Generalized pruritus without primary skin manifestations can be an early sign of serious systemic conditions, including plasma cell dyscrasias such as monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma. Although the pathophysiology of pruritus in these conditions remains incompletely understood, proposed mechanisms include inflammatory mediator release, neuropathic pathways, and paraprotein deposition in the skin. Effective management strategies are limited, and pruritus significantly impacts patients’ quality of life. Here, we describe 2 cases of generalized pruritus associated with plasma cell dyscrasias that improved with duloxetine therapy. Case 1 involves a 71-year-old male with IgG lambda MGUS and chronic refractory pruritus, who demonstrated significant improvement in symptoms with duloxetine 60 mg daily after failing multiple prior treatments, including biologicals and phototherapy. Case 2 details a 59-year-old female with recurrent IgA kappa multiple myeloma and a 10-year history of progressive pruritus, who similarly achieved substantial symptom control with duloxetine, supported by adjunctive therapies during disease recurrence. Both cases suggest that duloxetine, a serotonin-norepinephrine reuptake inhibitor with neuromodulatory and potential anti-inflammatory properties, may offer benefit in treating chronic pruritus in plasma cell dyscrasias, particularly when standard therapies fail. However, dose titration is critical to minimize adverse effects, notably sexual dysfunction observed at higher doses. Our findings support a multimodal approach to pruritus management, combining duloxetine with agents targeting neuropathic and inflammatory pathways. Further research is needed to better define duloxetine’s role, optimal dosing strategies, and patient selection criteria for treating pruritus in plasma cell dyscrasias. Early recognition and targeted management of pruritus in these patients may greatly improve quality of life and overall disease burden.
In most chronic itch conditions, antihistamines are ineffective, highlighting the necessity to study the mechanisms of non-histaminergic itch to develop new treatments. Polymodal C-fibers, transmitting non-histaminergic itch, can be experimentally activated by BAM8-22, a Mas-related G protein-coupled receptor X1 (MrgprX1) agonist. Moreover, TRPA1 ion channel activation could provoke non-histaminergic itch. This study aimed to explore TRPA1 and MrgprX1 interaction by modulating BAM8-22-induced non-histaminergic itch with the TRPA1 antagonist A-967079. Four areas on the forearms of 22 healthy subjects were treated as follows: vehicle+BAM8-22, A-967079+BAM8-22, A-967079+BAM8-22 (applied after 5 min), and A-967079+inactivated cowhage spicules. BAM8-22 (2 mg/mL) was applied through inactivated cowhage spicules, while A-967079 (0.5 mg/mL) and vehicle were intradermally injected (0.1 mL). After application, itch was scored for 9 minutes, followed by measurement of superficial blood perfusion and mechanical/thermal sensitivities. Itch evoked by A-967079+BAM8-22 (after 5 min) resulted in a lower (P<0.05) than vehicle+BAM8-22. In A-967079+BAM8-22 (after 5 min) area, mechanically evoked itch was reduced (P<0.05). The TRPA1 antagonist A-967079 reduced BAM8-22-induced non-histaminergic itch, confirming that the TRPA1 receptors may be involved in non-histaminergic itch generation and hence may provide new information helping manage non-histaminergic itch.
For patients with intellectual and developmental disabilities (IDD), a population often underserved in dermatology, we sought to highlight the unique challenges of managing pruritus and to provide equitable and efficacious recommendations. Tailored approaches such as thorough chart reviews, communication aids, and longer appointments are critical in evaluation. Recognition and mitigation of biases ensure accurate assessments. During physical examinations, accommodations like visual aids and stepwise approaches can alleviate anxiety and improve patient cooperation. Testing and therapy should emphasize the patient’s needs, promoting tolerability and shared decision-making. Through these means, clinicians can improve outcomes and promote health equity for this vulnerable population.
