ISSN 0001-5555 ActaDV Volume 99 2019 April, No. 5 Advances in Dermatology and Venereology A Non-profit International Journal for Interdisciplinary Skin Research, Clinical and Experimental Dermatology and Sexually Transmitted Diseases European S2k Guideline on Chronic Pruritus AUTHORS: Elke Weisshaar, Jacek C. Szepietowski, Florence Dalgard, Simone Garcovich, Uwe Gieler, Ana Gimenez-Arnau, Julien Lambert, Tabi Leslie, Official Journal of Thomas Mettang, Laurent Misery, - European Society for Dermatology and Ekin Savk, Markus Streit, Psychiatry Erwin Tschachler, Joanna Wallengren Affiliated with - The International Forum for the Study of Itch and Sonja Ständer Immediate Open Access Acta Dermato-Venereologica www.medicaljournals.se/adv ACTA DERMATO-VENEREOLOGICA The journal was founded in 1920 by Professor Johan Almkvist. Since 1969 ownership has been vested in the Society for Publication of Acta Dermato-Venereologica, a non-profit organization. Since 2006 the journal is published online, independently without a commercial publisher. (For further information please see the journal’s website https://www. medicaljournals.se/acta) ActaDV is a journal for clinical and experimental research in the field of dermatology and venereology and publishes high- quality papers in English dealing with new observations on basic dermatological and venereological research, as well as clinical investigations. Each volume also features a number of review articles in special areas, as well as Correspondence to the Editor to stimulate debate. New books are also reviewed. The journal has rapid publication times. Editor-in-Chief: Olle Larkö, MD, PhD, Gothenburg Former Editors: Johan Almkvist 1920–1935 Deputy Editors: Sven Hellerström 1935–1969 Anette Bygum, MD, PhD, Odense Nils Thyresson 1969–1987 Magnus Lindberg, MD, PhD, Örebro Lennart Juhlin 1987–1999 Lone Skov, MD, PhD, Copenhagen Anders Vahlquist 1999–2017 Kaisa Tasanen-Määttä, MD, PhD, Oulu Artur Schmidtchen 2018–2019 Section Editors: Tasuku Akiyama, Miami (Neurodermatology and Itch - Experimental) Dennis Linder, Graz/Padua (Psychoderm., Dermato­-epidemiology, e-Health) Nicole Basset-Seguin, Paris (Skin cancer) Elisabet Nylander, Umeå (Venereology and STI) Veronique Bataille, London (Melanoma, Naevi, Photobiology) Annamari Ranki, Helsinki (Cutaneous lymphoma) Josip Car, Singapore (Health Services Research and e-Health) Artur Schmidtchen, (Wound Healing and Innate immunity) Marco Cusini, Milan (Venereology and Genital dermatology) Matthias Schmuth, Innsbruck (Genodermatoses and Keratinizing disorders, Brigitte Dréno, Nantes (Acne and Rosacea) Ichthyosis and Retinoids) Regina Fölster-Holst, Kiel (Paediatric dermatology, Atopy and Parasitoses) Enikö Sonkoly, Stockholm (Psoriasis and related disorders) Jürg Hafner, Zürich (Skin cancer, Skin tumours, and Melanoma) Jacek Szepietowski, Wrocław (Psychodermatology) Jürgen Harder, Kiel (Cutaneous innate defense, Skin microbe interactions) Elke Weisshaar, Heidelberg (Itch and Neurodermatology) Roderick Hay, London (Cutaneous Infections) Margitta Worm, Berlin (Atopic dermatitis and Immunology) Kristian Kofoed, Copenhagen (STD and Microbiology) Magnus Ågren, Copenhagen (Wound healing & Extracellular matrix) Advisory Board: Magnus Bruze, Malmö Lars Iversen, Aarhus Jonathan Rees, Edinburgh Mona Ståhle, Stockholm Wilma Bergman, Leiden Kyu Han Kim, Seoul Jean Revuz, Paris Sonja Ständer, Münster Tilo Biedermann, Munich Irene Leigh, Dundee Johannes Ring, Munich Jouni Uitto, Philadelphia Earl Carstens, Davis Ruoyu Li, Beijing Matthias Ringkamp, Baltimore Peter van de Kerkhof, Nijmegen Thomas Diepgen, Heidelberg John McGrath, London Martin Röcken, Tübingen Shyam Verma, Vadodara Charlotta Enerbäck, Linköping Maja Mockenhaupt, Freiburg Inger Rosdahl, Linköping Gil Yosipovitch, Miami Hermann O. Handwerker, Erlangen Dedee Murrell, Sydney Thomas Ruzicka, Munich Giovanna Zambruno, Rome Rudolf Happle, Freiburg Lisa Naysmith, Edinburgh Hiroshi Shimizu, Sapporo Christos C. Zouboulis, Dessau All correspondence concerning manuscripts, editorial matters and subscription should be addressed to: Acta Dermato-Venereologica S:t Johannesgatan 22, SE-753 12 Uppsala, Sweden Editorial Manager, Mrs Agneta Andersson Editorial Assistant: Ms Anna-Maria Andersson E-mail: agneta@medicaljournals.se E-mail: anna-maria@medicaljournals.se Information to authors: Acta Dermato-Venereologica publishes papers/reports on scientific investigations in the field of dermatology and venereology, as well as reviews. Case reports and good preliminary clinical trials or experimental investigations are usually published as Short Communications. However, if such papers are of great news value they could still be published as full articles. Special contributions such as extensive feature articles and proceedings may be published as supplements to the journal. For detailed instructions to authors see https://www.medicaljournals.se/acta/instructions-to-author. Publication information: Acta Dermato-Venereologica (e-ISSN 1651-2057) volume 99 will be published in monthly issues (except August and December). Everything is Open Access and no subscription fee. For publication fees: see https://www.medicaljournals.se/acta/ instructions-to-author. Indexed in: See https://www.medicaljournals.se/acta/about/adv. 469 European S2k Guideline on Chronic Pruritus ActaDV In cooperation with the European Dermatology Forum (EDF) and the European Academy of Dermatology and Venereology (EADV) Elke WEISSHAAR1, Jacek C. SZEPIETOWSKI2, Florence DALGARD3,4, Simone GARCOVICH5, Uwe GIELER6, Ana GIMENEZ- ARNAU7, Julien LAMBERT8, Tabi LESLIE9, Thomas METTANG10, Laurent MISERY11, Ekin SAVK12, Markus STREIT13, Erwin TSCHACHLER14, Joanna WALLENGREN15 and Sonja STÄNDER16 1 Department of Clinical Social Medicine, Environmental and Occupational Dermatology, Ruprecht-Karls-University, Heidelberg, 2Department of Dermatology, Venereology and Allergology, Wroclaw Medical University, Wroclaw, Poland, 3Department of Dermatology and Venereology, Skåne Acta Dermato-Venereologica University Hospital, Lund University, Malmö, Sweden, 4National Centre for Dual Diagnosis, Innlandet Hospital Trust, Brummundal, Norway, 5 Institute of Dermatology, F. Policlinico Gemelli IRCCS, Università Cattolica del Sacro Cuore, Rome, Italy, 6Department of Psychosomatic Dermatology, Clinic for Psychosomatic Medicine, University of Giessen, Giessen, Germany, 7Department of Dermatology, Hospital del Mar – Institut Mar d’Investigacions Mèdiques (IMIM), Universitat Autònoma de Barcelona (UAB), Barcelona, Spain, Departments of Dermatology: 8 University Hospital of Antwerp, University of Antwerp, Belgium, 9Royal Free Hospital, London, UK, 10DKD Helios, Wiesbaden, Germany, 11 University Hospital Brest, France, 12Adnan Menderes University, Aydin, Turkey, 13Kantonsspital, Aarau, Switzerland and 14Medical University, Vienna, Austria, 15Department of Clinical Sciences Lund, Dermatology and Venereology, Lund University, Skåne University Hospital, Lund, Sweden, and 16Center for Chronic Pruritus, Department of Dermatology, University Hospital Muenster, Germany Corr: Elke Weisshaar, MD, Occupational Dermatology, Department of Dermatology, Ruprecht-Karls University Heidelberg, Voßstr. 2, DE-69115 Heidel- berg, Germany. E-mail: elke.weisshaar@med.uni-heidelberg.de ActaDV Abbreviations and explanations AD: Atopic dermatitis PAR: Proteinase-activated receptor AEP : Atopic eruption of pregnancy PBC: Primary biliary cirrhosis CGRP: Calcitonin gene-related peptide PEP : Polymorphic eruption of pregnancy CKD : Chronic kidney disease PG: Pemphigoid gestationis CNS: Central nervous system Pruritus: A skin sensation that elicits the urge to scratch Advances in dermatology and venereology CNPG: Chronic nodular prurigo PUO: Pruritus of undetermined origin CP: Chronic pruritus (longer than 6 weeks) PTH: Parathyroid hormone CPG : Chronic prurigo PV: Polycythaemia vera CSU: Chronic spontaneous urticaria RCT: Randomised controlled trials DIF: Direct immunofluorescence SSRI: Selective serotonin re-uptake inhibitors ICP: Intrahepatic cholestasis of pregnancy TRP: Transient receptor potential IFSI : International Forum on the Study of Itch UP : Uremic pruritus IIF: Indirect immunofluorescence UV: Ultraviolet IL: Interleukin VAS: Visual analogue scale Itch: Synonym of pruritus VIP: Vasoactive intestinal peptide NRS : Numerical rating scale VRS: Visual rating scale NSAID: Non-steroidal anti-inflammatory drugs This is an open access article under the CC BY-NC license. www.medicaljournals.se/acta doi: 10.2340/00015555-3164 Journal Compilation © 2019 Acta Dermato-Venereologica. Acta Derm Venereol 2019; 99: 469–506 470 E. Weisshaar et al. CONTENTS ActaDV 1. The challenge of writing this guideline 471 2. Definitions and clinical classification 471 3. Epidemiology of chronic pruritus 472 4. The clinical picture of chronic pruritus 472 4.1 472 4.1.1 Chronic Pruritus in lesional and non-lesional skin 472 4.1.2 Pruritus in kidney disease 473 4.1.3 Pruritus in hepatobiliary diseases (cholestatic pruritus) 473 4.1.4 Pruritus in metabolic and endocrine diseases 473 Acta Dermato-Venereologica 4.1.5 Pruritus in malignancy 473 4.1.6 Pruritus in infectious diseases 474 4.1.7 Pruritus in neurological diseases 474 4.1.8 Pruritus in psychiatric diseases 474 4.1.9 Drug-induced chronic pruritus 475 4.2 Specific patient populations 475 4.2.1 Chronic pruritus in the elderly 475 4.2.2 Chronic pruritus in pregnancy 475 4.2.3 Chronic pruritus in children 476 5. Diagnostic management 476 5.1 Patient history and clinical examination 476 5.2 Diagnostic algorithm and diagnostics 478 6. Therapy 478 6.1 Therapy: general principles including emollients 478 6.2 Causative therapy and aetiology-specific treatment 480 6.3 Topical therapy 481 6.3.1 Local anaesthetics 481 ActaDV 6.3.2 Zinc, menthol and camphor 482 6.3.3 Capsaicin 482 6.3.4 Topical glucocorticosteroids 483 6.3.5 Tacrolimus and pimecrolimus 483 6.3.6 Acetylsalicylic acid 483 6.3.7 Doxepin 483 6.3.8 Topical mast cell inhibitors 484 6.4 Systemic therapy 484 6.4.1 Antihistamines 484 Advances in dermatology and venereology 6.4.2 Mast cell inhibitors 485 6.4.3 Glucocorticosteroids 485 6.4.4 Opioid receptor agonists and antagonists 485 6.4.5 Gabapentin and pregabalin 486 6.4.6 Antidepressants 486 6.4.7 Serotonin receptor antagonists 487 6.4.8 Thalidomide 487 6.4.9 Leukotriene receptor antagonists and TNFα antagonists 487 6.4.10 Cyclosporine, methotrexate, azathioprine and tacrolimus 487 6.4.11 Neurokinin receptor 1 antagonist 488 6.4.12 Biologics 488 6.4.13 Physical treatment modalities 488 6.5 Ultraviolet phototherapy 489 6.6 Treament in special populations 490 6.6.1 Treatment of chronic pruritus in the elderly 490 6.6.2 Treatment of chronic pruritus in pregnancy 491 6.6.3 Treatment of chronic pruritus in children 491 6.7 Psychosomatic therapy (relaxation techniques and psychotherapy) 492 7. Key summary of discussion 492 8. References 493 www.medicaljournals.se/acta European Guideline on Chronic Pruritus 471 Pruritus is a frequent symptom in medicine. Popula- of this symptom, the multifactorial aetiologies of pruritus tion-based studies show that every 5th person in the and the lack of well-defined outcome measures, biomar- ActaDV general population has suffered from chronic pruritus kers and therapy targets. To complicate matters, RCTs ex- at least once in the lifetime with a 12-month incidence ist for some types of pruritus, but with conflicting results. of 7%. In patient populations its frequency is much However, new therapies for improved medical care have higher depending on the underlying cause, ranging been suggested and are summarised in this guideline. Ex- from around 25% in haemodialysis patients to 100% pert recommendations are also provided. In addition, if the in skin diseases such as urticaria and atopic dermatitis underlying cause is detected, disease-specific guidelines (AD). Pruritus may be the result of a dermatological should be consulted [e.g. atopic dermatitis (AD) (2–5), or non-dermatological disease. Especially in non-di- urticaria (6), scabies (7), adult palliative care (8)]. The seased skin it may be caused by systemic, neurological Acta Dermato-Venereologica or psychiatric diseases, as well as being a side effect health care systems in many countries and their social eco- of medications. In a number of cases chronic pruritus nomic situation with ever diminishing financial resources may be of multifactorial origin. Pruritus needs a pre- increase the need for guidelines. These recommendations cise diagnostic work-up. Management of chronic pruri- are based on a consensus of participating countries, while tus comprises treatment of the underlying disease and also allowing for adaptation to country-specific treatment topical treatment modalities, including symptomatic modalities and health care structures. Furthermore, it antipruritic treatment, ultraviolet phototherapy and should be borne in mind that several topical and systemic systemic treatment. Treating chronic pruritus needs to therapies can only be prescribed “off-label” and require be targeted, multimodal and performed in a step-wise informed consent. If such “off-label” therapies cannot procedure requiring an interdisciplinary approach. We be initiated in the physician’s office, cooperation with present the updated and consensus based (S2k) Euro- a specialised centre for pruritus might be helpful. The pean guideline on chronic pruritus by a team of Euro- guideline addresses all medical disciplines that work with pean pruritus experts from different disciplines. This patients suffering from CP. version is an updated version of the guideline that was This updated and revised guideline considers the published in 2012 and updated in 2014 (www.euro- Appraisal of Guideline Research and Evaluation Instru- derm.org). ment (AGREE 2015) and the methods of the GRADE working group (www.gradeworkinggroup.org). All con- sented recommendations are written at the end of each ActaDV 1. THE CHALLENGE OF WRITING THIS GUIDELINE section on treatment in Section 6. Chronic pruritus (CP) is a frequent symptom in the ge- neral population and in many skin and systemic diseases (1). Due to its severity and the fact that it is frequently 2. DEFINITIONS AND CLINICAL CLASSIFICATION refractory to therapy, it causes a high burden and impairs The definitions presented in this guideline are based quality of life. This guideline addresses all causes and on the terminology defined by the International Forum types of CP including chronic prurigo. In its early stage, for the Study of Itch (IFSI). The European participants CP is considered a symptom of the underlying disease. of this guideline agreed to use this terminology. All Advances in dermatology and venereology However, with time, CP may develop its own dynamics contributors accept pruritus and itch to be synonymous. that are no longer linked to the course of the underlying This guideline also defines pruritus/itch as a sensation disease. In this stage, and much like chronic pain, this that provokes the desire to scratch. Patients do not only can be considered a distinct syndrome (CP syndrome) scratch; they also rub, pinch or damage their skin with or even a disease in its own right. The observation that devices (all summarised from this point onward under different patients with CP report similar severity, course the term scratching). In some diseases involving itch, and burden of CP despite the diversity of the underlying patients’ scratching does not lead to skin damage (e.g. origins supports the view that CP requires independent urticaria); in other diseases, scratching leads to a wor- consideration. Nevertheless, this guideline presents a sening of itch (e.g. urticaria factitia) and is accordingly diagnostic and therapeutic approach that is applicable avoided. These differences hinder scratching or scratch to all types of CP. However, as a consequence of the lesions from serving as common objective markers for diversity of possible underlying diseases, each form of the severity of itch. CP should also be considered individually. Studies have According to the IFSI, CP is defined as pruritus las- demonstrated that early intervention in certain types of ting 6 weeks or longer (9). This is a practical distinction CP may lead to a significant improvement [e.g. therapy defined by clinicians in order to facilitate the decision to of polycythemia vera-associated aquagenic pruritus with perform a diagnostic work-up. In some cases, pruritus janus kinase (JAK) inhibitors]. may precede the diagnosis of the underlying disease by Still, there is a significant lack of randomised controlled years (premonitory pruritus); in others, it is the early trials (RCTs) investigating different types of CP in detail, sign of a neoplastic disease such as Hodgkin lymphoma which can be explained by the diversity and complexity (paraneoplastic disease). In line with the IFSI, the term Acta Derm Venereol 2019 472 E. Weisshaar et al. “pruritus sine materia” will not be used in this guideline up to 20% of affected patients (1). For example, pruritus (10). In patients with no identified underlying disease, is present in all patients with AD and urticaria (20) and ActaDV the term “pruritus of unknown origin” or “pruritus of in about 80% of psoriatic patients (21, 22). Systemic undetermined origin” (PUO) is used. The term “pruritus diseases such as primary biliary cirrhosis (PBC) and of unknown aetiology” should be avoided as in most CKD are associated with CP in 80–100% and 25–70%, clinically well-defined forms of pruritus the neurobio- respectively (23); however, the great variability of num- logical mechanisms of CP are unknown [e.g. chronic bers may be explained by a lack of disease definition kidney disease (CKD)-associated pruritus]. and prevalence estimates. The first representative