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Itch in patients with chronic kidney disease (CKD) is common, often very distressing and associated with depression, reduced quality of life, and increased death. The most common first-line treatment has been the use of antihistamines despite the lack of substantial evidence for its use for uraemic itch. Few recommendations and guidelines exist for treatment.We aimed to determine: 1) the benefits and harms (both absolute and relative) of all topical and systemic interventions for the treatment of uraemic itch, either alone or in combination, when compared with placebo or standard care; and, 2) the dose strength or frequency, stage of kidney disease or method of dialysis used (where applicable) in cases where the effects of these interventions vary depending on co-interventions.We searched the Cochrane Kidney and Transplant Register of Studies up to 17 December 2019 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov.Randomised controlled trials (RCTs) in adults with CKD stages 4 or 5 comparing treatments (pharmacological, topical, exposure, dialysis modality) for CKD associated itch to either placebo or other established treatments.Two authors independently abstracted study data and assessed study quality. Data were analysed using a random effects meta-analysis design estimating the relative effects of treatment versus placebo. Estimates of the relative effects between treatments are included where possible. For continuous measures of severity of itch up to three months, mean difference (MD) or standardised mean difference (SMD) were used. When reported, adverse effects were tabulated. The certainty of the evidence was estimated using GRADE.Ninety-two RCTs, randomising 4466 participants were included. Fifty-eight studies (3285 participants) provided sufficient data to be meta-analysed. Of these, 30 compared an intervention to a placebo or control. The 10 cm Visual Analogue Scale (VAS) was the dominant instrument utilized for itch reporting and the Duo score was used in a minority of studies. GABA analogues including, gabapentin and pregabalin, reduce itch in patients with CKD (5 studies, 297 participants: 4.95 cm reduction, 95% CI 5.46 to 4.44 lower in VAS compared to placebo; high certainty evidence). Kappa opioid agonists, including nalfurafine also reduced itch in this population (6 studies, 661 participants: 1.05 cm reduction, 95% CI 1.40 to 0.71 lower in VAS compared to placebo; high certainty evidence). Ondansetron had little or no effect on itch scores (3 studies, 183 participants: 0.38 cm reduction, 95% CI 1.04 lower to 0.29 higher in VAS compared to placebo; high certainty evidence). Reduction in the severity of itch was reported with oral montelukast, turmeric, zinc sulfate and topical capsaicin. For all other interventions, the certainty of the evidence was low to moderate, and the interventions had uncertain effects on uraemic pruritus. Six studies have disclosed significant financial support from their respective manufacturers, six were affected by lack of blinding, and 11 studies have 15 participants or less. Older, smaller RCTs often failed to follow intention-to-treat protocols with unexplained dropouts after randomisation. Adverse effects were generally poorly and inconsistently reported across all RCTs. No severe adverse events were reported for any intervention.The RCTs of this meta-analysis contain a large array of interventions with a diverse set of comparators. For many interventions, trials are sparse. This served to make informative meta-analysis challenging. Of all treatments for uraemic pruritus, gabapentinoids (gabapentin and pregabalin) were the most studied and show the greatest reduction in itch scores. Further RCTs, even of the scale of the largest trials included in this review, are unlikely to significantly change this finding. Kappa-opioid agonists (mainly nalfurafine) also may reduce itch, but indirect comparison suggests a much more modest effect in comparison to GABA analogues. Evidence for oral montelukast, turmeric, zinc sulfate, and topical capsaicin also showed an itch score reduction. However, these reductions were reported in small studies, and warrant further investigation. Ondansetron did not reduce itch. It is somewhat unlikely that a further study of ondansetron will change this result.