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Chronic pruritus (CP) is frequent in general medicine and the most common complaint in general dermatology. The prevalence of CP is expected to rise in the future due to the ageing population. The clinical presentation, underlying aetiology and treatment strategy of CP are heterogeneous. Also, individual treatment aims and physical, psychic and economic burdens of patients might vary. Chronic prurigo (CPG) is the most severe disease in the chronic pruritus spectrum, being associated with long-standing scratch-induced skin lesions and a therapy refractory itch-scratch-cycle. It is thus important to raise disease awareness for CP and CPG in the general public and among decision-makers in the health system. Further, there is a need to support a rational clinical framework to optimize both diagnostics and therapeutics. Currently, there is still a shortcoming regarding approved therapies and understanding CP/CPG as severe medical conditions. Therefore, the EADV Task Force Pruritus decided to publish this white paper based on several consensus meetings. The group consented on the following goals: (a) ensure that CP is recognized as a serious condition, (b) increase public awareness and understanding of CP and CPG as chronic and burdensome diseases that can greatly affect a person's quality of life, (c) clarify that in most cases CP and CPG are non-communicable and not caused by a psychiatric disease, (d) improve the support and treatment given to patients with CP to help them manage their disease and (e) publicize existing therapies including current guidelines. We aim to point to necessary improvements in access and quality of care directed to decision-makers in health policy, among payers and administrations as well as in practical care., (© 2024 The Authors. Journal of the European Academy of Dermatology and Venereology published by John Wiley & Sons Ltd on behalf of European Academy of Dermatology and Venereology.)

Background: The complexity, high prevalence, and substantial personal and socioeconomic burden collectively render atopic dermatitis (AD) a major public health concern. Using crowdsourced Internet data has the potential to provide unique insights into this concern, as demonstrated by several previous studies. However, a comprehensive comparison across European countries remains lacking., Objectives: The study aimed to investigate AD-related web searches across Europe to assess spatiotemporal variations and associations between disease-related and external factors., Methods: AD-related web search data were extracted for 21 European countries between February 2019 and January 2023. Descriptive analysis and autocorrelation functions were performed to examine spatiotemporal patterns. Correlations (r) were used to evaluate the associations between web searches and disease-related, socioeconomic and meteorological data., Results: Over 241 million AD-related web searches were identified, with search volume varying substantially among European countries (p < 0.001) and correlating with AD prevalence and disease burden (both r = 0.51, p = 0.019). Search volume increased between 2019 and 2023 in all countries and seasonally peaked in January and March. Negative correlations with median population age (r = -0.46, p = 0.039), number of general practitioners (r = -0.29, p = 0.226) and specialists (r = -0.27, p = 0.270) were observed. Moderate to strong correlations were found between search volume and cold, humid and windy weather with fewer sunshine hours, while higher online interest typically occurred 1-3 months after such weather conditions., Conclusion: The study highlights the great potential of online crowdsourced data analysis, for example, to investigate the impact of climate change or to identify unmet needs at a population level. Furthermore, the growing online interest in AD and the corresponding seasonal peaks emphasize the necessity of adapting treatment plans, intensifying public health campaigns, and disseminating reliable online information by governments and healthcare providers, especially during these periods., (© 2024 The Authors. Journal of the European Academy of Dermatology and Venereology published by John Wiley & Sons Ltd on behalf of European Academy of Dermatology and Venereology.)

The global application of the skin prick test (SPT) is attributed to the low costs, easy execution, and in vivo approach. Still, the healthcare professionals' technique and the lancet shape may challenge the standardization of the method. Thus, we investigated the influence of the shape of the lancet and the applied weight on the wheal size of SPT. Two allergic and one non-allergic individual were tested with allergens ( Dermatophagoides pteronyssinus and Phleum pratense ) and histamine solution (positive control), respectively. Horizontally (HS) and diagonally (DS) shouldered lancets with the same tip length (1 mm) were tested under two different conditions: either 60 g or 120 g weight pressure. The wheal size induced by the 4 different combinations was measured. The higher-weight device (120 g) induced a significantly larger and less variable wheal response with the tested allergens and histamine. However, the shape of the lancet affected the wheal size more than the applied weight. The least variable response was measured to histamine for the horizontal-shouldered lancet combined with the higher weight, whereas the same lancet with the lower weight resulted in a significant number of false negative results., Competing Interests: All authors state no conflict of interest., (© 2024 The Authors.)

Treating atopic dermatitis (AD) in pregnant or breastfeeding women, and in women and men with AD aspiring to be parents is difficult and characterized by uncertainty, as evidence to inform decision-making on systemic anti-inflammatory treatment is limited. This project mapped consensus across dermatologists, obstetricians and patients in Northwestern Europe to build practical advice for managing AD with systemic anti-inflammatory treatment in men and women of reproductive age. Twenty-one individuals (sixteen dermatologists, two obstetricians and three patients) participated in a two-round Delphi process. Full consensus was reached on 32 statements, partial consensus on four statements and no consensus on four statements. Cyclosporine A was the first-choice long-term systemic AD treatment for women preconception, during pregnancy and when breastfeeding, with short-course prednisolone for flare management. No consensus was reached on second-choice systemics preconception or during pregnancy, although during breastfeeding dupilumab and azathioprine were deemed suitable. It may be appropriate to discuss continuing an existing systemic AD medication with a woman if it provides good disease control and its benefits in pregnancy outweigh its risks. Janus kinase (JAK) inhibitors, methotrexate and mycophenolate mofetil should be avoided by women during preconception, pregnancy and breastfeeding, with medication-specific washout periods advised. For men preconception: cyclosporine A, azathioprine, dupilumab and corticosteroids are appropriate; a 3-month washout prior to conception is desirable for methotrexate and mycophenolate mofetil; there was no consensus on JAK inhibitors. Patient and clinician education on appropriate (and inappropriate) AD treatments for use in pregnancy is vital. A shared-care framework for interdisciplinary management of AD patients is advocated and outlined. This consensus provides interdisciplinary clinical guidance to clinicians who care for patients with AD before, during and after pregnancy. While systemic AD medications are used uncommonly in this patient group, considerations in this article may help patients with severe refractory AD., (© 2023 The Authors. Journal of the European Academy of Dermatology and Venereology published by John Wiley & Sons Ltd on behalf of European Academy of Dermatology and Venereology.)

