¹The George Washington University School of Medicine and Health Sciences, Washington, DC, USA
²Department of Dermatology, The George Washington Medical Faculty Associates, Washington, DC, USA

Conflict of interest: 
Adam Friedman is currently developing a nanoparticle encapsulated cannabinoid with Zylo Therapeutics – this work is not referenced in the manuscript. Dustin Marks has no conflicts of interest to report for this work.
Funding: The George Washington Department of Dermatology received no funding in support of this manuscript.

Abstract
Cannabinoids have demonstrated utility in the management of cancer, obesity, and neurologic disease. More recently, their immunosuppressive and anti-inflammatory properties have been identified for the treatment of several dermatologic conditions. This review thus assesses the therapeutic potential of phytocannabinoids, endoocannabinoids, and chemically synthetic cannabinoids in the management of cutaneous disease. The PubMed^® and Scopus^® databases were subsequently reviewed in December 2017 using MeSH and keywords, such as cannabinoid, THC, dermatitis, pruritus, and skin cancer. The search yielded reports on the therapeutic role of cannabinoids in the management of skin cancer, acne vulgaris, pruritus, atopic and allergic contact dermatitis, and systemic sclerosis. While cannabinoids have exhibited efficacy in the treatment of inflammatory and neoplastic skin conditions, several reports suggest pro-inflammatory and pro-neoplastic properties. Further investigation is necessary to understand the complexities of cannabinoids and their therapeutic potential in dermatology.

Key Words:
acne, cannabinoid, cannabis, dermatitis, endocannabinoid, fibrosis, palmitoylethanolamide, inflammatory skin disease, pruritus, skin cancer, sclerosis, THC, tetrahydrocannabinol

Introduction

While the term “cannabis” often draws association to marijuana, cannabinoids represent a diverse class of hydrophobic compounds, deriving from plants (phytocannabinoids), animals (endocannabinoids), and chemical synthetics (Table 1).¹ In mammalian tissue, two G protein-coupled cannabinoid receptors have been identified: cannabinoid receptor 1 (CB1R) in brain and neural cell lines and cannabinoid receptor 2 (CB2R) in the immune system.^2,3 The cannabinoid receptors, transporters, and enzymes form the endocannabinoid system (ECS).⁴ Furthermore, phytocannabinoids, endoocannabinoids, and chemically synthetic cannabinoids bind to the CB1R/CB2R and induce cannabimimetic responses via ECS activation as shown in Figure 1.⁵

The neuropathic properties of cannabinoids are well established and utilized in the treatment of obesity, cancer, spasticity, and tremor. More recently, the immunosuppressive and antiinflammatory effects of cannabinoids have been investigated in the treatment of inflammatory bowel disease, arthritis, vascular inflammation, and common dermatologic conditions.^5-9 Herein, we provide a literature review to assess the therapeutic potential of cannabinoids as it relates to their role in skin growth control and homeostasis, pruritus, inflammation, and fibrosis.

Cannabinoids in Skin Growth Control and Homeostasis

Cannabinoids influence the homeostasis of keratinocytes, melanocytes, and sebocytes through CB1R/CB2R-dependent and -independent mechanisms.^1,10,11 In the epidermis, CB1R activity in the stratum spinosum and stratum granulosum and CB2R in the basal layer may increase DNA methylation in human keratinocytes through a p38 MAP kinase to inhibit keratinocyte proliferation.⁸ In contrast, endocannabinoids inhibit keratinocyte proliferation independently of the CB1R/CB2R potentially through peroxisome proliferator-activated receptor gamma (PPAR-γ) and/or G-protein coupled receptor GPR55 activity.¹²

Non-Melanoma Skin Cancer (NMSC)

Given their role in keratinocyte homeostasis, cannabinoids influence basal and squamous cell carcinoma development.¹ Following long-term exposure to ultraviolet B (UVB) light, tumorigenesis was significantly increased in CB1R/CB2R+/+ mice in comparison to CB1R/CB2R–/– mice, suggesting a receptor-dependent role of UV-induced skin carcinogenesis.¹³ In contrast, Gegotek et al.¹⁴ defended the anti-neoplastic properties of cannabinoids. The authors found a significant reduction in endocannabinoid receptors, anandamide (AEA), and 2-arachidonoylglycerol (2-AG) in keratinocytes and fibroblasts following UVA and UVB radiation. They determined that AEA exhibits nuclear factor kappa B (NFkB) inhibitory activity independently of CB1/CB2R, supporting pro-apoptotic properties of cannabinoids.¹⁴