پیشینه: خارش در بیماران مبتلا به بیماری مزمن کلیه (chronic kidney disease; CKD) شایع بوده، اغلب بسیار ناراحت کننده است و منجر به افسردگی، کاهش کیفیت زندگی، و افزایش مرگ‌ومیر می‌شود. متداول‌ترین روش درمانی خط اول استفاده از آنتی‌هیستامین‌ها است، هر چند که شواهد اساسی در مورد استفاده از آنها برای خارش اورمیک وجود ندارد. توصیه‌ها و دستورالعمل‌های اندکی برای درمان این وضعیت وجود دارد. اهداف: هدف ما تعیین موارد زیر بود: 1) فواید و مضرات (هم مطلق و هم نسبی) همه مداخلات موضعی و سیستمیک برای درمان خارش اورمیک، چه به تنهایی و چه به صورت ترکیبی، در مقایسه با دارونما (placebo) یا مراقبت‌های استاندارد؛ و، 2) قدرت دوز یا فراوانی آن، مرحله بیماری کلیوی یا روش دیالیز مورد استفاده (در صورت وجود) در مواردی که اثرات این مداخلات بسته به مداخلات همزمان، متفاوت باشند. روش‌های جست‌وجو: ما پایگاه ثبت مطالعات گروه کلیه و پیوند در کاکرین را تا 17 دسامبر 2019 از طریق تماس با متخصص اطلاعات و با استفاده از اصطلاحات جست‌وجوی مرتبط با این مرور، بررسی کردیم. مطالعات موجود در پایگاه‌های ثبت از طریق جست‌وجوها در CENTRAL؛ MEDLINE و EMBASE، مجموعه مقالات کنفرانس‌ها، پورتال جست‌وجوی پایگاه ثبت کارآزمایی‌های بالینی بین‌المللی (International Clinical Trials Register; ICTRP) و ClinicalTrials.gov شناسایی شدند. معیارهای انتخاب: کارآزمایی‌های تصادفی‌سازی و کنترل شده (randomised controlled trials; RCTs) در بزرگسالان مبتلا به مراحل 4 یا 5 از CKD، که به مقایسه درمان (دارویی، موضعی، مواجهه، مدالیتی دیالیز) با دارونما یا سایر درمان‌های اثبات شده برای مدیریت CKD همراه با خارش پرداختند. گردآوری و تجزیه‌وتحلیل داده‌ها: دو نویسنده به‌طور مستقل از هم، داده‌ها را استخراج و محدودیت‌های مطالعه را ارزیابی کردند. داده‌ها با استفاده از یک طرح متاآنالیز اثرات تصادفی و با تخمین تأثیرات نسبی درمان در مقابل دارونما آنالیز شدند. برآوردهای اثرات نسبی بین درمان‌ها، در صورت امکان، گنجانده شدند. برای معیارهای پیوسته شدت خارش تا سه ماه، از تفاوت میانگین (MD) یا تفاوت میانگین استاندارد شده (SMD) استفاده شد. در جایی که عوارض جانبی گزارش شدند، به صورت جدول درآمدند. قطعیت شواهد با استفاده از GRADE ارزیابی شد. نتایج اصلی: نود و دو RCT وارد شدند، که 4466 شرکت‎‌کننده را تصادفی‌‎سازی کردند. پنجاه‌وهشت مطالعه (3285 شرکت‌کننده) داده‌های کافی را برای انجام متاآنالیز فراهم کردند. از این تعداد، 30 مطالعه، مداخله را با دارونما یا کنترل مقایسه كردند. مقیاس 10 سانتی‌متری آنالوگ بصری (Visual Analogue Scale; VAS) ابزاری غالب بود که برای گزارش‌دهی در مورد خارش مورد استفاده قرار گرفت و در تعدادی کمی از مطالعات از امتیاز Duo استفاده شد. آنالوگ‌های GABA شامل، گاباپنتین (gabapentin) و پرگابالین (pregabalin)، باعث کاهش خارش در بیماران مبتلا به CKD می‌شود (5 مطالعه، 297 شرکت‌کننده: کاهش 5.46 سانتی‌متری، 95% CI؛ 5.46 تا 4.44 کمتر در VAS در مقایسه با دارونما؛ شواهد با قطعیت بالا). آگونیست‌های کاپا‐اوپیوئید (kappa‐opioid)، از جمله نالفورافین (nalfurafine) نیز باعث کاهش خارش در این جمعیت شدند (6 مطالعه، 661 شرکت‌کننده: کاهش 1.05 سانتی‌متری، 95% CI؛ 1.40 تا 0.71 کمتر در VAS در مقایسه با دارونما؛ شواهد با قطعیت بالا). اندانسترون (ondansetron) تاثیری اندک یا بدون تاثیر بر نمرات خارش داشت (3 مطالعه، 183 شرکت‌کننده: کاهش 0.38 سانتی‌متری، 95% CI؛ 1.04 کمتر تا 0.29 بیشتر در VAS در مقایسه با دارونما؛ شواهد با قطعیت بالا). کاهش در شدت خارش با تجویز مونته‌لوکاست (montelukast) خوراکی، زردچوبه (turmeric)، سولفات روی (zinc sulfate) و کپسایسین (capsaicin) موضعی گزارش شد. برای تمامی مداخلات دیگر، سطح قطعیت شواهد پائین تا متوسط بود، و مداخلات تأثیرات نامشخصی روی خارش اورمیک بر جای گذاشتند. شش مطالعه دریافت حمایت مالی قابل توجهی را از تولید کنندگان مربوطه اعلام کردند، شش مورد تحت تأثیر عدم‐کورسازی قرار داشتند و 11 مطالعه با حضور 15 شرکت‌کننده یا کمتر انجام شدند. RCTهای قدیمی‌تر و کوچکتر نتوانستند از پروتکل‌های قصد درمان (intention‐to‐treat) تبعیت کنند و اغلب پس از تصادفی‌سازی، با خروج بدون دلیل بیماران از مطالعه روبه‌رو بودند. به‌طور کلی عوارض جانبی در تمام RCTها ضعیف و ناسازگار گزارش شدند. هیچ موردی از حوادث جانبی جدی برای هیچ مداخله‌ای گزارش نشد. نتیجه‌گیری‌های نویسندگان: RCTهای این متاآنالیز شامل مجموعه‌ای وسیع از مداخلات با مجموعه‌ای متنوع از مقایسه‌کننده‌ها هستند. برای بسیاری از مداخلات، تعداد کارآزمایی‌ها اندک بود. این مساله باعث شد که متاآنالیز حاوی اطلاعات مفید، چالش‌برانگیز باشد. از میان تمامی درمان‌های خارش اورمیک، گاباپنتینوئیدها (گاباپنتین و پرگابالین) بیشترین تعداد مطالعه را به خود اختصاص داده و بیشترین کاهش نمرات خارش را نشان دادند. RCTهای بعدی، حتی در مقیاس بزرگترین کارآزمایی‌های موجود در این مرور، بعید است که این یافته را به‌طور قابل توجهی تغییر دهند. آگونیست‌های کاپا‐اوپیوئید (عمدتا نالفورافین) نیز می‌توانند خارش را کاهش دهند، اما مقایسه غیر‐مستقیم، تأثیر بسیار متوسط‌ تری را از آن در مقایسه با آنالوگ‌های GABA نشان می‌دهد. شواهد مربوط به مونته‌لوکاست خوراکی، زردچوبه، سولفات روی، و کپسایسین موضعی نیز بیانگر کاهش نمره خارش هستند. با این حال، این کاهش‌ها در مطالعات کوچک گزارش شده، و انجام تحقیقات بیشتری را لازم می‌داند. اندانسترون خارش را کم نکرد. تا حدودی بعید است که انجام مطالعات بیشتر در مورد اندانسترون این نتیجه را تغییر دهند.

