Itch-Relieving Cosmetics

Abstract

This review aims to explore the evolving role of cosmetics in alleviating itch, transcending their traditional aesthetic function. With a focus on formulations enriched with natural oils and other bioactive components, we examine the efficacy and safety of various cosmetic ingredients designed to control itch. Highlighted are ingredients such as colloidal oatmeal, postbiotics, menthol, peppermint, cryosim-1, capsaicin, asivatrep, polidocanol, pramoxine hydrocholoride, and palmitoylethanolamide, which are recognized to reduce itch. Special attention is also given to phytochemicals that can modulate the Janus kinase/signal transducer and activator of transcription signaling pathway and carry the potential as an itch-relieving cosmetic ingredient. This review encompasses clinical studies that verify the itch relieving effect of these cosmetic ingredients. By integrating current scientific evidence, we aim to shed light on the potential of anti-itch cosmetics as an adjunct to standard itch treatment, thereby broadening our understanding of their role in dermatological care.

1. Introduction

The Federal Food, Drug & Cosmetic Act (FD&C Act) characterizes cosmetics as “articles intended to be rubbed, poured, sprinkled, or sprayed on, introduced into, or otherwise applied to the human body for cleansing, beautifying, promoting attractiveness, or altering the appearance” (FD&C Act, sec. 201(i)). This category encompasses a variety of products, such as moisturizers, perfumes, lipstick, nail polish, eye and facial makeup preparations, shampoo, hair coloring, toothpaste, and deodorant, along with any material intended for use as a component of a cosmetic product [1]. The role of cosmetics in skin health has undergone significant changes over the years, expanding beyond aesthetic improvement and elementary skin safeguarding. As part of this shift, moisturizers are now being developed and marketed in multiple formulations that focus on different skin issues [1]. The market for products designed to address specific skin concerns, such as xerosis, acne, and atopic dermatitis (AD), is rapidly growing. These products aim to not only provide general skin care but also to alleviate the discomfort associated with these skin conditions. One notable example of this trend is the debut of itch-relieving cosmetics, which underscores the advanced and tailored approach to skincare. This review aims to take a closer look at the details of anti-itch cosmetics, focusing particularly on the common cosmetic products marketed for anti-itch effects and their active ingredients. In addition, we will identify the mechanisms by which the active ingredients exert their anti-itch effects and summarize the clinical studies supporting their efficacy. By doing so, we seek to provide a comprehensive understanding of how these products work and their potential benefits in skincare.

2. Methods

A search was conducted in two electronic databases, PubMed and Cochrane Library, consisting of search terms including “itch”, “itching”, ”anti-itch”, “pruritus’, “pruritic”, “anti-pruritics”, “moisturizers”, “emollients”, “cosmetics”, “polyphenols”, “phytochemicals”, “eczema”, “dermatitis”, “dermatology”. English-language articles that assessed the use of active ingredients in moisturizers for targeting itch were included. Non-English articles and drug ingredients not classified as cosmetic ingredients were excluded. We specifically included active ingredients that are currently widely marketed in cosmetics for itch relief. Preference was given to high-quality, peer-reviewed articles, and reference lists were reviewed to include relevant studies. Additionally, we considered clinical studies on the ingredients, whether they were RCTs, non-randomized controlled, or even uncontrolled.

3. Itch

Itch is an unpleasant sensation of the skin that provokes the desire to scratch [2]. With a lifetime prevalence reaching up to 25%, chronic itch (>6 weeks) is ubiquitous in the general population [3,4]. Elderly people are particularly prone to chronic itch, which is likely due to the anatomical, functional, and physiologic changes in aged skin [4,5]. Studies have shown that itch is associated with higher levels of stress and anxiety, and can disrupt one’s sleep, concentration, and daily activities [6]. Not surprisingly, chronic itch exerts a substantial, negative impact on the quality of life (QoL) comparable to that of chronic pain [7].

Itch is often a symptom of a clinically evident skin condition such as AD, psoriasis, urticaria, scabies, bullous pemphigoid, and prurigo nodularis (PN) [8,9]. However, it may also be a prominent feature in many systemic diseases (i.e., acquired immunodeficiency syndrome, chronic kidney disease, liver disease, cholestatic disease, hematologic causes, thyroid disease, iron deficiency, malignancy), neuropathic disorders (i.e., nostalgia paresthetica, brachioradial itch, postherpetic itch), and psychologic conditions [3,10] (Table 1) Environmental pollutants and climate factors also trigger the itch sensation [5,11].

The Itch Pathway

Itch involves complex crosstalk between keratinocytes, the immune system, and sensory nerves and is ultimately provoked by the interaction between the itch mediators (pruritogens) and the pruriceptors [12]. There are two major neuronal itch pathways: the histaminergic and the non-histaminergic, the latter of which involves a diverse array of receptors that respond to itch-inducing agents other than histamine [12,13,14]. Acute itch is primarily triggered by histamine, which is released by mast cells, basophils, and keratinocytes within the skin [14,15]. On the other hand, chronic itch, which is our focus, involves a wider variety of pruritogens, such as proteases, cytokines/chemokines, and amines [16]. There are primarily two types of itch receptors: the G protein-coupled receptor (GPCR), which is the main subtype, and the interleukin receptor (ILR) that is coupled to the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling pathway. Both transmit itch signals downstream by activating the family of transient receptor potential (TRP) channels. The GRCRs include the histamine H1 and H4 receptors and the protease-activated receptors (PARs), mas-related G protein coupled receptors (MRGPRs), and neurokinin receptors. TRP ion channels, such as Transient Receptor Potential Vanilloid (TRPV) 1, Transient Receptor Potential Ankyrin (TRPA) 1, TRPV3, and TRPV4, play significant roles in both acute and chronic itch, as well as pain. The Nav1.7 sodium channel, essential for nerve signal transmission, is activated by TRPV1 and TRPA1 and conveys itch and pain signals [13,16,17,18].