cohort The IFSI classification comprises a clinical distinction study investigating CP in haemodialysis patients showed of patients with Group I pruritus on primarily diseased/ 25.2% to suffer from CP (point prevalence), while the Acta Dermato-Venereologica inflamed skin, Group II pruritus on normal skin and lifetime prevalence was 35.2% (24). Pruritus is a fre- Group III pruritus with chronic secondary scratch lesions quent symptom in patients with Hodgkin’s lymphoma, (9). According to this classification, the aetiology of CP occurring in more than 30% of this patient group (1). In is classified into categories as “dermatological”, “sys- a retrospective study on 139 patients with CP, most cases temic”, “neurological”, “somatoform”, “mixed origin” of severe and long-lasting itch were found in patients with and “others” (9). Neurological pruritus refers mostly to multiple systemic diseases and in patients with pruritus of diseases involving the central and/or peripheral nervous unknown origin, while pruritus of the scalp and face was system resulting in diseased or malfunctioning neurons often a presenting symptom of psychiatric disease (25). firing action potentials with origins at any point along Only few studies have addressed the frequency of the afferent pathway (11, 12). In most cases, this is better pruritus in primary care. According to the Australian described as neuropathic pruritus inducing an overlap of BEACH Program, a continuous national study of general pain, pruritus and par- or dysaesthetic sensations. So- practice activity, pruritus was the presenting complaint matoform pruritus is defined as pruritus where psychic, for 0.6% of consultations, excluding perianal, periorbital psychiatric and psychosomatic factors play a critical or auricular pruritus (26). In the UK, the fourth national role in the onset, intensity, aggravation or persistence study of morbidity statistics from general practice (27) of the pruritus. was conducted in 1991/1992 with 502,493 patients (1% sample of England and Wales), resulting in 468,042 person-years at risk. Pruritus and related conditions were ActaDV 3. EPIDEMIOLOGY OF CHRONIC PRURITUS present in 1.04% of consultations (male, 0.73%; female, Data on the prevalence of CP is very limited. The 1.33%). In Crete, where patients with cutaneous disorders prevalence of CP seems to increase with age (13), but mostly present to hospitals rather than to primary care epidemiological studies are lacking. It is estimated that centres, PUO was diagnosed in 6.3% of 3,715 patients about 60% of the elderly (over 65 years of age) suffer in 2003 (28). In Germany and the Netherlands the preva- from mild to severe occasional pruritus every week lence of pruritus as a reason for consultation in primary (14), referred to as pruritus in the elderly. A population- care resulted in approximately 0.7% of all consultations, based cross-sectional study in 19,000 adults showed most of these resulting in a diagnosis of skin disease (SESAM2 study from 1999–2000, unpublished data from Advances in dermatology and venereology that about 8–9% of the general population experienced acute pruritus, which was a dominant symptom across all the Dutch Transition project from 1995 to 2003) (29). age groups (15). Moreover, it was revealed that pruritus The reader is referred to Section 4.2 for a more detailed is strongly associated with chronic pain (16). Recent discussion of the epidemiology of CP in specific patient surveys indicate a point prevalence of CP to be around populations. 13.5% in the general adult population (17, 18) and 16.8% in employees seeking early detection cancer screenings 4. THE CLINICAL PICTURE OF CHRONIC (19). The 12-month-prevalence of CP was 16.4% and PRURITUS its lifetime prevalence 22.0% in a German population- based cross-sectional study (17). All these data suggest 4.1.1.Chronic pruritus in lesional and non-lesional skin. a higher prevalence of CP in the general population than CP may occur as a common symptom in patients with previously reported (17). For the first time, a recent study dermatoses with primary skin lesions and systemic, neu- found a 12-month cumulative incidence of CP of 7% rologic and psychiatric/psychosomatic diseases without and incident pruritus was significantly associated with primary skin lesions (9). In the 3 latter instances, the higher age (18). Multivariate analysis revealed eczema, skin may appear normal or have skin lesions induced dry skin, asthma, liver disease, an elevated body mass by scratching. In chronic and severe cases, patients can index and higher anxiety scores to be determinants of develop chronic prurigo (CPG), which may present as prevalent CP (18). chronic nodular prurigo (CNPG) or other subtypes (30). CP may be due to both dermatological and systemic In these cases, a clinical diagnosis is difficult to establish diseases. However, the origin of pruritus is unknown in and diagnostics should be performed. Systemic diseases www.medicaljournals.se/acta European Guideline on Chronic Pruritus 473 frequently accompanied by pruritus are summarised cholangitis (SSC). CP usually peaks in the evening and in Table I. In recent years, several entities of pruritus night, frequently presenting without any primary skin ActaDV on inflamed and normal skin have been characterised lesion but sometimes with secondary scratch lesions and in more detail. Some frequent patient populations and CPG. It is often generalised, affecting palms and soles systemic diseases inducing CP are presented in the fol- in the early stage (48). lowing sections. It has recently been shown that increased serum au- totaxin (ATX) [the enzyme that metabolises lysophospha- 4.1.2. Pruritus in kidney disease. The pathophysiology tidylcholine (LPC) into lysophosphatidic acid (LPA)] of CKD-associated pruritus is unknown. Implicated levels, and thereby increased LPA levels, are specific for mechanisms have included direct metabolic factors: pruritus in cholestasis, including intrahepatic cholestasis increased concentrations of divalent ions (calcium, Acta Dermato-Venereologica of pregnancy and paediatric cholestatic disorders (44, magnesium), parathyroid hormone (PTH), histamine 45, 47), but not for other forms of systemic pruritus and tryptase, dysfunction of peripheral or central nerves, the involvement of opioid receptors (µ- and κ-receptors) (49). Rifampicin significantly reduced itch intensity and xerosis cutis (dry skin) have been suggested as likely and ATX activity in pruritic patients. The beneficial candidates (31–39). Some data point to a possible role antipruritic action of rifampicin may be explained partly for micro-inflammation, which is relatively frequent in by pregnane X receptor (PXR)-dependent transcription uraemia (31, 40). Two uremic toxins, p-cresylsulfate and inhibition of ATX expression (49). Successful treatment indoxylsulfate, were recently suggested to be involved in with µ-receptor opioid antagonists such as nalmefene and the pathogenesis of CP in kidney disease (41). naltrexone supports the hypothesis that opioid receptors One representative study on CP in 177 haemodialysis and a high opioid tone influences ChP (50). patients showed that 43.5% had normal looking skin 4.1.4. Pruritus in metabolic and endocrine diseases. In (IFSI II), 37.9% had secondary scratch lesions including endocrine disorders such as hyperthyroidism and diabetes CPG (IFSI III) and 18.6% had a skin disease (IFSI I) (42). mellitus, less than 10% of patients report pruritus (51, 4.1.3. Pruritus in hepatobiliary diseases (cholestatic 52). In patients with hypothyroidism, pruritus is most pruritus). CP is a frequent symptom in patients with probably driven by xerosis of the skin. Patients with hepatobiliary disease and cholestasis due to mechanical primary hyperparathyroidism do complain of itch in a obstruction, metabolic disorders or inflammatory di- substantial number of cases (53). The pathophysiology ActaDV seases (43–45). It is termed cholestatic pruritus (ChP), of pruritus in primary hyperparathyroidism is not known. although cholestasis is not a prerequisite of pruritus These patients often experience a lack of vitamin D and related to diseases of the liver. ChP may be quite severe minerals (e.g. zinc etc.), which probably contributes to and can even precede the diagnosis of, e.g. primary CP. Iron deficiency may be associated with CP (54). biliary cholangitis (PBC) by years (46, 47). Pruritus is The mechanism for this is unknown. Iron overload as less frequent in patients with infectious liver disease in haemochromatosis may lead to CP (55, 56). CP in (hepatitis B or C) or toxic liver disease (e.g. alcohol- metabolic and endocrine disease frequently occurs as induced). The true prevalence of CP in hepatobiliary generalised pruritus, but localised forms such as genital diseases is not known due to lacking epidemiological CP may occur, e.g. in diabetes mellitus (51, 57). The Advances in dermatology and venereology data. It seems that CP is most frequent in PBC, primary clinical picture is not specific, frequently accompanied sclerosing cholangitis (PSC) and secondary sclerosing by dry skin and sometimes showing secondary scratch lesions (IFSI III) (1). Table I. Systemic diseases that can induce pruritus (examples) 4.1.5. Pruritus in malignancy. Several malignant dis- Metabolic and endocrine • Chronic kidney disease (CKD) orders including tumours, bone marrow diseases, my- diseases • Hepatobiliary diseases with or without cholestasis eloproliferative and lymphoproliferative disorders may • Hyperparathyroidism • Hyper- and hypothyroidism be accompanied by pruritus. The term “paraneoplastic • Iron deficiency pruritus” is used to describe pruritus in patients with • Diabetes mellitus Infective diseases • HIV and AIDS cancer (58). The true frequency of this symptom in • Parasitoses including helminthosis malignant disease is unclear and epidemiological data • Viral hepatitis Haematological disorders • Polycythemia vera, myeloproliferative diseases in this field are limited. One study in a cohort of can- • Lymphoma, e.g. Hodgkin lymphoma cer patients showed that 5.9% suffer from generalised Neurological diseases • Multiple sclerosis • Brain tumours itch (59). Gastrointestinal tumours and haematological • Notalgia paraesthetica malignancies were among the tumours that most com- • Brachioradial pruritus • Postherpetic neuralgia monly cause pruritus (59). Most of the patients affected • Small-fibre neuropathies do not exhibit specific dermatoses, but unaffected skin Psychiatric or psychosomatic diseases • • Depression Anxiety or non-specific eruptions with and without papules and • Delusional disorders excoriations. In general, the prevalence of pruritus in • Eating disorders haematological malignancies is higher compared to Acta Derm Venereol 2019 474 E. Weisshaar et al. non-haematological malignancies; it is estimated to be to develop pruritic papular eruption (PPE), a major cause around 30% in Hodgkin lymphoma, around 15–50% of CP in African HIV patients (1, 73). There is evidence ActaDV in non-Hodgkin lymphoma and around 15–50% in for a high association between prurigo and HIV infec- polycythemia vera (PV) (58, 60). The mechanisms of tion, but regional variations need to be considered (73). pruritus in malignancy are still not understood. Several Whether toxocariasis infections lead to pruritus in a mediators and mechanisms have been discussed in the substantial number of patients remains to be confirmed literature such as toxic products generated by the tumour (74). Pruritus has been reported in up to 15% of patients itself, allergic reactions to compounds released and a with chronic hepatitis C virus (HCV) infection and may direct affect on the brain or nerves (in brain tumours), be a presenting symptom (75). the latter being referred to as neuropathic pruritus (14, 4.1.7. Pruritus in neurological diseases. Space occupy- Acta Dermato-Venereologica 61). Recently, interleukin-31 (IL-31), a Th-2 cytokine, ing lesions (tumours, abscesses, haemorrhage) of the was found to be highly associated with itch in lymphoma nervous system and degenerative neurological diseases, and highly expressed in malignant T-cells (62). In PV, e.g. multiple sclerosis, are rare causes of neuropathic more than 50% of patients suffer from pruritus (60, 63, pruritus with variable clinical presentation (76–79). 64). Aquagenic pruritus with pinching sensations after Pruritus due to these neurological disorders may be the contact with water is a characteristic but not necessary presenting symptom prior to diagnosis and could be feature. It has been suggested that high levels of hista- transient, continuous or paroxysmal in nature (80). En- mine released by the augmented numbers of basophilic trapment syndromes of specific peripheral nerves such as granulocytes might trigger the itch (65). For PV this notalgia paraesthetica, brachioradial pruritus, cheiralgia seems to be most pronounced in patients showing the paraesthetica and meralgia paraesthetica present with JAK2 617V mutation (60, 66). pruritus localised to a specific anatomical area (81–85). Pruritus in Hodgkin’s disease often starts on the legs A typical accompanying clinical finding is the presence and is most severe at night, but generalised pruritus soon of various paraesthetic sensations, including a feeling ensues. Several factors such as secretion of leukopeptida- of electrical current, prickling, tingling, burning and ses and bradykinin, histamine release and high IgE levels numbness. A recently recognised clinical phenomenon is with cutaneous depositions may contribute to pruritus in generalised pruritus triggered by a localised neurological lymphoma (67). Patients with carcinoid syndrome may disorder, e.g. brachioradial pruritus (86, 87). In a broader ActaDV experience pruritus in addition to flushing, diarrhoea and perspective, neuropathy of small cutaneous nerve fibres cardiac symptoms (68). in dermatological disorders such as keloids, burns and A recent population-based cohort study in 8,744 pa- post-zoster pruritus may also be classified under pruritus tients with CP showed that CP without concomitant skin in neurological diseases (88–91). Analogously, pruritus changes is a risk factor for undiagnosed haematological in several systemic diseases associated with small fibre and bile-duct malignancy (69). A nationwide Danish neuropathy is similarly included, the list being led by cohort study based on registry data showed a 1-year diabetes (92). absolute cancer risk of 1.63%, and a 13% higher than expected number of both haematological and various so- 4.1.8. Pruritus in psychiatric diseases. It is estimated that at least 32% of psychiatric patients on a psychiatric Advances in dermatology and venereology lid cancers among patients with pruritus was found. This related in particular to haematological cancers, above all ward report itch (93). A large population survey showed Hodgkin lymphoma (70); however, the study was unable that adults with depression are twice as likely to expe- to differentiate between acute and chronic itch. rience itch (94) and that the severity of itch increases with symptoms of depression among adolescents (95). 4.1.6. Pruritus in infectious diseases. Acute or chronic The pathophysiological background seems to correlate pruritus may occur with skin infections and infestations, with production and interaction of neuropeptides such among which scabies is the most prominent example as serotonin (96). Individuals with anxiety tend to itch (71). Viral infections such as herpes simplex, herpes over time and this has implications for the therapeutic zoster and varicella can present with acute pruritus. CP approach (97). Symptoms of obsessive compulsive may occur in 4% of herpes zoster patients, which is disorder can manifest with CP, as seen in patients with termed post-herpetic itch (1). skin picking (98, 99). “Scalp itch” is often a symptom Some generalised infections are accompanied by of depression or a precursor to psychosis. CP can be a pruritus. Above all, patients infected with human im- symptom in psychotic patients, manifesting as delusio- munodeficiency virus (HIV) may develop CP, which nal parasitosis, a rare condition that is challenging to can be the initial presentation of HIV infection. The true treat both for dermatologists and for psychiatrists (100). prevalence is not known but could be as high as 45% Overall, the psychiatric population is little studied with according to cross-sectional study (72). In a significant regard to skin symptoms, but it is now established that number of HIV patients itching has no detectable cuta- psychiatric morbidity contributes to the pathophysiology neous or systemic cause; however, HIV patients are prone of CP in the absence of skin disease (101). www.medicaljournals.se/acta European Guideline on Chronic Pruritus 475 4.1.9. Drug-induced chronic pruritus. Drug-induced in winter months (12.8%) (107). In a Thai study, pruritic pruritus without visible skin lesions accounts for ap- diseases were the most common skin complaint (41%) ActaDV proximately 5% of adverse cutaneous reactions. Almost among the elderly, while xerosis was identified as the any drug may induce pruritus by various pathomecha- most frequent ailment (38.9%) in a total of 149 elderly nisms (Table II) (102). Some may cause urticarial or patients (108).The exact mechanisms of CP in the el- morbilliform rashes presenting with acute pruritus. derly are unknown. Pathophysiological changes of the Furthermore, drug-induced hepatoxicity or cholestasis, aged skin, decreased function of the stratum corneum, as well as drugs that cause xerosis, photoallergy or xerosis cutis, co-morbidities and polypharmacy may all phototoxicity may produce CP on normal skin (103). contribute to its aetiology (109). Increased release of pruritogens (histamine, serotonin, 4.2.2. Chronic pruritus in pregnancy. There are no epi- Acta Dermato-Venereologica neuropeptides), neurological alterations and neuronal demiological studies assessing the prevalence of CP in deposition in the skin have also been suggested, but the pregnancy. Pruritus is the leading dermatological symp- pathogenesis of drug-induced itch is not fully understood tom in pregnancy, estimated to occur in about 18% of (104). Hydroxyethyl starch (HES), a compound used for pregnancies (110). It can present as specific dermatoses fluid restoration, can induce generalised or localised CP of pregnancy [polymorphic eruption of pregnancy (PEP), in 12–42% of treated patients (105). Duration depends pemphigoid gestationis (PG), intrahepatic cholestasis of on the cumulative dose, usually persisting for an average pregnancy (ICP), atopic eruption of pregnancy (AEP)], of 15 months (after HES deposits in the tissues have but may also occur in other dermatoses coinciding by been metabolised). In approximately two-thirds of HES- chance with pregnancy or in pre-existing dermatoses induced pruritus it is generalised and presents without (110–113). Indeed, one of every 5 consultations for pru- any skin lesions (1, 102). ritus in pregnancy is not related to the specific dermatosis of pregnancy (114). 