Capsaicin is a widespread spice known for its analgesic qualities. Although a comprehensive body of evidence suggests pleiotropic benefits of capsaicin, including anti-inflammatory, antioxidant, anti-proliferative, metabolic, or cardioprotective effects, it is frequently avoided due to reported digestive side-effects. As the gut bacterial profile is strongly linked to diet and capsaicin displays modulatory effects on gut microbiota, a new hypothesis has recently emerged about its possible applicability against widespread pathologies, such as metabolic and inflammatory diseases. The present review explores the capsaicin–microbiota crosstalk and capsaicin effect on dysbiosis, and illustrates the intimate mechanisms that underlie its action in preventing the onset or development of pathologies like obesity, diabetes, or inflammatory bowel diseases. A possible antimicrobial property of capsaicin, mediated by the beneficial alteration of microbiota, is also discussed. However, as data are coming mostly from experimental models, caution is needed in translating these findings to humans.

Symptoms that resemble allergic reactions, such as pruritus, flushing, and hypotension, are common side effects of therapeutic drugs. In a true allergic reaction, Immunoglobulin E (IgE) antibodies recognize the drug and trigger mediator release from mast cells through cross-linking of IgE receptors. However, many drugs can bypass this pathway and can activate mast cells directly through MRGPRX2, a G protein-coupled receptor that responds to a wide range of small molecules, peptides, and proteins that have little in common except for a net positive charge. This review will provide an overview of MRGPRX2, including its expression pattern, studies of its pharmacology, and its orthologs. It also will review evidence for MRGPRX2 activation by many drugs closely associated with these reactions.

Your patient's pruritus absent skin lesions might be self-limiting-or indicate systemic disease. Probing the nature of the symptom can point to targeted treatment.

Ruxolitinib (RUX) cream demonstrated potent anti-inflammatory and antipruritic efficacy in a phase 2 study in adults with atopic dermatitis (AD).To evaluate 8-week efficacy and safety in 2 phase 3 studies of RUX cream in patients with AD.Topical Ruxolitinib Evaluation in Atopic Dermatitis Study 1 (NCT03745638) and Study 2 (NCT03745651) enrolled patients aged ≥12 years with AD for ≥2 years, an Investigator's Global Assessment score of 2/3, and 3%-20% affected body surface area. Patients were randomized 2:2:1 to twice-daily 0.75% RUX cream, 1.5% RUX cream, or vehicle cream for 8 continuous weeks. The primary endpoint was Investigator's Global Assessment treatment success at week 8 (Investigator's Global Assessment score of 0/1 and ≥2-grade improvement from baseline).In the Topical Ruxolitinib Evaluation in Atopic Dermatitis Study 1 and 2, 631 and 618 patients were randomized (631/577 analyzed for efficacy). Significantly more patients achieved Investigator's Global Assessment treatment success with 0.75% RUX cream (50.0%/39.0%) and 1.5% RUX cream (53.8%/51.3%) versus vehicle (15.1%/7.6%; P .0001) at week 8. Significant itch reductions versus vehicle were reported within 12 hours of first application of 1.5% RUX (P .05). Application site reactions were infrequent (1%) and lower with RUX versus vehicle; none were clinically significant.Longer-term safety data are not yet available.RUX cream showed anti-inflammatory and prompt antipruritic effects with superior efficacy versus vehicle and was well tolerated.

Transient receptor potential vanilloid type 1 (TRPV1) is found on sensory neurons, keratinocytes, sebocytes, and dendritic cells. Activated TRPV1 channels are believed to help propagate the itch sensation. Therefore, there has been great interest in targeting TRPV1 to treat pruritus. Since oral formulations aimed at TRPV1 have led to adverse effects such as hyperthermia, there has been emphasis on developing novel topical agents. Several companies are investigating topical TRPV1 anti-pruritic compounds and the initial data has been very promising. These drugs have the potential to be important treatment options for the management of itch. This paper reviews topical products in current development for pruritus that target TRPV1 channels.

Psoriasis and atopic dermatitis (AD) are two common chronic inflammatory skin diseases. Although showing different etiology and clinical manifestations, patients with either disease suffer from low health-related quality of life due to pruritus (dermal itch). Recent studies have revealed that more than 85% of psoriasis patients suffer from pruritus, and it is also the dominating symptom of AD. However, as this is a non-life treating symptom, it was partly neglected for years. In this review, we focus on current findings as well as the impact and potential treatments of pruritus in these two skin diseases. We first distinguish the type of itch based on involved mediators and modulators. This clear delineation between the types of pruritus based on involved receptors and pathways allows for precise treatment. In addition, insights into recent clinical trials aimed to alleviate pruritus by targeting these receptors are presented. We also report about novel advances in combinatorial treatments, dedicated to the type of pruritus linked to a causal disease. Altogether, we suggest that only a focused treatment tailored to the primary disease and the underlying molecular signals will provide fast and sustained relief of pruritus associated with psoriasis or AD.

Chronic pruritus is non-histaminergic and mediated through a complex interplay of peripheral and central immune and neural pathways. Significant developments in the understanding of chronic pruritus have emerged and paved the way for new, emerging therapies.This review details the emerging drug landscape for chronic pruritus treatment, focusing on monoclonal antibody agents that target key cytokines and their receptors as well as small molecule agents that inhibit mediators of the immune and neural pathways. The article provides background regarding the currently available therapies and the rationale for the development of new agents based on the current market and recent scientific developments.Identification of new targets along neuroimmune itch pathways has allowed for the development of targeted drugs which can be utilized for effective therapy. As we enter a new era of chronic itch treatments, we face exciting prospects and challenges.