Atopic dermatitis (AD) is a chronic, pruritic and inflammatory, dry skin condition with many known comorbidities. These include airway disease, food allergies, atopic eye disease and autoimmune conditions. Furthermore, there is often significant sleep disturbance as well as increased psychological distress and mental health problems. Severe AD therefore often has a significant impact on the quality of life of both patients and their families. In this review we discuss recent findings on the putative links between AD, its association with itch, sleep disturbance and neuropsychiatric morbidity, including the role of inflammation in these conditions. Itch was thought to predominantly drive sleep disruption in AD. We now understand changes in sleep influence immune cell distribution and the associated inflammatory cytokines, which suggests a bidirectional relationship between AD and sleep. We also increasingly recognize inflammation as a key driver in psychological symptoms and disorders. The link between cutaneous, systemic and possible brain inflammation could at least in part be driven by the sleep deprivation and itch-driven neuronal proliferation seen in AD., (© 2023 The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Background: Asthma is a chronic inflammatory disorder of the airways and one of the most important non-communicable diseases worldwide. Analyzing crowdsourced data can help understand public interest and unmet needs as well as potential factors influencing search behavior., Objective: The study aimed to investigate asthma-related web search data in Europe to identify possible regional and seasonal variations and to assess public interest., Methods: Google Ads Keyword Planner was used to measure search volume for search terms related to asthma , allergic asthma , and bronchial asthma in 21 European countries between January 2018 and December 2021. The top 10 keywords of each country were categorized qualitatively. Search volume per 100 000 inhabitants was descriptively assessed in terms of regional and seasonal trends. Spearman correlations between search volume and pollen concentration as well as coronavirus disease (COVID-19) cases were investigated., Results: The median search volume per 100 000 inhabitants for asthma and allergic asthma was highest in Northern and Western Europe, while the highest search volume for bronchial asthma was observed in Western and Eastern regions. A seasonal trend was identified for all search terms and in all regions. Correlations were found between search frequency and pollen load and search behavior and COVID-19 cases. Overall, Europeans were most interested in the diseases in general, their treatment options, and symptoms., Conclusion: These results highlighted the need for reliable and region-specific information about the disease and for public campaigns to improve asthma control. The study also emphasizes the importance of using crowdsourced data for a more encompassing overview beyond conventional healthcare data., Competing Interests: HW, SZ, AK, CTH, GZ, ES, AD, MB, LS, MS, TT, NB, PC, JB, TB and AZ have no conflicts of interest to declare relating to this work. LT was employed by ViiV Healthcare after the study was conducted. JE has participated in Advisory Board for AstraZeneca., (© 2023 The Author(s).)

Recruitment to the local tissue and alerted phenotype are the hallmarks of basophils in chronic urticaria (CU). Chemokine receptors such as chemokine (C-C motif) receptor 4 (CCR4) or CCR8 have been studied in skin diseases, e.g., atopic dermatitis, but not in CU. In this study, we aimed to define CU's basophil homing potential and receptor profile and the effect of Omalizumab treatment on these. Unstimulated and activated (anti-IgE, fMLP, C5a, and Substance P) whole blood basophils from 11 Omalizumab-treated CU patients and 10 healthy subjects were investigated with flow cytometry. Unstimulated basophils in CU showed higher expression of the skin-associated (CCR8) and scavenger (CCX-CKR) receptors and lower expression of the lung-associated (CCR3) receptor in contrast to healthy ones. IgE-mediated activation increased the percentage of CCR8 and CCX-CKR in CU compared to healthy group and elevated the expression of the lung-associated chemokine receptor, XCR1, in all groups. A trend of augmented expression of the coagulation cascade (CD87) and fMLP (FPR1) receptors was seen on basophils in CU, while a tendency of reduced expression was seen for itch (IL-31RA) and immunotolerance (CD109) receptors. fMLP and C5a increased the expression of CCR4, CCR8, CCX-CKR, and CD87 and decreased CCR2 and CCR3, though no changes between the groups were found. In conclusion, CU basophils exhibit skin-homing potential amplified by IgE-mediated stimulation.

Background: Evaluation of effectiveness and safety of new systemic treatments for atopic dermatitis (AD) after approval is important. There are few published data exceeding 52-week therapy with dupilumab., Objectives: To examine the safety, effectiveness and drug survival of dupilumab in a Danish nationwide cohort with moderate-to-severe AD up to 104 weeks exposure., Methods: We included 347 adult patients with AD who were treated with dupilumab and registered in the SCRATCH registry during 2017-2022., Results: At all visits, we observed improvement in AD severity measured by Eczema Area and Severity Index (EASI) [median (IQR)]. EASI score at baseline was 18.0 (10.6-25.2), at week 4: 6.5 (3.5-11.6), at week 16: 3.7 (1.2-6.2), at week 52: 2.0 (0.8-3.6), at week 104: 1.7 (0.8-3.8). While drug survival was high (week 52: 90%; week 104: 86%), AD in the head-and-neck area remained present in most patients at high levels; proportion with head-and-neck AD at baseline was 76% and 68% at week 104. 35% of patients reported any AE. Conjunctivitis was the most frequent (25% of all patients) and median time to first registration of conjunctivitis was 201 days., Conclusions: While 2-year drug survival was 86%, dupilumab was unable to effectively treat AD in the head-and-neck area, and conjunctivitis was found in 25% of patients., (© 2023 The Authors. Journal of the European Academy of Dermatology and Venereology published by John Wiley & Sons Ltd on behalf of European Academy of Dermatology and Venereology.)

Background: According to their parents, some children with aluminium contact allergy and vaccination granulomas may react to aluminium-containing foods by developing dermatitis, granuloma itch and subjective symptoms., Objectives: The objective of this study is to determine whether oral intake of aluminium-containing pancakes can cause adverse events and/or systemic contact dermatitis (SCD) in children with vaccination granulomas and aluminium contact allergy., Patients/methods: A total of 15 children aged 3-9 years (mean age, 5 years) with vaccination granulomas and positive patch-test results to aluminium chloride hexahydrate 2%/10% pet. completed a 3-week blinded randomized controlled crossover oral aluminium/placebo provocation study with pancakes. Granuloma itch and other subjective symptoms were evaluated daily on a visual analogue scale (VAS). Dermatitis was evaluated by the primary investigator, and sleep patterns were tracked with an electronic device. Aluminium bioavailability was assessed by measuring aluminium excretion in the urine. The children served as their own controls with the placebo provocations., Results: All 15 children completed the study. The mean VAS scores were slightly higher during aluminium provocations compared with placebo for granuloma itch (mean VAS, 1.5 vs. 1.4, p = 0.6) but identical for other subjective symptoms (0.6 vs. 0.6, p = 1). There were no differences in sleep patterns and no significant correlation between urinary aluminium excretion and symptom severity. Three children developed a symmetrical rash on the face or buttocks on day 4 of the aluminium provocations, but not during placebo provocations., Conclusions: No difference was found between oral aluminium intake and the occurrence of subjective symptoms and granuloma itch, but on a case-basis oral aluminium may be associated with the development of systemic contact dermatitis., (© 2022 European Academy of Dermatology and Venereology.)