4.2. Specific patient populations PEP is one of the most common gestational dermato- 4.2.1. Chronic pruritus in the elderly. Only a small num- ses, affecting around one in 160 pregnancies. While PG, ber of studies have investigated pruritus in the elderly. PEP and ICP characteristically present in late pregnancy, They are characterised by selection bias and differing AEP starts before the third trimester in 75% of cases (1, endpoints (pruritic skin disease or itch). An American 111). ICP is characterised by severe pruritus without any ActaDV study of cutaneous complaints in the elderly identified primary skin lesions; however, secondary skin lesions pruritus as the most frequent, accounting for 29% of occur due to scratching. It is more prevalent among all complaints (106). A Turkish study in 4,099 elderly native Indians in Chile (27.6%) and Bolivia (13.8%) patients found that pruritus was the most common skin depending on ethnic predisposition and dietary factors symptom, affecting 11.5% of patients. Women were (115, 116). ICP has decreased in both countries, e.g. to more frequently affected (12.0%) than men (11.2%). 14% in Chile. ICP is more common in women of advan- Patients older than 85 years showed the highest preva- ced maternal age, multiple gestations, a personal history lence (19.5%) and pruritus was present more frequently of cholestasis on oral contraceptives and during winter Advances in dermatology and venereology Table II. Drugs that may induce or maintain chronic pruritus (without a rash) Class of drug Substance (examples) ACE inhibitors Captopril, enalapril, lisinopril Anti-arrhythmic agents Amiodarone, disopyramide, flecainide Antibiotics Amoxicillin, ampicillin, cefotaxime, ceftriaxone, chloramphenicol, ciprofloxacin, clarithromycin, clindamycin, cotrimoxazole, erythromycin, gentamycin, metronidazole, minocycline, ofloxacin, penicillin, tetracycline Antidepressants Amitryptyline, citalopram, clomipramin, desipramine, doxepin, fluoxetine, fluvoxamine, imipramine, lithium, maprotiline, mirtazapine, nortriptyline, paroxetine, sertraline Antidiabetic drugs Glimepiride, metformin, tolbutamide Antihypertensive drugs Clonidine, doxazosin, hydralazine, methyldopa, minoxidil, prazosin, reserpine Anticonvulsants Carbamazepine, clonazepam, gabapentin, lamotrigine, phenobarbital, phenytoin, topiramate, valproic acid Anti-inflammatory drugs Acetylsalicylic acid, celecoxib, diclofenac, ibuprofen, indometacin, ketoprofen, naproxen, piroxicam Angiotensin II antagonists Irbesartan, telmisartan, valsartan Betablockers Acebutolol, atenolol, bisoprolol, metoprolol, nadolol, pindolol, propranolol Bronchodilators, mucolytic agents, respiratory stimulans Aminophylline, doxapram, ipratropium bromide, salmeterol, terbutaline Calcium antagonists Amlodipine, diltiazem, felodipine, isradipine, nifedipine, nimodipine, nisoldipine, verapamil Diuretics Amiloride, furosemide, hydrochlorothiazide, spironolactone, triamterene Hormones Clomifene, danazol, oral contraceptives, estrogens, progesterone, steroids, testosterone and derivates, tamoxifen Immunosuppressive drugs Cyclophosphamide, cyclosporin, methotrexate, mycophenolatmofetil, tacrolimus, thalidomide Antilipids Clofibrate, fenofibrate, fluvastatin, lovastatin, pravastatin, simvastatin Neuroleptics For instance, chlorpromazine, haloperidol, risperidone Plasmaexpanders, blood supplying drugs Hydroxyethyl starch, pentoxifylline Tranquilizers Alprazolam, chlordiazepoxidd, lorazepam, oxazepam, prazepam Uricostatics Allopurinol, colchicine, probenecid, tiopronin Acta Derm Venereol 2019 476 E. Weisshaar et al. months. Scandinavian and Baltic countries are also more Common medications associated with CP in adults play affected (1–2%). In Western Europe and North America a minor role in children due to limited use at that age. ActaDV ICP is observed in 0.4–1% of pregnancies (115–117). PEP is one the most common gestational dermatoses, affecting about one in 160 pregnancies. While PG, PEP 5. DIAGNOSTIC MANAGEMENT and ICP characteristically present in late pregnancy, 5.1. Patient history and clinical examination AEP starts before the third trimester in 75% of cases (1, 111). ICP is characterised by severe pruritus without any Patient history and clinical examination are key to cla- primary skin lesions, but secondary skin lesions occur rifying the aetiology of pruritus, which in turn allows due to scratching. It is a hormonally triggered, reversible adequate treatment. A number of typical features in the patient history may be helpful and sometimes even Acta Dermato-Venereologica cholestasis occurring in late pregnancy (late second or third trimester) in genetically predisposed women. diagnostic to identifying the cause of pruritus, e.g. du- The prevalence is around 1%, but varies: it is higher in ration, localisation, time course of pruritus and trigger Scandinavia, South America and South Africa (118). The factors, as well as a detailed personal and family history. aetiopathogenesis is multifactorial and involves genetic, To obtain this information from the patient, it is helpful hormonal and environmental factors such as seasonal to go through their history with a patient history-based variability and dietary factors (119). algorithm (Fig. 1). The following questions can help to compile a patient history: 4.2.3. Chronic pruritus in children. There are no epi- • Duration and onset of itch (“When did itch start?”) demiological studies assessing the prevalence of CP in enables a differentiation between acute and CP (more children (1, 110). The spectrum of differential diagnosis or less than 6 weeks) (9). of CP in children is wide (110, 120), but is dominated • Localisation of pruritus (“Where does it itch?”) ma- by skin diseases, in particular AD. The cumulative pre- kes it possible to distinguish localised pruritus from valence of AD is between 5% and 22% in developed generalized pruritus. countries. The German Atopic Dermatitis Intervention Localized pruritus is usually caused by itchy der- Study (GADIS) showed a significant correlation bet- matosis, when it occurs at localisations where inflamed ween the intensity and severity of pruritus in AD and skin is already present. Localised itch on primarily non- sleeplessness (121, 122). Chronic spontaneous urticaria inflamed skin is suggestive for neurological disease, ActaDV (CSU) is a source of pruritus in approximately 3% of especially when itch appears in an asymmetrical pattern children (123), for which a complete characterization (12, 92, 132–134): unilateral localized pruritus on the of the disease is needed. back is typical for notalgia paraesthetica, whereas itch A Norwegian cross-sectional questionnaire-based on lateral aspects of the arms (especially the forearms) population study in adolescents revealed a pruritus pre- is characteristic for brachioradial pruritus. Both diseases valence of 8.8%. Pruritus was associated with mental have a neuropathic origin (81, 135, 136). Pruritus may distress, gender, sociodemographic factors, asthma, occur in internal diseases, where it can occur in typical rhinoconjunctivitis and eczema (95). Itching of mild to localisations, e.g. on the back and legs in CKD-asso- moderate severity may occur in acne (124, 125). ciated pruritus (42, 137) and on the palms and soles in Advances in dermatology and venereology If children are aged > 6 years, the visual analogue cholestatic pruritus. Localised vulvar pruritus can be a scale (VAS), numerical rating scale (NRS) or verbal symptom of iron deficiency (138). rating scale can be employed (126). In order to ac- Generalised pruritus can be caused by itchy dermato- curately assess the impact of CP in a child’s life, some sis even if the inflamed skin does not show generalised recommended scales include Skindex-16, Skindex-Teen, spread, e.g. in patients with psoriasis (139). However, infant’s dermatology life quality index (127), children’s generalised pruritus on primarily normal skin is highly dermatology life quality index (128) and ItchyQoL suggestive for not only internal but also neuropathic or (129). Instruments that measure the effect of the fami- psychiatric diseases (140) or use of a drug that causes lies’ quality of life include the dermatitis family impact CP. Interestingly, in one study, whole-body pruritus was questionnaire (130). The course of advanced learning found more frequently in patients with dermatosis than for the management of itch (CALM-IT) task force in pruritus due to systemic disease (73). recommend a multidisciplinary and multidimensional • Intermittent pruritus can be distinguished from con- approach for children CP (120). stant itch by asking “When does it itch?”. Intermittent It must be assumed that systemic causes of CP in pruritus can be a symptom of spontaneous urticaria. children are mostly based on genetic diseases or syste- In patients with factitial urticaria, pruritus occurs mic diseases, e.g. biliary atresia or hypoplasia, familial intermittently, typically starting as localised itch and hyperbilirubinemia syndromes, polycystic kidney disease generalising with scratching. Constant pruritus is ty- or CKD (1, 131). Drug-induced pruritus without any pical for internal diseases, e.g. renal or liver diseases specific skin symptoms appears to be rare in children (1). or pruritus in patients with malignant lymphoma. www.medicaljournals.se/acta European Guideline on Chronic Pruritus 477 Patient with CP ActaDV Any pathological findings on the skin, eg. dermatoses ? Detailed history: Duration of itch, quality, localization Preceding skin changes? yes no Weight loss, fever, fatigue Emotional stress? Medication? Drug abuse? Are the lesions present/visible when itch occurrs? yes no Itch on primary Chronic scratch Itch on primary Acta Dermato-Venereologica diseased skin lesions normal skin yes Xerosis cutis of Elderly patient? yes old people? Prurigo nodularis Treat Lichen simplex PUO no no sympto- matically Childbearing age? yes yes Pregnancy? Itchy dermatosis no Psychiatric Bile acid disease? increased? Internal Drugs? disease? Change drugs Psychiatric therapy Any pathologic Disease- parameters? specific Evalution of yes further Skin disease evaluations. Sympto- matic and causative no treatment Atopy Skin Biopsy DIF Serological tests IDIF, ELISA Dermatosis? Laboratory tests: Specific laboratory test part II Any pathologic parameters? Treat skin disease Chest X-ray ActaDV Fig. 1. Diagnostic algorithm. • The time course of pruritus (“When is itch at its maxi- side effects, pregnancy or dermatosis without visible mum/minimum?”) can be indicative for a number of skin changes (9). diseases: nocturnal generalised pruritus in association • History of pruritus (“How did pruritus or the skin de- with chills, fatigue and B symptoms (weight loss, velop over time?”) shows the dynamic of the disease fever and nocturnal sweating) is suggestive of malig- course. Trigger factors and the relationship between nancy such as Hodgkin’s disease. Seasonal pruritus pruritus and specific activities can be important: pru- Advances in dermatology and venereology during wintertime (“winter pruritus”) is found in ritus appearing during physical activity can be caused exsiccation eczema in the elderly. by AD, cholinergic pruritus and cholinergic urticaria. • Identification of pre-existing skin diseases in the Pruritus provoked by skin cooling after emerging patient history is crucial, especially if pruritus on from a warm shower/bath can be a sign of aquagenic primarily inflamed skin is assumed. In such cases, a pruritus, polycythaemia vera or xerosis cutis. history of AD, psoriasis or lichen planus is suggestive • Intensity and quality of itch (burning, painful, sting- that pruritus has occurred due to an exacerbation of the ing, prickling) are best quantified with special tools known disease. An atopic background should always that have been developed for the assessment of pruri- be verified or excluded. It is not uncommon for an tus. For intensity, validated categorical or continuous atopic disposition to be the only explanation for the monodimensional scales, such as the NRS or VAS, are onset of pruritus in patients with PUO. However, the most commonly used. The quality of pruritus is asses- most important question to classify pruritus regards sed in a descriptive way by use of itch questionnaires. skin condition at the time of initial onset of pruritus A validated questionnaire for quality of life assessment (“How did the skin look when itch first appeared?”): is the ItchyQol (141). if pruritus first appeared on primarily diseased (in- • Knowledge of pre-existing internal diseases is of flamed) skin, pruritic dermatosis – which needs to importance when pruritus on primarily non-inflamed be diagnosed – is causative. If pruritus appeared on skin is assumed. In a patient with chronic renal failure normal looking skin [“pruritus on primarily non- or cholestatic liver disease, the primary disease will diseased (non-inflamed) skin”], one should consider initially be suspected to cause itch. Unfortunately, a systemic, neuropathic or psychiatric disease, drug there are no defined laboratory cut-off values (e.g. Acta Derm Venereol 2019 478 E. Weisshaar et al. blood creatinine levels) that are indicative for the In addition to examining the entire integument, a causative role of an internal disease. general physical examination should be performed in ActaDV • A complete history includes documentation of medi- all patients with unclear pruritus, including palpation cation use and change of medication in the preceding of abdominal organs and lymph nodes, and a rectal 12 months prior to the onset of pruritus. Drugs that examination. typically provoke pruritus include opioids, retinoids, Expert recommendation: We recommend taking a antibiotics and new drugs for cancer therapy, espe- detailed history of any patient with chronic pruritus. cially epidermal growth factor receptor (EGFR) and This should include general characteristics of pruritus vascular endothelial growth factor receptor (VEGFR) (e.g. duration, time course, localisation, intensity and inhibitors, as well as tyrosine kinase inhibitors. In quality), knowledge of the personal history, including Acta Dermato-Venereologica patients with a history of previous surgery and infu- precise information on medication and family history. sion treatments, hydroxyethyl starch (HES) should be We recommend a complete dermatological examination. considered as a possible cause. • Family history is indicative of familial skin diseases 5.2. Diagnostic algorithm and diagnostics or internal disorders that are accompanied by itch. Laboratory screening, clinical and technical approaches Finally, the personal environment may be instructive: and investigations are summarised in Tables III and IV. if multiple family members are affected by new-onset All this helps to follow a diagnostic algorithm (Fig. 1). of pruritus, scabies or other parasites should be con- sidered. Clinical examination of the patient should always include 6. THERAPY a thorough inspection of the entire skin including scalp, 6.1. Therapy: general principles including emollients nails, oral cavity and anogenital region. While examining skin lesions, the distinction between primary and secon- It is important to establish an individual antipruritic dary skin lesions is of the utmost importance, since this therapy regimen that takes into account the age of the allows a distinction between the 3 clinical presentations patient, pre-existing diseases, medications as well as the of pruritus as proposed by the IFSI classification (9). quality and intensity of CP. Elderly patients, pregnant If primary skin lesions such as macules/erythema, women and children need special attention (see Sections ActaDV vesicles, papulo-vesicles, blisters, pustules or wheals 6.6.1, 6.6.2 and 6.6.3). As the care of patients with CP are observable and, according to the patient history, have often extends over a long period, with initial uncertainty been present since the onset of itch, pruritus on prima- rily diseased (inflamed) skin can be diagnosed. Further Table III. Diagnostics: laboratory screening, diverse approaches and investigations investigations can be performed to determine the under- Chronic pruritus: first- • Differential blood cell count, erythrocyte lying dermatosis, including skin biopsy, microbiological step lab screening sedimentation rate (ESR) investigations and, in certain cases, laboratory testing • Creatinine, urea • Transaminases (ASAT,ALAT), alkaline phosphatase, (e.g. IgE, indirect immunofluorescence). gamma-glutamyltransferase (y-GT) Secondary skin lesions encompass excoriations, ulce- • Lactate dehydrogenase (LDH) Advances in dermatology and venereology • TSH rations, necrosis, crusts, papules, nodules, lichenification, • Glucose atrophy and scars, as well as hyper- and hypo-pigmen- • Ferritin, C-reactive protein (CRP) • Age > 40 y: stool occult blood tation of the skin. In patients with CP these lesions are Chronic pruritus: • Immunoelectrophoresis most likely caused by scratching. If a patient with CP further investigations • Hepatitis serology, cholesterol, triglycerides • Calcium, parathormone reports that no skin lesions were visible at onset, pruritus • Biopsy with DIF (mastocytosis, pemphigoid, etc.) on primarily non-diseased (non-inflamed) skin can be • Swab for candida (mucocutaneous pruritus) • Urine: mast cell metabolites diagnosed. An internal disease, medications, pregnancy • Further imaging studies and bone marrow or specific skin diseases could be causative. Laboratory investigation for mastocytosis and radiological investigations, adapted to the patient Chronic pruritus: approach I • Detailed history: preceding skin changes? • Weight loss, fever, night sweats, fatigue? history and pre-existing diseases, are mandatory to obtain • Emotional stress? • Medication? Drug abuse? a final diagnosis. • Physical examination If a patient presents with extensive scratch lesions • Subtle primary skin disorders: xerosis, scabies • Bath oil, emollient/education with a duration of many months or years (e.g. CPG, • Follow-up appointment after 2 weeks CPGN), pruritus with chronic secondary scratch lesions Chronic pruritus: • Detailed history renewed approach II is diagnosed. The underlying cause may be a systemic, • Lab screening (see above) • Detailed general physical examination: LN, rectal neurological, psychiatric or dermatological disease. • Stool for parasites Skin biopsy, laboratory and radiological investigations, • Chest X-ray • Biopsy as well as procedures suited to the patient’s history and • Complete internist work-up, further imaging • Follow-up pre-existing diseases will yield a final diagnosis. www.medicaljournals.se/acta European Guideline on Chronic Pruritus 479 Table IV. Laboratory and technical investigations in chronic pruritus (CP) due to systemic diseases Laboratory and technical screening-basic Complete blood count, creatinine, urea, ASAT, ALAT, alkaline phosphatase, y-GT, TSH, TSH, glucose, chest X-ray, (stool test ActaDV for parasites in genito-anal pruritus) Metabolic and endocrine diseases Renal insufficiency Lab I: Creatinine (and urea for elderly) Lab II: Calcium, phosphate, parathormone, HCO3, urinalysis with urine protein concentration. ANA, anti-ds-DNA-Ab, ANCAs, anti-GBM-Ab, etc. Tech: Sonography of the kidneys, CT or MRI Liver diseases with or without Lab I: ALAT, ASAT, y-GT, alkaline phosphatase, HBV-, HCV-serology cholestasis Lab II: Bilirubin, LDH, antimitochondrial antibodies (AMA), anti-smooth muscle Ab (SMA), antiactin Ab, ANA, ANCA Tech: sonography of the liver, CT or MRT, [magnetic resonance cholangiogram (MRC) or endoscopic retrograde cholangiogram (ERC) to rule out primary sclerosing cholangitis] Hyperparathyroidism Lab II: Only serum-calcium is elevated Calcium, parathormone phosphate, vitamin D (1,25-Vit D, 25-Vit D) Acta Dermato-Venereologica Tech: sonography of the parathyroid glands, scintigraphy, MRI Hyper- and hypothyroidism Lab I: TSH Lab II: fT3, fT4, thyroid peroxidase antibody; thyroglobulin antibody; thyroid stimulating hormone receptor antibody.Tech: Sonography of thyroid gland Anaemia Lab I: Complete blood count including MCV and MCHC, LDH, ferritin Lab II: Reticulocytes, haptoglobin, vitamin B12, folic acid. Lab II: Bone marrow aspiration Iron deficiency Lab I: Ferritin Lab II: Serum iron, transferrin, transferrin saturation (TSAT). stool occult blood Malabsorption Lab tests only in case of typical history (known pancreatic disease, history of intestinal surgery) or symptoms such as chronic diarrhoea or steatorrhoea and weight loss. Lab II: Serum protein and serum albumin, gliadin antibody Vitamin A (hyperkeratosis due to vitamin A deficiency), vitamin B12 (neuropathy due to vitamin B deficiency) Tech: endoscopy with biopsy Other diseases Pruritus of the elderly Lab I: Differential blood count, creatinine, urea, estimated glomerular filtration rate (eGFR), ALAT, ASAT, alkaline phosphatase, TSH Infectious diseases In the case of clinical suspicion due to history: HIV antibodies, In the case of clinical suspicion due to history and/or when eosinophilia was found in differentiated blood count: Stool culture and microscopic examination for parasites Haematological disorders Polycythemia vera Lab I: Blood count (elevated haematocrit and haemoglobin, increase of red blood cells, leukocytosis, thrombocytosis), ESR Lab II: To rule out secondary erythrocytosis: erythropoietin (EPO), JAK2 V617F Lab III: Bone marrow ActaDV Tech: Abdominal sonography, CT or MRI Lymphoma Lab I: Blood count, ESR Lab II: Bone marrow, flow cytometry Tech: Sonography, thoracoabdominal CT or MRI Neurological diseases In the case of suspected neurological disorder: Lumbar puncture and MRI Multiple sclerosis Lab: Cerebrospinal fluid analysis (oligoclonal bands?) Tech: MRI (CT) of brain Brain tumours Lab: Cerebrospinal fluid analysis with histopathology Tech: MRI (CT) of brain Notalgia paraesthetica Advances in dermatology and venereology MRI of thoracic spine Brachioradial pruritus MRI of thoracic and cervical spine Psychiatric or psychosomatic diseases Psychiatric assessment, with short questionnaire for depressive and anxiety disorders Pregnancy with or without cholestasis Lab I: ASAT, ALAT, AP, y-GT Lab II: Bile acids, bilirubin, serology for HAV, HBV, HCV, EBV and CMV, autoimmune screen for chronic active hepatitis and primary biliary cirrhosis (anti-smooth muscle and antimitochondrial antibodies) (113) Tech: liver ultrasound Drug induced pruritus Lab I: y-GT, AP, bilirubin, AST; ALT, LDH. Skin biopsy in the case of HES exposure (electron microscopy) about the origin of the pruritus, frustration regarding the report that cold showers reduce itch, no scientific studies failure of past therapies and general psychological stress have been performed to confirm this observation. On the frequently occurs. Taking a careful history on the occur- other hand, brief hot showers have shown itch-relieving rence and characteristics of pruritus is very important effects in experimental studies applying heat to chronic (see Section 5.1). The diagnostic procedures and therapy pruritus and atopic skin (142, 143). Also, lukewarm should be discussed with the patient in order to achieve baths with colloidal oatmeal may restore skin barrier and the best possible concordance and compliance. sooth pruritus (144). Moisturisers with water and liquid As a first step, the patient should be informed about paraffin base are used in soothing creams and emulsions. general pruritus-relieving measures (Table V). These Several active ingredients are used in emollients suitable include simple and helpful tips such as keeping room for dry skin. The effects of urea (5–10%) and glycerol temperatures low and applying moisturisers to improve (20%) on pruritus are the best studied (145, 146). Pro- skin barrier and reduce itching. Although many patients pylene glycol (20%) and lactic acid (1.5–5%) may also Acta Derm Venereol 2019 480 E. Weisshaar et al. Table V. General measures for treating chronic pruritus (CP) Application of ActaDV Soft clothing permeable to air, e.g. cotton. Dress in layers to avoid sweating Low room temperature at night Mild, non-alkaline, perfume-free soaps, moisturizing syndets and shower/bath oils Skin moisturizer on a daily basis, especially after showering and bathing. Emollients, especially at night: creams/lotions/gels with, e.g. urea (5–10%), glycerol (20%), camphor (2%), menthol (1%), zinc (10%), pramoxine (1%), polidocanol (2–10%) Luke-warm water, bath (max 20 min), possibly adding oatmeal or potassium permanganate, dabbing the skin dry after bathing Cooling wet or fat-moist wraps Avoidance of Factors that can contribute to dry skin, such as dry climate, sauna, alcoholic compresses, frequent washing and bathing Excitement, strain, negative stress Acta Dermato-Venereologica Very hot and spicy foods, large amounts of hot drinks and alcohol Contact with allergenic and irritant substances (e.g. fragrances, preservatives and surfactants) Relaxation techniques Autogenic training, relaxation therapy, psychosocial education Education Educational training programs for coping with the vicious itch-scratch-itch cycle (121, 122, 478) contribute to hydration of the skin and to a reduction in Prior to further symptomatic therapy, the patient should pruritus (147). In addition, propylene glycol and lactic undergo a careful diagnostic evaluation, as well as treat- acid have antimicrobial properties, making preservatives ment for any underlying disease (Fig. 1, Tables III and redundant. Another antipruritic agent with antimicrobial IV). Pharmacologic interventions for specific pruritic properties is potassium permanganate, which can be used diseases, e. g. AD and urticaria, should be performed as an active ingredient in baths. according to the current guideline of the specific disease Emollients containing N-palmitoylethanolamine and the field’s Cochrane Group (6, 7, 156–161). (PEA) (0.3%), an endogenous lipid, have been shown If pruritus continues to persist, consecutive or com- to significantly improve skin barrier function (148) and bined step-by-step symptomatic treatment is necessary weak to moderate antipruritic and analgesic effects in (Table VI). Before considering systemic treatment, experimentally induced pain, pruritus and erythema patient adherence to topical treatment, including skin by topical application (149, 150). In (non-vehicle con- ActaDV care, needs to be ensured (162). Severe generalised CP trolled) clinical trials and case series, it proved to often requires multiple treatment approaches, which may have antipruritic effects in CPG, AD, CKD-associated be administered alone or in different combinations and pruritus and PUO (151–153), as well as analgesic ef- sometimes repeated. Some therapies are not approved fects in postherpetic neuralgia (154). In a monocentric, for CP and can only be prescribed “off-label”, which double-blind RCT of 60 patients with AD it was shown requires separate informed consent. that the preservation and loss of moisture (measured by Expert recommendation: We recommend the use of transepidermal water loss) were greatly improved with moisturisers and emollients depending on the status of a PEA containing cream compared to the vehicle (148); the skin. Advances in dermatology and venereology however, a vehicle-controlled study with 100 subjects did not show any significant difference between the lotion 6.2. Causative therapy and aetiology-specific treatment with and without PEA (155). Thus a PEA-containing topical can be considered an emollient therapy. Aller- CP can be addressed by treating the underlying disease, genic compounds (e.g. fragrances or preservatives) and e.g. specific treatments for underlying dermatoses, avoi- irritant substances (e.g. surfactants) in emollients should dance of contact allergens, discontinuation of implicated be avoided. drugs, specific internal, neurological and psychiatric Table VI. Stepwise symptomatic-therapeutic approach in chronic pruritus (> 6 weeks) Therapy Step 1 • General therapeutic measures (Table V), especially basic therapy with moisturisers • Initial symptomatic therapy: systemic H1 antihistaminics*, topical corticosteroids Step 2 • Symptomatic causative-adapted therapy (Tables VII–X) if origin is unknown Step 3 • In pruritus of unknown origin or therapy refractory cases in step 2: • symptomatic topical therapy, especially in localised forms with, e. g. calcineurin inhibitors, cannabinoid agonists, capsaicin • and/or systemic therapy with gabapentin or pregabalin, antidepressants (doxepin, mirtazapine, paroxetine), UV phototherapy, naltrexone, immunosuppressants (cyclosporine) Concomitant treatment in every • Diagnostics and treatment of underlying disease step • General therapeutic measures (Table V) • In sleep disorders: sedative H1-antihistaminics, tranquilisers, tricyclic antidepressants or neuroleptics • Psychosomatic care, behavioural therapy for scratch behaviour • In erosive scratch lesions: topical antiseptics, topical corticosteroids *There is no evidence for the following diagnoses: cholestatic pruritus, nephrogenic pruritus. www.medicaljournals.se/acta European Guideline on Chronic Pruritus 481 Table VII. Therapeutic options in chronic kidney disease-associated Table IX. Antipruritic therapy of atopic dermatitis (AD) (5) and pruritus (160, 161) ActaDV Antipruritic effects in controlled studies Antipruritic effects confirmed in controlled studies • Activated charcoal 6g/day (61) • Glucocorticosteroids (topical and oral) • Gabapentin 300 mg 3x/week postdialysis (290), pregabalin 50 mg/every • Cyclosporin A other day (304) • Mycophenolate mofetil (MMF 2 g/day or EC-MPS 1440 mg/day) • Gamma-linolenic acid cream 3x/day (487) • Dupilimab (515) (300 mg/weekly or/2 weeks) • Capsaicin 3–5x/day (188, 189) • Tacrolimus ointment (2x/day) • UVB phototherapy (488) • Pimecrolimus cream (2x/dyay) • Acupuncture at the Quchi (LI11) acupoint (411) • Proactive therapy with steroids and tacrolimus ointments (2x/week) • Nalfurafine intravenously postdialysis (36) • Naltrexone 50 mg/day (283, 516) • Thalidomide 100 mg/day (356) Equivocal results • Montelukast 10 mg/day (489) • Antihistamines (topical and systemic) Equivocal effects in controlled studies • Allergen-specific immunotherapy (ASIT) Acta Dermato-Venereologica • Naltrexone 50 mg/day (37, 38) • Azathioprine (2–5 mg/kg/day, starting dose 50 mg/day) • Ondansetron 8 mg orally or i.v. (346, 347) • Methotrexate (5–25 mg 1x/week) Antipruritic effects in case reports • Apremilast (20–30 mg 2x/day; dosage from BNF) • Cholestyramine (61) • Interferon gamma, i.c. • Tacrolimus ointment 2x/day (221, 222) Antipruritic effects shown in case reports • Cream containing structured physiological lipids with endocannabinoids (152) • Intravenous immunoglobulins (IVIG) • Mirtazapine (329) • UVA1–/UVB 311 nm/PUVA therapy • Cromolyn sodium (490) • Leukotriene antagonists (e.g. zafirlukast/montelukast) • Erythropoetin 36 IU/kg body weight 3x/week (491) • Capsaicin (3–5x/day) • Immunoabsorption • Lidocaine 200 mg i.v./day (61) • Anti-TNFα therapy (infliximab 10 mg/kg for 7 cycles) • Ketotifen 1–2 mg/day (492) • Omalizumab (150 mg for 10 cycles) • Combination omalizumab with IVIG or rituximab therapies, surgical treatment of an underlying tumour or transplantation of organs. Normally, there is sudden Table X. Therapeutic options in polycythaemia vera relief of pruritus when the underlying disease improves, Effects shown in case reports e.g. when Hodgkin’s disease responds to chemotherapy • Paroxetine 20 mg/day (63, 316) • Hydroxyzine (63) or when a patient with PBC has received a transplant. For • Fluoxetine 10 mg/day (316) • Aspirin (517) some underlying diseases, specific treatments have proven • Cimetidine 900 mg/day (518, 519) to be successful in relieving pruritus, even if the underly- • Pizotifen 0.5 mg 3x/day (520) • Cholestyramine (521) ing disease is not treated. Aetiology-specific treatments • Ultraviolet B phototherapy (445) • Photochemotherapy (PUVA) (522, 523) act on a known or hypothetically assumed pathogenesis ActaDV • Transcutaneous electrical nerve stimulation (524) of pruritus in underlying diseases. Evidence of efficacy • Interferon-alpha (525–528) can be found in controlled studies for only a few of these treatments. Treatments for CP in specific diseases are presented in Tables VII–XI. When deciding the choice Table XI. Therapeutic options in aquagenic pruritus of treatment, consideration should be given to the level Effects confirmed in case reports (529-531) of evidence, side-effects, practicability, costs, availability • Topical capsaicin 0.025–1% thrice/day for 4 weeks of a treatment and individual factors such as patient age. • Glycerol trinitrate topically 2% • Transdermal application of scopulamin, topically 3% or 9% • Baths with sodium bicarbonate (0.5-1 kg/bath) Advances in dermatology and venereology Table VIII. Therapeutic options in hepatic and cholestatic pruritus • Bath and systemic PUVA, UVB, UVA + NB-UVB (447, 449-451, 532) • Propranolol 10 to 80 mg/day (533) Antipruritic effects in controlled studies • Atenolol 25 mg/day (534) • Cholestyramine 4–16 g/day (not in primarily biliary cirrhosis!) (46) • Clonidine 0.1 mg twice/day • Ursodesoxycholic acid 13–15 mg/kg/day (493, 494) • Astemizol 10 mg/day • Rifampicin 300–600 mg/day (495); (49) • Ibuprofen (prior to bathing) • Naltrexone 50 mg/day (277, 496) • Pregabalin 150-300 mg/day • Naloxone 0.2 µg/kg KG/min (274) • Antihistamines, e. g. hydroxizine 25 mg/day, chlorpheneramin 8 mg/day, • Nalmefene 20 mg 2x/day (275) cetirizine, loratadine, fexofenadine, terfinadine • Sertraline 75–100 mg/day (322) • H2-blockers: cimetidine 900 mg/day • Thalidomide 100 mg/day (497) • Opioid receptor antagonists, e. g. naltrexone 25–50 mg/day (535) Equivocal effects in controlled studies • Selective serotonin reuptake inhibitors, e. g. paroxetine 20 mg/day, fluoxetine 10 mg/day • Ondansetron 4 mg or 8 mg i.v. or 8 mg orally (333, 339, 340) • Interferon-alpha 2b 5x 3 mil IE 1st week, 3x3 mil IE 2nd–4th week • In PBC: bezafibrate 400 mg/day in combination with ursodesoxycholic acid (498, 499) Effects confirmed in RCT Antipruritic effects in case reports • Acetylic salicylic acid 300–500 mg/day • PBC: Nalfurafine (500) • Phenobarbital 2–5 mg/kg KG/day (501) • Stanozolol 5 mg/day (502) • Paroxetine (503) 6.3. Topical therapy • Phototherapy: UVA, UVB (504) • Bright light therapy (10,000 Lux) reflected toward the eyes up to 60 min 6.3.1. Local anaesthetics. Local anaesthetics (LA) are twice/day (505) a heterogeneous group of compounds, e.g. benzocaine, • Etanercept 25 mg sc. 2x/week (506) • Nasobiliary drainage (507) lidocaine and polidocanol. They act via different groups • Plasma perfusion (504) of skin receptors, interfering with peripheral neural • Extracorporeal albumin dialysis with Molecular Adsorbent Recirculating System (MARS) (508–513) transmission of pruritus. Topical LA are widely used • Liver transplantation (514) for the symptomatic treatment of localised forms of CP, Acta Derm Venereol 2019 482 E. Weisshaar et al. such as neuropathic pruritus, CKD-associated pruritus, Camphor, an essential oil-containing terpene, is so- post-burn pruritus and paraneoplastic pruritus, as well luble in alcohol (171). Applied to the skin, it causes a ActaDV as in the palliative care setting (163). sensation of warmth followed by a mild degree of anaes- In experimental studies, LA exhibited only limited thesia (171). Camphor has been used in dermatology for antipruritic effects in both histamine- and cowhage- decades in liniments, lotions and ointments at concen- induced pruritus, with short-term duration (10 min) after trations ranging from 2% to 20%. It has been shown to topical application (164, 165). Successful use in the specifically activate another constituent of the TRP ion treatment of localised forms of pruritus such as notalgia channel family, namely TRPV3 (177). Camphor was paraesthetica has been reported in case series (166, 167). recently demonstrated to activate the capsaicin receptor, Polidocanol, an anionic surfactant with local anaesthe- TRPV1, while menthol also activates the camphor recep- Acta Dermato-Venereologica tic properties, selectively reduces cowhage-induced tor, TRPV3. These findings illustrate the complexity of pruritus via PAR-2 inhibition (168). It is commonly used sensory perception and explain the efficacy of ointments in different galenic formulations, alone (polidocanol containing both menthol and camphor (171). 