Chronic pruritus (CP) is a highly prevalent, difficult-to-treat, and burdensome condition. Today, multiple topical and systemic therapy concepts are available for the treatment of CP. Current guidelines recommend, besides topical treatments, the use of a vast array of mostly off-label systemic drugs with different mechanisms, including antihistamines, gabapentinoids, antidepressants, immunosuppressive drugs, and μ‑opioid receptor antagonists. The choice of the right agent depends on the indication, the safety profile of the drug, and patient-specific features, such as comorbidities and comedication. Thanks to a deeper understanding of the pathophysiology of CP, novel drugs have been developed and have already shown antipruritic efficacy in clinical studies and case reports. Of note, phosphodiesterase‑4 inhibitors as topical agents and monoclonal antibodies, neurokinin‑1 receptor antagonists, Janus kinase inhibitors, and opioid receptor modulators as systemic agents are in the frontline of innovative CP treatment. Other promising targets include structures of the peripheral and central nervous system which are involved in itch signaling. This article provides an overview of currently available topical and systemic therapies for CP and their indications and discusses novel innovative agents and promising new targets in CP.

Patients with cholestatic liver diseases, such as primary biliary cirrhosis, usually suffer from pruritus. However, the pathogenesis of cholestatic pruritus is unclear, and there is no current effective treatment for it. In order to find a treatment for the condition, an appropriate mouse model should be developed. Therefore, here, we established a surgically-induced mouse model of cholestatic pruritus. The bile duct was ligated in order to block bile secretion from the anterior, right, and left lobes, with the exception of the caudate lobe. Serum levels of total bile acid increased after bile duct ligation (BDL). The spontaneous hind paw scratching was also increased in BDL mice. Spontaneous scratching was reduced in BDL mice by naloxone (µ-opioid receptor antagonist), U-50,488H (κ-opioid receptor agonist), and clonidine (α2-adrenoceptor agonist). Azelastine (H1 receptor antagonist with membrane-stabilizing activity) slightly reduced scratching. However, terfenadine (H1 receptor antagonist), methysergide (serotonin (5-HT)2 receptor antagonist), ondansetron (5-HT3 receptor antagonist), proteinase-activated receptor 2-neutralizing antibody, fluvoxamine (selective serotonin reuptake inhibitor), milnacipran (serotonin-noradrenalin reuptake inhibitor), and cyproheptadine (H1 and 5-HT2 receptor antagonist) did not affect scratching. These results suggested that partial obstruction of bile secretion in mice induced anti-histamine-resistant itching and that central opioid system is involved in cholestatic itching.

This study assessed the influence of High (H, 4.13%), Medium (M, 2.0%) and Low (L, 0.1%) doses of menthol on temperature perception and regulation, compared to a Placebo Condition (P).Sixteen participants underwent the aforementioned conditions on four separate days. During each test participants rested supine (Environmental conditions: 30 °C, 50% rh) for 30-min before 40 mL of L, M, H or P gel was applied to the anterior upper body, then rested 30-min thereafter. Primary measures included thermal sensation (TS), thermal comfort (TC), irritation (IRR), rectal temperature (Tre), and skin temperature (chest, forearm, thigh, calf), and EMG (trapezius, pectoralis major, sternocleidomastoid). The area under the curve (AUC) from minute 30 to 60 was compared between conditions using relevant non/parametric tests (alpha level = 0.05).A cooling trend in Tre was observed following Placebo gel application, but this significantly (p 0.05) reversed into a heat storage response in M and H. Both TS and TC significantly differed by condition (p 0.001) in a dose-dependent manner, with L, M, and H doses eliciting significantly cooler sensations and more discomfort than P (p 0.05). Irritation significantly differed by condition (p 0.01) in a dose-dependent manner, with L and M eliciting significantly greater irritation than P (p 0.01). No other differences were observed.Menthol exerts perceptual and thermoregulatory effects independent of skin temperature. A menthol dose-dependent perceptual cooling effect was evident with possible saturation at the moderate dose. A dose-dependent alteration in deep body temperature was also evident.

Pruritus is a debilitating symptom that significantly affects the quality of life of patients who suffer from it. Many current and emerging systemic treatments targeting the neural system have been successful in treating itch of various underlying etiologies.A complete search of the PUBMED and Google Scholar databases was completed and literature pertinent to current and emerging systemic anti-pruritic drugs which target the neural system was compiled. The purpose of this review is to give the reader with an overview of the current and emerging systemic therapeutic options which target the neural system for chronic pruritus. The authors then provide the reader with their expert perspectives on the future of these therapies.Exciting new anti-pruritic therapies targeting the neural system which show promise include NK-1 inhibitors, opioid receptor modulators, and drugs targeting specific itch receptors such as Mrgpr, Na