Background: Chronic urticaria (CU) is a skin condition driven by mast cells and basophils. The exact responsiveness profile of these cells, especially regarding the anti-IgE treatment, Omalizumab, is not fully investigated. We sought to characterize the surface activation profile of basophils in CU during Omalizumab treatment and their responsiveness to IgE and non-IgE stimulation., Methods: Whole blood basophils from 11 CU patients and 10 healthy controls were stimulated with either medium, anti-IgE, fMLP, C5a, or Substance P for 30 min and characterized by flow cytometry., Results: CU patients showed a broad range of basophil count as opposed to healthy subjects. An increased number of unstimulated CD69 + ( p  = 0.05), but not CD63 + basophils was observed in CU groups in comparison to healthy. The expression of CD203c and CD200R were comparable between all groups, whilst the FcεRI was reduced with the treatment. Both IgE and non-IgE mediated stimulations upregulated CD63, CD203c and CD200R, but not CD69 in all groups, however, no difference between the groups was observed. Among unstimulated basophils, expression of MRGPRX2 was higher in CU patients after Omalizumab treatment than in the healthy group (2.4% vs. 1.5%, p  = 0.01). The anti-IgE stimulation increased the number of MRGPRX2-expressing basophils in the CU group before and after omalizumab as compared to the healthy ( p  = 0.003; p  = 0.005). The fMLP and C5a stimulations showed a similar effect to the IgE-mediated stimulation. The MRGPRX2 ligand, Substance P did not activate basophils., Conclusion: CU basophils show increased expression of MRGPRX2 after IgE and non-IgE stimulation., Competing Interests: All authors declare no conflicts of interest., (© 2022 The Authors. Skin Health and Disease published by John Wiley & Sons Ltd on behalf of British Association of Dermatologists.)

Chronic itch is a socioeconomic burden with limited management options. Non-histaminergic itch, involved in problematic pathological itch conditions, is transmitted by a subgroup of polymodal C-fibres. Cowhage is traditionally used for studying experimentally induced non-histaminergic itch in humans but encounters some limitations. The present study, therefore, aims to design a new human, experimental model of non-histaminergic itch based on the application of bovine adrenal medulla (BAM)8-22, an endogenous peptide that activates the MrgprX1 receptor. Twenty-two healthy subjects were recruited. Different concentrations (0.5, 1 and 2 mg/ml) of BAM8-22 solution and vehicle, applied by a single skin prick test (SPT), were tested in the first session. In the second session, the BAM8-22 solution (1 mg/ml) was applied by different number of SPTs (1, 5 and 25) and by heat-inactivated cowhage spicules coated with BAM8-22. Provoked itch and pain intensities were monitored for 9 min, followed by the measurement of superficial blood perfusion (SBP) and mechanical and thermal sensitivities. BAM8-22 induced itch at the concentration of 1, 2 mg/ml (p < 0.05) and with the significantly highest intensity when applied through BAM8-22 spicules (p < 0.001). No concomitant pain sensation or increased SBP was observed. SBP increased only in the 25 SPTs area probably due to microtrauma from the multiple skin penetrations. Mechanical and thermal sensitivities were not affected by any of the applications. BAM8-22 applied through heat-inactivated spicules was the most efficient method to induce itch (without pain or changes in SBP and mechanical and thermal sensitivities) suggesting BAM8-22 as a novel non-histaminergic, human, experimental itch model., (© 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Data from real-world use of new systemic treatments in atopic dermatitis (AD) is important for assessing safety and efficacy. The aim of this study is to describe the baseline characteristics of adult patients with moderate-to-severe AD enrolled in the Danish nationwide Severe and ChRonic Atopic dermatitis Treatment CoHort (SCRATCH) database, between October 2017 and August 2021. A total of 282 adult patients were included. Most (62%) were men, the median age at baseline was 43 years (interquartile range (IQR) 29-54 years), and median age at onset of AD was 1 year (IQR 0-6 years). The median Eczema Area and Severity Index at treatment initiation was 19.1 (IQR 11.9-25.7); median Patient Oriented Eczema Measure 21.0 (IQR 16.0-25.0); median Dermatology Life Quality Index 13.0 (IQR 7.0-19.0); and median itch and sleep numerical rating scale scores 8.0 (IQR 6.0-9.0) and 6.0 (IQR 4.0-8.0). Differences were found between the sexes. This registry will provide a source for future efficacy and safety studies.

