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Review

Treatment Options for Troublesome Itch

by
Sumika Toyama
1,
Mitsutoshi Tominaga
1,2 and
Kenji Takamori
1,2,3,*
1
Juntendo Itch Research Center (JIRC), Institute for Environmental and Gender-Specific Medicine, Juntendo University Graduate School of Medicine, 2-1-1 Tomioka, Urayasu 279-0021, Chiba, Japan
2
Anti-Aging Skin Research Laboratory, Juntendo University Graduate School of Medicine, 2-1-1 Tomioka, Urayasu 279-0021, Chiba, Japan
3
Department of Dermatology, Juntendo University Urayasu Hospital, 2-1-1 Tomioka, Urayasu 279-0021, Chiba, Japan
*
Author to whom correspondence should be addressed.
Pharmaceuticals 2022, 15(8), 1022; https://doi.org/10.3390/ph15081022
Submission received: 10 June 2022 / Revised: 16 August 2022 / Accepted: 16 August 2022 / Published: 19 August 2022
(This article belongs to the Special Issue Novel Target for the Treatment of Itch (Pruritus) and Pruritus-Related Pain of Different Origin)
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Versions Notes

Abstract

:
Itch (or pruritus) is an unpleasant sensation, inducing the desire to scratch. It is also a major and distressing symptom of many skin and systemic diseases. The involvement of histamine, which is a major itch mediator, has been extensively examined. Recent studies suggest that histamine-independent pathways may play roles in chronic itch. Therefore, antihistamines are not always effective in the treatment of patients with chronic itch. The development of biologics and κ-opioid receptor (KOR) agonists has contributed to advances in the treatment of itch; however, since biologics are expensive for patients to purchase, some patients may limit or discontinue their use of these agents. Furthermore, KOR agonists need to be prescribed with caution due to risks of side effects in the central nervous system. Janus kinase (JAK) inhibitors are sometimes associated with side effects, such as infection. In this review, we summarize antidepressants, antineuralgics, cyclosporine A, antibiotics, crotamiton, phosphodiesterase 4 inhibitor, botulinum toxin type A, herbal medicines, phototherapy, and acupuncture therapy as itch treatment options other than antihistamines, biologics, opioids, and JAK inhibitors; we also explain their underlying mechanisms of action.

1. Introduction

Itch (or pruritus) is an unpleasant sensation that induces the desire to scratch, which reduces the quality of life (QOL) of patients [1]. Histamine is one of the major itch mediators and has been employed as the main agent in antipruritic therapies. However, antihistamines often lack efficacy in patients with chronic itch [2,3,4]. Intractable pruritus, for which antihistamines are ineffective, is a common symptom of skin diseases, such as atopic dermatitis (AD), psoriasis, and prurigo nodularis. Intractable pruritus also affects some patients with systemic diseases, including renal diseases [5], cholestasis liver disorder [6], and bowel diseases [7]. The lack of a response to high-potency antihistamines of different types in patients with chronic itch suggests the involvement of other mediators.
κ-opioid receptor (KOR) agonists (e.g., nalfurafine) have been shown to suppress pruritus in patients with chronic renal failure, and in patients with cholestasis [8]. However, nalfurafine is associated with the development of side effects in the central nervous system (CNS) [9], and is thus prescribed with caution. Dupilumab, a monoclonal antibody that specifically binds to the shared alpha chain subunit of the interleukin (IL)-4 and IL-13 receptors, was shown to improve clinical end points, including the attenuation of pruritus in AD [10]. However, biological products are expensive for patients to purchase, thus some patients may limit or discontinue their use. JAK inhibitors have also been suggested to ameliorate itching effectively. However, they are also associated with side effects, such as infection [11,12,13]. Although emollients also partly control intraepidermal nerve density, they have more of a preventive than a therapeutic effect. Therefore, it is necessary to control itch from a multifaceted perspective through the development of new treatments and drug repositioning.
In this review, we summarize alternative treatment options for troublesome itch, including antidepressants, antineuralgics, cyclosporine A, antibiotics, crotamiton, phosphodiesterase 4 (PDE4) inhibitor, herbal medicines, phototherapy, and acupuncture therapy (Table 1). This review may inform physicians seeking treatment options for patients unresponsive to mainstream itch treatments, such as KOR agonists, biological products, and JAK inhibitors.

2. Pharmacotherapeutic Options for Itch

2.1. Antidepressants

Antidepressants include tricyclics, tetracyclics, and serotonin noradrenaline reuptake inhibitors (SNRIs). Serotonin (5-hydroxytryptamine, 5-HT), which is produced by mast cells, basophils, and platelets, plays a role in itch in a transient receptor potential vanilloid 4 (TRPV4)-dependent manner via the 5-HT receptor. The antipruritic effects of selective serotonin reuptake inhibitors (SSRIs) have been investigated. SSRIs are safer than tricyclics and are currently the most widely used antidepressants [14,15,16].
Paroxetine (trade names include Aropax (GlaxoSmithKline, London, UK) among others), an SSRI, has been reported to exert antipruritic effects in cancer patients and on itch associated with true erythrocytosis and psychogenic diseases [17,18,19]. Paroxetine and fluvoxamine (Neuraxpharm, Langenfeld, Germany) were also shown to suppress itch in patients with severe chronic pruritus [20]. In pediatric patients with pruritus due to cholestasis, sertraline (Zoloft; Pfizer, NY, USA) attenuated itch and improved sleep quality [21].
A previous study demonstrated that mirtazapine (Remeron; Organon, NJ, USA), a noradrenergic and specific serotonergic antidepressant (NaSSA), significantly attenuated itch in tumor-associated cutaneous pruritus, and in pruritus at night without depression [22].
The intrathecal administration of milnacipran (Sigma, St. Louis, MO, USA), an SNRI, suppressed serotonin-induced itch in mice [23]. Therefore, antidepressants, such as SSRIs, SNRIs, and NaSSAs, may be useful for intractable itch by inhibiting the reuptake of the itch mediator serotonin; however, their antipruritic mechanisms have not yet been elucidated in detail. Serotonin binds to serotonin receptors on sensory nerves, which express TRPV4, inducing itching. However, the endogenous analgesic mechanism is exhibited by activating the descending inhibitory system in the CNS. A similar inhibitory mechanism may also reduce itch [24].
However, antidepressants are off-label and take a long time to exert therapeutic effects, and the risk of side effects (digestive symptoms, such as nausea; psychiatric symptoms, including anxiety; CNS depression; eye symptoms, such as dry eye and inflammation; and skin symptoms) needs to be considered [25,26,27,28].

2.2. Antineuralgics

A common feature of skin diseases that present with intractable itch is abnormal skin barrier function. The skin barrier prevents the entry of foreign substances and evaporation of water; however, when it is compromised by environmental or genetic factors, sensory nerve fibers penetrate the epidermis, causing hypersensitivity to itch [29]. Neuropathic itch is considered to involve a similar mechanism to that of neuropathic pain, which involves peripheral sensory nerve hypersensitivity and decreased capacity to suppress calcium ion influx and neurotransmitters, such as substance P (SP) and calcitonin gene-related peptide (CGRP), release to itch-dedicated interneurons in the spinal dorsal horn [30]. Therefore, pregabalin, which is effective against neuropathic pain, is also a useful treatment for neuropathic pruritus [30]. Pregabalin (Lyrica; Pfizer) was previously shown to suppress itch in patients with uremia, cancer, erythrocytosis, prurigo nodularis, and post-burn [31]. It has been suggested to exert its analgesic effects in the CNS by inhibiting calcium influx and N-methyl-D-aspartate (NMDA) receptors through binding to the α2δ subunit, which plays an auxiliary role in the function of voltage-gated calcium channels, and by suppressing the release of neurotransmitters, such as noradrenaline, glutamate, glycine, γ-aminobutyric acid (GABA), SP, CGRP, and acetylcholine [32,33,34]. Therefore, pregabalin is speculated to inhibit neurotransmitter release and exert antipruritic effects in the CNS by inhibiting calcium influx and NMDA receptors via binding to the α2δ subunit.
On the other hand, mirogabalin (Tarlige; Daiichi Sankyo Co., Ltd., Tokyo, Japan) was found to inhibit calcium influx in the peripheral nervous system and suppress neurotransmitter release, resulting in analgesia [35]. Therefore, mirogabalin may be useful for peripheral itch. However, these antineuralgics are off-label for itch and their application needs to be explained to patients.
Neurotropin (NTP, Nippon Zoki Pharmaceutical Co., Ltd., Osaka, Japan), a non-protein extract isolated from the inflamed skin of rabbits inoculated with vaccinia virus, is widely used in Japan and China to treat various chronic pain conditions. We previously reported the antipruritic effects of NTP following its intraperitoneal administration to AD model mice and a control group [36]. The antipruritic mechanism was attributed to the suppression of neurogenic inflammation via the inhibition of SP release from nerve endings and reduction in itch hypersensitivity by the prevention of intraepidermal nerve fiber (IENF) elongation [37,38] (Figure 1).