Opioid receptors, particularly mu-opioid receptors (MOR) and kappa-opioid receptors (KOR), have also been implicated in the regulation of itch, with activation of MORs generally exacerbating itch, whereas activation of KORs tends to suppress itch [19]. Pro-opiomelanocortin (POMC), as a precursor molecule, is also related with the opioid-mediated modulation of itch. It is cleaved into several bioactive peptides, including β-endorphins that primarily activate MORs, which can provide pain relief but also potentially increase itch. Conversely, other derivatives of POMC can interact with KORs to help suppress itch signals. This demonstrates the complex balance of opioid receptor activation by POMC derivatives in the nervous system [20,21].

The sensation of itch is primarily transmitted through unmyelinated type C and thinly myelinated type Aδ nerve fibers in the skin [22]. The cell bodies of these pruriceptors are in the dorsal root ganglia and their axons continue into the spinal cord typically synapsing in the dorsal horn with activating or inhibitory interneurons [13,22]. Other than transmitting the itch signal, primary sensory neurons intensify itch by secreting itch mediators [23]. Activated sensory neurons release neuropeptides such as calcitonin gene-related peptide (CGRP) and substance P (SP), which mediate mast cell degranulation and plasma extravasation. Cytokines and proteases released from keratinocytes and mast cells initiate a neurogenic inflammation further aggravating itch [24].

As for the immunomodulatory axis, type 2 cytokines interleukin (IL)-4, IL-13, and IL-31 are necessary in chronic itch settings [25,26,27,28]. Itch-induced scratching promotes TSLP and IL-33 release by epidermal keratinocytes, which perpetuates the itch-scratch cycle. Recently, the Th17/22 axis has also been implicated in the itch of psoriasis, AD [27,29,30,31], and PN [32,33], all of which are potential therapeutic targets.

4. Cosmetic Ingredients Tailored for Itch and Their Anti-Itch Mechanisms

Itch treatment aims at itch relief and beyond, which is the appropriate management of the underlying etiology. Due to its complex nature, most require multimodal treatment, utilizing both topicals and systemic agents [34]. The most commonly used topical medication is corticosteroids but the risk benefit ratio should be calculated if the intent is to treat large areas of the skin as topical corticosteroids can potentially suppress the hypothalamus-pituitary axis and cause skin thinning [35,36]. Alongside pharmaceuticals, consumers are increasingly drawn to cosmetic products that address itch while offering daily use convenience. Such a trend underscores the growing demand for safe and effective anti-itch formulations.

Dry skin increases intraepidermal nerve density and the expression of neuropeptides and cytokines, which enhances itch sensitivity through complex interactions with sensory neurons and keratinocytes [37]. Moisturizers, one of the most widely used preparations in cosmetics, restore the skin barrier and increase water content in the stratum corneum. Since dry skin and itch are intricately linked, the three main types of moisturizing ingredients (humectants, occlusives, and emollients) can help reduce itch. Additionally, moisturizers provide a barrier effect against environmental substances and leave the skin feeling fresh, further aiding in alleviating itch [38,39,40]. Beyond these functions, we will further focus on active ingredients with anti-itch properties (via targeting multiple components of the itch pathway) (Table 2) that may further supplement the itch-relieving effect of a regular moisturizer, with some already being commercialized (Table 3). By reviewing clinical studies that examine the itch relieving effect of these active ingredients, we offer insight into their potential therapeutic benefit (Table 4).

4.1. OatColloidal Oatmeal, Produced by Finely Grinding the Oat and Boiling It to Extract the Colloidal Material, Has Been Recognized for Its Skin-Soothing and Protective Effects

Currently, colloidal oatmeal is extensively utilized for skin conditions and has been acknowledged by the U.S. Food and Drug Administration (FDA) as a natural and safe over-the-counter (OTC) skin protectant. It is included in the FDA’s OTC monograph for skin protectant drug products, indicating its recognized safety and effectiveness. Recent evidence has indicated that colloidal oatmeal can also serve as a prebiotic, which could promote the growth of beneficial microorganisms, supporting the skin’s microbial balance [59]. The formulations of colloidal oatmeal are offered in various forms such as bath treatments, cleansing bars, body washes, shampoos, lotions, creams, and shaving gels [59]. It is also a common ingredient in many commercial moisturizers that are designed to combat dry skin and associated itching, and it is especially beneficial for conditions such as AD [60].

Removing potentially sensitizing proteins from oats might be crucial, especially for individuals with AD [61]. The development of Rhealba Oat Plant Extract is one example of this approach. Specifically designed for atopic skin by being free of oat proteins, Rhealba oat extract can minimize the risk of allergic reactions [61,62]. Oats primarily consist of starch, along with proteins, including enzymes, lipids, and fibers and beta-glucans. Within oats, avenanthramides are a group of phenolic compounds, about 20 different types, which are low in molecular weight and soluble. They are found in oats at concentrations of up to 300 parts per million, or 0.03% [41]. Many studies demonstrated that avenanthramides, bioactive compounds found in oats, exhibit anti-inflammatory, anti-proliferative, vasodilative, cytoprotective, and antioxidant properties as well as anti-itch activity [60,63].

Further research is needed to elucidate the mechanisms through which anti-pruritic actions are manifested; however, a recent in vitro study has revealed that components in oatmeal extract, notably avenanthramides, block the release of IL-8, thereby reducing inflammation and itch [41]. Additionally, it inhibits nuclear factor kappa B (NF-kB), arachidonic acid, and TNF-α, which are key in inflammatory skin diseases [41]. Interestingly, avenanthramides’ structural similarity to the antihistamine drug tranilast may suggest their itch-relief might stem from hindering histamine signaling. Applied topically at low concentrations, avenanthramides are reported to be effective in managing inflammation and itch, indicating their value as adjuvant as dermatological treatments [41].

