Laurent Misery Sonja Ständer Editors. Pruritus

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2 Pruritus

3 Sonja Ständer Editors Pruritus

4 Editors Department of Dermatology CHU Brest Brest France Sonja Ständer Department of Dermatology Competence Center Pruritus University Hospital Münster Von-Esmarch-Str Münster Germany ISBN e-isbn DOI / Springer London Dordrecht Heidelberg New York Library of Congress Control Number: Springer-Verlag London Limited 2010 Apart from any fair dealing for the purposes of research or private study, or criticism or review, as permitted under the Copyright, Designs and Patents Act 1988, this publication may only be reproduced, stored or transmitted, in any form or by any means, with the prior permission in writing of the publishers, or in the case of reprographic reproduction in accordance with the terms of licenses issued by the Copyright Licensing Agency. Enquiries concerning reproduction outside those terms should be sent to the publishers. The use of registered names, trademarks, etc., in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant laws and regulations and therefore free for general use. Product liability: The publisher can give no guarantee for information about drug dosage and application thereof contained in this book. In every individual case the respective user must check its accuracy by consulting other pharmaceutical literature. Printed on acid-free paper Springer is part of Springer Science+Business Media (

5 Foreword Toward the end of the last century (1994), I edited the first comprehensive medical textbook on itch. Since that time, clinical interest and research in itch have blossomed. (Afterwards, therefore, because of? A pleasing but grandiose notion.) There is now an International Forum for the Study of Itch ( and it has sponsored four International Workshops for the Study of Itch, where everything from chemical receptors to specific itch neurons to itch inhibitors to treatment in the clinic has been discussed. Over just the past 15 years there has been progress in every aspect of itch: neuroanatomy, neurophysiology, molecular biology, diagnosis, terminology, classification, and treatment. You will find it all here. In this book, every imaginable aspect of pruritus,* from bench to bedside, has been covered by experts. Misery and Ständer both recognized across the globe as leading itch workers have now produced the itch book for the twenty-first century. Jeffrey D. Bernhard, MD, FRCPedin * Itch and pruritus are synonymous and may be used interchangeably. According to the great philosopher Willard V.O. Quine, Faced with two terms for the same thing, one tends to cast about for a distinction. Most people now agree that giving these two terms different meanings is confusing, not to mention that itch is easier to say and to spell. v

6 Foreword The American poet Ogden Nash tells us that happiness is having a scratch for every Itch and there is much truth in that pithy aphorism. Unfortunately effective and practical solutions for the chronically itchy patient still remain elusive and those of us who work in the clinic are faced all too frequently with the very unhappy patient complaining of excruciating and intractable itching despite our best efforts. Up to the latter years of my career, itching though the dominant symptom of skin disease has attracted little or no attention from physiologists. When it had received attention in the past, it has all too often been relegated to the Cinderella status of a mild form of pain, despite self-evident differences such as the withdrawal reflex response to pain versus the scratch response to itch. Even that acute observer of skin physiology Thomas Lewis in his classic text The blood vessels of the human skin and their responses, in which he devotes several chapters to the actions of histamine, does not once mention itching. However, it has been my good fortune, during the new millennium, to witness an upsurge of interest in the mechanisms of itch at a molecular level, resulting in impressive advances in the understanding of the neurophysiology of itching, which offers real prospects of progress in the management of the itchy patient. These advances have been facilitated by the utilisation of advances in neurophysiological technology including microneurography and positron emission tomography of the human brain, and by improved methods of quantifying itch and its deleterious effect on quality of life. The realisation that itch can be generated centrally, by dysregulation of afferent neuronal traffic within the CNS a concept espoused by the late neurophysiologist Pat Wall has also had an impact on therapeutic strategies for itch. Although this book is not the first devoted to bringing together the multiple strands of research on itch, it has the advantage of a more solid foundation of new insights, particularly at a basic molecular level and also realistic prospects for the emergence of treatments. Edited by and Sonja Ständer, both of whom are in the forefront of current research in this field, the book successfully encapsulates all major advances. Their clinical background accounts for the emphasis placed in the book on translational research and there is much which should be of interest to the practising physician as well as the researcher. Altogether, this book will prove an invaluable acquisition to the libraries of the laboratory and the clinic alike. Malcolm W. Greaves Emeritus Professor of Dermatology, The Cutaneous Allergy Clinic, St John`s Institute of Dermatology, St Thomas Hospital, Lambeth Palace Rd, London SE1 7EH UK vii