Background: Parents report that children with aluminium contact allergy and vaccination granulomas may react to aluminium-containing sunscreen following application., Objectives: To evaluate whether contact dermatitis develops following repeated application of aluminium-containing sunscreens in children with aluminium sensitization and vaccination granulomas., Methods: Sixteen children aged 2-9 years (mean age 5 years) with vaccination granulomas and a positive patch test reaction to aluminium chloride hexahydrate 2%/10% petrolatum completed a blinded repeated open application test (ROAT) with two daily applications of two sunscreens for 14 days. One cream contained aluminium and the other did not. The children served as their own controls., Results: Sixteen children completed the study. Only one child (6%) had a positive skin reaction during ROAT on day 2 to the sunscreen with aluminium. None reacted to the sunscreen without aluminium., Conclusions: Use of aluminium-containing sunscreens may on a case basis lead to allergic contact dermatitis in aluminium allergic children., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Subpopulations of primary nociceptors (C- and Aδ-fibers), express the TRPV1 receptor for heat and capsaicin. During cutaneous inflammation, these afferents may become sensitized, leading to primary hyperalgesia. It is known that TRPV1 + nociceptors are involved in heat hyperalgesia; however, their involvement in mechanical hyperalgesia is unclear. This study explored the contribution of capsaicin-sensitive nociceptors in the development of mechanical and heat hyperalgesia in humans following ultraviolet-B (UVB) irradiation. Skin areas in 18 healthy volunteers were randomized to treatment with 8% capsaicin/vehicle patches for 24 h. After patches removal, one capsaicin-treated area and one vehicle area were irradiated with 2xMED (minimal erythema dose) of UVB. 1, 3 and 7 days post-UVB exposure, tests were performed to evaluate the development of UVB-induced cutaneous hyperalgesia: thermal detection and pain thresholds, pain sensitivity to supra-threshold heat stimuli, mechanical pain threshold and sensitivity, touch pleasantness, trans-epidermal water loss (TEWL), inflammatory response, pigmentation and micro-vascular reactivity. Capsaicin pre-treatment, in the UVB-irradiated area (Capsaicin + UVB area), increased heat pain thresholds (P < 0.05), and decreased supra-threshold heat pain sensitivity (P < 0.05) 1, 3 and 7 days post-UVB irradiation, while mechanical hyperalgesia resulted unchanged (P > 0.2). No effects of capsaicin were reported on touch pleasantness (P = 1), TEWL (P = 0.31), inflammatory response and pigmentation (P > 0.3) or micro-vascular reactivity (P > 0.8) in response to the UVB irradiation. 8% capsaicin ablation predominantly defunctionalizes TRPV1 + -expressing cutaneous nociceptors responsible for heat pain transduction, suggesting that sensitization of these fibers is required for development of heat hyperalgesia following cutaneous UVB-induced inflammation but they are likely only partially necessary for the establishment of robust primary mechanical hyperalgesia., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

To prevent pain associated with 8% capsaicin application, pretreatment with local anesthetics, such as EMLA (eutectic mixture of lidocaine 2.5% and prilocaine 2.5%), is considered an option. However, there is contradicting evidence regarding the effects of local analgesia on capsaicin-induced desensitization. In session 1, 2 skin areas in each forearm of 24 healthy volunteers were randomized to 2-hour pretreatment with EMLA/placebo cream. After pretreatment, 8% capsaicin patches were applied for 3 hours in 1 placebo and 1 EMLA pretreated area, obtaining the following four areas: Capsaicin + EMLA, Capsaicin + Placebo, EMLA alone, and Placebo. Pain intensity scores were assessed during the 3-hour application of capsaicin. Warmth detection, heat pain sensitivity, and microvascular reactivity were measured after the removal of capsaicin. After 24 hours, in session 2, all tests were repeated followed by histamine application in each area to examine itch intensity and neurogenic flare. Overall, EMLA caused significant reductions in capsaicin-induced pain compared with placebo (P= .007) and enhanced the capsaicin-induced increase in superficial blood perfusion immediately after the 3-hour capsaicin application (P< .01). Regardless of pretreatment, capsaicin induced heat hyperalgesia immediately after the application (P< .001). Twenty-four hours post application, heat pain sensitivity was normalized. However, WDT increased significantly (P< .001). Capsaicin tended to reduce the itch intensity and significantly reduced the neurogenic flare (P< .05) induced by histamine compared with EMLA alone. The findings suggest that pretreatment with topical analgesic cream reduces application site pain without interfering with the 8% topical capsaicin-induced desensitization. PERSPECTIVE: Pretreatment with local anesthetic EMLA cream might be considered a good therapeutic option to reduce the pain associated with 8% capsaicin application currently used for treatment of neuropathic pain syndromes. This study also suggests the existence of a synergistic effect of capsaicin and EMLA on the process of neurogenic inflammation., (Copyright © 2021 United States Association for the Study of Pain, Inc. Published by Elsevier Inc. All rights reserved.)

Background: Itch is a common symptom in the general population. Affected individuals often do not seek medical consultation and rely on Internet searches to obtain information regarding their itch., Objectives: The aim of this study was to attain insights into common concerns of the general population regarding itch can by analysing itch-related Internet search behaviour., Methods: Google AdWords Keyword Planner was used to assess search volumes for itch-related terms in 15 European countries between September 2014 and August 2018. All identified keywords were qualitatively categorized. Itch-related terms were descriptively analysed and are shown as number of searches/100 000 inhabitants., Results: The search volume for the keyword 'itch' per 100 000 inhabitants was highest in Northern Europe, followed by Eastern, Central and Southern Europe. In 4/15 countries, itch was searched for more often in the autumn/winter months compared to in the spring/summer months. Most itch-related terms were related to dermatological conditions such as inflammatory skin diseases (e.g. psoriasis, atopic dermatitis), allergic or immunologic conditions (e.g. urticaria), and infectious diseases or infestations (e.g. scabies). In terms of body location, genitoanal itch dominated the searches. Symptoms and signs related to itch, possible non-dermatological aetiologies, and treatment options were also among the most searched terms., Conclusions: These analyses provided for the first time insights into the search behaviour patterns related to itch across Europe. People from Northern and Eastern Europe are more likely to seek online information regarding itch. Causes for the itch, especially dermatological conditions, and genitoanal itch are the most important concerns for Internet users. This unconventional and inexpensive method identifies medical needs of people beyond the medical setting, including people who do not seek medical consultation. Accordingly, the data could be used to guide public health interventions and manage respective inhabitants' medical needs., (© 2020 The Authors. Journal of the European Academy of Dermatology and Venereology published by John Wiley & Sons Ltd on behalf of European Academy of Dermatology and Venereology.)

Background: Intradermal testing with delayed reading (IDTdr), used routinely in many centers, may identify delayed reactions to penicillins. However, few studies have compared the results of IDTdr with drug provocation test (DPT). The aim of this study was to examine the proportion of provocation-positive patients testing positive on IDTdr., Methods: Fifty-seven patients with a positive DPT occurring >2 h after intake of penicillin V, dicloxacillin, pivampicillin, or amoxicillin had an IDTdr with penicillin G, amoxicillin, ampicillin, and dicloxacillin. A control group included 18 patients with negative DPTs with the suspected penicillin., Results: In total 25% (n = 14) of provocation-positive patients tested positive on IDTdr. Among patients with positive IDTdr, 9/14 (64%) versus 11/43 (26%) in the IDTdr negative group (p < 0.05) had required oral steroids to treat skin reactions following DPT. No other differences between IDTdr positive and negative groups were found. No controls had a positive IDTdr., Conclusion: Investigating with IDTdr would have identified 25% of patients with a DPT-verified allergy with delayed reactions. It is difficult to target subgroups who will test positive on IDTdr. There were more patients who tested positive on IDT who had received oral steroids after DPT, and this may be an indication that skin reaction severity plays a role in skin testing diagnostics. Further potential predictors for positivity of IDTdr, such as duration of skin symptoms, should be assessed in large studies in order to optimize the investigations of nonimmediate drug allergic reactions., (© 2021 S. Karger AG, Basel.)

