Skip to main content

Advertisement

SpringerLink
Log in

Neurokinin-1 Receptor Antagonists: Promising Agents in the Treatment of Chronic Pruritus

  • Itch (E Lerner, Section Editor)
  • Published:
Current Dermatology Reports Aims and scope Submit manuscript

Abstract

Purpose of Review

Chronic pruritus (CP) is often refractory to conventional therapies leading to a substantial quality of life impairment. Better understanding of the underlying pathophysiological mechanisms allowed the development of novel drugs targeting specific mechanisms, such as neurokinin-1 receptor (NK1R) antagonists. This review aims to provide an overview of the mechanisms of action of NK1R antagonists and the evidence of its efficacy in the treatment of CP of various origins.

Recent Findings

NK1R and its endogenous ligand substance P mediate itch at peripheral and central levels. Novel NK1R antagonists have shown promising antipruritic properties in open-label studies and case series including patients with CP due to chronic prurigo, cutaneous T cell lymphoma, solid tumors, and biological antitumoral therapies.

Summary

NK1R antagonists are promising agents in the treatment of CP of different origins. First evidence from randomized controlled trials supports the potency of these agents as a therapeutic option for CP.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

Abbreviations

CP:

Chronic pruritus

EGFR:

Antiepidermal growth factor receptor

Mrgprs:

Mas-related G-protein coupled receptors

NGF:

Nerve growth factor

NK1R:

Neurokinin-1 receptor

RCT:

Randomized controlled trial

SP:

Substance P

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Hay RJ, Johns NE, Williams HC, et al. The global burden of skin disease in 2010: an analysis of the prevalence and impact of skin conditions. J Investig Dermatol. 2014;134(6):1527–34.

    Article  CAS  PubMed  Google Scholar 

  2. Stander S, Schafer I, Phan NQ, et al. Prevalence of chronic pruritus in Germany: results of a cross-sectional study in a sample working population of 11,730. Dermatology. 2010;221(3):229–35.

    Article  CAS  PubMed  Google Scholar 

  3. Matterne U, Apfelbacher CJ, Loerbroks A, et al. Prevalence, correlates and characteristics of chronic pruritus: a population-based cross-sectional study. Acta Derm Venereol. 2011;91(6):674–9.

    Article  PubMed  Google Scholar 

  4. Stander S, Weisshaar E, Mettang T, et al. Clinical classification of itch: a position paper of the International Forum for the Study of Itch. Acta Derm Venereol. 2007;87(4):291–4.

    Article  PubMed  Google Scholar 

  5. Pereira MP, Stander S. Chronic pruritus: current and emerging treatment options. Drugs. 2017;77(9):999–1007.

    Article  CAS  PubMed  Google Scholar 

  6. Stander S, Zeidler C, Augustin M, et al. S2k-Leitlinie zur Diagnostik und Therapie des chronischen Pruritus—Update—Kurzversion. J Dtsch Dermatol Ges. 2017;15(8):860–73.

    Google Scholar 

  7. Stander S, Pogatzki-Zahn E, Stumpf A, et al. Facing the challenges of chronic pruritus: a report from a multi-disciplinary medical itch centre in Germany. Acta Derm Venereol. 2015;95(3):266–71.

    Article  PubMed  Google Scholar 

  8. Patacchini R, Lecci A, Holzer P, et al. Newly discovered tachykinins raise new questions about their peripheral roles and the tachykinin nomenclature. Trends Pharmacol Sci. 2004;25(1):1–3.

    Article  CAS  PubMed  Google Scholar 

  9. Scholzen T, Armstrong CA, Bunnett NW, et al. Neuropeptides in the skin: interactions between the neuroendocrine and the skin immune systems. Exp Dermatol. 1998;7(2–3):81–96.

    Article  CAS  PubMed  Google Scholar 

  10. Azimi E, Reddy VB, Pereira PJS, et al. Substance P activates Mas-related G protein-coupled receptors to induce itch. J Allergy Clin Immunol. 2017;140(2):447–453.e443.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Azimi E, Reddy VB, Shade KC, et al. Dual action of neurokinin-1 antagonists on Mas-related GPCRs. JCI Insight. 2016;1(16):e89362.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Johanek LM, Meyer RA, Hartke T, et al. Psychophysical and physiological evidence for parallel afferent pathways mediating the sensation of itch. J Neurosci. 2007;27(28):7490–7.

    Article  CAS  PubMed  Google Scholar 

  13. Johanek LM, Meyer RA, Friedman RM, et al. A role for polymodal C-fiber afferents in nonhistaminergic itch. J Neurosci. 2008;28(30):7659–69.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Liu T, Ji RR. New insights into the mechanisms of itch: are pain and itch controlled by distinct mechanisms? Pflugers Arch. 2013;465(12):1671–85.