Keloids are benign fibrotic lesions that frequently cause persistent itch and pain, yet their underlying molecular mechanisms remain poorly defined. Aberrant transforming growth factor-beta (TGF-β) signaling, particularly through noncanonical pathways such as mitogen-activated protein kinase (MAPK), has been implicated in keloid pathogenesis. In this study, we investigated the effects of selective MEK1 inhibition in vitro using NL350-02 on human keloid fibroblasts via bulk RNA sequencing. Treatment with NL350-02 induced substantial transcriptomic reprogramming, including downregulation of TGF-β receptors, IL-6, IL-17 receptors, and proinflammatory chemokines, alongside the upregulation of proapoptotic genes and marked suppression of proliferation (eg, >3000-fold reduction in Ki-67 expression). Pathway analyses revealed significant enrichment in processes related to apoptosis, cytokine signaling, and TGF-β regulation. Despite paradoxical increases in certain collagen transcripts, the concurrent induction of apoptosis suggests an indirect antifibrotic mechanism. Furthermore, transcriptomic overlap with pruritic conditions and the downregulation of itch-related cytokines highlight MEK1 as a potential target for modulating neuroinflammation in keloid-associated itch. These findings suggest that MEK1 inhibition may offer a dual therapeutic benefit, attenuating both fibrosis and pruritus, and warrant further validation in preclinical keloid models.
Introduction: Atopic dermatitis (AD) is the most common and burdensome inflammatory skin disease worldwide1. AD is heterogeneous both in its clinical presentation and response to treatment, and it is important to understand how adult-onset AD differs from childhood-onset and whether prevention and treatment strategies should differ. Methods: We performed a cross-sectional study of 18 participants ages 18+ from UCSF dermatology clinics in which we performed clinical assessments and collected patient-reported outcome data using validated surveys. We measured skin barrier function using transepidermal water loss (TEWL) and stratum corneum hydration (SCH) and calculated a frailty score. Results: Adult-onset patients had greater AD severity, worse experience with AD, poorer quality of life, and greater pruritis. In contrast, investigators’ global assessment of AD severity was the same among both groups. Regarding barrier function, TEWL was comparable between both groups, and SCH was higher in childhood-onset AD. We observed several differences in clinical presentation between childhood-onset and adult-onset AD. Adult-onset patients had more severe AD in the trunk and lower extremities, had a higher tendency toward cutaneous infections, were more pruritic, had less facial pallor or erythema, less pityriasis alba, and less Dennie-Morgan infraorbital folds. Discussion: Patient-reported outcomes, including the NRS or more detailed clinical severity scores like EASI and SCORAD, may be more likely to identify differences in severity among adults with AD than a global assessment score. We encourage the use of scales like the NRS and DLQI among the adult AD population, as pruritus and mental health comorbidities are especially common in this population. We recommend the use of frailty scores, especially for older adults, as they can help providers understand the full burden of disease.
Atopic dermatitis (AD) is a chronic inflammatory skin disorder characterized by persistent itching of the skin with its prevalence increasing in the United States. AD has a complex pathogenesis that remains to be fully resolved, though it is shown to involve immune dysregulation and skin barrier dysfunction, with multiple environmental and genetic factors implicated. The interplay between the immune system and environmental exposures can incite immune responses with the release of cytokines, IgE, eosinophils, and mast cells, which trigger symptoms of AD in susceptible patients. There are many therapies used in AD; however, the first-line treatment for flares continues to be corticosteroids. The broad range of therapies available for AD is associated with adverse effects, poor adherence, and financial burden, accentuating the need to assess alternative therapies. A promising alternative therapy is the catechin family, a group of flavonoids with a unique structure that has anti-inflammatory, antimicrobial, antioxidant, and skin barrier modulating properties. In this review, we describe the structure and related properties of catechins, their function, and how they can be utilized in the treatment of AD. Furthermore, we describe limitations associated with the use of catechins and the necessity of further research in this area. The function of catechins has been widely shown to modulate the inflammatory pathway and skin barrier dysfunction that have been implicated in AD and reduce symptoms. While catechins can mitigate symptoms and reduce associated inflammatory markers, further research is required to develop a therapy that retains the beneficial functions of catechins without increasing cytotoxicity.