Itch is the commonest skin-related symptom, associated with a high psychosocial and economic burden. While the main focus of itch research lies on a few chronic skin diseases, only little is known about the perception of itch, itch-aggravating/-relieving factors and treatment preferences in patients with acute and chronic itch of various etiology. In this cross-sectional study we assessed these aspects in 126 patients (mean age 61.7 ±18.4 years, 67 females, median itch duration 3.9 years) using a 78-item questionnaire. The diseases were categorised into 11 diagnostic groups for descriptive analysis, the three most frequent groups ("Atopic dermatitis"; "Non-atopic eczema"; "Inflammatory dermatoses") were statistically compared. Itch was most often perceived as localised 42.9%, burning (40.5%) and worrying (39.7%) with worsening in the evening (49.2%), due to warmth (42.1%) and sweating (26.2%). Whilst itch perception, itch-aggravating factors and treatment preferences differed broadly amongst patients, the itch-relieving personal strategies were more uniform ("scratching by hand 70.6%, applying topicals 57.9%). 69.8% of patients suffered from itch-related sleep disturbance, consequently affecting their relatives in 30.0%. Subgroup comparisons revealed significant differences regarding itch-aggravating factors (p=0.0012) and itch duration (p=0.0082). Patients rated the antipruritic effectiveness of phototherapy, "Complementary & alternative medicine" and "Other tablets" as high, but oral antihistamines, "Cortisone tablets" and any topical as only moderately efficacious. The preferred administration of an ideal itch treatment was "Creams/ointments" (51.6%) or "Tablets" (35.7%), only few patients preferred "injections" or "patches". Consideration of such differences and similarities in itch characteristics and treatment preferences could help to better tailor treatment in itch patients. This article is protected by copyright. All rights reserved.

Introduction The Tobacco Heating System (THS) is a “heat-not-burn” tobacco product designed to generate significantly lower levels of harmful and potentially harmful constituents (HPHCs) and present lower risk of harm than cigarettes. This study assessed the exposure reduction to selected HPHCs in smokers switching to menthol Tobacco Heating System (mTHS) 2.2 compared with smokers continuing smoking menthol cigarettes (mCCs) and smoking abstinence (SA) for 5 days in a confined setting, followed by an 86-day ambulatory period. Methods A total of 160 healthy adult US smokers participated in this randomized, three-arm parallel group, controlled clinical study. Biomarkers of exposure to 16 HPHCs were measured in blood and 24-hour urine. Safety was monitored throughout the study. Information was also gathered on product evaluation, product use, subjective effects, and clinical risk markers (co-publication Part 2). Results Nicotine uptake was comparable in both exposure groups (mTHS:mCC ratio of 96% on day 90). On day 5, biomarker of exposure levels to other HPHCs were reduced by 51%–96% in the mTHS group compared with the mCC group, and these reductions were sustained for most biomarkers of exposure over ambulatory period. After 90 days of use, the level of satisfaction with mTHS and suppression of urge to smoke were comparable to mCC. Conclusion Switching from mCCs to mTHS significantly reduced the exposure to HPHCs to levels approaching those observed in subjects who abstained from smoking for the duration of the study. Implications This study compared the impact of switching to mTHS on biomarkers of exposure, relative to continued smoking or SA. Clinical Significance Trial Registration NCT01989156 (ClinicalTrials.gov).

The aim of this multicentre, randomized, double-blind, placebo-controlled, cross-over, phase-II study was to determine the antipruritic effect of aprepitant vs. placebo in 58 patients with anti-histamine-refractory chronic pruritus in chronic nodular prurigo. Patients were randomized to receive either first oral aprepitant 80 mg/day or placebo for 4 weeks. Following a 2-week wash-out phase, the patients were crossed-over to receive the other treatment for 4 weeks. Primary efficacy criterion was the intra-individual difference between mean itch intensity (visual analogue scale) at baseline compared with the end of treatment period. Prurigo lesions, pruritus course, quality of life, patient benefits, and safety were secondary parameters. No significant differences were found between aprepitant treatment and placebo for any of the parameters investigated. Under the experimental conditions of the study, aprepitant, 80 mg daily for 4 weeks, did not have an antipruritic effect in patients with chronic prurigo. (DRKS00005594; EudraCT Number: 2013-001601-85).

Pruritus is a common and stressful symptom in medicine with cutaneous manifestation. Therapy remains a challenge for physicians and patients because there are many causes/triggers and approved systemic therapies are lacking. Basically, there are two different options of treatment: topical treatment is selected for every degree of severity, while patients with severe symptoms and chronic disease course have to be treated with systemic and topical options. This article provides a summary of current topical therapeutic options and offers tips for daily practice.

Chronic pruritus (CP) is a highly prevalent, difficult to treat, and burdensome condition. Nowadays, multiple substances are available for the treatment of CP. Systemic therapies play a pivotal role in modern CP therapy, particularly in severe cases and those refractory to general antipruritic measures. Current guidelines recommend the use of a vast array of, mostly off-label, drugs with different mechanisms, including antihistamines, gabapentinoids, antidepressants, immunosuppressive drugs, and μ‑opioid receptor antagonists. The choice of the right agent depends on the indication, safety profile of the drug, and patient-specific features, such as comorbidities and comedication. Owing to a deeper understanding of the pathophysiology of CP, novel drugs have been developed and have already shown anti-pruritic efficacy in clinical studies and case reports. Of note, monoclonal antibodies, neurokinin‑1 receptor antagonists, Janus kinase inhibitors, and opioid receptor modulators are on the frontline of innovative CP treatment. Other promising targets include structures of the peripheral and central nervous system, e.g., histamine 4 receptors, which are involved in itch signaling. This review provides an overview of currently available systemic therapies for CP and their indications and discusses novel innovative agents and promising new targets in CP.