Background: Aluminum contact allergy is mostly seen in children with vaccination granulomas, following immunization with aluminum-adsorbed childhood vaccines., Objectives: To characterize a cohort of children with vaccination granulomas and aluminum allergy concerning early life conditions, exacerbating factors, avoidance behavior, treatments, and potential impact on quality of life., Methods: A questionnaire study was conducted among 177 children aged 0 to 15 years with vaccination granulomas and aluminum allergy, and a reference group of 61 children aged 3 to 14 years with various types of dermatitis undergoing patch testing., Results: All children in the granuloma group were reportedly affected by itch. Infection exacerbated the itch in 59%. Other worsening factors were eating tin-foiled/canned food (31%) and use of aluminum-containing sunscreen (46%). Many parents took precautions to avoid aluminum exposure. Children with granulomas were more likely to be nonadherent to the National Vaccination Program than the reference group (27% vs 2%, P < .001). Parents in the granuloma group reported a decreased life quality for both parents and children compared with the reference group., Conclusions: Itching vaccination granulomas and aluminum allergy have a considerable negative impact on affected children and their families, causing avoidance behavior, reduced adherence to vaccination programs, and a negative effect on the overall life quality., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

As well established for patients with chronic pain, patients suffering from chronic itch also exhibit signs of peripheral and central sensitization. This has been linked to parallel neuroplastic sensitization processes. However, for chronic itch, sensitization has not yet been systematically assessed, studied, and hence validated. This review (Prospero CRD42016043002) summarizes and meta-analytically evaluates whether sensory aberrations including sensitization for itch occur in chronic itch. Databases PubMed, Embase, and Cochrane Library were searched for studies investigating somatosensory sensitivity assessment by quantitative sensory testing stimuli, including experimental cutaneous chemical pruritic provocations, in patients with chronic itch from skin/neurological conditions and compared with healthy controls. Outcomes were extracted for lesional and nonlesional skin, and risk of biases were assessed. Meta-analyses were performed when sufficient quantitative data were available. Of 4667 identified articles, 46 were included and 25 were eligible for meta-analyses. Patients (66% atopic dermatitis [AD]) were found more sensitive than the controls to histamine-evoked itch in lesional skin (standardized mean difference [SMD]: 0.66 confidence interval [CI]: 0.16-1.15), but not nonlesionally (SMD: -0.26 [CI: -0.58 to 0.06]). Cowhage did not evoke more itch in nonlesional skin of patients as compared to the controls (SMD: 0.38 [CI: -0.04 to 0.81]). For numerous other chemical provocations as well as for mechanical, thermal, and electrical stimulation paradigms, results were ambiguous or based on few studies. Patients with chronic itch are only robustly sensitized to various chemical pruritic stimuli when applied lesionally. More studies on somatosensory aberrations in chronic itch conditions other than AD are needed to establish whether sensitization is robustly present across chronic itch conditions.

Chronic itch occurs frequently and is a highly distressing symptom, which is associated with a large variety of cutaneous, neuropathic and systemic conditions. The recent advancements in our understanding of itch transmission enables a coherent approach to antipruritic treatment in various common diseases, but accurate diagnosis remains vital. Based on the International Forum for the Study of Itch 2007 classification system this review summarises the first rational clinically based approach to categorising chronic itch conditions. Furthermore, the antipruritic treatment options available for each of the major four aetiological itch condition subcategories are presented.

Background: The term prurigo has been used for many decades in dermatology without clear definition, and currently used terminology of prurigo is inconsistent and confusing. Especially, itch-related prurigo remains unexplored regarding the epidemiology, clinical profile, natural course, underlying causes, available treatments and economic burden, although burdensome and difficult to treat., Objective: To address these issues, the multicentre European Prurigo Project (EPP) was designed to increase knowledge on chronic prurigo (CPG). In the first step, European experts of the EADV Task Force Pruritus (TFP) aimed to achieve a consensus on the definition, classification and terminology of CPG. Additionally, procedures of the cross-sectional EPP were discussed and agreed upon., Methods: Discussions and surveys between members of the TFP served as basis for a consensus conference. Using the Delphi method, consensus was defined as an agreement ≥75% among the present members., Results: Twenty-four members of the TFP participated in the consensus conference. Experts consented that CPG should be used as an umbrella term for the range of clinical manifestations (e.g. papular, nodular, plaque or umbilicated types). CPG is considered a distinct disease defined by the presence of chronic pruritus for ≥6 weeks, history and/or signs of repeated scratching and multiple localized/generalized pruriginous skin lesions (whitish or pink papules, nodules and/or plaques). CPG occurs due to a neuronal sensitization to itch and the development of an itch-scratch cycle., Conclusion: This new definition and terminology of CPG should be implemented in dermatology to harmonize communication in the clinical routine, clinical trials and scientific literature. Acute/subacute forms of prurigo are separated entities, which need to be differentiated from CPG and will be discussed in a next step. In the near future, the cross-sectional EPP will provide relevant clinical data on various aspects of CPG leading to new directions in the scientific investigation of CGP., (© 2017 European Academy of Dermatology and Venereology.)

Itch and pain share numerous mechanistic similarities. Patients with chronic itch conditions (for instance atopic dermatitis or neuropathic itch) often experience symptoms such as mechanical alloknesis and hyperknesis. These dysesthesias are analogous to the pain-associated phenomena allodynia and hyperalgesia, which are often observed, for example, in neuropathic pain conditions. Mechanical itch dysesthesias represent abnormal sensory states (caused by neuroplastic changes), wherein considerable itch is evoked, for instance by light cutaneous stimuli such as from clothing (alloknesis), or where increased itch is perceived in response to normally itch-evoking stimuli (hyperknesis). These itch sensitization phenomena have been explored in experimental human studies, observed in chronic itch patients, and in animal models of itch. Limited attention has been paid to these sensory phenomena in clinical studies, and it is unknown how they respond to antipruritics. Psychophysical quantitative sensory testing can quantify the presence, severity, and spatial extent of itch dysesthesias in chronic itch patients, providing a proxy measurement of itch sensitization. This review outlines current assessment techniques, knowledge on the mechanisms of mechanical alloknesis and hyperknesis, and presents the diverse results derived from clinical studies exploring the presence of itch dysesthesias in chronic itch patients. A key role of quantitative sensory testing and neuronal sensitization in patients with chronic pain is accepted and used in clinical assessments. However, the precise mechanisms and potential clinical implications of itch sensitization in chronic itch patients remain to be evaluated.