2.3. Cyclosporine A

Cyclosporine A (CsA, Neoral; Novartis, Basel, Switzerland), a calcineurin inhibitor, is an immunosuppressant that is widely used in the treatment of inflammatory diseases. Its efficacy against AD symptoms, including itch, has been demonstrated and it has been approved for the treatment of AD [39].
Previous studies have shown that IL-31 receptor A (IL-31RA) and NK-1 receptor (NK-1R) mRNA expression levels in dorsal root ganglion (DRG) of AD mice are significantly increased compared to DRG of control mice, and that these increases are significantly suppressed by CsA treatment. In addition, CsA suppressed epidermal thickness and the infiltration of immune cells, such as IL-31+ cells, CD4+ T cells, mast cells, and eosinophils, as well as the proliferation of IENFs [40] (Figure 2).
Skin lesions and blood IL-31 levels were significantly increased in AD patients and positively correlated with scores on a tool that assesses severity of AD (Severity SCORing Atopic Dermatitis; SCORAD), while CsA decreased blood IL-31 levels, which correlated with reduction in disease severity and the attenuation of itch [41].
CsA effectively reduced disease severity, attenuated itch, and improved QOL in patients with psoriasis [42]. Based on these findings, CsA may effectively ameliorate itch and inflammation not only in AD, but also in psoriasis. However, CsA dosing may be restricted in patients with liver or kidney damage who are taking colchicine, which is contraindicated.

2.4. Antibiotics

An abnormal composition of bacterial species, called dysbiosis, was found in AD skin lesions, and Staphylococcus aureus (S. aureus) was detected [43]. S. aureus colonization has been shown to enhance Th2 cell differentiation in AD [44]. Macrolide antimicrobials are known to exhibit not only antibacterial activity but also anti-inflammatory and immunomodulating activities and are presumed to be effective against various skin diseases. A recent study reported that the application of ointment containing josamycin (Adipogen, Liestal, Switzerland) to the skin of AD mice attenuated dermatitis, reduced the number of S. aureus by inhibiting S. aureus colonization and Th2 cell differentiation, down-regulated IL-31 expression, and suppressed itch in skin [45]. Furthermore, roxithromycin (Rulid, Sanofi, Paris, France) and clarithromycin (Brand name Biaxin, (Abbott Laboratories, IL, USA) among others) ameliorated itch in antihistamine-resistant AD patients and patients with psoriasis and chronic pruritus [46].
Itch signals generated in the peripheral skin excite primary sensory nerve fibers, which relay signals to the brain via spinal dorsal horn neurons [47]. We previously demonstrated that the number of microglia, a type of glial cell, was increased in the spinal dorsal horn of AD mice. Furthermore, the intrathecal administration of minocycline (minomycin; Pfizer, New York, NY, USA), an inhibitor of microglial activation, to AD mice suppressed itch and attenuated dermatitis [48]. These findings suggest that microglia in the dorsal horn of the spinal cord are involved in intractable pruritus and may be one of the therapeutic targets for intractable pruritus (Figure 3). However, these antibiotics are off-label for itch.

2.5. Crotamiton

Crotamiton is a drug that is applied externally as an antipruritic, as well as an antiscabies measure. Crotamiton (Wako Pure Chemical Industries, Ltd., Osaka, Japan) was shown to be effective against histamine-, serotonin-, SLIGRL-NH2 (Protease activated receptor (PAR) 2 agonist)-, and chloroquine-induced itch and DRG responses [49,50]. In addition, it inhibited the responses of DRG neurons to histamine, chloroquine, and GSK1016790A, a TRPV4-selective agonist [50,51]. Therefore, crotamiton suppresses PAR2, TRPV1, TRP ankyrin (A) 1, and TRPV4-mediated itch [52].

2.6. PDE4 Inhibitor

PDE4, which catalyzes the conversion of cyclic adenosine 3′,5′-monophosphate (cAMP) to 5′-AMP, plays a critical role in the pathogenesis of inflammatory disorders [53]. OPA-15406 ointment (Difamilast, Otsuka Pharmaceutical Co., Ltd., Tokyo, Japan), a PDE4 inhibitor, ameliorated AD symptoms, including itch, in pediatric and adult AD patients [54,55,56]. Apremilast (Brand name Otezla (Amgen, CA, USA) among others) attenuated the symptoms of AD, hidradenitis suppurativa, and psoriasis, including itch [57,58,59,60,61,62,63]. In addition, itch and other symptoms in AD were mitigated by crisaborole ointment (Eucrisa, Pfizer, New York, NY, USA) [64,65,66,67,68]. A previous study demonstrated that crisaborole attenuated AD symptoms by modulating epidermal hyperplasia/proliferation and Th2 and Th17/Th22 transcriptional profiles in AD lesions [66]. E6005 (Roivant Sciences Ltd., Basel, Switzerland) also suppressed symptoms, including itch, in AD model mice and AD patients, as well as SLIGRL-NH2-induced symptoms [53,69,70]. The expression of cAMP was up-regulated in skin and DRG treated with E6005. Furthermore, capsaicin-induced DRG neuron responses were inhibited by E6005, as well as the cAMP elevator, forskolin. In addition, SLIGRL-NH2-induced DRG neuron responses were suppressed by E6005 and 8-bromo-cAMP, an analog of cAMP. Based on these findings, E6005 may increase cAMP levels and suppress itch via PAR2 [53,71].
There are various types of PDE4 inhibitors, and further studies are warranted to examine their mechanisms of action and potential applications to the treatment of diseases. OPA-15406 has been shown to improve AD symptoms, and its use is covered by health insurance [72], which is applicable for psoriasis vulgaris and psoriatic arthritis.

2.7. Botulinum Toxin A

Acetylcholine has been demonstrated to mediate pruritus in AD. Botulinum toxin type A (BT-A) blocks the release of acetylcholine and many other neurotransmitters from the presynaptic vesicle by deactivating soluble N-ethylmaleimide sensitive factor attachment protein receptor (SNARE) proteins. BT-A (trade name Botox (KC Pharmaceuticals, Pomona, CF, USA)) relieved itching in patients with conditions, such as lichen simplex chronicus (LSC), brachioradial pruritus, inverse psoriasis, post-burning itch, lichen planus, hypertrophic lichen planus, and postherpetic neuralgia [73,74,75]. In addition, there were statistically significant post-treatment reductions in both the severity strata for eczema area and severity index (EASI) score in LSC cases and the psoriasis area and severity index (PASI) score in inverse psoriasis cases [75]. In patients with Fox–Fordyce disease, treatment with BT-A significantly improved not only pruritus but also hyperhidrosis [76]. BT-A inhibited degranulation of mast cells and suppressed histaminergic itch [77,78]. Moreover, BT-A also inhibited mast cell independent chloroquine-induced itch [78]. Triamcinolone acetonide (TAC) is widely used to treat pathologic scars, but scar itch was significantly reduced by TAC combined with BT-A than TAC alone. In rat, postburn itch was mitigated by treatment with TAC, BT-A, and TAC/BT-A. TAC/BT-A treatment significantly decreased the density of IENFs in burn lesions relative to untreated burn lesions and downregulated the expressions of nerve growth factor (NGF) and TRPV1 [79].
From the above, we can infer that BT-A is effective for the treatment of histaminergic and non-histaminergic itch.

2.8. Herbal Medicines

Herbal medicines have long been used as antipruritics. Byakko-ka-ninjin (Tochimoto Tenkaido, Osaka, Japan), licorice gel, Yokukansan (YKS; Tsumura & Co., Tokyo, Japan), Xiao-Feng-Sang (Sheng Chang Pharmaceutical Company, Taipei, Taiwan), Pei Tu Qing Xin (PTQX; Jiangyin Tian Jiang Pharmaceutical Co., Ltd., Jiangyin, China), and Huanglian Jiedu decoction (HLJDT) are known to be effective for itch of AD [80,81,82,83,84,85].
YKS was shown to inhibit the infiltration of immune cells, such as mast cells and eosinophils, and attenuate itch in AD model mice. Moreover, serum corticosterone levels were decreased in AD model mice [82]. PTQX inhibited mast cell infiltration into the skin region in AD model mice, suppressing dermatitis and itch and reducing serum IgE levels. In addition, CD4+IL-4+ T cell differentiation and regulatory T cell (Treg) infiltration were found to be inhibited, which suggested that PTQX regulates T cell differentiation and the Th17/Treg balance [84]. AD model mice treated with HLJDT showed it ameliorated dermatitis, reduced cytokine production, and decreased expression of molecules required by dendritic cells (DC) to activate T cells, such as co-stimulatory molecules. Collectively, these findings indicate that HLJDT suppresses inflammation and itch by regulating the functions of DC [85].
The leaf extract of Rhamnus davurica (LERD), which is used to treat ich, has been reported to inhibit the Fyn/Syk pathway in mast cells, suggesting that it suppresses allergic activity, including itch [86]. Spirodelae Herba (SH; Medicinal Materials Company, Ulsan, Korea), which is an effective treatment for itch in AD, ameliorated AD symptoms by modulating the activation of the calcium ion channels Orai1 and TPRV4 and inhibiting mast cell degranulation [87].
In non-AD itch, Osthole (Sigma-Aldrich Corp., St. Louis, MO, USA), an active coumarin isolated from Cnidium monnieri (L.) Cusson, suppressed histamine-induced itch by inhibiting TRPV1 activation [88].
Cnidium monnieri (Cnidii Fructus; Tochimoto Tenkaido Co., Ltd., Osaka, Japan) and Unsei-in (Kanebo, Tokyo, Japan) are also effective against SP-induced itch. Nitric oxide (NO) enhanced SP-induced itch and Unsei-in reduced SP-induced itch by suppressing the expression of NO synthase in lesional skin [89,90].
Therefore, herbal medicines are effective treatments for not only AD, but also various types of itch.