Chronic pruritus (CP) is often accompanied by paresthetic sensations like warmth, burning and stinging. The aim of this study was to analyze, whether divergent sensations are linked to structural and functional skin alterations in clinically diagnosed CP patients. Clinical responses to capsaicin, histamine, and to thermal and mechanical stimulation, intraepidermal nerve fiber density, and epidermal expression of transient receptor potential (TRP)-channels were investigated in healthy controls, and in CP patients, reporting either warmth (CP-W) or neuropathic sensations (CP-N). In CP-W, pinprick hyperalgesia and increased sensitivity to capsaicin were aligned with increased epidermal TRPV1 expression, while smaller histamine axon reflex erythema matched with significantly reduced intraepidermal nerve fiber density. CP-N showed earlier onset of sensations after capsaicin stimulation, significantly increased warmth detection threshold, and higher epidermal expression of TRPV4 compared to healthy controls. The present study contributes to the neurobiological understanding of the divergence of sensory sensations in CP, indicating new treatment targets.

Central sensitization induces pain augmentation in chronic pain states. An analogous mechanism is speculated for chronic pruritus. This study compared patients with chronic pruritus (n = 79) of different origins (atopic dermatitis, chronic pruritus on non-lesional skin, chronic prurigo) and healthy controls (HC, n = 54) with regard to itch intensity and qualities of sensory symptoms after selective peripheral nerve fibre activation by electrical stimulation at 5 Hz (surrogate for C-fibre function) and 2,000 Hz (surrogate for Aβ-fibre function) using a Neurometer®. Electrically-induced itch was more intense in patients with chronic pruritus than in HC, but patients with chronic pruritus did not report “itch” more often than HC at 5 Hz. Stimulation at 2,000 Hz induced more pricking and tingling, but less throbbing in patients with chronic pruritus compared with HC. Treatment with cooling compound reduced clinical and experimental itch, but did not alter the distribution of sensory symptoms. These data show hyperknesis in chronic pruritus of various origins, arguing for common central sensitization mechanisms.

Background ICU patients must be kept conscious, calm, and cooperative even during the critical phases of illness. Enteral administration of sedative drugs might avoid over sedation, and would be as adequate as intravenous administration in patients who are awake, with fewer side effects and lower costs. This study compares two sedation strategies, for early achievement and maintenance of the target light sedation. Methods This was a multicenter, single-blind, randomized and controlled trial carried out in 12 Italian ICUs, involving patients with expected mechanical ventilation duration > 72 h at ICU admission and predicted mortality > 12% (Simplified Acute Physiology Score II > 32 points) during the first 24 h on ICU. Patients were randomly assigned to receive intravenous (midazolam, propofol) or enteral (hydroxyzine, lorazepam, and melatonin) sedation. The primary outcome was percentage of work shifts with the patient having an observed Richmond Agitation-Sedation Scale (RASS) = target RASS ±1. Secondary outcomes were feasibility, delirium-free and coma-free days, costs of drugs, length of ICU and hospital stay, and ICU, hospital, and one-year mortality. Results There were 348 patients enrolled. There were no differences in the primary outcome: enteral 89.8% (74.1–100), intravenous 94.4% (78–100), p = 0.20. Enteral-treated patients had more protocol violations: n = 81 (46.6%) vs 7 (4.2%), p

Pruritus is a debilitating symptom of cholestatic diseases such as primary biliary cholangitis and primary sclerosing cholangitis and often results in major reduction in quality of life for afflicted patients. Classic treatment options for the treatment of cholestatic pruritus include antihistamines, bile acid resins, serotonin reuptake inhibitors, and mu-opioid antagonists. Unfortunately, these drugs are not always successful in treating pruritus of cholestasis and may be associated with adverse effects. Recent advances in our understanding of itch pathophysiology have led to the use of butorphanol, a kappa-opioid agonist and mu-opioid antagonist, for the treatment of various forms of pruritus. Reports of butorphanol to treat cholestatic itch specifically are rare. To better understand the role of butorphanol in the treatment of cholestatic pruritus, including characterization of its side effect profile. We present a case series of eight adult patients with cholestatic disease who were treated with butorphanol in hopes of alleviating intractable pruritus. Patients were identified through a clinical data request form serviced by University of Miami Information Technology. Five out of eight patients (62.5%) reported successful reductions in itch severity after treatment with butorphanol, two patients reported no (or transient) change in itch severity, and one patient reported a paradoxical increase in itching. Side effects included somnolence, sedation, nausea, vomiting, and dizziness. Butorphanol was safe and leads to clinically significant symptomatic improvement. Clinicians should be aware of butorphanol as an off-label treatment option for pruritus of cholestasis. Further studies are needed to better characterize the effect of butorphanol on cholestatic itch.

Prurigo nodularis is a chronic skin condition characterized by severely pruritic nodules that cause a profound negative impact on quality of life. The second article in this 2-part continuing medical education series focuses on reviewing the pathogenesis of prurigo nodularis and exploring management algorithms for this condition. In addition, we discuss some emerging and novel therapies for treating prurigo nodularis. The first article in this 2-part series describes the broader epidemiology, patient demographics, physical examination findings, and symptoms to aid in the timely recognition and diagnosis of prurigo nodularis.

Itch is the commonest skin-related symptom and can be influenced by visual cues as exemplified by the phenomenon of "contagious itch." Colors are visual cues able to modify somatosensory inputs. We explored the relationship of colors and itch and the impact of color viewing on itch intensity. In this cross-sectional study, patients suffering from itch with a mean intensity of ≥2 on a Numerical Rating Scale during the last 7 days were evaluated. The study consisted of a questionnaire-based part using The Manchester Color Wheel and the ItchyQoL, followed by an interventional part. All 72 itch patients were able to match their itchy sensation with a color: In 68 patients (94.4%) this "pruritic" basic color was red. Likewise, all patients were able to define a subjective "antipruritic" color: The leading basic color choice was blue (31/72, 43.0%) followed by green (21/72, 29.1%), yellow (7/72,9.7%) and others. The impairment of the itch-related quality of life (as measured by the ItchyQoL) correlated with the brightness and saturation of the pruritic and antipruritic colors. Ten patients were visually exposed to their subjective antipruritic and pruritic color during 10 minutes resulting in a significant decrease and increase of itch intensity compared to baseline (5.1 ± 1.52 vs. 2.8 ± 1.47 [0-10 Numerical Rating Scale, NRS], p=0.0004 and 4.9 ± 1.66 vs. 6.8± 2.09 NRS, p=0.0009). These results indicate that itch can be modified by color viewing and colors matter when treating itch patients. However, further investigations are required to elucidate the therapeutic potential of colors in itch patients.