Chronic kidney disease-associated pruritus (CKD-aP) is a prevalent and challenging symptom in patients with CKD and end-stage renal disease (ESRD). The aim of this review is to update existing evidence on the pathogenesis and treatments of pruritus in CKD and to shed light on areas that hold promise. The uncertain pathogenesis, and thus seemingly miscellaneous causes, identifies chronic itch as an important challenge in health care. A complex interaction of uremic toxin accumulation, micro and systemic inflammation, dysregulation of the opioid system, and mast cell activation may each contribute to the pathophysiology of CKD-aP. No highly satisfactory antipruritic therapeutics are available. Difelikefalin, considered to be a peripherally acting highly selective kappa-opioid receptor agonist, has been shown to have a positive impact on CKD-aP. Approved by the FDA in 2021 for intravenous administration, difelikefalin remains the most recent drug available. A developing area is that altered hemoglobin metabolism may lead to the activation of mas-related G protein-coupled receptors (MRGPRs). As this family of receptors is associated with itch, it is possible that drugs that target certain MRGPRs may be of future benefit in CKD-aP.
Objective: Agonizing itching (pruritus), heat, and burning are common symptoms of mosquito bites. In this study, we present a thermo-therapeutic medical device for the symptomatic treatment of mosquito bites. Current research suggests the potential of a thermal (heat) stimulus for pruriceptor counter-stimulation and reduced histamine-signaling to relieve the symptoms of mosquito bites. The purpose of this clinical investigation was to investigate the efficacy and safety of the thermo-therapeutic medical device (class II) in the symptomatic treatment of mosquito bites in an intraindividual comparison to a placebo device (PD) examined under standardized conditions. This was achieved by assessing pruritus and wheal size over time after induction of a mosquito bite on the volar forearm. Methods: The itching was rated on a Visual Analog Scale ranging from 0 mm (no itching) to 100 mm (worst imaginable itching). The wheal size was measured in approximation to the area of an eclipse before and ~30 minutes after the treatment with the investigational device. Local tolerability was assessed by the investigator according to a score ranging from 0 (no irritation) to 4 (very strong irritation) and the subjects stated if the itching sensation was completely gone after treatment (yes/no question). Results: The mean area under the curve of the difference to baseline for the treatment with the medical device was statistically significantly bigger than for the treatment with the PD (1311.71 vs 914.61, respectively; P = 0.0127). Conclusions: Treatment of a mosquito bite with a thermo-therapeutic medical device significantly reduced pruritus and led to a faster reduction of the itching sensation as compared with PD. A significant itch reduction started immediately (1 min) after treatment with the medical device (post hoc analysis). The treatment with the medical device was well tolerated by all subjects and no adverse events related to the medical device occurred.
Introduction: Atopic dermatitis (AD) is a chronic inflammatory skin disease with intractable itch. Dorsal root ganglion (DRG) plays an important role in signal transduction of itch. It has been reported that satellite glial cells (SGC) present around DRG neurons are involved in pain and itch through interactions with DRG neurons. However, it is unclear what factors in SGC are involved in inducing dermatitis and itch in DRG. In this study, we found that the expression of lipocalin-2 (LCN2) was increased in SGC of AD model NC/Nga mouse. Therefore, we also examined whether SGC-derived lipocalin-2 is involved in the induction of dermatitis and itch-related behavior in this model mice. Materials and methods: AD-like dermatitis was induced by the application of Dermatophagoides farinae body ointment to NC/Nga mice (AD-NC/Nga mice). Protein and gene expression in the DRG and spinal cord of AD-NC/Nga mice were examined. The effect of the LCN2 antibody on dermatitis pathology in AD-NC/Nga mice was confirmed. Results: LCN2 expression in DRG of AD-NC/Nga mice was higher than that of control NC/Nga mice. Immunohistochemical analysis revealed that LCN2 was expressed on SGC in DRG. Gene expression level of LCN2 in the DRG was significantly increased faster than in the spinal cord during the process of induction of AD-like dermatitis. LCN2 increased gene expression of MMP-9 in mouse DRG. Intrathecally administrated anti-LCN2 antibody twice a week for 3 weeks at the same time as induction of AD-like dermatitis reduced dermatitis score without inhibiting scratching behavior. Discussion: In conclusion, our data suggest that SGC-derived LCN2 is involved in the pathogenesis of dermatitis rather than itch-related behavior in AD-NC/Nga mice.