    Article  CAS  PubMed  Google Scholar 

  15. Liu JY, Zhao YZ, Peng C, et al. Effect of cetirizine hydrochloride on the expression of substance P receptor and cytokines production in human epidermal keratinocytes and dermal fibroblasts. Yao Xue Xue Bao. 2008;43(4):383–7.

    CAS  PubMed  Google Scholar 

  16. Li WW, Guo TZ, Liang DY, et al. Substance P signaling controls mast cell activation, degranulation, and nociceptive sensitization in a rat fracture model of complex regional pain syndrome. Anesthesiology. 2012;116(4):882–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Kawana S, Liang Z, Nagano M, et al. Role of substance P in stress-derived degranulation of dermal mast cells in mice. J Dermatol Sci. 2006;42(1):47–54.

    Article  CAS  PubMed  Google Scholar 

  18. Jarvikallio A, Harvima IT, Naukkarinen A. Mast cells, nerves and neuropeptides in atopic dermatitis and nummular eczema. Arch Dermatol Res. 2003;295(1):2–7.

    Article  PubMed  Google Scholar 

  19. Haas S, Capellino S, Phan NQ, et al. Low density of sympathetic nerve fibers relative to substance P-positive nerve fibers in lesional skin of chronic pruritus and prurigo nodularis. J Dermatol Sci. 2010;58(3):193–7.

    Article  CAS  PubMed  Google Scholar 

  20. Nakamura M, Toyoda M, Morohashi M. Pruritogenic mediators in psoriasis vulgaris: comparative evaluation of itch-associated cutaneous factors. Br J Dermatol. 2003;149(4):718–30.

    Article  CAS  PubMed  Google Scholar 

  21. Akiyama T, Nguyen T, Curtis E, et al. A central role for spinal dorsal horn neurons that express neurokinin-1 receptors in chronic itch. Pain. 2015;156(7):1240–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Takeda M, Takahashi M, Matsumoto S. Suppression of neurokinin-1 receptor in trigeminal ganglia attenuates central sensitization following inflammation. J Peripher Nerv Syst. 2012;17(2):169–81.

    Article  CAS  PubMed  Google Scholar 

  23. Pavlovic S, Daniltchenko M, Tobin DJ, et al. Further exploring the brain-skin connection: stress worsens dermatitis via substance P-dependent neurogenic inflammation in mice. J Investig Dermatol. 2008;128(2):434–46.

    Article  CAS  PubMed  Google Scholar 

  24. Munoz M, Rosso M, Robles-Frias MJ, et al. The NK-1 receptor is expressed in human melanoma and is involved in the antitumor action of the NK-1 receptor antagonist aprepitant on melanoma cell lines. Lab Investig. 2010;90(8):1259–69.

    Article  CAS  PubMed  Google Scholar 

  25. Kramer MS, Cutler N, Feighner J, et al. Distinct mechanism for antidepressant activity by blockade of central substance P receptors. Science. 1998;281(5383):1640–5.

    Article  CAS  PubMed  Google Scholar 

  26. Hesketh PJ, Grunberg SM, Gralla RJ, et al. The oral neurokinin-1 antagonist aprepitant for the prevention of chemotherapy-induced nausea and vomiting: a multinational, randomized, double-blind, placebo-controlled trial in patients receiving high-dose cisplatin--the Aprepitant Protocol 052 Study Group. J Clin Oncol. 2003;21(22):4112–9.

    Article  CAS  PubMed  Google Scholar 

  27. Singh PM, Borle A, Rewari V, et al. Aprepitant for postoperative nausea and vomiting: a systematic review and meta-analysis. Postgrad Med J. 2016;92(1084):87–98.

    Article  PubMed  Google Scholar 

  28. Frenkl TL, Zhu H, Reiss T, et al. A multicenter, double-blind, randomized, placebo controlled trial of a neurokinin-1 receptor antagonist for overactive bladder. J Urol. 2010;184(2):616–22.

    Article  CAS  PubMed  Google Scholar 

  29. Sandweiss AJ, Vanderah TW. The pharmacology of neurokinin receptors in addiction: prospects for therapy. Subst Abuse Rehabil. 2015;6:93–102.

    PubMed  PubMed Central  Google Scholar 

  30. Tauscher J, Kielbasa W, Iyengar S, et al. Development of the 2nd generation neurokinin-1 receptor antagonist LY686017 for social anxiety disorder. Eur Neuropsychopharmacol. 2010;20(2):80–7.

    Article  CAS  PubMed  Google Scholar 

  31. Ratti E, Bettica P, Alexander R, et al. Full central neurokinin-1 receptor blockade is required for efficacy in depression: evidence from orvepitant clinical studies. J Psychopharmacol. 2013;27(5):424–34.

