafter, both forearms were pricked with histamine. The flare and itch were evaluated after 5 minutes, the weal after 15 minutes.

Results

Topical application of aprepitant, 5%, did not attenuate clinical pruritus (Figure). Erythema of dermatitis in those who had it was also unchanged.

The mean (SD) VAS scores for pruritus were 4.5 (2.0) prior to treatment with aprepitant, 4.1 (2.2) after 30 minutes, and 2.8 (1.6) after 2 hours. The corresponding values on the vehicle-treated side were 5.1 (2.2), 3.4 (1.9), and 2.8 (1.9), respectively. Both treatments improved the skin barrier with significant reduction in TEWL: 4.0 g/m2h after aprepitant application; 5.1 g/m2h after application of vehicle alone; baseline TEWL, −10.4 g/m2h (P = .001).

The mean (SD) VAS scores for pruritus induced by prick-test reactions to histamine were 4.3 (3.4) on the aprepitant-treated side and 4.8 (2.4) on the vehicle-treated side (P = .22). Also, the mean (SD) area of the histamine-induced flare (900.0 [246.4] mm2 vs 816.8 [296.1] mm2) (P = .17) and volume of the weal (47.5 [28.6] mm3 vs 54.6 [34.9] mm3) (P = .30) were unchanged.

Comment

A single topical application of the aprepitant in our study failed to attenuate clinical itch and erythema. This finding is in line with previous observations of aprepitant having no effect on erythroderma in 8 patients with T-cell lymphoma.1,2 The lack of effect of aprepitant in the present study could be explained by insufficient permeation of the skin by our formulation. However, the TEWL values indicate that both formulations were absorbed into the skin.

The rationale for treatment of pruritus with aprepitant is the occurrence of tachykinins in sensory nerve fibers as well as in the central nervous system. Injected into the skin, tachykinins induce a dose-dependent itch and flare that can be inhibited by antihistamines.5 In the present study, aprepitant failed to inhibit either pruritus or flare when histamine was pricked into the skin. This finding contradicts the explanation that aprepitant may prevent mast-cell activation.4

The discrepancy between our results using topical aprepitant and the reported effects of systemic treatment on itch associated with chronic skin disease may be due to the effects being mediated by central neuronal mechanisms.5 However, systemic aprepitant has been shown to be ineffective in the treatment of pain.6,7

In conclusion, the previously reported effects of a systemic aprepitant on pruritus in chronic skin disease were not obtained by the peripheral mechanisms studied here. Placebo-controlled studies are needed to confirm the efficacy of aprepitant in the treatment of pruritic skin disorders.

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Article Information

Correspondence: Dr Wallengren, Department of Dermatology, Skane University Hospital, Getingev 221 85, Lund, Sweden (Joanna.Wallengren@med.lu.se).

Accepted for Publication: February 15, 2012.

Financial Disclosure: None reported.

Funding/Support: The study was supported by the Skane County Foundation and the Welander and Finsen Foundation.

Additional Contributions: Nurses Inger Nordgren, RN, Anne Nielsen, RN, Jonna Gammelmark, RN, Anna E. Mårtensson, RN, and Carina Lundblad, RN, helped recruit the patients. APL, Umeå, Sweden, manufactured the aprepitant formulation, which was purchased at regular price for purposes of this study.

References
1.
Duval A, Dubertret L. Aprepitant as an antipruritic agent?  N Engl J Med. 2009;361(14):1415-1416PubMedArticle
2.
Torres T, Fernandes I, Selores M, Alves R, Lima M. Aprepitant: evidence of its effectiveness in patients with refractory pruritus continues.  J Am Acad Dermatol. 2012;66(1):e14-e15PubMedArticle
3.
Ständer S, Siepmann D, Herrgott I, Sunderkötter C, Luger TA. Targeting the neurokinin receptor 1 with aprepitant: a novel antipruritic strategy.  PLoS One. 2010;5(6):e10968PubMedArticle
4.
Gerber PA, Buhren BA, Homey B. More on aprepitant for erlotinib-induced pruritus.  N Engl J Med. 2011;364(5):486-487PubMedArticle
5.
Wallengren J. Neuroanatomy and neurophysiology of itch.  Dermatol Ther. 2005;18(4):292-303PubMedArticle
6.
Hill R. NK1 (substance P) receptor antagonists—why are they not analgesic in humans?  Trends Pharmacol Sci. 2000;21(7):244-246PubMedArticle
7.
Mantyh PW. Neurobiology of substance P and the NK1 receptor.  J Clin Psychiatry. 2002;63:(suppl 11)  6-10PubMed
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