2–10%) or in combination with other active substances Expert recommendation: We recommend topical appli- (urea) to treat larger skin areas, i.e. atopic skin. cation of menthol and its derivates. We suggest topical Topical 1% pramoxine hydrochloride has been shown application of camphor or zinc. to ameliorate CKD-associated pruritus in a double-blind, 6.3.3. Capsaicin. Capsaicin (trans-8-metyl-N-vanillyl- placebo-controlled study and can be used to treat larger 6-nonenamide) is the pungent agent of chilli peppers skin areas, also in combination with other antipruritic and is used as a pain-relieving medication (178). Topical compounds (lactic acid, hydrocortisone) (169). application of capsaicin activates sensory C-fibres to Ethyl chloride spray, a topical cooling and anaesthe- release neurotransmitters that induce dose-dependent tic agent, reportedly reduces histamine-induced itch in erythema and burning. After repeated applications of experimental studies and finds limited application in capsaicin, the burning fades due to tachyphylaxis and localised pruritus secondary to allergy skin testing (170). retraction of epidermal nerve fibres (178). However, Expert recommendation: We suggest the application pruritus recurs some weeks following discontinuation of topical anaesthetics for localised pruritus including of therapy, indicating no permanent degeneration of the polidocanol for selected cases of generalised pruritus. nerve fibres (179). ActaDV 6.3.2. Zinc, menthol and camphor. Although zinc oxide The greater the initial dose of capsaicin and the more has been used in dermatology for over 100 years due to its frequent the applications, the sooner desensitization will anti-inflammatory, antiseptic and antipruritic properties appear and pruritus will disappear. The burning sensation and its safety, there is only scarce literature on its effects. accompanying topical treatment may be reduced by lido- Prescriptions of zinc are frequent, with concentrations caine or cooling of the skin (180–182). Unusual adverse varying from 10–50% in creams, liniments, lotions, effects include cough or sneezing due to inhalation of ointments and pastes that are useful in the treatment of capsaicin from the skin or from the jar, as well as its effect pruritus, especially localised forms of pruritus, in child- on sensory nerve fibres in the mucous membranes (178). ren as well as in adults (171). Calamine, which is often A lower concentration of capsaicin and less frequent Advances in dermatology and venereology found in cooling liniments, contains 98% zinc oxide applications will induce tachyphylaxis later, but may (171). In an experimental study zinc oxide was shown ensure better compliance. The concentration of capsaicin to be as effective as moderate potency corticosteroid in varies in different studies, but 0.025% capsaicin is well suppressing contact dermatitis (172). tolerated by most patients. If capsaicin is not available in Menthol is an alcohol obtained from mint oils, or this concentration as a standard drug, it can be produced prepared synthetically. Applied to the skin and mucous using a lipophilic vehicle. Capsaicin is also readily solu- membranes, it causes a sensation of coldness, followed ble in alcohol (0.025% capsaicin in spir dil) suitable to by an analgesic effect (171). Menthol is used in dusting treat burning scalp. A weaker concentration of 0.006% powders, liniments, lotions and ointments in concentra- capsaicin is recommended for intertriginous skin, e.g. tions from 1% to 10% (171). It has been shown to have a pruritus ani (183). High dose capsaicin treatment (8% cooling effect for up to 70 min and to act as a counter-ir- patch) for neuropathic pruritus induced CP relief for up ritant (173). Menthol binds to the TRPM8 receptor (174), to 12 weeks and longer (184). which belongs to the same TRP family of excitatory ion Topical capsaicin’s effects have been confirmed in channels as TRPV1, the capsaicin receptor. These two controlled clinical trials for different pain syndromes receptors have been shown to occasionally co-exist in and neuropathy, as well as notalgia paraesthetica (185), the same primary afferent neurons and promote thermo- brachioradial pruritus (83), pruritic psoriasis (186, 187) sensations at a wide range of temperatures, 8–28°C and and haemodialysis-related pruritus (188, 189). Case re- >42ºC, respectively (174). First studies showed that ports and case series described effects in hydroxyethyl topicals containing the TRPM8 agonist combination or starch-induced pruritus (190, 191), prurigo nodularis menthoxypropanediol ameliorate CP (175, 176). (191–194), lichen simplex (191, 193), nummular ec- www.medicaljournals.se/acta European Guideline on Chronic Pruritus 483 zema (191), aquagenic pruritus (195) and psoralen and on the skin (207, 208). Furthermore, 0.1% tacrolimus ultraviolet A (PUVA)-associated pruritus (196). High- ointment is more effective at reducing symptoms of ActaDV concentration topical capsaicin for the treatment of AD when compared with low-potency corticosteroids, postherpetic neuralgia and HIV neuropathy have been 0.03% tacrolimus and 1% pimecrolimus cream (209). evaluated in a Cochrane review (197). Clinical trials have shown benefit of both pimecrolimus Expert recommendation: We suggest topical capsaicin and tacrolimus in seborrhoeic dermatitis, genital lichen for localized forms of CP. sclerosus, intertriginous psoriasis and cutaneous lupus erythematosus and – only for tacrolimus – in resistant 6.3.4. Topical glucocorticosteroids. Topical glucocor- pruritus ani (210–218). Both substances can be used ticosteroids are the first line therapy for inflammatory to treat localised forms of CP such as genital pruritus dermatoses and the antipruritic effect they display has Acta Dermato-Venereologica (219). In other diseases, the available data are limited to been attributed to an indirect consequence of their anti- small case series, or individual cases, e.g. hand eczema inflammatory properties. Thus they are not currently (pimecrolimus), rosacea (tacrolimus), graft-versus- recommended for the treatment of pruritus in the absence host disease (tacrolimus), vulval pruritus (tacrolimus) of a skin disease. Once- or twice-daily application of a or Netherton’s syndrome (tacrolimus, pimecrolimus). medium or high potency glucocorticosteroid to the trunk Topical tacrolimus has been shown anecdotally to be and extremities or a low potency preparation on the face effective in pruritus associated with systemic diseases or intertriginous areas for approximately 1–3 weeks is such as PBC (220) and chronic renal insufficiency (221, recommended in the case of pruritic dermatoses (198). 222). Despite early reports of efficacy of tacrolimus on Prolonged use and application to large areas is to be av- CKD-associated pruritus, these observations have not oided. Children, pregnant women and elderly patients are been confirmed in a controlled study and so it is not especially susceptible to the adverse effects of glucocor- recommended in these patients, although it may have ticosteroids and should be closely monitored (199, 200). some benefit in combination with systemic therapies Some recent data hint at the possibility of an alterna- (e.g. nalfurafine) (223–225). tive mode of antipruritic action of glucocorticosteroids. Numerous clinical trials have demonstrated the safety Pruritus experimentally induced by histamine was sig- of using TCIs routinely, in children as well as adults nificantly suppressed by topical hydrocortisone when (209, 226). The transient burning upon application compared to placebo (201). In another experimental diminishes after 5–10 days of regular (e.g. twice-daily) ActaDV model itch relief from nickel allergy provided by met- application in most cases (227). Some patients may hylprednisolone aceponate was very rapid and preceded experience flushing upon taking alcohol; however, this resolution of all other eczema findings, suggesting a can be blocked with acetylsalicylic acid (500 mg) taken direct antipruritic effect of the agent rather than just an in advance of drinking alcohol (208). Long-term studies indirect anti-inflammatory one (202). are required to assess the risk of lymphoma in both adult Some studies suggest that topical corticosteroids such and paediatric patients using TCIs; however, this seems as betamethasone valerate are effective in CNPG (203, to be extremely rare (228). In the elderly population TCIs 204). Intralesional application in single nodules of CPG are recommended for inflammatory skin diseases and, if may be considered but there are no studies verifying the effective, can be used indefinitely (229). Advances in dermatology and venereology efficacy of this therapy. Expert recommendation: We suggest tacrolimus and Expert recommendation: We recommend application of pimecrolimus for the treatment of localized forms of CP. topical glucocorticosteroids in CP associated with inflam- matory dermatoses and CPG. We recommend against 6.3.6. Acetylsalicylic acid. Topical acetylsalicylic acid topical glucocorticosteroids in CP on non-inflamed skin. (acetylsalicylic acid/dichlormethane solution) has been We recommend against long-term treatment with topical described to have antipruritic effects in occasional pa- glucocorticosteroids. tients with lichen simplex and CPG (230, 231). However, this beneficial effect could not be confirmed in experi- 6.3.5. Tacrolimus and pimecrolimus. The effects of the mentally induced itch with histamine (232). topical calcineurin inhibitors (TCIs) tacrolimus and Expert recommendation: We cannot make a recommen- pimecrolimus on pruritus are mediated both through dation with respect to topical acetylsalicylic acid for the their immunological and their neuronal properties (205). treatment of CP. Paradoxically, while they can induce transient pruritus at the beginning of treatment, in the medium-term they may 6.3.7. Doxepin. The tricyclic antidepressant doxepin provide an alternative treatment for many causes of pruri- showed antipruritic effects when applied as a 5% cream tus. An initial burning sensation upon application, which in double-blind studies for treatment of AD (233), lichen may be due to activation of TRPV1, can be a biomarker simplex, nummular dermatitis and contact dermatitis of antipruritic effect on individual patients with CP (206). (234). Topical doxepin therapy is not licensed and not TCIs are highly effective against pruritus in AD, and do used in any European country except for the UK (Xepin©) not have the atrophying effects of topical corticosteroids (235–237). Acta Derm Venereol 2019 484 E. Weisshaar et al. 6.3.8. Topical mast cell inhibitors. Pruritus in AD re- cytosis, as well as mosquito bite allergy and urticaria sponds to topical sodium cromoglycate (238), which in both adults and children (250). In adult patients ActaDV was confirmed by a placebo-controlled study (239). with confirmed mosquito-bite allergy, rupatadine 10 Comparison with vehicle showed that topical sodium mg administered prophylactically has been shown to cromoglycate (especially 4%) was effective in histamine- be effective in reducing subsequent wealing and skin induced itch (240). pruritus (251). The newest antihistamine, bilastine, is Expert recommendation: We suggest against the use of highly selective for the H1 receptor. With properties of topical mast cell inhibitors for the treatment of CP. rapid onset, prolonged duration of action, no need for dose adjustment, and low potential for central nervous 6.4. Systemic therapy system (CNS) impairment or drug–drug interaction, bi- Acta Dermato-Venereologica lastine is a front runner among other second-generation 6.4.1. Antihistamines. Antihistamines are the most widely antihistamines in the management of chronic urticaria used systemic antipruritic drugs in dermatology (241). (252). European guidelines on urticaria (6) recommend Drugs that target the H1 receptor can effectively block the second-generation anti H1-antihistamines as the first- acute itch of cutaneous conditions as urticaria or insect line therapy for chronic spontaneous urticaria, starting bites, among others (242). at licensed doses and being increased to up to 4 times First-generation antihistamines, such as chlorphenira- the dose if licensed doses fail to control the disease. mine, clemastine, cyproheptadine, diphenhydramine, hy- Systemic H1-antihistamines are often employed to treat droxyzine, and promethazine are known to bind not only pruritus in AD. The older, sedating H1-antihistamines to H1-receptors, but also to muscarinic, α-adrenergic, may be more useful for this indication especially in dopamine or serotonin receptors and have a central acute AD flares, improving sleep quality in the short sedative effect. Hydroxizine is the most commonly term, although these are not recommended for long-term used first-generation antihistamine showing sedative, use in children (159). The European guideline on AD anxiolytic and antipruritic activities. In adult patients it does not recommend the general use of any antihista- is recommended as an antipruritic agent at a dosage of mines for AD, since there is no high-level evidence that 25 mg at night, increasing to 25 mg 3 to 4 times a day if non-sedating antihistamines reduce itch in AD, or that necessary. In children under 6 years the effective dose sedating antihistamines are of benefit, except for aiding is up to 50 mg/day in divided doses, and 50–100 mg/ sleep (253, 254). ActaDV day in children aged 6–12 years (243). However, the It is currently thought that pruritus in psoriasis is also sedative effect of such antihistamines induce impaired not histamine-mediated, and therefore antihistamines are sleep, interfering with the REM phase. A prospective not routinely recommended (242). Recently, however, cohort study recently suggested that its cumulative long- both sedating and non-sedating antihistamines have term use (and other cholinergic drugs) is associated with been shown to be moderately effective in reducing itch increased risk of dementia (244). Increased drowsiness in patients with psoriasis, but further studies are needed may be problematic in the elderly (229). Due to these side on larger patient groups (255). effects, the use of sedative antihistamines is nowadays Antihistamines are widely used as first-line drugs for limited, and the dose modified accordingly, especially in the treatment of CP associated with various systemic Advances in dermatology and venereology vulnerable populations (245). diseases such as chronic renal failure, cholestasis, he- Second-generation antihistamines such as cetirizine, matopoetic diseases and thyroid disorders. However, levocetirizine, loratadine, desloratadine, ebastine, fexo- conventional doses of antihistamines in the treatment fenadine, rupatadine or bilastine have minimal activity of pruritus in internal diseases have not proven to be on non-histaminic receptors, little sedative effect, and a effective (246). longer duration of action compared to the first genera- Antihistamines have been shown to be safe in specific tion (246). For the treatment of PUO, loratadine (10 populations. However, while there is no particular anti- mg), fexofenadine (180 mg) or cetirizine (10 mg) are histamine that is universally effective for the treatment of helpful. Cetirizine may be preferred for its mild seda- pruritus, certain antihistamines [e.g. loratadine, cetirizine tive properties (247). Oral cetirizine has been shown to or rupatadine (256)] are thought to be safer for use in be preferable in CP to