7 Foreword I am delighted to write this foreword for the book Pruritus by MD and Sonja Ständer MD and congratulate both of them on this excellent contribution. For many years they have pioneered clinical and experimental research on cutaneous neurobiology and neuroinflammation which ultimately has resulted in an improved understanding of itch as well as the development of novel therapeutic strategies. Pruritus or Itch is an important danger signal of the body to external noxious stimuli or a variety of diseases involving many organs, which due to lack of knowledge has been neglected in the past as the little sister of pain. It may develop to be very distressing, and substantially impairing the quality of life and in some cases may even provoke patients to contemplate suicide. The enormous progress in our understanding of the pathophysiology and molecular basis of pruritus resulted in a new classification of itching. As a consequence, several novel compounds became available and others are currently being investigated to define an individual treatment depending on the underlying cause of itch. The most current knowledge of the complex epidemiological, clinical, experimental and therapeutic aspects of pruritus is contributed by leading experts in the field. The book has been very thoughtfully divided into three parts, each having a logical sequence of chapters. The first part deals with basic aspects such as neuroanatomy, central and peripheral transmission, neuropeptides and their receptors, neuroimaging, tools for measurement and finally animal models. The chapters of the second part are dedicated to the clinical aspects of the different forms of pruritus as well as diseases associated with itch and psychological aspects. In the third part several chapters address the most up-to-date therapeutic developments with regard to their specific efficacy for the distinct forms of itch. I am convinced that this excellent book which provides important insights into a rapidly developing field will be a must for any clinician involved in the management of patients suffering from this distressing symptom. For scientists interested in pruritus research this book will provide an excellent update on the most recent developments. Thomas A. Luger Professor and Chairman Department of Dermatology University of Münster Münster, Germany ix

8 Preface Pruritus or itch is an unpleasant sensation that makes a person want to scratch this definition has remained unchanged for almost 350 years. 1,3 However, pruritus as a protection mechanism will exist as long as animals and human beings have skin or fur. Acute and chronic pruritus is also a common manifestation of dermatologic and non-dermatologic diseases. Recent epidemiological studies have revealed that chronic itch is very frequent (in almost one third of the population ). 2 All patients suffering from itch know that it is a very disturbing sensation with a high impact on the quality of life. Unfortunately, this major symptom was considered the little brother and not severe by comparison to pain until the beginning of the 1990s. The consequences of this paradigm were that research on this field was hindered and development of effective antipruritic drugs delayed. Recently, new concepts and genuine discoveries of itch have completely modified our understanding of itch and suggested new therapeutic modalities. International collaboration is now really effective, with the creation of the first Society dedicated to pruritus research: the International Forum for Studies on Itch (IFSI) Our objectives were to provide a book on itch that would be convenient for doctors who are confronted by patients suffering from itch, by giving practical data on the causes and treatments of pruritus and to present all the new data about pathophysiology and therapeutics. This book could not have been completed without experts and friends world-wide; therefore we want to thank all the authors who have contributed to this book. Sonja Ständer References 1. Bernhard JD. Itch. Mechanisms and Management of Pruritus. Mac Graw-Hill; 1994: Dalgard F, Lien L, Dalen I. Itch in the community: associations with psychosocial factors among adults. J Eur Acad Dermatol Venereol. 2007;21: Hafenreffer S. Nosodochium, in quo cutis, eique adhaerentium partium, affectus omnes, singulari methodo, et cognoscendi et curandi fidelissime traduntur. Ulm, Typis & expensis Balthasar. Kühnen, reipubl. ibid. typogr. & biblopolae;1660. xi