3. Other Therapeutic Options for Itch

3.1. Phototherapy

Ultraviolet (UV)-based therapies, such as psoralen ultraviolet A (PUVA), narrowband-ultraviolet B (NB-UVB), and excimer lamps, are effective treatments for chronic pruritus in patients with AD and psoriasis [91,92,93]. In the guidelines for AD, phototherapy is indicated as a treatment for patients who do not respond to or cannot be controlled with steroid ointments, topical moisturizers, calcineurin inhibitors, and other treatments [94].
NB-UVB is a device with an irradiation range centered at 311 nm, which removes the harmful wavelengths present in UVB and is a highly effective treatment, while excimer lamps are local devices that generate rays at 308 nm. UVA (320–400 nm) is subdivided into UVA2 (320–340 nm) and UVA1 (340–400 nm); PUVA uses UVA1. UVA rays penetrate deeper than UVB, while UVB is more readily absorbed by DNA than UVA [95].
We previously demonstrated that PUVA therapy exerted anti-pruritic effects by eliminating the hyperplasia of IENFs in AD patients and a dry skin model. Furthermore, the expression of nerve elongation factor (NGF) was down-regulated in the PUVA-treated group, whereas that of semaphorin 3A (Sema3A), a nerve repulsive factor, was significantly up-regulated in the skin of AD patients and slightly elevated in the skin of dry skin model mice [96,97]. In dry skin model mice, NB-UVB therapy exerted more potent quenching effects on IENFs than did PUVA, significantly down-regulated NGF expression, and significantly up-regulated Sema3A expression in the epidermis [97]. Excimer lamps suppressed itch more potently than did NB-UVB in AD model mice by suppressing IENFs, the number of which was increased in dry skin [97,98]. In contrast to NB-UVB and PUVA, excimer lamp therapy directly affected IENFs without altering the expression of axon guidance molecules and induced neurodegeneration, resulting in the disappearance of IENFs [98]. These findings suggest that PUVA and NB-UVB suppress itch by normalizing the balance of the expression of axon guidance molecules in epidermal keratinocytes, whereas excimer lamps act directly on nerve fibers to suppress itch (Figure 4).
Therefore, phototherapy is useful in the treatment of itch, while PUVA therapy requires the administration of soralen, as described above, and long-term PUVA therapy has been reported to increase the risk of skin carcinogenesis [99,100]. NB-UVB therapy does not significantly increase the risk of skin cancer but needs to be avoided in patients with photosensitivity [100].

3.2. Acupuncture Therapy

Acupuncture is used to treat pruritus. Symptoms, including itch, were attenuated by acupuncture in AD model animals and patients [101,102,103,104,105,106,107] and in uremic pruritus patients [108,109].
The antipruritic mechanism of acupuncture treatment at LI11 for AD was previously reported to be mediated by dynorphin in the spinal cord and the blockade of 5-HT2 receptors (R) and 5-HT7R to inhibit serotonin-induced itch [101,107]. Acupuncture treatment at LI11, PC6, HT7, SP10, ST36, and ear was also shown to be effective for histamine-induced itch, both therapeutically and prophylactically [110,111,112]. Brain-focused studies demonstrated that a decreased response in the putamen, an itch-evoked activation region, and part of the midcingulate cortex (pMCC) were involved in the suppressive effects of acupuncture at LI11, PC6, HT7, SP10, ST36, and HT3 on itch [106,112].
Itch in a dry skin model mouse induced by an acetone/diethyl ether and water treatment was also suppressed by acupuncture at LI4 and LI11. In this model, itch was inhibited by suppressing gastrin-releasing peptide receptor (GRPR) expression via the activation of KOR in the dorsal horn of the spinal cord [113].
A previous study reported that morphine-induced itch was ameliorated by acupuncture at LI11 and SP10 through the Toll-like receptor (TLR) 2/4-myeloid differentiation factor (MyD) 88-NF-κB pathway of the spinal cord [114]. Moreover, itch induced by one of the secondary bile acids, deoxycholic acid, was attenuated by acupuncture at LI4 and LI11 via suppressing the activation of microglia [115]. Thus, acupuncture therapy is useful for the treatment of itch caused by various factors.

4. Discussion

Itch (pruritus) is a self-defense system against external foreign objects and an alarm reaction that alerts the whole body, including the skin, of abnormalities. Histamine is one of the major itch mediators, but recent studies have showed histamine-dependent and histamine-independent pathways in transmitting itch. Other systems, including proteases, neuropeptides, cytokines, and opioids, and their cognate receptors, such as thermoreceptors, PARs, Mas-related G protein-coupled receptors (Mrgprs) and opioid receptors, are involved in the histamine-independent itch pathway. The sensation of itch is generated by the binding of itch-inducing substances to specific receptors on peripheral sensory afferent, such as unmyelinated C-fiber afferents and the myelinated Aδ fiber afferents. This excitatory information from sensory nerve fibers transmits itch signals by various neurotransmitters to secondary neurons distributed in the dorsal horn of the spinal cord. The information from the spinal cord passes through the thalamus and posterior parietal cortex and is ultimately processed at multiple regions of the brain [47,116,117]. Many kinds of mediators, receptors, and channels are involved in itch signaling among the skin nervous system, skin cells, and central nervous systems, including Mrgprs, TLR, cytokines, and TRP channels [47]. Therefore, we need to provide treatment tailored to the pathology, and treatment guidelines for troublesome itch have not yet been established.
Of the itch treatments described in this review, none are covered by insurance except for CsA, OPA-15406, and phototherapy. However, the insurance coverage described in this review has limitations from a global perspective. Moreover, NTP is currently available only in Japan and China. In addition, emollients also have a certain therapeutic effect, but patients often find the application of ointments cumbersome, which may reduce compliance [118]. In light of the above, even with the treatment methods presented here, topical medication should take into consideration the patient’s compliance with local preparations. Therefore, it is also important to provide guidance for patients on treatment methods.

5. Conclusions

This review summarized the antipruritic effects and mechanisms of action of treatment options for itch, such as antidepressants, antineuralgics, cyclosporine, antibiotics, crotamiton, PDE4 inhibitors, botulinum toxin type A, herbal medicine, phototherapy, and acupuncture. Itch is an equally or even more distressing sensation than pain and significantly reduces the QOL of patients. Recent advancements have been achieved in the establishment of objective assessments of itch and development of animal models, and the molecular and cellular mechanisms underlying itch are being elucidated. In the future, the antipruritic mechanisms of the treatments and novel agents introduced here will be clarified through the development of bidirectional clinical and basic medical research.

Author Contributions

Writing—original draft preparation, S.T. and M.T.; writing—review and editing, K.T. All authors have read and agreed to the published version of the manuscript.

Funding

This research was partly supported by a Grant-in-Aid for Research Activity Start-up (Grant number 17H07096), a Grant-in-Aid for Early-Career Scientists (Grant number 19K17817 and 21K16307), a Grant-in-Aid for Scientific Research (B) (Grant number 20H03568 and 22H02956), and the Inohana Foundation (Chiba University) Grant-in-Aid (IFCU-2021-06).

Data Availability Statement

Data sharing not applicable.

Conflicts of Interest

The authors have no conflict of interest to declare.