narrowband (NB) ultraviolet B children, pregnancy and lactation, and so may be prefer- (UVB) phototherapy, for reasons of cost-effectiveness red in these patients (206). The use of first-generation and time-saving (248). antihistamines is to be avoided in pregnant women (257). In general, the non-sedative H1-receptor antagonists For the paediatric management of pruritus, long-term use offer an effective reduction of CP in diseases associated of first-generation antihistamines is not recommended with increased mast cell degranulation such as urticaria (158, 159). The associated psychomotor impairment or mastocytosis (249). Rupatadine, a dual inhibitor of may impact the education and safety of children, and histamine H1 and PAF receptors, has been shown to remains even while the child becomes used to the seda- significantly reduce the severity of pruritus in masto- ting effects (258). Second-generation antihistamines with www.medicaljournals.se/acta European Guideline on Chronic Pruritus 485 appropriate dose adjustment are the first-line therapy for lymphoma-related pruritus via suppression of IL-31 pro- chronic urticaria in children (259). duction, which has been shown to correlate with pruritus ActaDV Although identified in human skin, H2-receptors play a severity, was reported using dexamethasone (270, 271). minor role in pruritus, and H2-receptor antagonists alone Prednisone is the most commonly selected oral corti- have no antipruritic effect (260, 261). A combination costeroid, initially at a daily dose ranging from 2.5 mg to of H2-antihistamines and H1-antihistamines has been 100 mg or more, usually starting at a dose of 30–40 mg used in the treatment of pruritus in small trials, but the daily. In exceptional cases i.v. methylprednisolone is used results are conflicting (260, 261). It has recently been at a dose of 500 mg–1 g/day, due to its high potency and found that H3- and H4-histamine receptors are involved low sodium-retaining activity. It is important to remem- in pruritus, with the H4 in particular being associated ber that the dosage should be tapered in accordance with Acta Dermato-Venereologica with mast cell function, as well as T cells, dendritic pruritus severity. Before discontinuing systemic therapy, cells, monocytes and eosinophils (262). The efficacy of one may change to topical corticosteroid therapy. Cor- an H4 receptor antagonist is currently under research in ticosteroids should be used with caution in children, the clinical studies and may be available as an antipruritic elderly and in patients with relevant metabolic disorders therapy in the near future (263). There is pre-clinical such as diabetes. evidence that local antagonism of the H3 receptor can Expert recommendation: We suggest systemic gluco- induce scratching; therefore, new drugs that target the corticoids as a short-term treatment in selected cases of H3R are anticipated in the field, with the hope that more refractory CP, especially in paraneoplastic pruritus and effective treatment of chronic pruritus can be offered to palliative care. patients in the future (264). A case series suggests that updosing of antihistamines 6.4.4. Opioid receptor agonists and antagonists. Experi- may also be beneficial in CP (265). mental and clinical observations have demonstrated that Expert recommendation: We recommend treating CP pruritus can be evoked or intensified by endogenous or in urticaria with non-sedating H1-antihistamines. We exogenous μ-opioids (272). This phenomenon can be suggest non-sedating H1-antihistamines in CP in mas- explained by activation of CNS opioid receptors, mainly tocytosis. We suggest non-sedating and/or sedating H1- μ-opioid receptors. Reversing this effect with μ-opioid antihistamines as an initial symptomatic therapy of CP. antagonists thus leads to an inhibition of pruritus (154). The opposite is true for κ-opioids. Their binding to ActaDV 6.4.2. Mast cell inhibitors. Ketotifen (1 mg twice daily), κ-opioid receptors leads to inhibition of pruritus (273). showed antipruritic effects in patients with CKD-associ- Several clinical studies have demonstrated that dif- ated pruritus, but less than gabapentin (266). Cromolyn ferent μ-opioid receptor antagonists may significantly sodium and placebo were compared in 62 haemodialysis diminish pruritus (43, 50, 274–278). In double-blind patients and a significant decrease in itch was seen in RCT, μ-opioid receptor antagonists such as nalmefene, the treatment group, but without effects on tryptase naloxone and naltrexone have exhibited high antipruri- level (267). tic potency. For example, pruritus in chronic urticaria, Expert recommendation: We suggest against the use of AD and cholestatic pruritus has shown therapeutic re- systemic mast cell inhibitors for the treatment of CP. sponse to nalmefene (10 mg twice daily) and naltrexone Advances in dermatology and venereology 6.4.3. Glucocorticosteroids. Systemic glucocorticoids (50–100 mg/day) (279, 280). Controlled studies have (GCs) are commonly used to treat severe CP associated also been performed in patients with CKD-associated with inflammatory skin disease or systemic disease, pruritus (37, 38, 281, 282). Results were variable, rang- supported only by limited clinical evidence. In clinical ing from significant reduction of pruritus to no response. experience, pruritus ceases within approximately 30 min Naltrexone (50 mg/day) was more effective than placebo of i.v. glucocorticosteroids in the treatment of urticaria on CP in patients with AD (283). Case reports have or drug-induced exanthema. Likewise, in AD, allergic demonstrated efficacy of naltrexone in several pruritic contact dermatitis, dyshidrosis and bullous pemphigoid dermatoses. a rapid reduction in pruritus is observed, which can Nalfurafine, a preferential κ-opioid receptor agonist, be explained by their high anti-inflammatory potency. was investigated in CKD-associated CP in two large Thus, while systemic glucocorticosteroids should not RTCs (36, 284). Both trials demonstrated significant be considered as an antipruritic for long-term therapy, clinical benefit of nalfurafine in patients with CKD- short-term use is possible in cases of severe pruritus in associated pruritus (273) within the first 7 days of treat- inflammatory skin diseases; however, they should not ment. Similar outcomes in terms of results and adverse be used for a period of more than 2 weeks (268) due to drug effects were obtained in an open-label long-term their severe side-effects. study with 5 mg nalfurafine given orally in 211 haemo- Severe, intractable lymphoma-related paraneoplastic dialysis patients over a period of 52 weeks (285). In a CP can be successfully treated with short courses of sys- RCT on 318 patients with refractory cholestatic pruritus temic GCs (269). An improvement in cutaneous T-cell nalfurafine (2.5 and 5.0 mg given orally per day) reduced Acta Derm Venereol 2019 486 E. Weisshaar et al. itch significantly more than placebo as measured on a 6.4.4. Antidepressants. Recent systematic reviews de- VAS scale (28.56 and 27.46 vs. 19.25) (286). The drug monstrate evidence that antidepressants are effective ActaDV is currently licensed only in Japan. particularly in refractory pruritus, pruritus in CKD, Expert recommendation: We suggest mu-opioid receptor cholestasis or neoplasm (306), as well as in other forms antagonists in refractory CP, especially in cholestatic of CP (307, 308). Psycho-emotional factors are known pruritus. to modulate the “itch threshold” (309). Under certain circumstances, they can trigger or enhance CP (310). Itch 6.4.5. Gabapentin and pregabalin. Gabapentin is an is a strong stressor and can elicit psychiatric disease and antiepileptic and anxiolytic drug also used in neuropathic psychological distress. Depressive disorders are present pain and pruritus (287). The mechanisms of action of ga- in about 10% of patients with CP (311) and have a clear bapentin, a 1-amino-methyl-cyclo-hexane acetic acid and Acta Dermato-Venereologica correlation (312). Antidepressants probably also exert an a structural analogue of the inhibitory neurotransmitter effect on pruritus through their pharmacological action γ-aminobutyric acid (GABA), remain unclear. It is used on serotonin and histamine (306). in postherpectic neuralgia (288), especially with paroxys­ The antipruritic action of serotonin reuptake inhibi- mal pain or pruritus. Pilot studies have been performed tors (SSRIs) does not start until after 2–3 weeks and for the treatment of pruritus caused by burns and wound the maximum effect is usually seen at 4–6 weeks after healing in children demonstrating antipruritic effects of initiation of therapy (313); only escitalopram 10–40 gabapentin (289). Double-blind RCTs were performed mg/day might have a slightly shorter efficacy period. for CKD-associated pruritus (300 mg thrice weekly or SSRIs such as paroxetine can have an antipruritic ef- 400 mg twice weekly after haemodialysis sessions) (290, fect on patients with PV, psychogenic or paraneoplastic 291) and cholestatic pruritus (292). Gabapentin was pruritus and other patients with chronic PUO (314, 315). safe and effective for treating CKD-associated pruritus Paroxetine (20 mg/day) has exhibited antipruritic effects (293, 294). It was shown to be effective in 6 cases of in pruritus due to PV (316), paraneoplastic pruritus (317, brachioradial pruritus, but more disappointing in notal- 318) and psychiatric disease (315, 319). In two patients gia paraesthetica (295, 296). An anecdotal indication is pruritus was induced by discontinuation of paroxetine cutaneous T-cell lymphoma (297). treatment for depression (320). An RCT in pruritus of Pregabalin is similar to gabapentin and a more recent non-dermatologic origin confirmed the antipruritic effect drug. Its use has been suggested in a case of cetuximab- of paroxetine (314). In a two-armed proof-of-concept ActaDV related pruritus, aquagenic pruritus and in CKD patients study with paroxetine and fluvoxamine, patients with CP unable to tolerate gabapentin (298–300). A controlled of dermatological origin reported a significant antipruritic trial demonstrated a significant antipruritic effect of pre- effect (321). Sertraline proved effective in cholestatic gabalin in patients on haemodialysis within one month pruritus both in adults (322) and children (323), as well (301). In another study on uremic itch, treatment with 75 as in CKD-associated pruritus (324, 325). In a recent mg of pregabalin given orally twice weekly in dialysis- double-blind RCT among 50 haemodialysis patients, dependent patients was compared either to ondansetron sertraline was shown to be effective in reducing uremic or placebo. While a significant effect of pregabalin could pruritus (326), while Doxepin also showed positive ef- be documented, the use of ondansetron and placebo did fects in 7 patients (304). Doxepin may be administered Advances in dermatology and venereology not yield significant results (302). In an open study 30 in a dose from 25–50 mg/day. patients with CNPG were treated with 75 mg pregabalin Tricyclic antidepressants like doxepin (327) have been per day orally. Treatment improved itch in 76% of pa- effective in urticaria, AD, cutaneous T-cell lymphoma, tients after a 3-month treatment course (303). Pregabalin carcinoma en cuirasse and HIV-related pruritus. It shows 50 mg every other day or 10 mg doxepin given daily for almost identical effects compared with hydroxyzine 4 weeks in patients with CKD-associated pruritus led (327). Amitriptyline 25 mg/day has shown a reduction to a significant improvement of pruritus in both groups, in pruritus in patients with brachioradial pruritus. Trime- but was significantly more effective in patients receiving prazine and trimipramine are older antidepressants that pregabalin (304). exhibit some antipruritic effects in AD (328). However, regarding the use of gabapentin or pregaba- Mirtazapine 15–45 mg/ day is an atypical antidepres- lin an analysis by the US Renal Data System on a large sant, both noradrenergic and serotonergic, and has been cohort issued a caveat to the use of these drugs. Their shown to be effective in the treatment of CP (297, 329, use was associated with much higher hazards of altered 330). In brachioradial pruritus antidepressants showed mental status, falls and fractures (305). moderate effects to decrease pruritus (331). Expert recommendation: We recommend gabapentin and Side effects of antidepressants are common and include pregabalin in neuropathic CP and in CKD-associated drowsiness, fatigue and headache, mostly initially, but pruritus. We suggest gabapentin and pregabalin for re- also cardiovascular and gastrointestinal symptoms occur; fractory CP and PUO. therefore, caution should be shown in elderly patients www.medicaljournals.se/acta European Guideline on Chronic Pruritus 487 (306). Recommended treatment doses for pruritus in Expert recommendation: We suggest thalidomide for malignant diseases are paroxetine 20–40 mg/day or selected cases of refractory CP after informing the patient ActaDV mirtazapine 15–30 mg/day; for patients with cholestasis about teratogenicity and dose-related risk of neuropathy. or CKD amitriptyline 25–50 mg/day or doxepin 25–20 6.4.9. Leukotriene receptor antagonists and TNFα mg/day. antagonists. Leukotriene receptor antagonists (e.g. Expert recommendation: We recommend selected montelukast) and TNFα antagonists influence the patho­ antidepressants (e.g. paroxetine, mirtazapine, doxepin, genesis of AD. They have been used in combination with amitryptiline) for psychogenic CP and for refractory CP, antihistamines as antipruritic therapy. Montelukast has especially in malignant, cholestatic and chronic kidney also been used in several types of urticaria as well as disease. in combination with antihistamines. A combination of Acta Dermato-Venereologica 6.4.7. Serotonin receptor antagonists. Due to the patho­ H1-antihistamine with a leukotriene antagonist has been physiological significance of serotonin in various di- reported to alleviate pruritus in chronic urticaria (348). seases, e.g. kidney and liver diseases, serotonin receptor Expert recommendation: We suggest against leukotriene antagonists (of the 5-HT3 type) such as ondansetron receptor antagonists in the treatment of CP. (8 mg 1–3x/day), topisetron (5 mg/day) and granise- 6.4.10. Cyclosporine, methotrexate, azathioprine and tron (1 mg/day) have been used anecdotally to treat tacrolimus. Controlled clinical studies investigating pruritus(332–338). Contradictory or negative results the efficacy of systemic anti-inflammatory drugs on CP have been reported in partly controlled studies using are scarce. Cyclosporine is the only drug that has been ondansetron for cholestatic pruritus (332, 339, 340) approved for the treatment of pruritus in AD (162). The and opioid-induced pruritus (341–343). An antipruritic effect of methotrexate and azathioprine on pruritus is effect was reported for ondansetron in CKD-associated mainly documented in retrospective case reports. All pruritus (344). However, this could not be confirmed in these therapies are associated with significant systemic subsequent controlled studies (345–347). toxicity and require careful patient monitoring. The choi- Expert recommendation: We recommend against seroto- ce of systemic therapy for CP depends on comorbidities nin receptor antagonists in the treatment of CP. (existing or prior neoplasms or cardiovascular disease), 6.4.8. Thalidomide. A number of mechanisms for the blood tests (haematology, liver and kidney function), age antipruritic action of thalidomide have been proposed, and history of alcohol abuse. ActaDV including a central depressant effect (348), a local effect Pruritus in AD responds to treatment with cyclosporine on proliferated neural tissue in PN (349) and antagonism as demonstrated in several double-blind controlled of tumour necrosis factor-α (TNFα) (350). studies (162, 360, 361). Cyclosporine has also proved The best results with thalidomide in CP have been effective in pruritus associated with refractory chronic ur- achieved in PN. Several studies have shown a rapid ticaria (362). Cyclosporine has been administered in PN decrease in pruritus on thalidomide (50–300 mg/day) for 24–36 weeks, using doses of 3.0–4.5 mg/kg/day. Im- (351, 352). In a very recent review the authors refer to provement was observed in both pruritus and skin lesions how patients were started on higher doses of 200 mg or after 2 weeks of treatment (363, 364). It seems likely that, more daily in earlier studies (353). In the majority of in these diseases, cyclosporine acts on pruritus through Advances in dermatology and venereology studies since then, however, patients received an initial its immunological effects. However, direct effects on dose ranging from 50 to 200 mg/day, following which nerve endings are also possible (365). Successful use of the dosage was tailored according to response or the cyclosporine in non-immunological disease was repor- development of side effects. A prospective open trial of ted in several studies, e. g. 10 patients with pruritus of thalidomide 100 mg/day, followed by NB-UVB (TL- senescence were treated with cyclosporine 5 mg/kg/day 01) showed a high response with minimal side effects for 8 weeks (366). All patients in this uncontrolled, open (354). Likewise, good results have been seen in HIV- study responded. Case reports describe antipruritic effects positive patients with PN (355). There is one randomised, in dystrophic epidermolysis bullosa-associated CP (367). double-blind cross-over trial of the successful treatment Methotrexate, licensed for psoriasis, has proved effec- of CKD-associated pruritus with thalidomide (356). tive for psoriasis-associated pruritus (368). Patients with Thalidomide is teratogenic and there