9 Contents Part I Neurophysiology 1 Neuroanatomy of Itch... 3 Akihiko Ikoma 2 Neuroreceptors and Neuromediators... 7 Sonja Ständer and Thomas A. Luger 3 The Brain in the Skin: Neuro-Epidermal Synapses Nicholas Boulais and 4 Central Transmission: From Skin to Brain Tejesh Surendra Patel and Gil Yosipovitch 5 Modulation of Pruritus: Peripheral and Central Sensitisation Martin Schmelz 6 Interaction of Pruritus and Pain Martin Schmelz 7 Neuroimaging Florian Pfab, Michael Valet, Thomas Tölle, Heidrun Behrendt, Johannes Ring, and Ulf Darsow 8 Measurement of Itch Joanna Wallengren 9 Experimental Models of Itch Ulysse Pereira and Part II Clinics Section 1 10 Pruritus, Pain and Other Abnormal Skin Sensations xiii

10 xiv Contents 11 The Epidemiology of Pruritus Florence Dalgard and Elke Weisshaarh 12 Classification Sonja Ständer 13 Examination of Patients Elke Weisshaar Section 2 Dermatology 14 Inflammatory Diseases Jacek C. Szepietowski and Adam Reich 15 Pruritus in Autoimmune Diseases Yozo Ishiuji and Alan B. Fleischer, Jr. 16 Urticaria Ulrike Raap, Alexander Kapp, and Bettina Wedi 17 Pruritic Skin Diseases in Travellers Eric Caumes 18 Pruritus in Cutaneous T-cell Lymphoma Tobias Görge and Meinhard Schiller 19 Anal Pruritus Sylvia Proske and Wolfgang Hartschuh 20 Secondary Reactive Conditions in Pruritic Skin Joanna Wallengren 21 Aquadynia and Aquagenic Pruritus Sensitive Skin and Sonja Ständer Section 3 Pruritus in Neurology 23 Neurogenic Pruritus with Cerebral and/or Medullary Abnormalities Camille Fleuret and 24 Localized Neuropathic Pruritus Martin Marziniak, Esther Pogatzki-Zahn, and Stefan Evers 25 Brachioradial Pruritus Martin Marziniak and Sonja Ständer

11 Contents xv 26 Other Neurological Causes of Itch Martin Marziniak, Esther Pogatzki-Zahn, and Stefan Evers Section 4 Pruritus in Internal Medicine 27 Chronic Kidney Disease-Associated Pruritus Thomas Mettang 28 Pruritus in Patients with Hepatobiliary Diseases Andreas E. Kremer, Ronald P.J. Oude-Elferink, and Ulrich Beuers 29 Endocrine Diseases Elke Weisshaar 30 Pruritus in the Course of Malignancy Zbigniew Zylicz and Malgorzata Krajnik 31 Drugs Jacek C. Szepietowski and Adam Reich Section 5 Psychosomatics and Psychiatry 32 Interaction Between Pruritus and Stress or Other Psychosomatic Factors Psychosomatic Aspects and Psychiatric Conditions Gudrun Schneider 34 Psychosomatics and Psychiatry: Psychological Approach Sabine Dutray and 35 Psychogenic Pruritus Section 6 Other Specialities 36 Pruritus in Children Matthieu Gréco and 37 Pruritus Vulvae Micheline Moyal-Barracco Part III Treatment Section 1 38 General Principles and Guidelines Elke Weisshaar