Studies have also shown that oatmeal in skin products can help by acting as a natural buffer, keeping skin moist and forms a protective layer to lock in moisture [64]. In line with these findings, there is ongoing research into cosmetic products with 1% colloidal oat designed to alleviate itching by restoring the natural balance of the skin’s microbiome [65]. A previous randomized, open-label trial study has shown effectiveness of oat extract-based emollient in managing chronic pruritus in elderly patients with xerosis by comparing treatment to non-treatment in 30 participants [42]. Additionally, previous studies have demonstrated the topical corticosteroids sparing effect of emollient containing oat extracts, as well as its effectiveness in reducing the severity of AD and minimizing flare-ups in patients with the condition [66,67]. Matheson et al. evaluated the efficacy of liquid paraffin with 5% colloidal oatmeal in comparison with other contained liquid paraffin in the management of patients with burn injuries, and reported that product contains liquid paraffin with 5% colloidal oatmeal significantly decreased itching and patients requested significantly less antihistamine [68].

Additionally, the impact of Rhealba oat plantlet extract on chronic pruritus was assessed in a randomized crossover study involving elderly patients aged 60 and above. The emollient containing Rhealba oat plantlet extract provided significant relief from pruritus, and there were notable improvements in sleep quality and xerosis [42].

4.2. Postbiotics (Aquaphilus dolomiae, Vitreoscilla filiformis, Streptococcus thermophilus, and Lactobacillus johnsonii Extract)

Research has shown that creams containing Aquaphilus dolomiae extract (ADE-G1), derived from a type of cyanobacteria in Avène Thermal Spring Water, have been successful in alleviating itchiness and dry skin across various skin and systemic conditions [69]. In vitro research indicates that ADE-G1 has multiple beneficial effects for the management of pruritus and xerosis, such as immunomodulatory and anti-inflammatory actions that adjust the levels of various inflammatory markers [43]. Moreover, ADE-G1 has been shown to possess anti-itch properties, inhibiting the activation of PAR2 and reducing the secretion of cytokines by T helper cells (Th1, Th2, and Th17) [43]. A controlled clinical trial using the cowhage-itch model further validated the anti-itch properties of an emollient containing ADE-G1, also demonstrating its targeted inhibition of the non-histaminergic itch pathway [44]. Research has highlighted the effectiveness of topical lotions or creams with bacterial extracts from Vitreoscilla filiformis, Streptococcus thermophilus, and Lactobacillus johnsonii in alleviating symptoms of AD [70,71,72]. These benefits are possibly related to reducing the harmful impacts of S. aureus and Malassezia, leading to improved clinical outcomes such as reduced erythema, scaling, and itching.

Numerous research efforts focusing on microbiome cosmetics to enhance skin health and address associated itching suggest that the area of microbiome dermocosmetics could emerge as a promising field in the future.

4.3. Menthol and Cryosim-1

Transient receptor potential cation channel subfamily M member 8 (TRPM8) channels, located in various organs and particularly in sensory neurons, are responsible for sensing non-noxious cold temperatures and are activated by cooling compounds like menthol [73]. Cooling has been proven effective in reducing the discomfort of itches, positioning TRPM8 channels as promising targets for developing itch-relief therapies [74]. In previous double-blind, randomized study, a cooling lotion with TRPM8 agonists was effective for relieving chronic itching in people with dry skin, with up to 84% of users reporting better results than a standard lotion [47].

Menthol, an organic compound derived from peppermint (Mentha piperita) and other mint plants, is widely recognized for its cooling sensation when applied to the skin. This cooling effect can help alleviate itching by creating a counterirritant sensation that distracts from the itch [45]. Menthol works by activating TRPM8 receptors in the skin. These receptors are part of the body’s temperature-sensing system. When activated, they produce a cooling sensation, which can help to soothe and distract from the sensation of itching [45,46].

Previous research evaluated a moisturizing cream with 3% menthol and ceramides for its safety and anti-itch efficacy. Among 60 volunteers, including those with AD, the cream significantly reduced itch intensity with no adverse effects reported except for one individual who experienced a stinging sensation. The improvement in itch scores was noted as early as one week and sustained through a month of use, indicating the cream’s effectiveness and safety for dermatitis-related itch relief [75].

In addition, a study has shown that a cream with menthoxypropanediol, an activator of the TRPM8 channel, rapidly alleviates itching in individuals with AD. Most patients reported significant itch relief shortly after application, with over 90% satisfaction after 15 min. Despite some side effects, the study supports the use of TRPM8 agonists in managing itch and suggests potential mechanisms, including direct effects on nerve endings and involvement of Merkel cells, which are known to express TRPM8 [76]. Another study found that topical application of peppermint oil significantly improved chronic pruritus due to underlying hepatic, renal, and diabetic cause compared to petrolatum, suggesting it to be effective in managing chronic pruritus [77].

Cryosim-1, a synthesized compound that stimulates TRPM8 receptors, is being utilized as a component in anti-itch cosmetic products. In previous study, cryosim-1 gel led to a reduction in itching for individuals with conditions like AD and urticaria, enhancing their QoL [78]. In a clinical study involving 30 subjects with PN, by the eighth week, those treated with Cryosim-1 gel reported a notable decrease in itching and sleep disturbances compared to those given a placebo, along with greater satisfaction with the treatment [79]. A randomized controlled trial (RCT) demonstrated that cryosim-1 significantly reduced itch in patients with eczema and urticaria, providing rapid relief within minutes and maintaining anti-itch effects for up to two hours, indicating its potential as an effective treatment for pruritus [80]. In another RCT, Cryosim-1 gel for scalp pruritus significantly lowered Numerical Rating Scale scores within two hours of application compared to a control treatment, offering quick itch relief. This improvement also led to enhanced QoL for the participants [78].

The use of topical menthol is recommended fort management of chronic pruritus in current European S2k guideline [34].