is a dose-related severe AD refractory to topical therapy may respond to risk of neuropathy, especially in high daily doses (> 100 methotrexate with greatly reduced pruritus (162, 369). mg/day) (357). In most cases the peripheral neuropathy In a retrospective report on 13 patients with CNPG, 10 is reversible (353). Thalidomide could be considered markedly improved on methotrexate at doses of 7.5–20 particularly in a palliative setting (358). mg once weekly for a minimum of 6 months (370). In The scarce information on lenalidomide, a more potent a recent multicenter study, a 90% overall response rate analogue of thalidomide, seems promising (359). More was reported in 39 patients with difficult-to-treat prurigo studies are needed to evaluate the effectiveness and using methotrexate with a median weekly dose of 15 tolerability of this analogue of thalidomide. mg (371). Acta Derm Venereol 2019 488 E. Weisshaar et al. Azathioprine, licensed as a corticosteroid-sparing drug the levels of free IgE and the density of the high-affinity for blistering diseases, has proved effective in pruritus IgE receptor, both of which are essential in mast cell ActaDV associated with bullous pemphigoid in doses of 50–200 and basophil activation and consequently degranulation mg/day (372). Patients with severe AD refractory to to- (388). Omalizumab was approved in 2014 in Europe pical therapy may respond to azathioprine with greatly (300 mg) and the US (150 and 300 mg), administered reduced pruritus (162, 369). In a retrospective review subcutaneously every 4 weeks for recalcitrant chronic 96 patients with life-altering CP who had previously spontaneous urticaria refractory to H1-antihistamines in responded to systemic steroids were reported. A daily adults and children (aged 12 years and above). The itch azathioprine dose ranging from 25 to 275 mg resulted severity score was the primary endpoint assessed in the in relief of pruritus with a reduction in VAS from 9.2 phase III clinical trials. Omalizumab showed effective Acta Dermato-Venereologica prior to treatment to 1.6 post treatment. The mean dura- and rapid reduction of itch in a dose-dependent manner tion of therapy in this study was 53 months and 33% of that was maintained over the treatment period. An im- the patients were forced to discontinue treatment due to provement in the number of hives, need for emergency adverse drug effects (373). medication and quality of life of patients with chronic Data on systemic treatment with tacrolimus in CP spontaneous urticaria, as well as good tolerance and sa- are sparse. Besides case reports (374), one open-label fety profiles, were also reported (389–391). A clinically study on a sequential treatment with oral (6 weeks) and relevant response is seen within a few weeks of initial topical tacrolimus (11 weeks) in 12 patients with severe administration. Side effects are usually mild or moderate AD resulted in a substantial reduction in pruritus (375). and include mainly headache, nasopharyngitis, myalgia In contrast to these results, a case series in 4 patients and local symptoms at the injection site. with AD treated with 5 mg tacrolimus twice daily for 14 With regard to AD, monoclonal antibodies that block months showed poor results in 3 of the patients (376). signalling of both IL-4 and IL-13, key T helper cell 2 Expert recommendation: We suggest cyclosporine, met- (Th2) cytokines, are in development. Dupilumab, a fully hotrexate and azathioprine for refractory CP associated human monoclonal antibody directed against the IL-4 with inflammatory dermatoses and CPG. receptor α (IL-4R α), has been shown to be efficient in controlling patients’ assessment of CP as measured by 6.4.11. Neurokinin receptor 1 antagonist. Substance P the pruritus NRS score at week 16, with a significant (SP) plays a dominant role in pruritus induction after reduction of pruritus seen as early as week 1 (dupilumab ActaDV release from cutaneous sensory neurons. Via binding 300 mg once a week) in severe adult AD patients in the to the neurokinin 1 receptor (NK1R) on keratinocytes, phase 2b trial (392) A number of trials are currently blood vessels and mast cells, SP promotes inflammation ongoing with different targets such as IL-31, IL-22, and mast cell degranulation. Cutaneous SP levels are TSLP and CRTH. increased in conditions with hyperplasia of skin nerves Pruritus-reducing effects of biologic treatment on (AD, PN). Accordingly, inhibition of the pruritogenic psoriatic pruritus have been reported (393-401). One effects of SP by blocking the corresponding receptor single report of cases referred to persistent CP (402). may have antipruritic effects. Several case series and Secukinumab significantly improved CP in a phase 3 case reports suggest a positive role of the NK1R anta- study (398). Ixekizumab showed long-term effects on CP Advances in dermatology and venereology gonist aprepitant in CP, e.g. cutaneous T-cell lymphoma, in psoriasis in a phase 3 clinical trial and maintenance solid tumours, drug-induced pruritus, CP with atopic therapy sustained improvements in psoriasis severity predisposition and CNPG (377–382). However, recent over more than 1 year (397, 400). According to a sys- controlled trials including a randomized double-blind, tematic review anti-IL 17, JAK inhibitors, adalimumab, placebo-controlled phase-II study using topical or sys- and apremilast are effective in reducing CP in psoriasis, temic aprepitant failed to show a benefit compared to with anti-IL-17 showing the largest effect in reducing placebo (383–385). Serlopitant is a novel NK1R anta- psoriasis (401). gonist that can be administered for long-term therapy. According to the different pathogenic mechanisms in- RCTs demonstrated a significant effect on pruritus of volved in pruritus, potential new monoclonal antibodies CPG and was well tolerated (386, 387). will be developed that, e.g. target Na V1.7, a voltage Expert recommendation: We suggest NKR1 antagonists sensor for pain and itch relief (403). However, these such as serlopitant in refractory CP and CPG. developments lie in the future. Expert recommendation: We suggest omalizumab for 6.4.12. Biologics. Biologic therapies have burst onto the refractory CP in CSU and dupilumab for refractory CP armamentarium to treat CP in certain cutaneous diseases. in AD. We cannot make a recommendation with respect In addition, some biologic approaches have been deve- to the use of monoclonal antibodies in CP of other origin. loped to control CP alone. This is the case with omalizu- mab for CSU. This humanized recombinant monoclonal 6.4.13. Physical treatment modalities. Physical treat- antibody binds specifically to the Cε3 domain of the im- ments such as transcutaneous electrical (field) stimulation munoglobulin E (IgE) heavy chain. Omalizumab reduces and acupuncture have been described for the treatment www.medicaljournals.se/acta European Guideline on Chronic Pruritus 489 of CP (404, 405). Acupuncture is the oldest and best In an open trial on 19 patients (16 patients with neuro- studied alternative option with evidence-based effect on pathic pruritus and 3 patients with generalized pruritus) ActaDV pain, but much less evidence of its antipruritic effects. using CFS once daily for 25 min for 5 weeks, pruritus A few placebo-controlled experimental studies have was reduced by 49% at the end of treatment (419). Skin shown that local treatment with acupuncture needling biopsies revealed a significant reduction in epidermal reduces histaminergic itch in healthy volunteers and nerve fibres following the treatment (419). In this study, allergen-induced itch in patients with AD (406–408). The pruritus relapsed gradually after discontinuation of CFS, effect of acupuncture on sensory innervation in the skin indicating nerve fibre regeneration in the epidermis. was investigated in 10 subjects that were treated with Expert recommendation: We cannot make a recom- 10 acupuncture needles subcutaneously during twice- mendation with respect to physical treatment for the Acta Dermato-Venereologica weekly 25-min sessions over 5 weeks and skin biopsies treatment of CP. revealed reduced density of sensory nerve fibres (409). In a retrospective study, symptomatic relief of neuro- 6.5. Ultraviolet phototherapy pathic pruritus (brachioradial CP, notalgia paresthetica, meralgia paresthetica) in 12 of 16 patients treated with UV-based therapy is well established for treating pruritus acupuncture was reported (410). Relapse occurred in and utilizes UVB (290–320 nm) and UVA (320–400 37% of patients within 1–12 months following treat- nm). The light sources include broadband UVB (BB- ment. In a placebo-controlled study of 6 patients with UVB, 290–320 nm, peaks at 313 nm), narrowband intractable pruritus in CKD, electrical needle stimulation UVB (NB-UVB, 311 nm), broadband UVA (320–400 at the point of the elbow reduced severity, frequency nm, peaks at 355 nm) and UVA1 (340–400 nm, peaks at and distribution of itch both day and night (410), while 365 nm) (420). Immunomodulatory effects due mostly control treatment with superficial electrical stimulation to the release of anti-inflammatory neuropeptides, or was ineffective. Che-Yi et al. randomised 40 patients with the inhibition of pro-inflammatory mediators (e.g. IL-1, refractory uremic pruritus into two groups: acupuncture TNFa), make these different UV treatments particularly needling was applied either unilaterally at the acupoint useful for treating pruritus associated with inflammatory of the elbow or at a non-acupoint (control). The patients dermatoses (421). were treated 3 times weekly for 1 month. At the end of For the treatment of AD, phototherapy is a common the treatment period and at 3 months follow-up, only and valid treatment, inhibiting pruritus by reducing ActaDV the acupoint group showed a 50% reduction in pruritus numbers of nerve fibres in the epidermis and normali- (411). The rationale for the use of acupuncture in the sing the expression of axonal guidance molecules (e.g. treatment of itch, as well as its effects in uremic pruritus nerve growth factor, semaphorin 3A) in atopic skin (422, and allergic diseases has been reviewed (409, 412, 413). 423). Treatment with phototherapy can improve, or even A double-blind randomised placebo-controlled study resolve, AD with remission of up to 6 months and no in 30 patients with AD revealed that acupuncture achie- reported serious adverse effects in the short-term (5). ved a significant reduction of itch (414). In another study Preference is given to UVA-1 and NB-UVB as modali- in 40 patients with refractory UP, an acupuncture needle ties, since both have been found to be equally effective was inserted at the Quchi acupoint and then removed after in improving pruritus of AD, although it is noted that Advances in dermatology and venereology 1 h. Patients undergoing this treatment showed a sub- NB-UVB has the dual advantage of less heat load and stantial improvement in itch compared to controls (411). shorter duration of phototherapy (424, 425). Systemic Transcutaneous electrical nerve stimulation (TENS), PUVA has also been shown to effectively treat the itch which activates electrically myelinated nerve fibres (α of AD, but with side effects including burning, pain, and δ), is widely used for the treatment of chronic pain nausea, headache, erythema and lentigenes (426). A (415). Fjellner & Hägermark studied the effect of TENS study comparing bath-PUVA with NB-UVB found both on CP of various origin in 41 patients for 5–47 days. to be very effective measures, reporting that relief from Initially, TENS ameliorated pruritus in 63% of patients, pruritus was usually achieved in the first 2 weeks, and but the effect declined over the course of therapy and consistently preceded the resolution of skin lesions (427). was regarded as placebo (416). UVB laser may be still more effective than NB-UVB, Another technique, cutaneous field stimulation (CFS), with localised AD and associated pruritus being suc- was developed to electrically stimulate unmyelinated C- cessfully treated with 308-nm xenon chloride excimer fibres at the dermo-epidermal junction in order to treat laser (428). pruritus (417). In an experimental study on 21 subjects, Both AD and lichen amyloidosis have been success- the pruritus induced by histamine iontophoresis was fully treated by combinations of NV-UVB with steroids completely abolished by CFS (417). In a controlled or cyclosporine A (421). study, 27 atopic patients with CP were treated with CFS For the treatment of CPG, PUVA, UVA1 and NB-UVB and TENS (418), CP was significantly surpressed for 7 proved to be effective in a RCT, with PUVA and UVA1 h after cessation of CFS, but not after TENS. superior to NB-UVB (429). Acta Derm Venereol 2019 490 E. Weisshaar et al. For many other skin diseases, a number of studies have with 21 patients (33% primary pruritus, 66% eosinophilic demonstrated the efficacy of UV treatment, e.g. psoria- folliculitis) (452). Phototherapy has been useful in trea- ActaDV sis, lichen planus, T-cell lymphoma, solar, chronic and ting idiopathic pruritus in some HIV patients, as well as idiopathic urticaria, as well as urticaria pigmentosa and HIV-associated dermatoses (453). folliculitis of pregnancy (421, 430). UVB mainly affects Common adverse effects of UVB phototherapy are epidermal keratinocytes and Langerhans cells, due to tanning and erythema. Both UVA and UVB have been its limited penetration into the skin. UVA1, in contrast, associated with skin ageing. The potential carcinogenic reaches to the dermis and therefore can affect T lympho- effect of phototherapy is of concern. In general, the use cytes, mast cells and dermal dendritic cells, e.g. induces of UVB has shown no or little association with skin can- apoptosis of these cells (420). However, UVB-induced cer and is considered a very safe treatment option (454, Acta Dermato-Venereologica apoptosis of mast cells has been postulated to explain re- 455). However, studies of PUVA-treated patients and lief of pruritus (431). Furthermore, phototherapy leads to associated cancer risk have reported increased incidence a reduction in CGRP-immunoreactive nerve fibres in the of melanoma (particularly squamous cell carcinoma) and skin (432). No further benefit has been found by adding recommend careful selection of patients with rigorous UVA in combination with NB-UVB phototherapy for the follow-up (456, 457). treatment of pruritic inflammatory skin disease (433). A Expert recommendation: We suggest UVA and UVB novel treatment that has proven beneficial in pilot studies (NB-UVB/BB-UVB) phototherapy for refractory CP is a topical cream that filters solar UVB (434). This has in inflammatory skin diseases, cutaneous lymphoma the advantage of saving time, inconvenience and expense CPG and selected cases of systemic pruritus (e.g. CKD- associated with traditional UV therapy. associated pruritus, cholestatic pruritus, aquagenic pruri- Pruritus associated with mastocytosis can be treated tus). We suggest UV phototherapy in combination with with oral PUVA, although alleviation is only short-term, topical and/or systemic treatment, with the exception of or with NB-UVB if PUVA is not tolerated (435). calcineurin inhibitors and immunosuppressant drugs. UV phototherapy has been used with some success in conditions with pruritus on primarily non-inflamed or 6.6. Treatment in special populations normal appearing skin. It has been particularly effective in many cases of CKD-associated pruritus (224, 436, 6.6.1. Treatment of chronic pruritus in the elderly. El- 437). In an open pilot study using NB-UVB 14/20, CKD- derly patients with CP require special attention, even ActaDV associated pruritus patients responded well to treatment though the general principles of treatment apply. The (438). Also in a recent study NB-UVB appeared to be older patient with CP characteristically presents a mixed effective in the reduction of CKD-associated pruritus clinical picture of comorbidities and polypharmacy, in- (439). However, a later RCT failed to demonstrate a cluding physical and cognitive limitations; some degree significant difference in the reduction of pruritus intensity of xerosis cutis is omnipresent in most cases (458–460). in patients receiving NB-UVB compared with a control Any underlying condition such as CKD, hepatobiliary group (440). In another case NB-UVB treatment was disease or malignancies should be addressed primarily unsuccessful, but BB-UVB helped (441). For end-stage (460). Treatment is therefore challenging and needs to renal disease BB-UVB is recommended at a frequency be tailored to each case. Advances in dermatology and venereology of 3 times per week, tapering to one or two maintenance The application of topical soothing agents and, if re- sessions per week to achieve control of pruritus (442). quired, anti-inflammatory treatment are recommended UV therapy has also been reported to be effective for the management of xerosis. Fingernails should be in a number of cases of pruritus associated with other kept short and soap should be avoided or restricted to the systemic diseases, including hepatic and metabolic dis- axilla, groin, scalp and soles, preferably using acidic pH orders, as well as malignancy (443). BB-UVB was found soap. Furthermore, less frequent bathing, preferably in to reduce cholestatic-induced pruritus in 10/13 patients tepid water, and the avoidance of astringents and lactic (444). In polycythemia vera, 8/10 patients responded to acid (>5%) are also recommended. The application of NB-UVB in an open study (445). In a single case report petroleum-containing moisturisers immediately after a patient with Hodgkin’s disease responded well to BB- bathing is helpful. More aggressive hydration might be UVB (446). necessary: after a 20-min soak, an