Introduction Despite the overall decline in the prevalence of cigarette use in the United States, menthol cigarette use among smokers is rising, and evidence shows that it may lead to more detrimental effects on public health than regular cigarette use. One of the mechanisms by which nicotine sustains tobacco use and dependence is due to its cognitive enhancing properties, and basic science literature suggests that menthol may also enhance nicotine’s acute effect on cognition. Aims and Methods The purpose of this review is to suggest that the cognitive enhancing effects of menthol may be a potentially important neuropsychological mechanism that has yet to be examined. In this narrative review, we provide an overview of basic science studies examining neurobiological and cognitive effects of menthol and menthol cigarette smoking. We also review studies examining menthol essential oils among humans that indicate menthol alone has acute cognitive enhancing properties. Finally, we present factors influencing the rising prevalence of menthol cigarette use among smokers and the importance of this gap in the literature to improve public health and smoking cessation treatment. Conclusions Despite the compelling evidence for menthol’s acute cognitive enhancing and reinforcing effects, this mechanism for sustaining tobacco dependence and cigarette use has yet to be examined and validated among humans. On the basis of the basic science evidence for menthol’s neurobiological effects on nicotinic receptors and neurotransmitters, perhaps clarifying menthol’s effect on cognitive performance can help to elucidate the complicated literature examining menthol and tobacco dependence. Implications Menthol cigarette use has continued to be a topic of debate among researchers and policy makers, because of its implications for understanding menthol’s contribution to nicotine dependence and smoking persistence, as well as its continued use as a prevalent flavoring in tobacco and nicotine products in the United States and internationally. As international tobacco regulation policies have begun to target menthol cigarettes, research studies need to examine how flavoring additives, specifically menthol, may acutely influence neurobiological and cognitive functioning as a potential mechanism of sustained smoking behavior to develop more effective treatments.

Background Patients with breast cancer undergoing radiation therapy can experience dermatologic adverse events. Oncology nurses can advocate for radiation dermatitis (RD) prophylaxis to minimize dermatologic adverse events. Objectives This quality improvement project was conducted to evaluate the effect of implementing an RD prevention protocol. The objectives of this study were to (a) improve clinicians' knowledge of screening, assessment, and prevention of RD in patients with breast cancer and (b) decrease the incidence of RD by 10% at a tertiary care cancer center. Methods Center-wide standards of care were created and implemented. A retrospective chart analysis was performed before and after protocol implementation. An education session was used to analyze protocol effectiveness. Findings Surveys completed by nurses (N = 11) before and after the education session demonstrated a significant increase in overall confidence in assessing RD. Statistically significant increases were noted in using topical steroids for prophylaxis.

Prurigo nodularis occurs with chronic pruritus and the presence of single to multiple symmetrically distributed, hyperkeratotic, and intensively itching nodules. Diverse dermatologic, systemic, neurologic, or psychiatric conditions can lead to prurigo nodularis. Structural analysis demonstrated a reduced intraepidermal nerve fiber density and increased dermal levels of nerve growth factor and neuropeptides such as substance P and calcitonin gene-related peptide. Novel therapy concepts such as inhibitors at neurokinin-1, opioid receptors, and interleukin-31 receptors have been developed. The mainstays of prurigo nodularis therapy comprise topical steroids, capsaicin, calcineurin inhibitors, phototherapy, and the systemic application of anticonvulsants, μ-opioid receptor antagonists, or immunosuppressants.

Chronic inflammation is a potential systemic risk factor for many bladder dysfunctions, including interstitial cystitis (IC). However, the underlying mechanism through which a healthy bladder protects itself from inflammatory triggers remains unknown. In this study, we identified odor compounds in urine obtained from IC patients and healthy controls. Using comprehensive solid-phase microextraction-gas chromatography-time-of-flight-mass spectrometry (SPME-GC-TOF-MS) profiling and bioinformatics, we found that levels of urinary volatile metabolites, such as menthol, were significantly reduced in IC patients, compared to healthy controls. In an attempt to understand the mechanistic meaning of our volatile metabolites data and the role of menthol in the immune system, we performed two independent experiments: (a) cytokine profiling, and (b) DNA microarray. Our findings suggest that lipopolysaccharide (LPS)-stimulated inflammatory events, such as the production and secretion of inflammatory cytokines (e.g., TNF-α, IL-6, and IL-1β) and the activation of NF-κB and associated proteins within a large signaling network (e.g., Akt, TLR1, TNFAIP3, and NF-κB), are suppressed by the presence of menthol. These findings broaden our knowledge on the role of urinary menthol in suppressing inflammatory events and provide potential new strategies for alleviating both the odor and inflammation associated with IC.

Neuropathic pruritus is a challenging condition that can be caused by injury or dysfunction in any part of the nervous system. A vast array of clinical pictures exist, including both localized and generalized pruritus, and their principal entities are described in this article. Diagnosis is often difficult and depends on patient history, imaging, and neurophysiologic studies. Other causes of chronic itch should be excluded. The management of neuropathic itch is demanding and the majority of interventions are not curative. The best treatment options include anticonvulsants, topical anesthetics, and capsaicin.