4.4. Capsaicin and Asivatrep

Pruriceptive nociceptors that respond to histamine or non-histamine pruritogens often express TRPV1, a channel that reacts to capsaicin and heat. Capsaicin, a compound found in capsicum plants like chili peppers, jalapeños, and cayenne pepper, is renowned for its sharp taste and irritation of nerve endings [81]. It boasts various effects, including analgesic, anti-inflammatory and anti-pruritogenic activities [48]. Capsaicin has been demonstrated to trigger the release of substance P, a neuropeptide known for causing a severe burning and pricking that can be felt as either pain or itchiness. Paradoxically, prolonged use of capsaicin results in pain relief and itch reduction, as it causes desensitization in the sensory neurons that express TRPV1 [48,49].

Various OTC capsaicin creams with differing concentrations have been suggested to be effective in managing skin-related neuropathic conditions like brachioradial pruritus, uremic pruritus, hemodialysis-related pruritus, aquagenic pruritus, PN, and AD [82,83,84,85,86,87,88]. A study with 33 patients explored how applying capsaicin cream, in concentrations from 0.025% to 0.3%, could treat PN. Applied up to six times daily for as long as ten months, the treatment completely relieved itchiness within 12 days suggesting effectiveness of capsaicin for this condition [86]. Several studies have reported the impact of topical capsaicin cream, in 0.025% or 0.03% concentrations, applied four times a day for the treatment of chronic kidney disease-associated uremic itching, compared against a placebo cream. Findings suggest that capsaicin cream application likely offers significant relief from symptoms of uremic itching compared to placebo [82,83,89]. In addition, the Cochrane Review on interventions for itch in people with advanced chronic kidney disease concluded that topical capsaicin likely reduces uremic pruritus, even though it noted that additional high-quality evidence is needed before a definitive conclusion [90]. Treatment of localized chronic pruritus with capsaicin may be considered according to current European S2k guidelines, especially in case of brachioradial pruritus and notalgia paresthetica treatment [34].

Asivatrep is a highly potent and selective antagonist of TRPV1. In AD-like murine models, topical application of asivatrep cream effectively reduced inflammation by lowering levels of type 2 cytokines IL-4 and IL-13 [91]. This in turn, might inhibit the release of pruritogenic neuropeptides substance P and CGRP, thereby reducing itch [50]. It also improves skin barrier function by promoting the production of key epidermal differentiation markers such as loricrin, filaggrin, involucrin, and other differentiation-related keratins [91]. The anti-itch effect of asivatrep can be attributed to its ability to reduce TRPV1 expression, which helps to alleviate dermatitis and pruritus while strengthening the skin barrier [51]. In a phase 2b clinical trial, asivatrep decreased pruritus and inflammation in AD patients [92]. In addition, a phase 3 study demonstrated that asivatrep cream significantly improved clinical signs and symptoms of AD, including pruritus, compared to a vehicle [51].

Although there are limited laboratory and clinical studies on asivatrep, it is included as an active ingredient in moisturizers for its itch control effects and is expected to be applied to a wider range of conditions associated with pruritus in the future.

4.5. Polidocanol

Polidocanol, a polyethylene glycol ether of lauryl alcohol, have been investigated by cosmetic industries for its antipruritic and local anesthetic properties [93,94]. Polidocanol formulations are currently available in various commercial products, including a topical aqueous leave-on tonic, lotions, and creams. Previous studies have shown that polidocanol is beneficial in managing urticarial pigmentosa [93]. In a previous study on anti-itch effect of polidocanol involving 45 subjects, applying 3% topical polidocanol for 1 h significantly reduced cowhage-induced itch not affecting histamine-induced itch [95]. Although the exact mechanism behind the anti-itch effects of polidocanol is not yet fully understood, its association with PAR-2 receptors is suggested. These receptors, found on keratinocytes and small unmyelinated C-nerve fibers, are involved in the histamine-independent itch pathway, also known as cowhage-sensitive C fibers [52]. Enhanced PAR-2/PAR-4 signaling, which is associated with cowhage-induced itch, has been linked to AD [96]. Neurons activated by cowhage have higher conduction velocity and discharge rates compared to histamine-responsive neurons, making them more susceptible to inhibition by lower concentrations of local anesthetics [97,98]. Further research on the precise mechanism of anti-itch action of polidocanol and its association with PAR-2 receptors is needed.

4.6. Pramoxine Hydrochloride

Pramoxine hydrochloride is a topical local anesthetic agent that shows relatively fast onset of action, providing itch relief within 3 to 5 min [53]. It works by blocking voltage-gated sodium channels, reducing sodium ion permeability, and preventing nerve signal transmission, which provides both anesthetic and antipruritic effects. It is used off-label in dermatology to manage various conditions with pruritus. In a study involving 200 patients with various itchy skin conditions, pramoxine effectively controlled pruritus in 57% of cases, with the cream formulation being more effective and preferred over the gel [99]. Study on hemodialysis patients with uremic pruritus showed a significant reduction in itch intensity by using pramoxine hydrochloride lotion compared to the control group [100]. In addition, combination of lactic acid and pramoxine hydrochloride significantly improved skin hydration and reduced dryness and itch among 24 women [101]. Ceramide-containing pramoxine hydrochloride formulations provided rapid and long-lasting relief in AD, with itch severity reduced by 24.6% two minutes post-application and 58.0% eight hours post-application, comparable to ceramide cream with hydrocortisone [102]. Another combination of hydrocortisone acetate and pramoxine cream showed significant itch reduction after a single day of use, with a mean percentage reduction in itch intensity of 31.74% [103].