References

  1. Ikoma, A. Updated Neurophysiology of Itch. Biol. Pharm. Bull. 2013, 36, 1235–1240. [Google Scholar] [CrossRef]
  2. Greaves, M.W. Antihistamines in Dermatology. Skin Pharmacol. Physiol. 2005, 18, 220–229. [Google Scholar] [CrossRef]
  3. Ikoma, A.; Steinhoff, M.; Ständer, S.; Yosipovitch, G.; Schmelz, M. The neurobiology of itch. Nat. Rev. Neurosci. 2006, 7, 535–547. [Google Scholar] [CrossRef]
  4. Paus, R.; Schmelz, M.; Bíró, T.; Steinhoff, M. Frontiers in pruritus research: Scratching the brain for more effective itch therapy. J. Clin. Investig. 2006, 116, 1174–1185. [Google Scholar] [CrossRef]
  5. Mettang, T.; Kremer, A.E. Uremic pruritus. Kidney Int. 2015, 87, 685–691. [Google Scholar] [CrossRef]
  6. Düll, M.M.; Kremer, A.E. Treatment of Pruritus Secondary to Liver Disease. Curr. Gastroenterol. Rep. 2019, 21, 48. [Google Scholar] [CrossRef]
  7. Iwamoto, S.; Tominaga, M.; Kamata, Y.; Kawakami, T.; Osada, T.; Takamori, K. Association Between Inflammatory Bowel Disease and Pruritus. Crohn Colitis 360 2020, 2, otaa012. [Google Scholar] [CrossRef]
  8. Bigliardi, P.L.; Tobin, D.J.; Gaveriaux-Ruff, C.; Bigliardi-Qi, M. Opioids and the skin-where do we stand? Exp. Dermatol. 2009, 18, 424–430. [Google Scholar] [CrossRef]
  9. Inan, S.; Dun, N.J.; Cowan, A. Nalfurafine prevents 5′-guanidinonaltrindole- and compound 48/80-induced spinal c-fos expression and attenuates 5′-guanidinonaltrindole-elicited scratching behavior in mice. Neuroscience 2009, 163, 23–33. [Google Scholar] [CrossRef]
  10. Simpson, E.L.; Bieber, T.; Guttman-Yassky, E.; Beck, L.A.; Blauvelt, A.; Cork, M.J.; Silverberg, J.I.; Deleuran, M.; Kataoka, Y.; Lacour, J.-P.; et al. Two Phase 3 Trials of Dupilumab versus Placebo in Atopic Dermatitis. N. Engl. J. Med. 2016, 375, 2335–2348. [Google Scholar] [CrossRef]
  11. Heinz, K.C.; Willems, D.; Hiligsmann, M. Economic evaluation of a JAK inhibitor compared to a monoclonal antibody for treatment of moderate-to-severe atopic dermatitis from a UK perspective. J. Med. Econ. 2022, 25, 491–502. [Google Scholar] [CrossRef]
  12. Blauvelt, A.; Teixeira, H.D.; Simpson, E.L.; Costanzo, A.; De Bruin-Weller, M.; Barbarot, S.; Prajapati, V.H.; Lio, P.; Hu, X.; Wu, T.; et al. Efficacy and Safety of Upadacitinib vs. Dupilumab in Adults With Moderate-to-Severe Atopic Dermatitis: A Randomized Clinical Trial. JAMA Dermatol. 2021, 157, 1047–1055. [Google Scholar] [CrossRef]
  13. Gunawan, A.; Harrington, P.; Garcia-Curto, N.; McLornan, D.; Radia, D.; Harrison, C. Ruxolitinib for the Treatment of Essential Thrombocythemia. HemaSphere 2018, 2, e56. [Google Scholar] [CrossRef]
  14. Conti, P.; Shaik-Dasthagirisaheb, Y.B. Mast Cell Serotonin Immunoregulatory Effects Impacting on Neuronal Function: Implications for Neurodegenerative and Psychiatric Disorders. Neurotox. Res. 2015, 28, 147–153. [Google Scholar] [CrossRef]
  15. Yamaguchi, T.; Nagasawa, T.; Satoh, M.; Kuraishi, Y. Itch-associated response induced by intradermal serotonin through 5-HT2 receptors in mice. Neurosci. Res. 1999, 35, 77–83. [Google Scholar] [CrossRef]
  16. Akiyama, T.; Ivanov, M.; Nagamine, M.; Davoodi, A.; Carstens, M.I.; Ikoma, A.; Cevikbas, F.; Kempkes, C.; Buddenkotte, J.; Steinhoff, M.; et al. Involvement of TRPV4 in Serotonin-Evoked Scratching. J. Investig. Dermatol. 2016, 136, 154–160. [Google Scholar] [CrossRef]
  17. Zylicz, Z.; Krajnik, M.; van Sorge, A.A.; Costantini, M. Paroxetine in the treatment of severe non-dermatological pruritus: A randomized, controlled trial. J. Pain Symptom Manag. 2003, 26, 1105–1112. [Google Scholar] [CrossRef]
  18. Tefferi, A.; Fonseca, R. Selective serotonin reuptake inhibitors are effective in the treatment of polycythemia vera–associated pruritus. Blood 2002, 99, 2627. [Google Scholar] [CrossRef]
  19. Biondi, M.; Arcangeli, T.; Petrucci, R. Paroxetine in a Case of Psychogenic Pruritus and Neurotic Excoriations. Psychother. Psychosom. 2000, 69, 165–166. [Google Scholar] [CrossRef]
  20. Ständer, S.; Böckenholt, B.; Schürmeyer-Horst, F.; Weishaupt, C.; Heuft, G.; Schneider, T. Treatment of Chronic Pruritus with the Selective Serotonin Re-uptake Inhibitors Paroxetine and Fluvoxamine: Results of an Open-labelled, Two-arm Proof-of-concept Study. Acta Derm. Venereol. 2009, 89, 45–51. [Google Scholar] [CrossRef]
  21. Thébaut, A.; Habes, D.; Gottrand, F.; Rivet, C.; Cohen, J.; Debray, D.; Jacquemin, E.; Gonzales, E. Sertraline as an Additional Treatment for Cholestatic Pruritus in Children. J. Pediatr. Gastroenterol. Nutr. 2017, 64, 431–435. [Google Scholar] [CrossRef]
  22. Hundley, J.L.; Yosipovitch, G. Mirtazapine for reducing nocturnal itch in patients with chronic pruritus: A pilot study. J. Am. Acad. Dermatol. 2004, 50, 889–891. [Google Scholar] [CrossRef]
  23. Andoh, T.; Gotoh, Y.; Kuraishi, Y. Milnacipran inhibits itch-related responses in mice through the enhancement of noradrenergic transmission in the spinal cord. J. Pharmacol. Sci. 2013, 123, 199–202. [Google Scholar] [CrossRef]
  24. Browning, J. Long-term efficacy of sertraline as a treatment for cholestatic pruritus in patients with primary biliary cirrhosis. Am. J. Gastroenterol. 2003, 98, 2736–2741. [Google Scholar] [CrossRef]
  25. Yrondi, A.; Fiori, L.M.; Frey, B.N.; Lam, R.W.; MacQueen, G.M.; Milev, R.; Müller, D.J.; Foster, J.; Kennedy, S.H.; Turecki, G. Association Between Side Effects and Blood microRNA Expression Levels and Their Targeted Pathways in Patients With Major Depressive Disorder Treated by a Selective Serotonin Reuptake Inhibitor, Escitalopram: A CAN-BIND-1 Report. Int. J. Neuropsychopharmacol. 2020, 23, 88–95. [Google Scholar] [CrossRef]
  26. Sadegzadeh, F.; Sakhaie, N.; Dehghany, R.; Adak, O.; Saadati, H. Effects of adolescent administration of fluoxetine on novel object recognition memory, anxiety-like behaviors, and hippocampal brain-derived neurotrophic factor level. Life Sci. 2020, 260, 118338. [Google Scholar] [CrossRef]
  27. Zhang, X.; Yin, Y.; Yue, L.; Gong, L. Selective Serotonin Reuptake Inhibitors Aggravate Depression-Associated Dry Eye Via Activating the NF-kappaB Pathway. Investig. Ophthalmol. Vis. Sci. 2019, 60, 407–419. [Google Scholar] [CrossRef]
  28. Krasowska, D.; Szymanek, M.; Schwartz, R.A.; Myśliński, W. Cutaneous effects of the most commonly used antidepressant medication, the selective serotonin reuptake inhibitors. J. Am. Acad. Dermatol. 2007, 56, 848–853. [Google Scholar] [CrossRef]
  29. Tominaga, M.; Takamori, K. Itch and nerve fibers with special reference to atopic dermatitis: Therapeutic implications. J. Dermatol. 2014, 41, 205–212. [Google Scholar] [CrossRef]
  30. Fehrenbacher, J.C.; Taylor, C.P.; Vasko, M.R. Pregabalin and gabapentin reduce release of substance P and CGRP from rat spinal tissues only after inflammation or activation of protein kinase C. Pain 2003, 105, 133–141. [Google Scholar] [CrossRef]
  31. Foroutan, N.; Etminan, A.; Nikvarz, N.; Abadi, M.S.S. Comparison of pregabalin with doxepin in the management of uremic pruritus: A randomized single blind clinical trial. Hemodial. Int. 2016, 21, 63–71. [Google Scholar] [CrossRef] [PubMed]
  32. Cevikbas, F.; Steinhoff, M.; Ikoma, A. Role of Spinal Neurotransmitter Receptors in Itch: New Insights into Therapies and Drug Development. CNS Neurosci. Ther. 2010, 17, 742–749. [Google Scholar] [CrossRef] [PubMed]
  33. Chen, J.; Li, L.; Chen, S.R.; Chen, H.; Xie, J.D.; Sirrieh, R.E.; Maclean, D.M.; Zhang, Y.; Zhou, M.-H.; Jayaraman, V.; et al. The α2δ-1-NMDA Receptor Complex Is Critically Involved in Neuropathic Pain Development and Gabapentin Therapeutic Actions. Cell Rep. 2018, 22, 2307–2321. [Google Scholar] [CrossRef]