Other reports, in comparison, have supported a CB1/CB2- dependent pathway as anti-neoplastic.^15,16 WIN-55,212-2 (a mixed CB1/CB2 agonist) and JWH-133 (a CB2 agonist) decreased the viability of the skin tumor cells in mice with PDV.C57 epidermal tumor cells. The antitumoral activity resulted from an induction of apoptosis and impaired tumor vascularization with decreased expression of vascular endothelial growth factor (VEGF), placental growth factor, and angiopoietin 2.¹⁵

The paradoxical findings (i.e., cannabinoids exhibit both pro- and anti-neoplastic properties) may be explained by concentration-dependent effects.¹ Nanomolar levels of endogenous cannabinoids associated with UVB and chemical carcinogens may stimulate NMSC tumorigenesis, while micromolar levels of exogenous cannabinoids may decrease NMSC growth. Data supports a similar concentration-dependent effect of cannabinoids on melanoma development.¹

Melanoma Skin Cancer

Human melanomas express CB1R/CB2R and activation of these receptors is associated with decreased growth and increased apoptosis in mice.¹⁰ In vitro and in vivo, tetrahydrocannabinol (THC) induced autophagy, loss of cell viability, and apoptosis in melanoma A375, SK-MEL-28, and CHL-1 cell lines. Compared to temozolomide, THC and cannabidiol inhibited melanoma viability, proliferation, and tumor growth in mice with BRAF wild-type melanoma xenografts.¹⁶

Nonetheless, CB1R activation may promote tumor growth in melanoma. Compared to control, melanoma cells without CB1R showed reduced p-Akt and p-ERK expression, reduced colonyforming ability and cell migration, and increased cell cycle arrest at G1/S.¹⁷ The influence of cannabinoids in the development of skin cancers is evidently complex. While most reports validate the anti-neoplastic properties of cannabinoids, the evidence remains equivocal.^1,10,14-16 Given the immunomodulation properties of cannabinoids, further investigation of its effects on immunosurveillance is imperative to appreciating the principal therapeutic effects.⁴

Acne Vulgaris

Similarly, the regulatory function of cannabinoids on sebocytes has been implicated in acne vulgaris treatment.^11,18,19 Sebocytes positively regulate sebaceous gland lipid homeostasis and negatively regulate sebocyte survival via CB2R.²⁰ Specifically, cannabidiol inhibited the lipogenic actions of arachidonic acid, linoleic acid, and testosterone, and thus decreased sebocyte proliferation and lipogenesis.11 The principal investigator reinforced the sebostatic properties of cannabichromene and THC but noted pro-sebaceous activity of cannabigerol and cannabigerovarin.¹⁸ In a single-blinded, split-face study, 3% cannabis seed extract cream decreased skin sebum and erythema content, demonstrating a potential treatment for acne vulgaris and seborrhea.¹⁹

Cannabinoids in Pruritus

Activation of CB1R/CB2R in cutaneous nerve fiber bundles may decrease excitation of these nerve fibers and thus attenuate axon reflex flare responsible for the sensation of pruritus.^21,22 Utilizing an acute allergic murine model, Schlosburg et al.²³ established that systemic THC reduced scratching response induced by compound 48/80. Additional mice were treated with an inhibitor of fatty acid amide hydrolase (FAAH), the principal enzyme responsible for degradation of anandamide, which displayed equivalent scratch-reduction to loratadine and dexamethasone administration. The authors concluded that neuronal FAAH suppression reduces pruritus via CB1R activation, establishing the therapeutic role of cannabinoids in pruritus.²³

WIN-55,212-2 has also exhibited anti-pruritic activity in murine models.²⁴ Following intradermal serotonin injection, WIN- 55,212-2 displayed a significant and dose-dependent reduction in pruritus. Notably, reduced levels of monoamines in spinal tissue, secondary to artificial neurotoxic destruction, showed no impact on the anti-pruritic activity of WIN-55,212-2. These findings suggest that cannabinoid’s anti-pruritic properties act distinctly and independently from descending serotonergic and noradrenergic pathways.²⁴

In human skin, peripheral administration of HU210, a cannabinoid receptor agonist, reduced histamine-induced itch in 18 participants.²¹ HU210 reduced vasodilation and neurogenic flare reaction with decline in neuropeptide (namely CGRP) release. However, co-administration of HU210 and histamine amplified protein extravasation significantly higher than histamine alone.²¹ Although cannabinoids exhibit predominant anti-pruritic properties, this additional finding indicates a more complex relationship between cannabinoid receptors and histamine.