4.7. Palmitoylethanolamide (PEA)

PEA is a bioactive lipid similar to endocannabinoids naturally produced in mammalian tissues [104]. It is commonly utilized in the management of acute or chronic status, recognized for its effectiveness in regulating various systems involved in inflammation, itching, and pain [56,57,104]. Research has indicated that PEA can significantly reduce itch by inhibiting the TRPV1 ion channel, primarily present in nociceptive neurons of the peripheral nervous system [54,55]. Preclinical studies have shown that the effectiveness of PEA relies on the peroxisome proliferator-activated receptor-alpha receptor, which is known to play a significant role in regulating inflammatory processes [58,104,105]. Moreover, the application of phospholipids like PEA may help prevent the breakdown of lipids and boost their production in the stratum granulosum, potentially aiding in the fight against dry skin and reducing associated itching [56].

One study showed that cream containing PEA decreased itch symptoms drastically in patients with specific skin conditions with pruritus including prurigo and lichen simplex [106]. Additionally, PEA-based cream has shown promising results in alleviating symptoms of AD, offering an affordable alternative to traditional treatments [107]. Another study on topical Levagen+, a novel PEA formulation, showed significantly reduced eczema symptom severity, including redness, dryness, and total Patient-Oriented Eczema Measure score, compared to a standard moisturizer over a 4-week period [104]. In patients with AD including pediatrics, PEA-containing lamellar matrix cream also led to a significant reduction in the severity of symptoms including erythema, pruritus, lichenification, and dryness over a period of 4–6 weeks [108]. PEA is included as an active ingredient in various moisturizers on the market for its anti-itch effects.

Table 4. Application of itch relief cosmetics in skin conditions (summary of clinical studies).

Author	Formulation	Study Detail	Key Findings
Oat
Theunis et al. (2017) [42]	Topical emollient containing Rhealba® oat extract	30 patients aged ≥ 60 years with xerosis associated with chronic pruritus Applied for 2 weeks RCT	Improvement of pruritus and xerosis
Mengeaud et al. (2015) [67]	Topical emollient cream containing oat plantlets	108 children (ages 6 months-6 years) with moderate AD Applied twice daily for 3 months Absence of control group, open-label	Improvement of AD clinical symptoms (SCORAD and PO-SCORAD indexes) Fewer flare-ups Less topical corticosteroid use
Grimalt et al. (2006) [66]	Topical emollient containing Rhealba® oat extract	173 infants under 12 months old with AD Applied twice daily for 6 weeks RCT	Reduced the high-potency topical corticosteroid consumption in infants with AD
Postbiotics
Deleuran et al. (2020) [69]	Topical emollient containing an Aquaphilus dolomiae extract	5910 patients of all age with a range of dermatologic and systemic diseases with pruritus and xerosis Applied for 7 days Absence of control group, real world study	Improvement of pruritus, xerosis and quality of life
Blanchet-Rethore et al. (2017) [72]	Topical lotion containing the heat-treated Lactobacillus johnsonii NCC 533	31 patients with mild to moderate AD Applied for 3 weeks Absence of control group	Reduction in S. aureus load Decrease in local objective SCORAD
Gueniche et al. (2008) [109]	Topical cream contining Vitreoscilla filiformis lysate	75 patients with mild AD Applied for 4 weeks RCT	Improvement of SCORAD and pruritus
Gueniche et al. (2008) [110]	Topical cream containing Vitreoscilla filiformis extract	10 patients with mild to moderate AD Applied for 4 weeks Left-right comparison study	Improvement of AD lesions and pruritus
Di Marzio et al. (2003) [70]	Topical cream containing sonicated Streptococcus thermophilus	11 patients with AD Applied for 2 weeks Compared with healthy volunteers	Improvement of AD (erythema, scaling, pruritus)
Menthol and cryosim-1 (TRPM8)
Choi et al. (2024) [79]	Topical serum containing cryosim-1	30 patients with prurigo nodularis RCT	Improvement of pruritus Reduced sleep disorder
Kang et al. (2022) [78]	Topical gel containing cryosim-1	In part A, 31 patients with recalcitrant scalp itch In part B, 25 subjects with scalp itch RCT	Improvement of scalp pruritus and quality of life
Jung et al. (2021) [80]	Topical gel containing cryosim-1	39 patients with recalcitrant itch (eczema and urticaria) RCT	Improvement of pruritus and quality of life
Misery et al. (2019) [76]	Topical cream containing menthoxypropanediol	22 patients with AD Applied for 7 days Absence of control group	Improvement of pruritus
Ständer et al. (2017) [47]	Topical lotion containing the TRPM8 agonist	70 dry skin patients with pruritus Applied twice daily for 4 weeks RCT	Improvement of severe pruritus
Elsaie et al. (2016) [77]	Topical peppermint oil	50 subjects with chronic pruritus due to hepatic, renal, or diabetic cause Applied twice daily for 2 weeks	Improvement of chronic pruritus
Capsaicin and asivatrep (TRPV1)
Park et al. (2022) [51]	Topical asivatrep cream 1.0%	240 AD patients between age of 12–70 Applied for 8 weeks RCT	Improvement of AD severity and pruritus
Lee et al. (2019) [91]	Topical asivatrep cream 0.1%, 0.3% and 1.0%	194 mild to moderate AD patients Applied for 8 weeks RCT	Improvement of AD severity and pruritus
Makhlough et al. (2010) [89]	Topical capsaicin 0.03%	34 patients on hemodialysis with uremic pruritus Applied for 4 weeks RCT	Improvement of pruritus
Ständer et al. (2001) [86]	Topical cream with capsaicin 0.025% to 0.3%	33 patients with prurigo nodularis Applied 4 to 6 times daily for 2 weeks up to 10 months Absence of control group	Improvement of skin lesions and pruritus
Lotti et al. (1994) [84]	Topical cream with capsaicin 0.025%, 0.025%, 0.5% or 1.0%	5 patients with aquagenic pruritus Applied three times daily for 4 weeks Absence of control group	After treatment, contact with water did not evoke pruritus
Tarng et al. (1996) [83]	Topical cream with capsaicin 0.025%	19 hemodialysis patients with idiopathic, moderate to severe pruritus Applied four times daily Double-blind, placebo-controlled, crossover study	Improvement of pruritus
Breneman et al. (1992) [82]	Topical cream with capsaicin 0.025%	29 patients undergoing long-term hemodialysis with pruritus Applied four times daily for 6 weeks Open-label, uncontrolled (21 patients) and double-blind, vehicle-controlled study (7 patients)	Improvement of pruritus
Pramoxine hydrochloride
Zirwas et al. (2017) [102]	Topical ceramide-containing cream with pramoxine hydrochloride 1%	66 patients with history of AD RCT	Improvement of pruritus
Young et al. (2009) [100]	Topical lotion with pramoxine hydrochloride 1%	28 moderate to severe uremic pruritus patients receiving hemodialysis Applied for 4 weeks RCT	Improvement of pruritus
Grove et al. (2004) [101]	Topical cream with lactic acid 12% neutralized with ammonium hydroxide and pramoxine hydrochloride 1%	24 women with a history of dry itchy skin Applied for 7 days Open-label, observer-blinded, controlled trial	Improvement of pruritus and dryness
Noojin et al. (1954) [99]	Topical cream and gel with pramoxine hydrochloride 1%	200 dermatosis patients with localized or generalized pruritus	Improvement of pruritus
Palmitoylethanolamide
Rao et al. (2023) [104]	Topical palmitoylethanolamide (Levagen+)	72 patients with AD Applied for 4 weeks RCT	Improvement of AD severity
Yuan et al. (2014) [56]	Topical cream with N-palmitoylethanolamine and N-acetylethanolamine	60 patients with AD Applied for 4 weeks RCT	Improvement of pruritus and skin barrier function
Eberlein et al. (2008) [108]	Topical cream with a unique lamellar matrix containing N-palmitoylethanolamine	2456 patients with mild to moderate AD Observational, non-controlled, prospective cohort study	Improvement of pruritus, loss of sleep and quality of life
Ständer et al. (2006) [106]	Topical cream containing N-palmitoyl ethanolamine	22 patients with prurigo, lichen simplex and pruritus Open label observational study	Improvement of pruritus