12 xvi Contents Section 2 Topical 39 Menthol and Sonja Ständer 40 Capsaicin Topical Immunomodulators Cannabinoid-Receptor Agonists Sonja Ständer 43 Other Topical Treatments Section 3 Systemical 44 Antihistamines Caroline Gaudy-Marqueste 45 Anticonvulsants for the Treatment of Pruritus Nora V. Bergasa and Deewan Deewan 46 Opioid Receptor Antagonists or Agonists Serotonin Reuptake Inhibitors and Other Antidepressants in the Treatment of Chronic Pruritus Zbigniew Zylicz and Małgorzata Krajnik 48 Systemic Immunosuppressants in the Treatment of Pruritus Silvia Moretti, Francesca Prignano, and Torello Lotti 49 Other Systemic Treatments Sonja Ständer Section 4 Other Approaches 50 Psychological Intervention Sabine Dutray and 51 Ultraviolet Phototherapy of Pruritus Joanna Wallengren 52 Itch and Acupuncture and Laurence Potin-Richard

13 Contents xvii Section 5 Future Perspectives 53 Future Perspectives: Outlook Sonja Ständer and Index

14 Contributors Heidrun Behrendt ZAUM Center for Allergy and Environment, Division of Environmental Dermatology and Allergy Helmholtz Zentrum/TUM, Technische Universität München, Munich, Germany Nora V. Bergasa Department of Medicine, Metropolitan Hospital Center, New York, USA Ulrich Beuers Department of Gastroenterology and Hepatology, Liver Center, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands Nicholas Boulais Laboratory of Skin Neurobiology, Unit of Compared and Integrative Physiology, University Hospital of Brest, Brest, France Eric Caumes Département des Maladies Infectieuses et Tropicales, Hôpital Pitié-Salpêtrière, Paris, France Florence Dalgard Institute of General Practice and Community Medicine, University of Oslo and Judge Baker Children s Center, Harvard Medical School, Boston, Massachusetts, USA Ulf Darsow Department of Dermatology and Allergy Biederstein, Technische Universität München, Munich, Germany Deewan Deewan Medicine, Woodhull Medical and Mental Health Center, Brooklyn, New York, USA Sabine Dutray Dermatology, University and Regional Hospital Center, Brest Cedex, France Stefan Evers Department of Neurology, University of Münster, Münster, Germany Alan B. Fleischer, Jr. Department of Dermatology, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA xix

15 xx Contributors Camille Fleuret Service de Dermatologie, CHIC Laënnec, Quimper, France Caroline Gaudy-Marqueste Dermatology Department, STE Marguerite Hospital, Marseille, France Tobias Görge Department of Dermatology, University Hospital Münster, Münster, Germany Matthieu Gréco Department of Dermatology, University Hospital, Brest, France Wolfgang Hartschuh Department of Dermatology, University of Heidelberg, Heidelberg, Germany Akihiko Ikoma Department of Dermatology, University of California, San Francisco, San Francisco, USA Yozo Ishiuji Department of Dermatology, Jikei University School of Medicine, Tokyo, Japan Alexander Kapp Department of Dermatology and Allergology, Hannover Medical School, Hannover, Germany Malgorzata Krajnik Nicolaus Copernicus University, Collegium Medicum, Bydgoszcz, Poland Andreas E. Kremer Department of Gastroenterology and Hepatology, Liver Center, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands Torello Lotti Department of Dermatology, Faculty of Medicine, University of Florence, Florence, Italy Thomas A. Luger Department of Dermatology, University of Münster, Münster, Germany Martin Marziniak Department of Neurology, University of Münster, Münster, Germany Thomas Mettang Nephrology, Deutsche Klinik für Diagnostik, Wiesbaden, Germany Department of Dermatology and Laboratory of Skin Neurophysiology, University of Western Brittany, Brest, France Silvia Moretti Department of Dermatology, Faculty of Medicine, University of Florence, Florence, Italy Micheline Moyal-Barracco Department of Dermatology, Hôpital Ambroise Paré, Boulogne, France