effective moisturiser Aquagenic pruritus showed response to bath-PUVA is applied on patted-dry skin, which is then covered therapy (447) and systemic PUVA (448, 449) for the with kitchen clingfilm (plastic wrap) or a moist garment. duration of therapy. To treat aquagenic pruritus, PUVA This technique is called the “soak and smear” method was found to be superior to BB-UVB in 5 patients (458, 461). Oatmeal baths can also be useful, likely due (450). Recently, two patients with aquagenic pruritus to the anti-inflammatory properties of oatmeal (462). were reported to show a good, but transient response Other topical treatments with urea solutions, ment- to NB-UVB (451). In HIV patients with pruritus, UVB hol, pramoxine, pimecrolimus, tacrolimus and topical produced significant relief of pruritus in an open study amitriptyline-ketamine with lidocaine can be beneficial; www.medicaljournals.se/acta European Guideline on Chronic Pruritus 491 however, topical corticosteroids should be avoided on corticosteroids were applied over the course of the entire elderly skin due to skin thinness. pregnancy (464). Systemic treatments such as systemic ActaDV Systemic treatment of CP in an elderly patient de- glucocorticosteroids, a limited number of antihistamines mands special caution. Second-generation non-sedating and UV phototherapy, e.g. UVA, may be necessary in antihistamines may be useful, but first-generation severe and generalised forms of CP in pregnancy. UV sedating antihistamines should be avoided, as well as phototherapy is a useful alternative therapy for pruritus tricyclic antidepressants such as doxepin due to anticho- during pregnancy that is refractory to steroids or anti- linergic effects. Long-term systemic steroids should also histamines (421). be avoided, since impaired immunity and comorbidities There is a lack of knowledge concerning the pharma- are often present in the elderly patient (460). The antie- cokinetics of the use of antihistamines during pregnancy. Acta Dermato-Venereologica pileptic drugs gabapentin and pregabalin are useful, The use of first-generation antihistamines is to be avoided but dizziness and sedation may occur with increasing in pregnant women (257); on the other hand, they are dose. In elderly patients, lower dosages of gabapentin also considered safe on the basis that they have already and pregabalin are usually sufficient to control CP. The been prescribed for a very long time. Of the second- tetracyclic antidepressant mirtazapine can be effective generation antihistamines, loratadine and cetirizine are against nocturnal itch (463). SSRIs such as paroxetine the best studied (466). They can be prescribed after the and fluvoxamine are also effective in the elderly, but first trimester in the case of well-considered indications. can exacerbate sexual dysfunction and insomnia (460). Administration immediately prior to or after birth must Sertraline is a good option for the treatment of cholesta- be avoided. NB as well as BB UVB phototherapy is tic itch. The use of µ-opioid receptor antagonists and safe; however, since folic acid levels may decrease with κ-opioid receptor agonists should be approached with both (467), follow-up of folic acid levels is indicated. In caution as a result of hepatotoxicity, gastrointestinal summary, the treatment of pruritus in pregnancy is prima- symptoms and dizziness. Thalidomide might be a good rily focused on topical treatment in order to relieve CP, option for the elderly patient with chronic itch (460). possibly complemented by UV phototherapy. Caution Successful use of cyclosporine was reported in several should be shown with systemic therapy due to possible studies, e. g. 10 patients with pruritus of senescence effects on the foetus. were treated with cyclosporine 5 mg/kg per day for 8 6.6.3. Treatment of chronic pruritus in children. The weeks (366). ActaDV management of CP in children is based on the diagnosed UV phototherapy is an option in the elderly; however, systemic or skin condition. Nevertheless, some general caution must be taken in case of increased photosensiti- considerations must be taken into account once topical vity or phototoxicity caused by multiple drug ingestion or systemic drugs are used, such as the body volume/ (229). Overall, phototherapy such as NB-UVB (TL01) body surface area rate and the total weight. In addition, is a good treatment option, since it can avoid further the licensed age for any drug must be taken into account. polypharmacy; however, skin cancer needs to be borne Individualised management is recommended. in mind. Phototherapy in the elderly depends on the Topical treatments for pruritus should be focussed on patient’s mobility. In summary, treatment of pruritus in the cause if possible. Avoidance of the specific and non- the elderly is primarily focused on efficient hydration of Advances in dermatology and venereology specific provocation factors is necessary. Such factors the skin. Caution should be shown with systemic therapy include, e.g.: inhalants, microbial agents, foods, textiles, due to polypharmacy, interactions and adverse effects. chemicals and emotional stress. The use of emollients 6.6.2. Treatment of chronic pruritus in pregnancy. Due to in an attempt to preserve barrier function is always re- potential effects on the foetus, the treatment of pruritus in quired. Low- (class 1, 2) to medium-strength (class 3) pregnancy requires prudent consideration of whether the glucocorticosteroids may be administered in children. severity of the underlying disease warrants treatment and Topical immunomodulators are used for AD and pruritus careful selection of the safest treatments available. Topi- in children aged 2 years and older, but in some European cal corticosteroids are the most frequently used drugs for countries pimecrolimus, for instance, is licensed for use treating skin conditions and are prescribed to more than in children older than 3 months. Topical capsaicin is not 6% of pregnant women (464). However, little is known used in children <10 years. New topical active princip- about the effects of local corticosteroids on the foetus. les are in development for CP in children, such as a 4% According to a very recent Cochrane review update, cutaneous emulsion of sodium cromoglicate (468) or a there are no causal associations between maternal ex- 2% topical ointment of crisaborole (phosphodiesterase-4 posure to topical corticosteroids of all potencies and inhibitor) (469). pregnancy outcomes, including mode of delivery, The dosages of systemic drugs need to be adjusted congenital abnormalities, preterm delivery, fetal death in children. The most common drugs used to control and low Apgar score (465). A recent study showed a pruritus in AD and CSU in children is an H1-receptor significantly increased risk of low birth weight in cases inverse agonist. The common use of first-generation where more than 300 g of potent or very potent topical antihistamines (e.g. hydroxyzine dichlorhydrate) to Acta Derm Venereol 2019 492 E. Weisshaar et al. avoid scratching during the night in AD has long been 6.7. Psychosomatic therapy (relaxation techniques and discussed based on the controversial role of histamine psychotherapy) ActaDV in dermatitis and on the defined adverse events, e.g. The vicious itch–scratch cycle needs to be considered drowsiness and impaired attention. There is no mecha- when a patient is treated for CP. The psychosomatic nistic rationale for treating non-histaminergic pruritus- approach recognises the pruritus patient with regard to related AD with antihistamines (120). The treatment coping behaviour and possible stress attempts as cause of CSU in infants and children is based on the use of or provocation factors in CP. Essentially, psychosomatic second-generation H1-antihistamines according to the treatment could complement topical and systemic therapy same algorithm recommended for adults (158, 470). and should be differentiated into unimodal psychological Cetirizine, desloratadine, fexofenadine, levocetirizine treatment and multimodal psychological treatment for Acta Dermato-Venereologica and loratadine have been studied in children and their CP (97). Depending on the factors involved, a unimodal long-term safety has been well established in the paedia- (progressive muscular relaxation, autogenic training) or tric population. Rupatadine has been recently approved multimodal psychological approach is recommended for the treatment of CSU in children aged 2–11 years (97). In addition to causal and symptomatic therapy, old based on a double-blind trial showing safe efficacy behavioural therapy to avoid scratching should be con- with respect to placebo at 1 mg/ml (256). Certain anti- sidered, e. g. conscious suppression of the reflex by histamines (e.g. loratadine, ceterizine) are thought to be safer for use in children, and thus may be preferred intense concentration, distraction or alternative scrat- in these patients (206). In children aged under 6 years ching techniques such as habit reversal (472). This is the effective dose of hydroxyzine is up to 50 mg/day in very important in patients with CPG who might show divided doses, and 50–100 mg/day in children aged 6–12 unconscious automatic scratching behaviour. years (243). In summary, for the paediatric management Adjuvant psychosocial programmes focused on CP of pruritus, long-term use of first-generation antihista- are most effective in AD (122, 473–475). Such program- mines is not recommended (158, 208). The associated mes include strategies for breaking the vicious circle of psychomotor impairment may impact the education itching and scratching, relaxation and stress management and safety of children and persists even after the child techniques, as well as strategies for dealing with relapses. has become accustomed to the sedating effects (258). There are more than 10 RCTs showing slightly beneficial Second-generation antihistamines with appropriate dose effects; these were recommended for treatment by a ActaDV adjustment are first-line therapy for CP in children such Cochrane review on psychological interventions (476). as urticaria (259). A similar educational programme was developed for Other therapies could also be considered, such as UV patients with CP (477, 478). It is currently established phototherapy, but the indication and protocol should for in-patient hospital treatment of patients with pruritic be carefully considered together with the family due dermatoses using behavioural therapy in the context of to possible long-term photo damage to the skin. A an integrated psychosomatic treatment (479, 480). In retrospective analysis of children up to the age of 18 patients with coexisting depression, psychotherapy in years suffering from AD and psoriasis suggests NB- combination with psychotropic medication can be helpful UVB treatment (471). In children, longer follow-up is even to treat CP of different aetiology (481). Most pu- Advances in dermatology and venereology essential to determine the true carcinogenic risk of UV blications on psychotherapeutic/ psychopharmacologic therapy. An adjuvant psychological intervention as well interventions, however, refer to small groups or single as an educational approach can also be highly useful in case reports. In neurotic excoriations, combined psy- children (120). chopharmacotherapy is also often indicated (481–484). Other systemic treatments such as cyclosporine are Internet-delivered (eHealth) self-management was not licensed in children younger than 16 years due to a investigated in recent years, mostly with cognitive beha- lack of clinical studies. They may be used in treatment- vioural interventions. Results demonstrate effects similar refractory cases (110). to face-to-face psychotherapy (485). Studies specifically In summary, the treatment of pruritus in children for dermatologic patients are promising (486). is primarily focused on treatment of the skin disease, Expert recommendation: We recommend educational especially AD. Topical corticosteroids, topical immuno- programs. We suggest relaxation and habit reversal techni- modulators and some antihistamines can be administered ques as a complementary treatment for managing CP. in children, but national regulations must be considered. UV phototherapy may be initiated depending on the 7. KEY SUMMARY OF DISCUSSION child’s skin type and age. Caution should be shown with systemic therapy due to the lack of data and off-label • Chronic pruritus is frequent in medicine and needs a use in children. precise diagnostic work-up. Its management compri- www.medicaljournals.se/acta European Guideline on Chronic Pruritus 493 ses treatment of the underlying disease, topical treat- 3. Misery L, Alexandre S, Dutray S, Chastaing M, Consoli SG, Audra H, et al. Functional itch disorder or psycho- ment modalities including symptomatic antipruritic ActaDV genic pruritus: suggested diagnosis criteria from the treatment, UV phototherapy and systemic treatments. French psychodermatology group. Acta Derm Venereol. • Sedative or non-sedating H1 antihistamines are sug- 2007;87(4):341-4. 4. Magerl M, Borzova E, Gimenez-Arnau A, Grattan CE, Lawlor gested as an initial symptomatic therapy in severe CP F, Mathelier-Fusade P, et al. The definition and diagnostic and sleep loss. Studies on the systemic administration testing of physical and cholinergic urticarias--EAACI/ of higher doses of non-sedating antihistamines seem GA2LEN/EDF/UNEV consensus panel recommendations. Allergy. 2009;64(12):1715-21. to be promising, but RCTs need to be conducted. 5. Wollenberg A, Oranje A, Deleuran M, Simon D, Szalai Z, • Systemic glucocorticosteroids are not recommended Kunz B, et al. ETFAD/EADV Eczema task force 2015 position for first-line treatment of CP, with the exception of paper on diagnosis and treatment of atopic dermatitis in adult and paediatric patients. J Eur Acad Dermatol Venereol. Acta Dermato-Venereologica extremely severe and acute cases of inflammatory 2016;30(5):729-47. dermatoses and as a short-term treatment in selected 6. Zuberbier T, Aberer W, Asero R, Abdul Latiff AH, Baker cases of refractory CP, especially in paraneoplastic D, Ballmer-Weber B, et al. The EAACI/GA²LEN/EDF/WAO Guideline for the Definition, Classification, Diagnosis and pruritus and palliative care. Management of Urticaria. The 2017 Revision and Update. • UV phototherapy is recommended for refractory CP Allergy. 2018. in inflammatory skin diseases, cutaneous lymphoma, 7. Salavastru CM, Chosidow O, Boffa MJ, Janier M, Tiplica GS. European guideline for the management of scabies. J Eur CPG and selected cases of systemic pruritus (e.g. Acad Dermatol Venereol. 2017;31(8):1248-53. CKD-associated pruritus, cholestatic pruritus, aqua- 8. Siemens W, Xander C, Meerpohl JJ, Buroh S, Antes G, genic pruritus), especially in elderly pruritus patients Schwarzer G, et al. Pharmacological interventions for pru- ritus in adult palliative care patients. Cochrane Database or in case of contraindications for systemic therapy. Syst Rev. 2016;16(11):CD008320. We suggest UV phototherapy in combination with to- 9. Ständer S, Weisshaar E, Mettang T, Szepietowski JC, pical and/or systemic treatment, with the exception of Carstens E, Ikoma A, et al. Clinical classification of itch: a position paper of the International Forum for the Study of calcineurin inhibitors and immunosuppressant drugs. Itch. Acta Derm Venereol. 2007;87(4):291-4. • Gabapentinoids (gabapentin, pregabalin) are recom- 10. Ständer S, Weisshaar E, Mettang T, Streit M, Darsow U, mended in neuropathic CP and in CKD-associated Schneider G, et al. [Clinical classification of chronic pruri- tus. Interdisciplinary consensus proposal for a diagnostic pruritus and suggested for the treatment of refractory algorithm]. Hautarzt. 2006;57(5):390-4. CP and PUO. 11. Twycross R, Greaves MW, Handwerker H, Jones EA, Libretto • We suggest µ-opioid receptor antagonists in refractory SE, Szepietowski JC, et al. Itch: scratching more than the ActaDV surface. QJM. 2003;96(1):7-26. CP, especially in cholestatic pruritus. 12. Oaklander A. Common neuropathic itch syndromes. Acta • Selected antidepressants are recommended for psy- Derm Venereol. 2012;92(2):118-25. chogenic CP and for refractory CP, especially in 13. Rea JN, Newhouse ML, Halil T. Skin disease in Lambeth. A community study of prevalence and use of medical care. malignant, cholestatic and chronic kidney disease. Br J Prev Soc Med. 1976;30(2):107-14. • Neurokinin receptor 1 antagonists like e.g. serlopitant 14. Zylicz Z, Twycross R, Jones EA. Pruritus in advanced di- can be recommended in refractory CP and CPG. sease. Oxford: Oxford University Press; 2004. 15. Dalgard F, Svensson A, Holm JO, Sundby J. Self-reported • Serotonin receptor antagonists are not recommended skin morbidity in Oslo. Associations with sociodemograp- for the treatment of CP and CPG. hic factors among adults in a cross-sectional study. Br J Advances in dermatology and venereology Dermatol. 2004;151(2):452-7. 16. Dalgard F, Dawn AG, Yosipovitch G. Are itch and chronic pain associated in adults? Results of a large population ACKNOWLEDGEMENTS survey in Norway. Dermatology. 2007;214(4):305-9. We thank Mrs Christine Schaefer for her help with editing, langu- 17. Matterne U, Apfelbacher CJ, Loerbroks A, Schwarzer T, Butt- ner M, Ofenloch R, et al. Prevalence, correlates and cha- age correction and arranging the list of references. racteristics of chronic pruritus: a population-based cross- Conflict of Interest: see Appendix S11. sectional study. Acta Derm Venereol. 2011;91(6):674-9. 18. Matterne U, Apfelbacher CJ, Vogelgsang L, Loerbroks A, Composition of the guideline group: Experts in the field from Weisshaar E. Incidence and determinants of chronic pruri- Europe. 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