Table 4. Application of itch relief cosmetics in skin conditions (summary of clinical studies).

Author	Formulation	Study Detail	Key Findings
Oat
Theunis et al. (2017) [42]	Topical emollient containing Rhealba® oat extract	30 patients aged ≥ 60 years with xerosis associated with chronic pruritus Applied for 2 weeks RCT	Improvement of pruritus and xerosis
Mengeaud et al. (2015) [67]	Topical emollient cream containing oat plantlets	108 children (ages 6 months-6 years) with moderate AD Applied twice daily for 3 months Absence of control group, open-label	Improvement of AD clinical symptoms (SCORAD and PO-SCORAD indexes) Fewer flare-ups Less topical corticosteroid use
Grimalt et al. (2006) [66]	Topical emollient containing Rhealba® oat extract	173 infants under 12 months old with AD Applied twice daily for 6 weeks RCT	Reduced the high-potency topical corticosteroid consumption in infants with AD
Postbiotics
Deleuran et al. (2020) [69]	Topical emollient containing an Aquaphilus dolomiae extract	5910 patients of all age with a range of dermatologic and systemic diseases with pruritus and xerosis Applied for 7 days Absence of control group, real world study	Improvement of pruritus, xerosis and quality of life
Blanchet-Rethore et al. (2017) [72]	Topical lotion containing the heat-treated Lactobacillus johnsonii NCC 533	31 patients with mild to moderate AD Applied for 3 weeks Absence of control group	Reduction in S. aureus load Decrease in local objective SCORAD
Gueniche et al. (2008) [109]	Topical cream contining Vitreoscilla filiformis lysate	75 patients with mild AD Applied for 4 weeks RCT	Improvement of SCORAD and pruritus
Gueniche et al. (2008) [110]	Topical cream containing Vitreoscilla filiformis extract	10 patients with mild to moderate AD Applied for 4 weeks Left-right comparison study	Improvement of AD lesions and pruritus
Di Marzio et al. (2003) [70]	Topical cream containing sonicated Streptococcus thermophilus	11 patients with AD Applied for 2 weeks Compared with healthy volunteers	Improvement of AD (erythema, scaling, pruritus)
Menthol and cryosim-1 (TRPM8)
Choi et al. (2024) [79]	Topical serum containing cryosim-1	30 patients with prurigo nodularis RCT	Improvement of pruritus Reduced sleep disorder
Kang et al. (2022) [78]	Topical gel containing cryosim-1	In part A, 31 patients with recalcitrant scalp itch In part B, 25 subjects with scalp itch RCT	Improvement of scalp pruritus and quality of life
Jung et al. (2021) [80]	Topical gel containing cryosim-1	39 patients with recalcitrant itch (eczema and urticaria) RCT	Improvement of pruritus and quality of life
Misery et al. (2019) [76]	Topical cream containing menthoxypropanediol	22 patients with AD Applied for 7 days Absence of control group	Improvement of pruritus
Ständer et al. (2017) [47]	Topical lotion containing the TRPM8 agonist	70 dry skin patients with pruritus Applied twice daily for 4 weeks RCT	Improvement of severe pruritus
Elsaie et al. (2016) [77]	Topical peppermint oil	50 subjects with chronic pruritus due to hepatic, renal, or diabetic cause Applied twice daily for 2 weeks	Improvement of chronic pruritus
Capsaicin and asivatrep (TRPV1)
Park et al. (2022) [51]	Topical asivatrep cream 1.0%	240 AD patients between age of 12–70 Applied for 8 weeks RCT	Improvement of AD severity and pruritus
Lee et al. (2019) [91]	Topical asivatrep cream 0.1%, 0.3% and 1.0%	194 mild to moderate AD patients Applied for 8 weeks RCT	Improvement of AD severity and pruritus
Makhlough et al. (2010) [89]	Topical capsaicin 0.03%	34 patients on hemodialysis with uremic pruritus Applied for 4 weeks RCT	Improvement of pruritus
Ständer et al. (2001) [86]	Topical cream with capsaicin 0.025% to 0.3%	33 patients with prurigo nodularis Applied 4 to 6 times daily for 2 weeks up to 10 months Absence of control group	Improvement of skin lesions and pruritus
Lotti et al. (1994) [84]	Topical cream with capsaicin 0.025%, 0.025%, 0.5% or 1.0%	5 patients with aquagenic pruritus Applied three times daily for 4 weeks Absence of control group	After treatment, contact with water did not evoke pruritus
Tarng et al. (1996) [83]	Topical cream with capsaicin 0.025%	19 hemodialysis patients with idiopathic, moderate to severe pruritus Applied four times daily Double-blind, placebo-controlled, crossover study	Improvement of pruritus
Breneman et al. (1992) [82]	Topical cream with capsaicin 0.025%	29 patients undergoing long-term hemodialysis with pruritus Applied four times daily for 6 weeks Open-label, uncontrolled (21 patients) and double-blind, vehicle-controlled study (7 patients)	Improvement of pruritus
Pramoxine hydrochloride
Zirwas et al. (2017) [102]	Topical ceramide-containing cream with pramoxine hydrochloride 1%	66 patients with history of AD RCT	Improvement of pruritus
Young et al. (2009) [100]	Topical lotion with pramoxine hydrochloride 1%	28 moderate to severe uremic pruritus patients receiving hemodialysis Applied for 4 weeks RCT	Improvement of pruritus
Grove et al. (2004) [101]	Topical cream with lactic acid 12% neutralized with ammonium hydroxide and pramoxine hydrochloride 1%	24 women with a history of dry itchy skin Applied for 7 days Open-label, observer-blinded, controlled trial	Improvement of pruritus and dryness
Noojin et al. (1954) [99]	Topical cream and gel with pramoxine hydrochloride 1%	200 dermatosis patients with localized or generalized pruritus	Improvement of pruritus
Palmitoylethanolamide
Rao et al. (2023) [104]	Topical palmitoylethanolamide (Levagen+)	72 patients with AD Applied for 4 weeks RCT	Improvement of AD severity
Yuan et al. (2014) [56]	Topical cream with N-palmitoylethanolamine and N-acetylethanolamine	60 patients with AD Applied for 4 weeks RCT	Improvement of pruritus and skin barrier function
Eberlein et al. (2008) [108]	Topical cream with a unique lamellar matrix containing N-palmitoylethanolamine	2456 patients with mild to moderate AD Observational, non-controlled, prospective cohort study	Improvement of pruritus, loss of sleep and quality of life
Ständer et al. (2006) [106]	Topical cream containing N-palmitoyl ethanolamine	22 patients with prurigo, lichen simplex and pruritus Open label observational study	Improvement of pruritus