Importance: Neuropathic pruritus is a debilitating condition lacking a uniform approach to nomenclature and diagnosis. Objective: A panel of dermatologist experts in pruritus was convened to develop definitions, diagnostic recommendations, and treatment guidelines for neuropathic pruritus. Evidence review: A roundtable discussion of 10 experts was conducted on November 3, 2021, via the Zoom platform. This study follows the Standards for Reporting Qualitative Research reporting guidelines for qualitative studies. A systematic review of prior literature on the definition, scope, diagnostic, and treatment was performed, looking at sources of treatment from 1991 to 2021. Consensus was defined as >70% agreement for acceptance of a definition or recommendation. A draft of evidence was subjected to revision by all participants and was endorsed by all participants. Findings: The roundtable identified definitions for neuropathic pruritus, which included different forms of the condition based on cause and presentation such as brachioradial pruritus, notalgia paresthetica, and scalp pruritus. Diagnostic and treatment guidelines were also established. Limitations of this process included lack of randomized controlled studies. These recommendations are also based on expert consensus and must be further supported by evidence-based outcomes research. Conclusions: Neuropathic pruritus contains numerous subtypes, causes, diagnostic methods, and treatment modalities. The recommendations developed by this panel are meant to serve as shared nomenclature for future clinical studies.
Nemolizumab was approved in Japan in August 2022 to treat patients with atopic dermatitis (AD). The study objective was to evaluate its effectiveness in controlling AD symptoms in the real world postmarketing. Eleven Japanese patients with AD treated with nemolizumab were assessed at 12 weeks for clinical manifestations, AD scores Visual Analog Scale and Eczema Area and Severity Index, and serum biomarkers. Visual Analog Scale and Eczema Area and Severity Index scores were significantly decreased by 80% and 66.4%, showing nemolizumab improved both itch and skin lesions. However, several serum AD biomarkers did not change during treatment with nemolizumab.
Mechanical alloknesis develops with dry skin and reduces the quality of life of people afflicted. Nobiletin (NOB) is a major citrus flavonoid with various health benefits. We investigated whether oral administration of NOB or 4’-demethyl NOB inhibits dry skin-induced alloknesis in a mouse model. As a result, both treatments were effective to inhibit mechanical alloknesis. These compounds may be promising candidates to lead to the development of therapeutic agents for mechanical alloknesis.
Background: The effects of repeated topical applications of local anesthetics are poorly investigated as they may, in addition to analgesia, impact peripheral nerve endings in a cumulative manner. In the present study, the effects of 6 repetitive applications of eutectic mixture of lidocaine (EMLA 2.5% and prilocaine 2.5%) were investigated on experimentally induced pain, histaminergic and nonhistaminergic itch, and neurogenic inflammation. Methods: Four skin areas on the forearms of 24 subjects were randomized to receive 3 hours of application of EMLA or placebo twice a day for 3 consecutive days. After each application, superficial blood perfusion (SBP), mechanical (mechanically evoked itch, mechanical pain threshold, and mechanical pain sensitivity), and thermal sensitivity (warm detection threshold, heat pain threshold, and suprathreshold heat sensitivity) were assessed. After the last application of EMLA/placebo, histamine and cowhage was applied (2 areas each) and itch and pain intensity and SBP were assessed. Results: After 3 hours of EMLA application, significant mechanical and thermal hypoalgesia were found with no cumulative efficacy over the 3 days. EMLA alone had no effect on SBP. Significantly increased SBP, reduced cowhage-induced itch, but the unaffected histamine-induced itch was found when applying EMLA ahead of histamine and cowhage. Conclusions: EMLA induced a reduction of mechanical and thermal sensitivity without a cumulative-dose effect. EMLA reduced nonhistaminergic itch and pain but not the experimentally provoked histaminergic itch. Selective action of EMLA on polymodal C-fibers could explain these effects.