  34. Taylor, C.P.; Angelotti, T.; Fauman, E. Pharmacology and mechanism of action of pregabalin: The calcium channel α2–δ (alpha2–delta) subunit as a target for antiepileptic drug discovery. Epilepsy Res. 2007, 73, 137–150. [Google Scholar] [CrossRef] [PubMed]
  35. Domon, Y.; Arakawa, N.; Inoue, T.; Matsuda, F.; Takahashi, M.; Yamamura, N.; Kai, K.; Kitano, Y. Binding Characteristics and Analgesic Effects of Mirogabalin, a Novel Ligand for the alpha2delta Subunit of Voltage-Gated Calcium Channels. J. Pharmacol. Exp. Ther. 2018, 365, 573–582. [Google Scholar] [CrossRef]
  36. Kamo, A.; Tominaga, M.; Matsuda, H.; Kina, K.; Kamata, Y.; Umehara, Y.; Ogawa, H.; Takamori, K. Neurotropin suppresses itch-related behavior in NC/Nga mice with atopic dermatitis-like symptoms. J. Dermatol. Sci. 2015, 81, 212–215. [Google Scholar] [CrossRef]
  37. Kamo, A.; Tominaga, M.; Taneda, K.; Ogawa, H.; Takamori, K. Neurotropin inhibits the increase in intraepidermal nerve density in the acetone-treated dry-skin mouse model. Clin. Exp. Dermatol. 2013, 38, 665–668. [Google Scholar] [CrossRef]
  38. Taneda, K.; Tominaga, M.; Tengara, S.; Ogawa, H.; Takamori, K. Neurotropin inhibits both capsaicin-induced substance P release and nerve growth factor-induced neurite outgrowth in cultured rat dorsal root ganglion neurones. Clin. Exp. Dermatol. 2009, 35, 73–77. [Google Scholar] [CrossRef]
  39. Schmitt, J.; Schmitt, N.; Meurer, M. Cyclosporin in the treatment of patients with atopic eczema? A systematic review and meta-analysis. J. Eur. Acad. Dermatol. Venereol. 2007, 21, 606–619. [Google Scholar] [CrossRef]
  40. Ko, K.; Tominaga, M.; Kamata, Y.; Umehara, Y.; Matsuda, H.; Takahashi, N.; Kina, K.; Ogawa, M.; Ogawa, H.; Takamori, K. Possible Antipruritic Mechanism of Cyclosporine A in Atopic Dermatitis. Acta Derm. Venereol. 2016, 96, 624–629. [Google Scholar] [CrossRef]
  41. Kabashima, K.; Irie, H. Interleukin-31 as a Clinical Target for Pruritus Treatment. Front. Med. 2021, 8, 638325. [Google Scholar] [CrossRef] [PubMed]
  42. Touw, C.; Roijen, L.H.-V.; Verboom, P.; Paul, C.; Rutten, F.; Finlay, A. Quality of life and clinical outcome in psoriasis patients using intermittent cyclosporin. Br. J. Dermatol. 2001, 144, 967–972. [Google Scholar] [CrossRef] [PubMed]
  43. Catinean, A.; Neag, M.A.; Mitre, A.O.; Bocsan, C.I.; Buzoianu, A.D. Microbiota and Immune-Mediated Skin Diseases—An Overview. Microorganisms 2019, 7, 279. [Google Scholar] [CrossRef] [PubMed]
  44. Matsui, K.; Tamai, S.; Ikeda, R. Effects of Macrolide Antibiotics on Th1 Cell and Th2 Cell Development Mediated by Langerhans Cells. J. Pharm. Pharm. Sci. 2016, 19, 357–366. [Google Scholar] [CrossRef] [PubMed]
  45. Matsui, K.; Nakamura, M.; Obana, N. Effects of Josamycin on Scratching Behavior in NC/Nga Mice with Atopic Dermatitis-Like Skin Lesions. Biol. Pharm. Bull. 2021, 44, 798–803. [Google Scholar] [CrossRef]
  46. Tamaki, K. Antipruritic Effect ofMacrolide Antibiotics. J. Dermatol. 2000, 27, 66–67. [Google Scholar]
  47. Moniaga, C.; Tominaga, M.; Takamori, K. Mechanisms and Management of Itch in Dry Skin. Acta Derm. Venereol. 2020, 100, adv00024. [Google Scholar] [CrossRef]
  48. Torigoe, K.; Tominaga, M.; Ko, K.C.; Takahashi, N.; Matsuda, H.; Hayashi, R.; Ogawa, H.; Takamori, K. Intrathecal Minocycline Suppresses Itch-Related Behavior and Improves Dermatitis in a Mouse Model of Atopic Dermatitis. J. Investig. Dermatol. 2016, 136, 879–881. [Google Scholar] [CrossRef]
  49. Sekine, R.; Satoh, T.; Takaoka, A.; Saeki, K.; Yokozeki, H. Anti pruritic effects of topical crotamiton, capsaicin, and a corticosteroid on pruritogen-induced scratching behavior. Exp. Dermatol. 2011, 21, 201–204. [Google Scholar] [CrossRef]
  50. Choi, D.-S.; Ji, Y.; Jang, Y.; Lee, W.-J.; Shim, W.-S. Crotamiton, an Anti-Scabies Agent, Suppresses Histamine- and Chloroquine-Induced Itch Pathways in Sensory Neurons and Alleviates Scratching in Mice. Biomol. Ther. 2020, 28, 569–575. [Google Scholar] [CrossRef]
  51. Kittaka, H.; Yamanoi, Y.; Tominaga, M. Transient receptor potential vanilloid 4 (TRPV4) channel as a target of crotamiton and its bimodal effects. Pflüg. Arch.-Eur. J. Physiol. 2017, 469, 1313–1323. [Google Scholar] [CrossRef] [PubMed]
  52. Tominaga, M.; Takamori, K. Peripheral itch sensitization in atopic dermatitis. Allergol. Int. 2022, 71, 265–277. [Google Scholar] [CrossRef] [PubMed]
  53. Andoh, T.; Kuraishi, Y. Antipruritic mechanisms of topical E6005, a phosphodiesterase 4 inhibitor: Inhibition of responses to proteinase-activated receptor 2 stimulation mediated by increase in intracellular cyclic AMP. J. Dermatol. Sci. 2014, 76, 206–213. [Google Scholar] [CrossRef]
  54. Hanifin, J.M.; Ellis, C.; Frieden, I.J.; Fölster-Holst, R.; Gold, L.F.S.; Secci, A.; Smith, A.J.; Zhao, C.; Kornyeyeva, E.; Eichenfield, L.F. OPA-15406, a novel, topical, nonsteroidal, selective phosphodiesterase-4 (PDE4) inhibitor, in the treatment of adult and adolescent patients with mild to moderate atopic dermatitis (AD): A phase-II randomized, double-blind, placebo-controlled study. J. Am. Acad. Dermatol. 2016, 75, 297–305. [Google Scholar] [CrossRef]
  55. Saeki, H.; Kawashima, M.; Sugaya, S.; Oshiden, K.; Tsubouchi, H. Efficacy and safety of topical OPA-15406, a new phosphodiesterase 4 inhibitor, in Japanese patients with atopic dermatitis for 8 weeks: A phase 2, randomized, double-blind, placebo-controlled study. J. Dermatol. 2019, 46, 672–679. [Google Scholar] [CrossRef] [PubMed]
  56. Saeki, H.; Baba, N.; Oshiden, K.; Abe, Y.; Tsubouchi, H. Phase 2, randomized, double-blind, placebo-controlled, 4-week study to evaluate the safety and efficacy of OPA-15406 (difamilast), a new topical selective phosphodiesterase type-4 inhibitor, in Japanese pediatric patients aged 2-14 years with atopic dermatitis. J. Dermatol. 2019, 47, 17–24. [Google Scholar] [PubMed]
  57. Samrao, A.; Berry, T.M.; Goreshi, R.; Simpson, E.L. A Pilot Study of an Oral Phosphodiesterase Inhibitor (Apremilast) for Atopic Dermatitis in Adults. Arch. Dermatol. 2012, 148, 890–897. [Google Scholar] [CrossRef] [PubMed]
  58. Farahnik, B.; Beroukhim, K.; Nakamura, M.; Abrouk, M.; Zhu, T.H.; Singh, R.; Lee, K.; Bhutani, T.; Koo, J.; Liao, W. Use of an oral phosphodiesterase-4 inhibitor (apremilast) for the treatment of chronic, severe atopic dermatitis: A case report. Dermatol. Online J. 2017, 23, 9. [Google Scholar] [CrossRef]
  59. Vossen, A.R.; van Doorn, M.B.; van der Zee, H.H.; Prens, E.P. Apremilast for moderate hidradenitis suppurativa: Results of a randomized controlled trial. J. Am. Acad. Dermatol. 2019, 80, 80–88. [Google Scholar] [CrossRef]
  60. Strand, V.; Fiorentino, D.; Hu, C.; Day, R.M.; Stevens, R.M.; Papp, K. Improvements in patient-reported outcomes with apremilast, an oral phosphodiesterase 4 inhibitor, in the treatment of moderate to severe psoriasis: Results from a phase IIb randomized, controlled study. Health Qual. Life Outcomes 2013, 11, 82. [Google Scholar] [CrossRef]
  61. Paul, C.; Cather, J.; Gooderham, M.; Poulin, Y.; Mrowietz, U.; Ferrandiz, C.; Crowley, J.; Hu, C.; Stevens, R.M.; Shah, K.; et al. Efficacy and safety of apremilast, an oral phosphodiesterase 4 inhibitor, in patients with moderate-to-severe plaque psoriasis over 52 weeks: A phase III, randomized controlled trial (ESTEEM 2). Br. J. Dermatol. 2015, 173, 1387–1399. [Google Scholar] [CrossRef] [PubMed]
  62. Sobell, J.; Foley, P.; Toth, D.; Mrowietz, U.; Girolomoni, G.; Goncalves, J.; Day, R.; Chen, R.; Yosipovitch, G. Effects of Apremilast on Pruritus and Skin Discomfort/Pain Correlate with Improvements in Quality of Life in Patients with Moderate to Severe Plaque Psoriasis. Acta Derm. Venereol. 2016, 96, 514–520. [Google Scholar] [CrossRef] [PubMed]