Pruritus is a common symptom in cutaneous T-cell lymphoma (CTCL) and critically affects the quality of life of patients. Understanding the pruritogenesis has led to development of new therapeutic agents with promising outcomes in management of this recalcitrant symptom. Clinical assessments are warranted to aid in evaluation of treatment response or disease recurrence. Severe pruritus scores may require further investigation of emotional distress for a better patient approach. Dermatologists play a key role in the treatment of CTCL-pruritus by guiding the patient in the importance of preserving the integrity of the skin barrier.

Chronic pruritus, or itch lasting greater than 6 weeks, is an increasingly common and debilitating medical problem. Recent studies have unveiled previously unrecognized neuroimmune axes whereby inflammatory cytokines act directly on the nervous system to promote itch. Thus, the emergence of newer targeted biologic therapies has generated the possibility of novel treatment strategies for chronic itch disorders. This article reviews the pathophysiology of multiple chronic itch disorders, including atopic dermatitis, chronic idiopathic pruritus, chronic urticaria, and prurigo nodularis. Furthermore, new and emerging immunomodulatory therapies that will likely alter current treatment paradigms are discussed.

Chronic pruritus (>6 week's duration) in the geriatric population (≥65 years old), is an increasing health care problem. The pathophysiologic predisposing factors are abnormalities of the epidermal barrier, immune system, and nervous system. Causes can be dichotomized into histaminergic and nonhistaminergic pruritus. Topical treatments are generally safe. Systemic treatments are chosen depending on the condition, comorbid diseases, and drug interactions. Treatment options are limited. Progress has been made in identifying itch-selective mediators over the last decade. Numerous new medications are currently undergoing clinical trials and they are anticipated to enter the clinics in the near future.

Impaired sleep due to nocturnal pruritus is a common symptom in patients with chronic pruritus. However, there is no standardized, simplified instrument for assessing sleep-related problems in patients with chronic pruritus. After a literature search, we conducted 50 interviews with patients with chronic pruritus and tested 12 items most frequently used in routine sleep questionnaires. Afterwards, 2 sleep assessment questionnaires (Pittsburgh Sleep Quality Index; Regensburg Insomnia Scale) were selected for use in 88 patients with chronic pruritus with sleep impairment due to pruritus. They were completed twice; once before optimizing their individual pruritus therapy and once again after 4 weeks. During the latter survey, 21 patients reported that pruritus no longer negatively affected their sleep. These patients also achieved a significant improvement in their sleeping behaviour in the Regensburg Insomnia Scale. Therefore, the Regensburg Insomnia Scale appears to be well-suited to assessing sleep impairment in patients with chronic pruritus.

Atopic dermatitis (AD) is characterized by chronic, eczematous, severe pruritic skin lesions caused by skin barrier dysfunction and T helper (Th)2 cell-mediated immunity. Interleukin (IL)-31 is a potent pruritogenic cytokine primarily produced by Th2 cells. Both IL-31 transgenic mice and wild-type mice treated with IL-31 exhibit AD-like skin lesions and scratching behaviour. IL-31 receptor α-chain (IL-31RA) is also expressed in peripheral nerves and epidermal keratinocytes, and the roles of IL-31 on pruritus and skin barrier have been investigated. Recently, an anti-IL-31 receptor antibody was shown to significantly improve pruritus in AD patients. This review focuses on IL-31 and IL-31RA in AD.

BACKGROUND Topical capsaicin shows efficacy in the treatment of brachioradial pruritus (BRP); however, its mechanisms of action remain unclear. OBJECTIVE The effect of capsaicin on the epidermis (i.e. peripheral expression of non-neuronal sensory receptors on keratinocytes, morphological changes in innervation) is still unknown. We aimed to investigate the effect of topical capsaicin on keratinocyte expression of TRP channels and on the intraepidermal nerve fibre density (IENFD) in patients with BRP. METHODS Thirty-one patients with BRP received an 8% capsaicin patch. Biopsies in lesional and non-lesional skin were taken to assess epidermal morphology, keratinocyte expression of TRP channels and IENFD before and 3 weeks after treatment. RESULTS Treatment with the capsaicin patch led to a significant decrease in itch and paresthetic symptoms (P < 0.05). Keratinocyte morphology is unaltered after capsaicin therapy. Reduced keratinocyte expression of TRPV1 in lesional skin (P = 0.009; n = 9) normalized 3 weeks after treatment (P = 0.016; n = 10), but not the IENFD, which remained reduced in lesional epidermis. CONCLUSION The normalization of the decreased TRPV1 expression may account for the effectiveness of topical capsaicin, which does not reconstitute the reduced IENFD, arguing for a role of epidermal TRPV1 in the maintenance of BRP.

Primary biliary cholangitis (formerly known as primary biliary cirrhosis, PBC) is an autoimmune liver disease in which a cycle of immune mediated biliary epithelial cell injury, cholestasis and progressive fibrosis can culminate over time in an end-stage biliary cirrhosis. Both genetic and environmental influences are presumed relevant to disease initiation. PBC is most prevalent in women and those over the age of 50, but a spectrum of disease is recognised in adult patients globally; male sex, younger age at onset (1.67 × upper limit of normal and/or elevated bilirubin) should be considered for second-line therapy, of which OCA is the only currently licensed National Institute for Health and Care Excellence recommended agent. Follow-up of patients is life-long and must address treatment of the disease and management of associated symptoms.