Chronic pruritus is a debilitating condition affecting 23-44 million Americans. Recently, kappa opioid agonists (KOAs) have emerged as a novel class of potent antipruritic agents. In 2021, the Food and Drug Administration approved difelikefalin (Korsuva) for the treatment of moderate-to-severe pruritus associated with chronic kidney disease in adults undergoing hemodialysis. Difelikefalin is a potent, peripherally restricted KOA that is intravenously available. Although promising, difelikefalin is currently available as an intravenous composition only, limiting the scope of use. Oral formulations of difelikefalin did not meet the primary endpoint criteria in recent phase 2 clinical trials; however, additional clinical studies are ongoing. The future for KOAs in the treatment of pruritus is encouraging. Orally active pathway-biased KOAs, such as triazole 1.1, may serve as viable alternatives with broader applications. Extended-release compositions, such as the TP-2021 ProNeura subdermal implant, may circumvent the pharmacokinetic issues associated with peptide-based KOAs. Lastly, dual-acting kappa opioid receptor agonist/mu opioid receptor antagonists are orally bioavailable and may be useful in the treatment of various forms of chronic itch. In this review, we summarize the results of KOAs in clinical and preclinical trials and discuss future directions of drug development.
The relationship between itch and heat pain has been vastly explored. A 70-year-old study, showed the development of paradoxical itch following heat stimulation of anesthetized skin. The aim of this study was to re-evaluate, with more modern technologies and systematic approaches, this paradoxical itch effect. Escalating heat stimuli were applied to the local anesthetized skin of 19 healthy subjects, itch, and pain intensities were continuously assessed during the stimulation. As expected, pain sensation was significantly reduced by local intradermal anesthesia, however, no paradoxical itch sensations were observed for any of the stimulation temperatures.
Introduction: Itch is an unpleasant sensation that evokes a scratching behavior which often damages the skin. Nalfurafine is a kappa opioid receptor (KOR) agonist known as an effective drug used to control the intractable itch. Mechanistically, the spinal cord is a target of nalfurafine, however, little is known about the specific sites important to the antipruritic effects of nalfurafine. Therefore, the aim of this study was an investigation to uncover the sites of action of nalfurafine in the spinal neuronal pathway of itch. Materials and Methods: To reveal the antipruritic action of nalfurafine in the murine spinal dorsal horn, we conducted in vivo electrophysiology, behavioral experiments, and high-sensitive in situ hybridization (ISH) using normal C57BL/6J mice. Results: Behavioral analyses indicated that intrathecal injection of nalfurafine reduced, but not entirely eliminated the gastrin-releasing peptide (GRP)-evoked scratching bouts. In vivo electrophysiological recordings revealed that nalfurafine administration suppressed chloroquine (CQ)-responsive dorsal horn neurons in 15.8% (3/19) of mice. In fact, only 1 of 3 nalfurafine-suppressed mice responded to GRP. ISH in 3 sections of the spinal cord showed that 24.8% (154/623) were double-positive for GRP and KOR and 13.6% (68/431) for GRP receptor (GRPR) and KOR in total KOR + cells. Most KOR + cells were negative for GRP and GRPR. Intrathecal injection of dynorphin-saporin did not change the number of scratching bouts caused by GRP. However, it reduced the number of scratching bouts evoked by intradermal injection of CQ. Discussion: In conclusion, our data suggest that nalfurafine targets both GRP + KOR + and GRPR + KOR + cells which are present in a 2:1 ratio and suppresses CQ-induced itch in the spinal dorsal horn. These findings suggest that GRP + KOR - or GRPR + KOR - cells may function as interneurons in the spinal neuronal pathway of itch.