5. JAK-STAT Signaling Pathway and Itch

The JAK–STAT pathway plays a central role in modulating multiple immune axes involved in the immunopathogenesis of inflammatory skin diseases, including AD. Furthermore, it is involved in maintaining the epidermal barrier and modulating peripheral nerves related to the sensation of itch. Hyperactivation of JAK1 has been reported to be associated with overexpression of cutaneous serine protease, resulting in skin barrier dysfunction [111]. STAT3, a key transcription factor, regulates keratinocyte differentiation and maintains skin integrity. In a study using a murine dry skin model, the JAK inhibitor delgocitinib, which blocks JAK1, JAK2, and JAK3, was shown to inhibit STAT3 activation and improve skin barrier function by increasing levels of epidermal proteins such as filaggrin, loricrin, and natural moisturizing factors [112].

Regarding itch, the activation of STAT3 mediates astrogliosis in the spinal dorsal horn, which amplifies itchiness and leads to chronic itch [113]. In this signaling pathway, lipocalin-2 is reported as distinctly upregulated factor that enhances itch signals and triggers the vicious itch-scratch cycle [114]. Notably, IL-31 stimulates nerve elongation and directly communicates with primary cutaneous afferent neurons, which pruritogens require to transduce itch signals [25]. IL-31 is known to trigger the production of pro-inflammatory cytokines and chemokines through the activation of the JAK1/JAK2 and STAT3 pathways [115]. In an AD-like murine model, topical delgocitinib has shown to suppress IL-31-promoted nerve elongation in vivo and the morphological changes of peripheral nerves from the dorsal root ganglion in vitro [116]. Additionally, it significantly reduced scratching behavior in AD mouse models.

Recently, various JAK-STAT inhibitors have been applied in the treatment of AD and inflammatory diseases. Moreover, clinical applications and research on natural polyphenol phytochemicals that could potentially modulate the JAK/STAT signaling pathway are actively being conducted (Table 5). These polyphenol phytochemicals hold potential for use as cosmetic ingredients to manage itch.

5.1. Polyphenol Phytochemicals on the JAK-STAT Signaling Pathway

5.1.1. Apigenin

Apigenin is a plant-derived flavonoid that is abundant in parsley, chamomile, celery, vine spinach, artichokes, and oregano [131]. Apigenin has been reported to possess numerous biological applications including anti-inflammatory, antioxidant, anti-cancer, anti-allergic, neuroprotective, and cardioprotective effects, and its application in cosmetics has been increasing recently [132]. Specifically, apigenin has also been reported in various studies to have itch-relieving effects [132]. Research has shown that apigenin reduced IL-31 expression in human mast cells and mouse skin with AD itch model by suppressing mitogen-activated protein kinase (MAPK) and NF-κB pathways [117]. In a study using BALB/c mice with ovalbumin-induced allergic rhinitis, apigenin regulated a balance between Th1 and Th2 cells through the downregulation of the NF-κB pathway, while also decreasing histamine levels, IL-4, 5, 13, IgE, and STAT6 [118]. Moreover, orally applied apigenin was found to decrease levels of IgE and IFN-γ in the serum of NC/Nga mice and mitigate skin damage caused by picrylchloride [119]. It also inhibited the phosphorylation of STAT6 in IL-4 stimulated mouse spleen cells, indicating suppression of inflammatory pathways [119]. Collectively, apigenin may ease the symptoms of AD and itching by inhibiting the MAPK, NF-κB, and JAK-STAT pathways, which leads to a reduction in pro-inflammatory cytokines, including IL-31 and IL-33, suggesting its potential applicability in itch relief cosmetic formulations.