Exaggerated itch responses to pruritic chemical provocations and mechanical stimuli are evident in patients with chronic itch, for example, in atopic dermatitis. Currently used human models of itch do not account for such itch sensitization features, and the mechanisms underlying clinical itch sensitization are unknown. This study utilized two established human models of cutaneous nociceptive sensitization to explore how pre-established inflammatory hyperalgesia (ultraviolet-B-irradiation; "UVB") and non-inflammatory neurotrophic pain sensitization (nerve growth factor; "NGF") alter sensitivity to chemical and mechanically evoked itch. Twenty healthy volunteers participated in the UVB experiment. Six volar forearm areas (2 cm diameter) were UVB irradiated with ≤2 × minimal erythemal dose, and two non-irradiated areas were used as controls. Sixteen healthy volunteers participated in the NGF experiment and had 2 μg intradermally injected (4 × 50 μL in 2 cm diameter areas) into both volar forearms. Isotonic saline was applied as control. Pain sensitivity measurements (mechanical and heat pain thresholds) were conducted to validate the models. Subsequently, itch was evoked using histamine and cowhage spicules in the sensitized skin areas, and itch/pain was rated using visual analogue scales. Mechanical hyperknesis (increased itch to punctuate stimuli) was probed with von Frey filaments before/after each itch provocation. Both UVB- and NGF models induced robust primary mechanical hyperalgesia (P < .01) and hyperknesis (P < .05). Neither of the models augmented itch in response to chemical itch provocations but significant increases specifically for pain ratings were observed for both histamine and cowhage (P < .05). This suggests that these models are of limited value as proxies for itch sensitization to pruritogens observed, e.g., in inflammatory dermatoses., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Little is known about endogenous descending control of itch. In chronic pain, descending pain inhibition is reduced as signified by lowered conditioned pain modulation. There are indications that patients with chronic itch may also exhibit reduced endogenous descending inhibition of itch and pain. This study aimed to investigate whether and the extent to which itch can be modulated by conditioning itch and pain stimuli. Twenty-six healthy volunteers participated. The study consisted of 5 conditions designed to systematically assess endogenous modulation of itch or pain: 1) itch-induced modulation of contralateral itch, 2) pain-induced modulation of contralateral itch, 3) pain-induced modulation of ipsilateral itch, 4) pain-induced modulation of contralateral pain, and 5) itch-induced modulation of contralateral pain. Conditioning stimuli were cold pressor-induced pain and histamine-evoked itch, whereas the test stimuli were electrical stimulation paradigms designed to evoke itch or pain. Pain was significantly reduced (conditioned pain modulation-effect) by the conditioning pain stimulus (P < .001), but not by the conditioning itch stimulus (negative control condition). Itch was significantly reduced (conditioned itch modulation-effect) by contra- as well as ipsilateral applied conditioning pain (both P < .001), whereas conditioning itch stimulation only marginally reduced itch. Endogenous descending itch inhibition through mechanisms that are independent of segmental gating can be readily evoked by heterotopic conditioning pain stimulation. However, robust descending inhibition of itch cannot be evoked with conditioning itch stimulation., Perspective: The study showed a hierarchical prioritization favoring pain-induced central descending modulation of itch as well as pain in humans. Future studies addressing potential aberrations in pain-evoked descending modulation of itch in chronic itch patients are warranted., (Copyright © 2017 American Pain Society. Published by Elsevier Inc. All rights reserved.)

Objective: To evaluate the efficacy of transcranially applied pulsed electromagnetic fields (PEMF) on functional impairments and symptom severity in multiple chemical sensitivity (MCS) patients., Methods: The study was conducted as a nationwide trial in Denmark using a randomised, parallel-group, double-blind and placebo-controlled design. Sample size was estimated at 40 participants. Eligibility criteria were age 18-75 years and fulfilment of the MCS case criteria. Participants received either PEMF or placebo PEMF (no stimulation) applied transcranially for 6 weeks. The primary outcome was the Life Impact Scale (LIS) of the Quick Environmental Exposure and Sensitivity Inventory (QEESI). Secondary outcomes were the Symptom Severity Scale (SSS) and the Chemical Intolerance Scale of QEESI., Results: A total of 39 participants were randomised to PEMF or placebo treatment. No significant difference was observed on QEESI LIS between groups with a mean change score of -5.9 in the PEMF group compared with -1.5 in the placebo group (p=0.35, effect size=-0.31). However, a significant decrease was detected on QEESI SSS within and between groups with a mean change score of -11.3 in the PEMF group compared with -3.2 in the placebo group (p=0.03, effect size=-0.60)., Conclusion: PEMF treatment of 6 weeks showed no effect on functional impairments in MCS. However, a significant decrease in symptom severity was observed.

Chronic or episodic severe itch is recurrent in atopic dermatitis (AD). Nonhistaminergic itch pathways are suggested to dominate in AD itch, contributing to an "itch-scratch-itch cycle" that prolongs and worsens itch, pain, and skin lesions. We hypothesized that nonhistaminergic neuronal sensitization contributes to itch in AD. Hence, we compared sensitivity with thermal, mechanical, and chemical pruritic stimuli in patients with AD and controls. The study comprised 25 patients with AD with chronic itch and 25 healthy controls. Questionnaires on itch characteristics were administered, and sensory tests were conducted intralesionally, extralesionally, and in homologous areas of controls. Thermal and mechanical quantitative sensory testing (QST) as well as histamine and cowhage provocations were performed. Subsequently, hyperknesis and vasomotor reactivity were assessed. Average itch and associated pain among patients with AD were 60.7 ± 4.3 and 39.7 ± 5.2 (VAS0-100), respectively. Patients experienced significantly higher itch from cowhage both intralesionally and extralesionally compared with controls, whereas histamine-evoked itch intensity was not significantly different between groups. No group differences were found for thermal quantitative sensory testings or pain evoked by itch provocations. Patients had decreased mechanical detection thresholds intralesionally and increased mechanical pain sensitivity intralesionally and extralesionally. Lastly, patients exhibited intralesional and extralesional hyperknesis before chemical itch provocations and augmented hyperknesis after itch provocations. Increased itch in response to cowhage (but not histamine) suggests nonhistaminergic pathway-specific itch sensitization in AD, whereas increased susceptibility to mechanically evoked itch and pain, particularly intralesionally suggests sensitization of mechanosensitive circuitry not normally associated with itch. Drugs targeting the nonhistaminergic (PAR2/TRPA1) itch pathway and itch sensitization are promising for treating AD itch.