    Article  CAS  PubMed  Google Scholar 

  32. Trower MK, Fisher A, Upton N, et al. Neurokinin-1 receptor antagonist orvepitant is an effective inhibitor of itch-associated response in a Mongolian gerbil model of scratching behaviour. Exp Dermatol. 2014;23(11):858–60.

    Article  CAS  PubMed  Google Scholar 

  33. • Stander S, Siepmann D, Herrgott I, et al. Targeting the neurokinin receptor 1 with aprepitant: a novel antipruritic strategy. PLoS One. 2010;5(6):e10968. Open-label study showing antipruritic efficacy of aprepitant in CP of various origins.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Duval A, Dubertret L. Aprepitant as an antipruritic agent? N Engl J Med. 2009;361(14):1415–6.

    Article  CAS  PubMed  Google Scholar 

  35. Torres T, Fernandes I, Selores M, et al. Aprepitant: evidence of its effectiveness in patients with refractory pruritus continues. J Am Acad Dermatol. 2012;66(1):e14–5.

    Article  PubMed  Google Scholar 

  36. Booken N, Heck M, Nicolay JP, et al. Oral aprepitant in the therapy of refractory pruritus in erythrodermic cutaneous T-cell lymphoma. Br J Dermatol. 2011;164(3):665–7.

    CAS  PubMed  Google Scholar 

  37. Vincenzi B, Fratto ME, Santini D, et al. Aprepitant against pruritus in patients with solid tumours. Support Care Cancer. 2010;18(9):1229–30.

    Article  PubMed  Google Scholar 

  38. Santini D, Vincenzi B, Guida FM, et al. Aprepitant for management of severe pruritus related to biological cancer treatments: a pilot study. Lancet Oncol. 2012;13(10):1020–4.

    Article  CAS  PubMed  Google Scholar 

  39. Ito J, Fujimoto D, Nakamura A, et al. Aprepitant for refractory nivolumab-induced pruritus. Lung Cancer. 2017;109:58–61.

    Article  PubMed  Google Scholar 

  40. Vincenzi B, Tonini G, Santini D. Aprepitant for erlotinib-induced pruritus. N Engl J Med. 2010;363(4):397–8.

    Article  CAS  PubMed  Google Scholar 

  41. Ally MS, Gamba CS, Peng DH, et al. The use of aprepitant in brachioradial pruritus. JAMA Dermatol. 2013;149(5):627–8.

    Article  PubMed  Google Scholar 

  42. • Ohanyan T, Schoepke N, Eirefelt S, et al. Role of substance P and its receptor neurokinin 1 in chronic prurigo: a randomized, proof-of-concept, controlled trial with topical aprepitant. Acta Derm Venereol. 2017. Interesting RCT reporting an itch improvement after treatment with topical aprepitant in patients with chronic prurigo, however not superior to placebo.

  43. •• http://www.drugdevelopment-technology.com/news/newsmenlos-serlopitant-meets-endpoints-in-phase-ii-trial-for-prurigo-nodularis-patients-5758874. Accessed 4 Sept 2017. Press release reporting promising antipruritic effects of serlopitant in patients with chronic prurigo.

  44. •• http://www.prnewswire.com/news-releases/vanda-pharmaceuticals-announces-tradipitant-phase-ii-proof-of-concept-study-results-for-chronic-pruritus-in-atopic-dermatitis-300045700.html. Accessed 4 September 2017. Although no differences could be shown between tradipitant and placebo in the treatment of atopic pruritus, individuals with high levels of exposure to tradipitant revealed clinical relevant effects on various outcome measures.

Download references

Author information

Authors and Affiliations

  1. Department of Dermatology and Center for Chronic Pruritus, University Hospital Münster, Von-Esmarch-Str. 58, 48149, Münster, Germany

    Manuel P. Pereira & Sonja Ständer

Authors
  1. Manuel P. Pereira
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sonja Ständer
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Sonja Ständer.

Ethics declarations

Conflict of Interest

Dr. Ständer reports personal fees from Almirall, Astellas, Beiersdorf, Celegne, Chugai Pharma, Creabilis, Daiichi Sankyo, Galderma, Helsinn, Kiniska, Kneipp, Maruho Merz, NeRRe, Novartis, Pierre Fabre, Sienna, Ziarco, Dermasence, Menlo, Trevi, and Vanda, outside the submitted work.

Manuel P. Pereira has no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Additional information

This article is part of the Topical Collection on Itch

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Pereira, M.P., Ständer, S. Neurokinin-1 Receptor Antagonists: Promising Agents in the Treatment of Chronic Pruritus. Curr Derm Rep 6, 273–278 (2017). https://doi.org/10.1007/s13671-017-0203-8

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13671-017-0203-8

Keywords

Search

Navigation