5.1.2. Quercetin

Quercetin, a flavonoid found in apples, onions, red wine, red grapes, tea (Camellia sinensis), capers, broccoli, lovage, and various berries, serves as one of the most important natural antioxidants utilized in cosmetics [133]. Along with its antioxidant activity, quercetin is also known for its effects on the skin, including anti-inflammatory, anti-aging, anti-bacterial, skin whitening, anti-allergic, and anti-itching. Previous studies demonstrated anti-AD effects of quercetin by activating the nuclear factor erythroid 2-related factor 2 and heme oxygenase pathways [120]. Additionally, studies with mouse models showed that quercetin could suppress the expression of Th2-related cytokines, such as thymus and activation-regulated chemokine and TSLP and 12-O-tetradecanoylphorbol-13-acetate-induced skin inflammation [121,134]. Furthermore, it is suggested to play a significant role in regulating the dysregulation of the JAK-STAT pathway and excessive production of IL-4, 5, and 13 in skin conditions with inflammation [122].

5.1.3. Curcumin

Turmeric, specifically its bioactive compound curcumin, is extensively researched for its therapeutic potential in skin conditions due to its anti-inflammatory, antioxidant, antiviral, and antifungal properties [135]. Curcumin’s effectiveness stems from its ability to modulate various inflammatory pathways and cytokines, suggesting a promising organic option for dermatological treatments amid concerns over side effects from conventional medications [136]. Curcumin is known for its potent anti-inflammatory properties. Previous studies have indicated that curcumin regulates suppressor of cytokine signaling (SOCS) protein expression via JAK/STAT pathways in various experimental models [123,135]. It has shown anti-inflammatory properties by suppressing the expression of SOCS1 and SOCS3 in lipopolysaccharide-stimulated murine macrophages, suggesting its potential therapeutic use in chronic inflammatory conditions [137].

In a recent study involving ovalbumin-induced AD mice, curcumin treatment significantly reduced the levels of cytokines associated with the TH2 immune response and inhibit the STAT6 activation, showing its potential benefit in treating AD and associated infections [124]. In addition, it could suppress pro-inflammatory mediators including lipoxygenase, cyclooxygenase-2, and inducible nitric oxide synthase, and cytokines such as TNF, IL-1, IL-6, IL-8 [125,138,139]. Additionally, it inhibits NF-KB, a key factor in activating pro-inflammatory genes. Overall, curcumin exhibits broad-spectrum anti-inflammatory capabilities [126].

Curcumin has also been researched for its anti-pruritic effects. Two RCTs assessed curcumin tablets for pruritus treatment. In one study, patients with pruritus from sulfur mustard saw significant improvements after taking 500 mg of curcuminoids with 5 mg piperine for 4 weeks, including a 30% reduction in pruritus score [140]. Another RCT with end stage renal disease patients found a 56.9% reduction in pruritus scores after 8 weeks of 1500 mg turmeric tablets, significantly better than the placebo [141].

5.1.4. Resveratrol

Resveratrol, a natural bioactive polyphenol and antioxidant, is present in various plants, such as teas, berries, grapes, grains, and nuts [135]. Pharmacologically, resveratrol is known to have antitumor, anti-inflammatory, antioxidant, and cardioprotective effects [142,143,144]. Additionally, resveratrol can aid in treating various dermatological issues such as acne, exfoliative eczema, psoriasis, and UV-induced skin damage [127].

In a prior study, resveratrol was shown to enhance production of SOCS1 in LPS-stimulated RAW 264.7 macrophages by suppressing micro RNAs, which are known to play a crucial role as negative regulators of cytokine signaling by inhibiting the JAK-STAT pathway [128]. Additionally, resveratrol was found to block STAT3 signaling through the induction of SOCS1 in head and neck squamous cell carcinoma cells [129]. In models of AD, resveratrol delayed the onset of skin lesions and alleviated inflammation induced by 2,4-dinitrochlorobenzene (DNCB) in mice by decreasing levels of pro-inflammatory cytokines and chemokine [127,130]. A different study demonstrated that treatment with rice enriched with resveratrol decreased scratching and reduced the secretion of cytokines, including IL-6, 31, and IgE in mice with DNCB-induced AD-like lesions [130]. These findings suggest that resveratrol could be applied as an adjuvant treatment for managing chronic itch as well as skin inflammations associated with AD.

6. Limitations

There are several limitations to this review. First, we assessed only English-language papers, excluding studies published in other languages. Second, ingredients included in the review were primarily those with anti-itch efficacy as their main function in cosmetics, and other ingredients were not included. Finally, the specific search queries used in this review were not documented, and thus are not reported.

7. Conclusions

This review highlights the expanding role of cosmetics in managing itch, emphasizing the beneficial potential of active ingredients. While these ingredients show promise in alleviating itch with high patient acceptability and minimal adverse effects, further research is needed to identify new active ingredients and optimize existing formulations. Unexplained issues such as the long-term effects of these ingredients and their interactions with other treatments warrant deeper investigation. As the demand for non-pharmacological treatments grows, itch-relieving cosmetics could become a pivotal part of dermatological care, offering a holistic approach to skin health and comfort.