  63. Reich, K.; Gooderham, M.; Bewley, A.; Green, L.; Soung, J.; Petric, R.; Marcsisin, J.; Cirulli, J.; Chen, R.; Piguet, V. Safety and efficacy of apremilast through 104 weeks in patients with moderate to severe psoriasis who continued on apremilast or switched from etanercept treatment: Findings from the LIBERATE study. J. Eur. Acad. Dermatol. Venereol. 2018, 32, 397–402. [Google Scholar] [CrossRef] [PubMed]
  64. Paller, A.S.; Tom, W.L.; Lebwohl, M.G.; Blumenthal, R.L.; Boguniewicz, M.; Call, R.S.; Eichenfield, L.F.; Forsha, D.W.; Rees, W.C.; Simpson, E.L.; et al. Efficacy and safety of crisaborole ointment, a novel, nonsteroidal phosphodiesterase 4 (PDE4) inhibitor for the topical treatment of atopic dermatitis (AD) in children and adults. J. Am. Acad. Dermatol. 2016, 75, 494–503.e6. [Google Scholar] [CrossRef] [PubMed]
  65. Yosipovitch, G.; Gold, L.; Lebwohl, M.; Silverberg, J.; Tallman, A.; Zane, L. Early Relief of Pruritus in Atopic Dermatitis with Crisaborole Ointment, A Non-steroidal, Phosphodiesterase 4 Inhibitor. Acta Derm. Venereol. 2018, 98, 484–489. [Google Scholar] [CrossRef] [PubMed]
  66. Bissonnette, R.; Pavel, A.B.; Diaz, A.; Werth, J.L.; Zang, C.; Vranic, I.; Purohit, V.S.; Zielinski, M.A.; Vlahos, B.; Estrada, Y.D.; et al. Crisaborole and atopic dermatitis skin biomarkers: An intrapatient randomized trial. J. Allergy Clin. Immunol. 2019, 144, 1274–1289. [Google Scholar]
  67. Eichenfield, L.F.; Yosipovitch, G.; Stein Gold, L.F.; Kalabis, M.; Zang, C.; Vlahos, B.; Sanders, P.; Myers, D.E.; Bushmakin, A.G.; Paller, A.S.; et al. Improvement in disease severity and pruritus outcomes with crisaborole ointment, 2%, by baseline atopic dermatitis severity in children and adolescents with mild-to-moderate atopic dermatitis. Pediatr. Dermatol. 2020, 37, 1030–1037. [Google Scholar] [CrossRef]
  68. Spergel, J.M.; Blaiss, M.S.; Lio, P.; Kessel, A.; Cantrell, W.C.; Takiya, L.; Werth, J.L.; O’Connell, M.A.; Zang, C.; Cork, M.J. Efficacy and safety of crisaborole in patients with mild-to-moderate atopic dermatitis and other atopic comorbidities. Allergy Asthma Proc. 2021, 42, 425–431. [Google Scholar] [CrossRef]
  69. Furue, M.; Kitahara, Y.; Akama, H.; Hojo, S.; Hayashi, N.; Nakagawa, H.; The JAPANESE E6005 Study Investigators. Safety and efficacy of topical E6005, a phosphodiesterase 4 inhibitor, in Japanese adult patients with atopic dermatitis: Results of a randomized, vehicle-controlled, multicenter clinical trial. J. Dermatol. 2014, 41, 577–585. [Google Scholar] [CrossRef]
  70. Andoh, T.; Yoshida, T.; Kuraishi, Y. Topical E6005, a novel phosphodiesterase 4 inhibitor, attenuates spontaneous itch-related responses in mice with chronic atopy-like dermatitis. Exp. Dermatol. 2014, 23, 359–361. [Google Scholar] [CrossRef]
  71. Wakita, H.; Ohkuro, M.; Ishii, N.; Hishinuma, I.; Shirato, M. A putative antipruritic mechanism of the phosphodiesterase-4 inhibitor E6005 by attenuating capsaicin-induced depolarization of C-fibre nerves. Exp. Dermatol. 2015, 24, 215–216. [Google Scholar] [CrossRef] [PubMed]
  72. Saeki, H.; Ito, K.; Yokota, D.; Tsubouchi, H. Difamilast ointment in adult patients with atopic dermatitis: A phase 3 randomized, double-blind, vehicle-controlled trial. J. Am. Acad. Dermatol. 2022, 86, 607–614. [Google Scholar] [CrossRef] [PubMed]
  73. Heckmann, M.; Heyer, G.; Brunner, B.; Plewig, G. Botulinum toxin type A injection in the treatment of lichen simplex: An open pilot study. J. Am. Acad. Dermatol. 2002, 46, 617–619. [Google Scholar] [CrossRef] [PubMed]
  74. Kavanagh, G.; Tidman, M. Botulinum A toxin and brachioradial pruritus. Br. J. Dermatol. 2011, 166, 1147. [Google Scholar] [CrossRef]
  75. Gharib, K.; Mostafa, A.; Elsayed, A. Evaluation of Botulinum Toxin Type A Injection in the Treatment of Localized Chronic Pruritus. J. Clin. Aesthet. Dermatol. 2020, 13, 12–17. [Google Scholar]
  76. Klager, S.; Kumar, M.G. Treatment of pruritus with botulinum toxin in a pediatric patient with Fox-Fordyce disease. Pediatr. Dermatol. 2021, 38, 950–951. [Google Scholar] [CrossRef]
  77. Gazerani, P.; Pedersen, N.; Drewes, A.; Arendt-Nielsen, L. Botulinum toxin type A reduces histamine-induced itch and vasomotor responses in human skin. Br. J. Dermatol. 2009, 161, 737–745. [Google Scholar] [CrossRef]
  78. Ramachandran, R.; Marino, M.J.; Paul, S.; Wang, Z.; Mascarenhas, N.L.; Pellett, S.; Johnson, E.A.; DiNardo, A.; Yaksh, T.L. A Study and Review of Effects of Botulinum Toxins on Mast Cell Dependent and Independent Pruritus. Toxins 2018, 10, 134. [Google Scholar] [CrossRef]
  79. Huang, S.-H.; Wu, K.-W.; Lo, J.-J.; Wu, S.-H. Synergic Effect of Botulinum Toxin Type-A and Triamcinolone Alleviates Scar Pruritus by Modulating Epidermal Hyperinnervation: A Preliminary Report. Aesthet. Surg. J. 2021, 41, NP1721–NP1731. [Google Scholar] [CrossRef]
  80. Tohda, C.; Sugahara, H.; Kuraishi, Y.; Komatsu, K. Inhibitory effect of Byakko-ka-ninjin-to on itch in a mouse model of atopic dermatitis. Phytother. Res. 2000, 14, 192–194. [Google Scholar] [CrossRef]
  81. Saeedi, M.; Morteza-Semnani, K.; Ghoreishi, M. The treatment of atopic dermatitis with licorice gel. J. Dermatol. Treat. 2003, 14, 153–157. [Google Scholar] [CrossRef] [PubMed]
  82. Jiang, J.; Yamaguchi, T.; Funakushi, N.; Kuhara, T.; Fan, P.-S.; Ueki, R.; Suto, H.; Kase, Y.; Ikeda, S.; Ogawa, H. Oral administration of Yokukansan inhibits the development of atopic dermatitis-like lesions in isolated NC/Nga mice. J. Dermatol. Sci. 2009, 56, 37–42. [Google Scholar] [CrossRef]
  83. Cheng, H.-M.; Chiang, L.-C.; Jan, Y.-M.; Chen, G.-W.; Li, T.-C. The Efficacy and Safety of a Chinese Herbal Product (Xiao-Feng-San) for the Treatment of Refractory Atopic Dermatitis: A Randomized, Double-Blind, Placebo-Controlled Trial. Int. Arch. Allergy Immunol. 2010, 155, 141–148. [Google Scholar] [CrossRef]
  84. Yan, F.; Zhang, J.; Li, X.; Mo, X.; Liu, J.; Ye, S.; Lin, Y.; Qiu, X.; Lee, S.M.; Chen, D. Therapeutic Effects of Chinese Herbal Formula (PTQX) on NC/Nga Mice with Atopic Dermatitis-Like Skin Lesions. Evid.-Based Complement. Altern. Med. 2019, 2019, 8359252. [Google Scholar] [CrossRef] [PubMed]
  85. Xu, Y.; Chen, S.; Zhang, L.; Chen, G.; Chen, J. The Anti-Inflammatory and Anti-Pruritus Mechanisms of Huanglian Jiedu Decoction in the Treatment of Atopic Dermatitis. Front. Pharmacol. 2021, 12, 735295. [Google Scholar] [CrossRef] [PubMed]
  86. Kim, J.H.; Kim, A.-R.; Kim, H.S.; Kim, H.W.; Park, Y.H.; You, J.S.; Park, Y.M.; Her, E.; Kim, H.S.; Kim, Y.M.; et al. Rhamnus davurica leaf extract inhibits Fyn activation by antigen in mast cells for anti-allergic activity. BMC Complement. Altern. Med. 2015, 15, 80. [Google Scholar] [CrossRef]
  87. Nam, J.H.; Jung, H.W.; Chin, Y.W.; Yang, W.M.; Bae, H.S.; Kim, W.K. Spirodela polyrhiza extract modulates the activation of atopic dermatitis-related ion channels, Orai1 and TRPV3, and inhibits mast cell degranulation. Pharm. Biol. 2017, 55, 1324–1329. [Google Scholar] [CrossRef]
  88. Yang, N.-N.; Shi, H.; Yu, G.; Wang, C.-M.; Zhu, C.; Yang, Y.; Yuan, X.-L.; Tang, M.; Wang, Z.-L.; Gegen, T.; et al. Osthole inhibits histamine-dependent itch via modulating TRPV1 activity. Sci. Rep. 2016, 6, 25657. [Google Scholar] [CrossRef]
  89. Basnet, P.; Yasuda, I.; Kumagai, N.; Tohda, C.; Nojima, H.; Kuraishi, Y.; Komatsu, K. Inhibition of Itch-Scratch Response by Fruits of Cnidium monnieri in Mice. Biol. Pharm. Bull. 2001, 24, 1012–1015. [Google Scholar] [CrossRef]
  90. Andoh, T.; Al-Akeel, A.; Tsujii, K.; Nojima, H.; Kuraishi, Y. Repeated Treatment With the Traditional Medicine Unsei-in Inhibits Substance P-Induced Itch-Associated Responses Through Downregulation of the Expression of Nitric Oxide Synthase 1 in Mice. J. Pharmacol. Sci. 2004, 94, 207–210. [Google Scholar] [CrossRef]