Background: Chronic pain patients with sensitization may exhibit decreased sensitivity to normally pruritogenic sensory stimuli and moreover occasionally perceive these as painful. This study explored the relationship between itch and pain, by evaluating histaminergic and non-histaminergic itch evoked in capsaicin-induced allodynic and hyperalgesic areas., Methods: In 28 healthy volunteers, capsaicin (100 μg/0.1 mL) was injected intradermally in the volar forearm to establish secondary dysesthesias. After the capsaicin-induced pain subsided, the areas of allodynia and hyperalgesia were mapped and itch was provoked inside these areas by histamine (10 mg/mL) and cowhage (25-40 spicules). The evoked itch and pain were recorded on a visual analogue scale (VAS 0-10 cm). Contralateral injection of 0.1 mL isotonic saline served as a control., Results: Histaminergic and non-histaminergic evoked itch were significantly decreased when provoked in allodynic skin (p < 0.05). The area-under-the-curve of the evoked itch was reduced -43% from 18.0 ± 2.6 cm 10 min in normal skin to 10.3 ± 1.8 cm 10 min in allodynic skin (p < 0.01) for cowhage and -56% from 20.0 ± 3.5 cm 10 min in normal skin to 8.8 ± 2.3 cm 10 min allodynic skin (p < 0.001) for histamine. The pain responses to the pruritogens were not significantly altered between the areas of allodynia and normal skin (p > 0.1). An additional experiment showed that pinprick hyperalgesia in the absence of allodynia was sufficient to evoke the observed reduced sensitivity to itch stimuli., Conclusions: Cutaneous sensitization (secondary allodynia and hyperalgesia) reduced itch responses regardless of the type of itch model applied and without attenuation of the associated pruritogen-induced pain responses. This could explain the decreased sensitivity to itch provocations previously observed in patients with chronic pain., Significance: This study shows that the neuronal sensitization processes underlying the development secondary hyperalgesia involve significant gating of histaminergic as well as non-histaminergic pruriceptive transmission. Because these itch provocations normally target specific subpopulations of C-nociceptors they could be of relevance for exploratory purposes in pain patients., (© 2017 European Pain Federation - EFIC®.)

Background: Chronic itch is difficult to treat. Low-concentration topical capsaicin (0·006-0·05%) has previously been applied in itch therapy but evidence on its efficacy is contradictory., Objectives: This vehicle-controlled, double-blinded study investigated the effect of topical capsaicin 8% after 1- and 24-h application on evoked itch, neurogenic inflammation and itch-associated dysaesthesia., Methods: Sixteen healthy volunteers (aged 22 ± 0·5 years, nine female) were treated with capsaicin for 1 h and 24 h, and vehicle for 24 h on each volar forearm. Subsequently, histamine (1%, administered prick test lancets) and cowhage (40-45 spicules) were applied to the pretreated areas. Evoked itch and pain intensities were recorded for 10 min using a visual analogue scale (0-10 cm), while sensitivity to touch-evoked itch was evaluated using von Frey filaments before and after itch provocations. Neurogenic inflammation was assessed using perfusion imaging., Results: In the vehicle areas peak itch responses to histamine and cowhage were 4·67 ± 0·58 and 5·15 ± 0·71, respectively. Capsaicin pretreatment reduced peak itch responses to histamine and cowhage after 24-h pretreatment to 1·41 ± 0·58 (P = 0·003) and 0·81 ± 0·18, (P < 0·001), respectively. Capsaicin pretreatment for 1 h reduced only cowhage-induced itch (P = 0·023). Furthermore, 24-h capsaicin pretreatment abolished punctuate hyperknesis and lowered histamine-induced neurogenic inflammation but did not affect weal reactions., Conclusions: Topical capsaicin 8% pretreatment for 24 h reduced histaminergic and nonhistaminergic itch by about 75%, while a significant reduction (≈60%) was achieved for only nonhistaminergic itch in a standard 1-h treatment. Further investigations are needed to elucidate the clinical potential of high-concentration capsaicin as an antipruritic., (© 2017 British Association of Dermatologists.)

Introduction: Little is known about the topographical distribution of pruriception (in particular for nonhistaminergic itch), although conditions with chronic itch frequently occur in distinct anatomic and often bilateral patterns. This study aimed to investigate regional differences in the sensitivity to itch stimuli by assessing the intensity of itch, pain, and cutaneous neurogenic flare evoked by histamine and cowhage in different anatomic regions in 20 healthy volunteers., Methods: Itch was induced by 1% histamine applied with a prick lancet or by insertion of 25±5 cowhage spicules in 4 regions: volar/dorsal forearm, lower back, and chin. The duration and intensity of itch and pain following each pruritic stimulus were measured by a continuous visual analogue scale (VAS 0-100 ). Sensitivity to touch-evoked itch was assessed by von Frey filaments and cutaneous flare was quantified by full-field laser perfusion imaging., Results: Peak itch intensity was lower at the chin (19.4±3.6) compared with other areas (mean of 3 locations; 41.3±4.4), independently of whether histamine or cowhage was applied ( P <0.01). Baseline sensitivity to touch-evoked itch was higher on the chin ( P <0.01), but here hyperknesis did not develop in contrast to other areas ( P <0.05). Cutaneous flare was more intense but had a smaller dispersion at the chin, compared with other areas ( P <0.01)., Discussion: In conclusion, sensitivity to histaminergic and non-histaminergic itch diverges considerably between body regions. Lower density of pruriceptive CMH and CMI-neurons or distinct neuronal substrates for itch in the mandibular part of the trigeminal area may explain the observed reduced itch and vasomotor responses.