Chronic pruritus of unknown origin (CPUO) is a common condition that is underrecognized and underdiagnosed. Patients suffer from 6 or more weeks of pruritus with no identified cause, or with multiple potential causes, of which the primary cause cannot be determined. Despite being a common condition and prevalent in nearly 30% of the elderly in certain populations, most patients suffer from CPUO for years from inadequate treatments for itch and are made to undergo extensive diagnostics. There is no FDA-approved treatment for CPUO, and providers are often tasked to treat CPUO patients with limited knowledge and guidance on CPUO and its treatments. However, recent breakthroughs in antipruritic therapeutics have led to an increase in therapies available for CPUO patients. These include a variety of both pharmacological and nonpharmacological interventions, as well as topical and systemic therapies. Newer therapies such as biologics and Janus kinase inhibitors are currently under investigation due to their therapeutic effects in other pruritic diseases and are promising for treating CPUO. Here, we review the various therapeutic options that are currently available or are on the horizon, with a special emphasis on the therapies antipruritic mechanism, available clinical evidence of efficacy and safety, and the appropriate contexts for their application. By doing so, we hope to educate clinicians on the known treatments for pruritus and their applicability to CPUO to guide optimal management of this highly prevalent disease.
Chronic pain and chronic pruritus are both debilitating conditions that cause a significant burden to patients. Oxidative stress—driven by an imbalance between reactive oxygen species and antioxidants—has been shown to play a role both in pain disorders and conditions in which chronic itch is a prominent symptom. Antioxidants can be useful in treating oxidative stress-driven diseases and have shown promise in treating chronic pain conditions such as fibromyalgia and osteoarthritis. However, their role in treating pruritus and pruritic conditions such as psoriasis and atopic dermatitis remains unclear. Many of the current treatments for chronic itch are costly, associated with side effects, and have limited efficacy. Therefore, further controlled studies exploring antioxidants as a potential therapeutic option for chronic pruritus are warranted.
Workup for chronic itch in older adults varies significantly across practices. Patch testing remains an important piece of the workup for chronic pruritic rashes in this population, however, there remains a subset of these patients who test negative. This descriptive study sought to better characterize shared clinical and histopathologic features of patch negative older adults to improve understanding of contributing etiologies for itch in this group.
Introduction: Itch (or pruritus) is a common symptom of atopic dermatitis (AD), which significantly decreases the patient’s quality of life. Tacrolimus ointment reduces pruritus in AD; however, the underlying mechanism is not fully understood. Methods: In the present study, we used a diet-induced AD mouse model to examine the antipruritic mechanism of tacrolimus. After induction of AD symptoms, the tacrolimus-containing ointment was applied once daily for 7 days. Responsiveness of isolated dorsal root ganglion (DRG) cells to various stimuli was examined by monitoring intracellular Ca 2+ levels. Results: Repeated application of tacrolimus ointment attenuated spontaneous itch-related responses, even when skin barrier dysfunction, skin inflammation, and epidermal nerve sprouting were not ameliorated. Tacrolimus-treated mice also exhibited reduced scratching behavior induced by several pruritogens, such as histamine, SLIGRL-NH 2 , and chloroquine (CQ), although capsaicin-induced pain behavior was not affected. DRG cells from tacrolimus-treated mice showed significantly lower Ca 2+ responses to CQ. Furthermore, a reduction in CQ-sensitive DRG neurons was observed after in vitro treatment with either tacrolimus or rapamycin. Discussion: CQ-sensitive (MrgprA3-expressing) DRG neurons are implicated as itch-specific sensory neurons. Therefore, topically applied tacrolimus may act directly on itch-signaling neurons, consequently suppressing various itch responses in AD mice.