  91. Meduri, N.B.; Vandergriff, T.; Rasmussen, H.; Jacobe, H. Phototherapy in the management of atopic dermatitis: A systematic review. Photodermatol. Photoimmunol. Photomed. 2007, 23, 106–112. [Google Scholar] [CrossRef] [PubMed]
  92. Evers, A.W.M.; Kleinpenning, M.M.; Smits, T.; Boezeman, J.; Van De Kerkhof, P.; Kraaimaat, F.W.; Gerritsen, M.J.P. Itch and scratching as predictors of time to clearance of psoriasis with narrow-band ultraviolet B therapy. Br. J. Dermatol. 2009, 161, 542–546. [Google Scholar] [CrossRef] [PubMed]
  93. Baltas, E.; Csoma, Z.; Bodai, L.; Ignacz, F.; Dobozy, A.; Kemény, L. Treatment of atopic dermatitis with the xenon chloride excimer laser. J. Eur. Acad. Dermatol. Venereol. 2006, 20, 657–660. [Google Scholar] [CrossRef]
  94. Sidbury, R.; Davis, D.M.; Cohen, D.E.; Cordoro, K.M.; Berger, T.G.; Bergman, J.N.; Chamlin, S.L.; Cooper, K.D.; Feldman, S.R.; Hanifin, J.M.; et al. Guidelines of care for the management of atopic dermatitis: Section 3. Management and treatment with phototherapy and systemic agents. J. Am. Acad. Dermatol. 2014, 71, 327–349. [Google Scholar] [CrossRef] [PubMed]
  95. Juarez, M.C.; Grossberg, A.L. Phototherapy in the Pediatric Population. Dermatol. Clin. 2020, 38, 91–108. [Google Scholar] [CrossRef] [PubMed]
  96. Tominaga, M.; Tengara, S.; Kamo, A.; Ogawa, H.; Takamori, K. Psoralen-ultraviolet A therapy alters epidermal Sema3A and NGF levels and modulates epidermal innervation in atopic dermatitis. J. Dermatol. Sci. 2009, 55, 40–46. [Google Scholar] [CrossRef]
  97. Kamo, A.; Tominaga, M.; Tengara, S.; Ogawa, H.; Takamori, K. Inhibitory effects of UV-based therapy on dry skin-inducible nerve growth in acetone-treated mice. J. Dermatol. Sci. 2011, 62, 91–97. [Google Scholar] [CrossRef]
  98. Kamo, A.; Tominaga, M.; Kamata, Y.; Kaneda, K.; Ko, K.C.; Matsuda, H.; Kimura, U.; Ogawa, H.; Takamori, K. The Excimer Lamp Induces Cutaneous Nerve Degeneration and Reduces Scratching in a Dry-Skin Mouse Model. J. Investig. Dermatol. 2014, 134, 2977–2984. [Google Scholar] [CrossRef]
  99. Archier, E.; Devaux, S.; Castela, E.; Gallini, A.; Aubin, F.; Le Maître, M.; Aractingi, S.; Bachelez, H.; Cribier, B.; Joly, P.; et al. Carcinogenic risks of Psoralen UV-A therapy and Narrowband UV-B therapy in chronic plaque psoriasis: A systematic literature review. J. Eur. Acad. Dermatol. Venereol. 2012, 26, 22–31. [Google Scholar] [CrossRef]
  100. Hearn, R.; Kerr, A.; Rahim, K.; Ferguson, J.; Dawe, R. Incidence of skin cancers in 3867 patients treated with narrow-band ultraviolet B phototherapy. Br. J. Dermatol. 2008, 159, 931–935. [Google Scholar] [CrossRef]
  101. Jung, D.-L.; Lee, S.-D.; Choi, I.-H.; Na, H.-S.; Hong, S.-U. Effects of electroacupuncture on capsaicin-induced model of atopic dermatitis in rats. J. Dermatol. Sci. 2014, 74, 23–30. [Google Scholar] [CrossRef] [PubMed]
  102. Kang, S.; Kim, Y.-K.; Yeom, M.; Lee, H.; Jang, H.; Park, H.-J.; Kim, K. Acupuncture improves symptoms in patients with mild-to-moderate atopic dermatitis: A randomized, sham-controlled preliminary trial. Complement. Ther. Med. 2018, 41, 90–98. [Google Scholar] [CrossRef] [PubMed]
  103. Jiao, R.; Yang, Z.; Wang, Y.; Zhou, J.; Zeng, Y.; Liu, Z. The effectiveness and safety of acupuncture for patients with atopic eczema: A systematic review and meta-analysis. Acupunct. Med. 2020, 38, 3–14. [Google Scholar] [CrossRef] [PubMed]
  104. Pfab, F.; Huss-Marp, J.; Gatti, A.; Fuqin, J.; Athanasiadis, G.I.; Irnich, D.; Raap, U.; Schober, W.; Behrendt, H.; Ring, J.; et al. Influence of acupuncture on type I hypersensitivity itch and the wheal and flare response in adults with atopic eczema–A blinded, randomized, placebo-controlled, crossover trial. Allergy 2009, 65, 903–910. [Google Scholar] [CrossRef]
  105. Pfab, F.; Kirchner, M.T.; Huss-Marp, J.; Schuster, T.; Schalock, P.C.; Fuqin, J.; Athanasiadis, G.I.; Behrendt, H.; Ring, J.; Darsow, U.; et al. Acupuncture compared with oral antihistamine for type I hypersensitivity itch and skin response in adults with atopic dermatitis: A patient- and examiner-blinded, randomized, placebo-controlled, crossover trial. Allergy 2012, 67, 566–573. [Google Scholar] [CrossRef]
  106. Napadow, V.; Li, A.; Loggia, M.L.; Kim, J.; Schalock, P.; Lerner, E.; Tran, T.-N.; Ring, J.; Rosen, B.R.; Kaptchuk, T.J.; et al. The Brain Circuitry Mediating Antipruritic Effects of Acupuncture. Cereb. Cortex 2014, 24, 873–882. [Google Scholar] [CrossRef]
  107. Park, H.-J.; Ahn, S.; Lee, H.; Hahm, D.; Kim, K.; Yeom, M. Acupuncture ameliorates not only atopic dermatitis-like skin inflammation but also acute and chronic serotonergic itch possibly through blockade of 5-HT2 and 5-HT7 receptors in mice. Brain Behav. Immun. 2021, 93, 399–408. [Google Scholar] [CrossRef]
  108. Akça, N.K.; Taşcı, S. Acupressure and Transcutaneous Electrical Acupoint Stimulation for Improving Uremic Pruritus: A Randomized, Controlled Trial. Altern. Ther. Health Med. 2016, 22, 18–24. [Google Scholar]
  109. Che-Yi, C.; Wen, C.Y.; Min-Tsung, K.; Chiu-Ching, H. Acupuncture in haemodialysis patients at the Quchi (LI11) acupoint for refractory uraemic pruritus. Nephrol. Dial. Transplant. 2005, 20, 1912–1915. [Google Scholar] [CrossRef]
  110. Pfab, F.; Hammes, M.; Bäcker, M.; Hussmarp, J.; Athanasiadis, G.; Tolle, T.; Behrendt, H.; Ring, J.; Darsow, U. Preventive effect of acupuncture on histamine-induced itch: A blinded, randomized, placebo-controlled, crossover trial. J. Allergy Clin. Immunol. 2005, 116, 1386–1388. [Google Scholar] [CrossRef]
  111. Kesting, M.R.; Thurmueller, P.; Hölzle, F.; Wolff, K.; Holland-Letz, T.; Stücker, M. Electrical Ear Acupuncture Reduces Histamine-induced Itch (Alloknesis). Acta Derm. Venereol. 2006, 86, 399–403. [Google Scholar] [CrossRef] [PubMed]
  112. Min, S.; Kim, K.-W.; Jung, W.-M.; Lee, M.-J.; Kim, Y.-K.; Chae, Y.; Lee, H.; Park, H.-J. Acupuncture for Histamine-Induced Itch: Association With Increased Parasympathetic Tone and Connectivity of Putamen-Midcingulate Cortex. Front. Neurosci. 2019, 13, 215. [Google Scholar] [CrossRef] [PubMed]
  113. Li, H.-P.; Wang, X.-Y.; Chen, C.; Li, J.-J.; Yu, C.; Lin, L.-X.; Yu, Z.-E.; Jin, Z.-Y.; Zhu, H.; Xiang, H.-C.; et al. 100 Hz Electroacupuncture Alleviated Chronic Itch and GRPR Expression Through Activation of Kappa Opioid Receptors in Spinal Dorsal Horn. Front. Neurosci. 2021, 15, 625471. [Google Scholar] [CrossRef] [PubMed]
  114. Ye, Y.S.; Pan, A.Z.; Zhen, Y.; Kang, M.R.; Zhang, B.; Yi, W.M. Antipruritic effects of electroacupuncture on morphine-induced pruritus model mice through the TLR2/4-MyD88-NF-kappaB pathway. Neuroreport 2019, 30, 331–337. [Google Scholar] [CrossRef]
  115. Lee, Y.-C.; Lin, C.-H.; Hung, S.-Y.; Chung, H.-Y.; Luo, S.-T.; MacDonald, I.; Chu, Y.-T.; Lin, P.-L.; Chen, Y.-H. Manual acupuncture relieves bile acid-induced itch in mice: The role of microglia and TNF-α. Int. J. Med Sci. 2018, 15, 953–960. [Google Scholar] [CrossRef]
  116. Tominaga, M.; Takamori, K. An Update on Peripheral Mechanisms and Treatments of Itch. Biol. Pharm. Bull. 2013, 36, 1241–1247. [Google Scholar] [CrossRef]
  117. Komiya, E.; Tominaga, M.; Kamata, Y.; Suga, Y.; Takamori, K. Molecular and Cellular Mechanisms of Itch in Psoriasis. Int. J. Mol. Sci. 2020, 21, 8406. [Google Scholar] [CrossRef]
  118. Yosipovitch, G.; Misery, L.; Proksch, E.; Metz, M.; Ständer, S.; Schmelz, M. Skin Barrier Damage and Itch: Review of Mechanisms, Topical Management and Future Directions. Acta Derm. Venereol. 2019, 99, 1201–1209. [Google Scholar] [CrossRef]