Numerous exploratory, proof-of-concept and interventional studies have used histaminergic and non-histaminergic human models of itch. However, no reliability studies for such surrogate models have been conducted. This study investigated the test-retest reliability for the response to histamine- and cowhage- (5, 15, 25 spiculae) induced itch in healthy volunteers. Cowhage spiculae were individually applied with tweezers and 1% histamine was applied with a skin prick test (SPT) lancet, both on the volar forearm. The intensity of itch was recorded on a visual analogue scale and self-reported area of itch was assessed 5 and 10 min after itch provocation. Reliability of the evoked itch (area under the curve and peak intensity) was assessed by the coefficient of variation (CV), intra-class correlation coefficient (ICC), and sample size estimation for parallel and cross-over designs. Cowhage (ICC = 0.57-0.77, CVbetween = 97%, CVwithin = 41%) and histamine: (ICC = 0.83-0.93, CVbetween = 97%, CVwithin = 20%) exhibited moderate-to-excellent intra-individual reliability and moderate inter-individual reliability for the itch intensity. For a test-retest observation period of one week, SPT-delivered histamine and application of cowhage-spiculae are reproducible human models of itch. The high inter-individual and low intra-individual variability suggests cross-over designed studies when applicable.

Allergic contact dermatitis (ACD) is a common skin condition caused by a type-IV hypersensitivity reaction. Even though ACD is considered as a T-cell mediated disease, indications exists that peptidergic nerve fibers at the site of allergen exposure and associated with the draining lymph node play a prominent role in both induction and elicitation of ACD. This neuro-immune cross talk seems rely on neuropeptides such as Substance P secreted by nerve fiber terminals. It is hypothesized that local complete or partial cutaneous denervation/defunctionalization of peptidergic fibers in humans could be a feasible approach towards treating allergic contact dermatitis. Recently, human experimental protocols for prominent, temporary defunctionalization of peptidergic fibers have been published relying on prolonged application of 8% topical capsaicin patches. Combined with human experimental ACD models the importance of peptidergic nerve fibers in the induction and elicitation phases of ACD could be accurately established. Understanding the role of cutaneous peptidergic fibers in the pathogenesis and potentially of ACD and how contact sensitization can be modulated by topical defunctionalization of these fibers could lead to new approaches to treatment for ACD. In patients with localized ACD occurring to an allergen that is difficult or unfeasible to evade this would have particular relevance., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

A frequent empirical observation is that cold-induced counter-irritation may attenuate itch. The aim of this randomized, single-blinded, exploratory study was to evaluate the counter-irritation effects of cold-stimulation and topical application of transient receptor potential TRPA1/M8-agonists (trans-cinnamaldehyde/L-menthol, respectively), on histamine-induced itch, wheals and neurogenic inflammation in 13 healthy volunteers. Histamine 1% was applied to the volar forearms using skin prick-test lancets. Recorded outcome-parameters were itch intensity, wheal reactions, and neurogenic inflammation (measured by laser-speckle perfusion-imaging). Homotopic thermal counter-irritation was performed with 6 temperatures, ranging from 4°C to 37°C, using a 3 × 3-cm thermal stimulator. Chemical "cold-like" counter-irritation was conducted with 40% L-menthol and 10% trans-cinnamaldehyde, while 5% doxepin was used as a positive antipruritic control/comparator. Cold counter-irritation stimuli from 4°C to 22°C inhibited itch in a stimulus-intensity-dependent manner (p < 0.05) and, to a lesser extent, also wheal reactions and neurogenic inflammation. Chemical "cold-like" counter-irritation with both L-menthol and trans-cinnamaldehyde had antipruritic efficacy similar to doxepin (p < 0.05). Cold-induced counter-irritation had an inhibitory effect on histaminergic itch, suggesting that agonists of cold transduction receptors could be of potential antipruritic value.

Background: Skin prick test (SPT) is a common test for diagnosing immunoglobulin E-mediated allergies. In clinical routine, technicalities, human errors or patient-related biases, occasionally results in suboptimal diagnosis of sensitization., Objective: Although not previously assessed qualitatively, lancet weight is hypothesized to be important when performing SPT to minimize the frequency of false positives, false negatives, and unwanted discomfort., Methods: Accurate weight-controlled SPT was performed on the volar forearms and backs of 20 healthy subjects. Four predetermined lancet weights were applied (25 g, 85 g, 135 g and 265 g) using two positive control histamine solutions (1 mg/mL and 10 mg/mL) and one negative control (saline). A total of 400 SPTs were conducted. The outcome parameters were: wheal size, neurogenic inflammation (measured by superficial blood perfusion), frequency of bleeding, and the lancet provoked pain response., Results: The mean wheal diameter increased significantly as higher weights were applied to the SPT lancet, e.g. from 3.2 ± 0.28 mm at 25 g to 5.4 ± 1.7 mm at 265 g (p<0.01). Similarly, the frequency of bleeding, the provoked pain, and the neurogenic inflammatory response increased significantly. At 265 g saline evoked two wheal responses (/160 pricks) below 3 mm., Conclusion and Clinical Relevance: The applied weight of the lancet during the SPT-procedure is an important factor. Higher lancet weights precipitate significantly larger wheal reactions with potential diagnostic implications. This warrants additional research of the optimal lancet weight in relation to SPT-guidelines to improve the specificity and sensitivity of the procedure.

This study investigated whether itch induced by intra-epidermal histamine is subjected to modulation by a standardized conditioned pain modulation (CPM) paradigm in 24 healthy volunteers. CPM was induced by computer-controlled cuff pressure algometry and histamine was introduced to the volar forearm by skin prick test punctures. Moreover, neurogenic inflammation and wheal reactions induced by histamine and autonomic nervous system responses (heart rate variability and skin conductance) were monitored. CPM did not modulate the intensity of histamine-induced itch suggesting that pruriceptive signaling is not inhibited by pain-recruited endogenous modulation, however, CPM was found to aggravate histamine-induced neurogenic inflammation, likely facilitated by efferent sympathetic fibers.

Within the last decade understanding of the mechanistic basis of itch has improved significantly, resulting in the development of several human surrogate models of itch and related dysesthetic states. Well-characterized somatosensory models are useful in basic studies in healthy volunteers, in clinical studies for diagnostic and segmentation purposes, and in pharmacological studies to evaluate the antipruritic efficacy of existing and novel compounds. This review outlines recently introduced histamine-independent human models of itch, their mechanisms, their ability to induce clinically relevant phenomena, such as alloknesis, and the results obtained through their use. The article also introduces recent advances in the understanding of itch and provides an overview of the methods to assess experimentally-induced itch and associated manifestations. Major improvements are warranted in the treatment of chronic pruritus, and reliable human surrogate models are a valuable tool in achieving them, both for basic researchers and for clinicians.