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Figure 1. Antipruritic mechanism of NTP for intractable itch in AD. NTP inhibits SP release from nerve endings, which presumably suppresses neurogenic inflammation caused by nerve-SP-mast cells. In addition, NTP inhibits the elongation of IENFs and reduces itch hypersensitivity.
Figure 1. Antipruritic mechanism of NTP for intractable itch in AD. NTP inhibits SP release from nerve endings, which presumably suppresses neurogenic inflammation caused by nerve-SP-mast cells. In addition, NTP inhibits the elongation of IENFs and reduces itch hypersensitivity.
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Figure 2. Antipruritic mechanism of CsA for intractable itch in AD. CsA down-regulates expressions of IL-31RA and NK1R in peripheral nerves. CsA also inhibits the infiltration of immune cells, such as CD4+ T cells, mast cells, and eosinophils. In addition, CsA reduces the perception of itch stimuli by suppressing the proliferation of IENFs.
Figure 2. Antipruritic mechanism of CsA for intractable itch in AD. CsA down-regulates expressions of IL-31RA and NK1R in peripheral nerves. CsA also inhibits the infiltration of immune cells, such as CD4+ T cells, mast cells, and eosinophils. In addition, CsA reduces the perception of itch stimuli by suppressing the proliferation of IENFs.
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Figure 3. Antipruritic mechanism of minocycline in AD. The number of microglia is increased in the dorsal horn of the spinal cord of mice with AD. The administration of minocycline decreases the number of microglia in the spinal dorsal horn and suppresses itch and dermatitis.
Figure 3. Antipruritic mechanism of minocycline in AD. The number of microglia is increased in the dorsal horn of the spinal cord of mice with AD. The administration of minocycline decreases the number of microglia in the spinal dorsal horn and suppresses itch and dermatitis.
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Figure 4. Antipruritic mechanism of phototherapy. In dry skin, the up-regulated expression of NGF and down-regulated expression of Sema3A increase the number of IENFs. When various types of phototherapy are used for dry skin, they inhibit IENF hyperplasia in the order of PUVA therapy < NB-UVB < excimer lamps. The inhibitory effects of PUVA and NB-UVB therapy on IENF proliferation are due to the down-regulated expression of nerve elongation factors and up-regulated expression of nerve repulsion factors in keratinocytes; however, excimer lamps act directly on IENFs and induce neurodegeneration without altering the expression of these axon guidance molecules.
Figure 4. Antipruritic mechanism of phototherapy. In dry skin, the up-regulated expression of NGF and down-regulated expression of Sema3A increase the number of IENFs. When various types of phototherapy are used for dry skin, they inhibit IENF hyperplasia in the order of PUVA therapy < NB-UVB < excimer lamps. The inhibitory effects of PUVA and NB-UVB therapy on IENF proliferation are due to the down-regulated expression of nerve elongation factors and up-regulated expression of nerve repulsion factors in keratinocytes; however, excimer lamps act directly on IENFs and induce neurodegeneration without altering the expression of these axon guidance molecules.
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Table
Table 1. Therapeutic methods for troublesome itch.
Table 1. Therapeutic methods for troublesome itch.
CategoryTherapeutic MethodsMechanisms of Action
Oral therapyAntidepressants
• SSRIs (Paroxetine, Fluvoxamine, and Sertraline), NaSSA (Mirtazapine)		Inhibits reuptake of serotonin.
Activates the descending inhibitory system in CNS.
Analgesics
• Pregabalin, Mirogabalin, Neurotropin		Pregabalin may inhibit calcium influx and the release of neurotransmitters, such as glutamate.
Mirogabalin may inhibit calcium influx in the peripheral nervous system and suppress the release of neurotransmitter.
Neurotropin inhibits neuropeptide release and decreases IENF density.
Calcineurin inhibitor
• Cyclosporine A		Activates T cells and inhibits immune cell infiltration.
Inhibits the release of inflammatory cytokines.
Decreases IENF density.
Suppresses itch mediator receptor expression.
Antibiotics
• Roxithromycin, Clarithromycin, Minomycin		Anti-inflammatory effects.
Immunomodulation.
Minomycin suppresses microglia.
PDE4 inhibitor
• Apremilast		Unknown
Herbal remedies
• Yokukansan (YKS), Xiao-Feng-Sang, Pei Tu Qing Xin (PTQX), and Huanglian Jiedu decoction (HLJDT), leaf extract of Rhamnus davurica (LERD), Spirodelae Herba (SH), Osthole, Cnidium monnieri, and Unsei-in		YKS and PTQX inhibit the infiltration of immune cells.
HLJDT regulates DC functions.
LERD inhibits the Fyn/Syk pathway in mast cells.
SH modulates the activation of Orai1 and TPRV4 and inhibits mast cell degranulation.
Osthole inhibits TRPV1 activation.
Unsei-in inhibits the expression of NO synthase.
Topical medicationAntidepressants
• SNRI (Milnacipran)		Inhibits reuptake of serotonin.
Activates the descending inhibitory system in CNS.
Antibiotics
• Josamycin		Inhibits Staphylococcus aureus colonization.
Inhibits Th2 cell differentiation.
⇒suppresses IL-31 production.
CrotamitonInhibits TRPV1, TRPA1, and TRPV4 on nerves.
PDE4 inhibitors
• OPA-15406, crisaborole, and E6005		Crisaborole modulates epidermal hyperplasia/proliferation and Th2 and Th17/Th22 transcriptional profiles.
E6005 increases cAMP.
Botulinum toxin type ABlocks the release of acetylcholine and neurotransmitters from the presynaptic vesicle by deactivating SNARE proteins.
Inhibits degranulation of mast cells.
Normalizes the expression of nerve elongation factors and nerve repulsion factors.
⇒decreases IENF density.
PhototherapyPUVA and NB-UVBNormalizes the expression of nerve elongation factors and nerve repulsion factors.
⇒decreases IENF density.
Excimer lampDecreases IENF density.
Acupuncture therapy Treatment LI11 blocks 5-HT2R and 5-HT7R.
Treatments LI11, PC6, HT7, SP10, ST36 and HT3 decrease responses in the putamen, pMCC.
Treatments LI4 and LI11 suppress GRPR expression via KOR activation.
Treatments LI11 and SP10 inhibit the TLR2/4-MyD88-NF-κB pathway.
Treatments LI4 and LI11 suppress activation of microglia.
SSRIs = selective serotonin reuptake inhibitors, NaSSA = noradrenergic and specific serotonergic antidepressant, IENF = intraepidermal nerve fiber, TPRV = transient receptor potential vanilloid, NO = Nitric oxide, SNRI = serotonin noradrenaline reuptake inhibitors, TRPA = TRP ankyrin, cAMP = cyclic adenosine 3′,5′-monophosphate, SNARE = soluble N-ethylmaleimide sensitive factor attachment protein receptor, PUVA = psoralen ultraviolet A, NB-UVB = narrowband-ultraviolet B, 5-HT = 5-hydroxytryptamine, pMCC = part of the midcingulate cortex, GRPR = gastrin-releasing peptide receptor, TLR = Toll-like receptor, MyD88 = myeloid differentiation factor 88, NF-κB = nuclear factor-κ B.
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Toyama, S.; Tominaga, M.; Takamori, K. Treatment Options for Troublesome Itch. Pharmaceuticals 2022, 15, 1022. https://doi.org/10.3390/ph15081022

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Toyama S, Tominaga M, Takamori K. Treatment Options for Troublesome Itch. Pharmaceuticals. 2022; 15(8):1022. https://doi.org/10.3390/ph15081022

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Toyama, Sumika, Mitsutoshi Tominaga, and Kenji Takamori. 2022. "Treatment Options for Troublesome Itch" Pharmaceuticals 15, no. 8: 1022. https://doi.org/10.3390/ph15081022

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Toyama, S., Tominaga, M., & Takamori, K. (2022). Treatment Options for Troublesome Itch. Pharmaceuticals, 15(8), 1022. https://doi.org/10.3390/ph15081022

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