The endocannabinoid palmitoylethanolamide (PEA) also exhibits anti-pruritic properties when applied topically. In an open-label application of a PEA-containing emollient (PEACE), 14 of 22 patients with prurigo nodularis, lichen simplex, and pruritus had an average itch reduction of 86.4%.²⁵ Similarly, in an observational, prospective cohort study of 2456 patients with atopic dermatitis, the average itch on standard visual analogue scale (VAS) was reduced from 4.89 to 1.97 after 39 days of treatment with PEACE (P < 0.001). While the tolerance was assessed by physicians as very good or good in 66.3% and 25.7% of participants, 3.4% displayed poor tolerance with significant pruritus, burning, erythema, and/or miscellaneous events.²⁶

Hemodialysis patients, likewise, demonstrated improved uremic pruritus following use of topical AEA and PEACE. After twicedaily application, 8 of 21 (38.1%) participants had resolved uremic pruritus as validated by both VAS and questionnaire method.²⁷ Overall, these findings indicate a therapeutic role for cannabinoids in the management of itch but double-blinded, placebo-controlled studies are necessary to further determine their efficacy.⁸

Cannabinoids in Inflammation and Fibrosis

While pro-inflammatory properties have been identified, cannabinoids exert a largely anti-inflammatory effect by cannabinoid receptor-dependent and -independent mechanisms.^5,6 In mice modules, WIN-55,212,2 decreased tumor necrosis factor (TNF), interleukin (IL)-12, IL-1β and CXCL8 (IL-8), while THC decreased TNF and IL-6 when coadministered with lipopolysaccharides, but increased these cytokines when co-administered with Legionella pneumophila. Furthermore, cannabinoids suppress T helper type 1 (TH1)-cell immunity and promote TH2-cell immunity through cannabinoid type 2 receptor (CB2R) on B, T, and antigen-presenting cells.⁶ These potential anti-inflammatory properties have been indicated in the treatment of atopic dermatitis (AD), allergic contact dermatitis (ACD), and systemic sclerosis.

Atopic Dermatitis

Related to their anti-inflammatory and anti-pruritic effects, cannabinoids may function to treat AD.⁹ CB1R– mice displayed an increased response to fluorescein isothiocyanate-induced atopic-like dermatitis and decreased epidermal barrier repair. Specifically, IL-4, thymic stromal lymphopoietin (TSLP), and CCL8 cytokine were elevated in these mice, suggesting that CB1R maintains epidermal barrier homeostasis and attenuates type 2 CD4+ T helper cell response.²⁸

Clinically, PEACE has demonstrated efficacy in the treatment of AD.^26,29,30 In the aforementioned cohort study discussed in the section on pruritus, PEACE not only reduced pruritus but improved dryness, excoriation, lichenification, scaling, and erythema in 70% of patients with AD, as determined by physician assessment. Globally, AD symptoms improved substantially in 56.3% of participants and reduced weekly topical steroid use by 62%.²⁶

In an investigator-blinded, split-body trial of 25 children and 18 adults with AD, Del Rosso²⁹ similarly demonstrated the therapeutic value of PEACE. The combination of PEACE and topical corticosteroid resulted in faster AD clearance when compared to moisturizer and topical corticosteroid. Additionally, PEACE prolonged the mean time to flare by 28 days compared to moisturizer.²⁹ A similar split-body trial of 74 participants found that PEACE versus emollient alone prolonged time to AD flare by a median of 43 days and 29 days respectively. Mild stinging and burning was reported by 9 (12.2%) participants.³⁰

In addition to topical application, dietary hempseed oil may improve AD. In a randomized, crossover study, daily consumption of 30 ml hempseed oil decreased skin dryness, itchiness, and use of dermal medications compared to consumption of olive oil. Symptomatic improvement may have resulted from the high concentration of polyunsaturated fatty acids in hempseed oil.³¹

As evidenced by several clinical studies, PEACE is efficacious in the treatment and further management of AD.^26,29,30 Its therapeutic role has been suggested not to replace topical corticosteroids but rather to complement and reduce their use.^26,29 Further research is necessary to understand the potentially synergistic mechanism of combination PEACE and topical steroids.

Allergic Contact Dermatitis

The anti-inflammatory properties of cannabinoids may also serve to treat ACD.⁹ Specifically, CB1R/CB2R–/– mice had increased cutaneous contact hypersensitivity induced by 2,4-dintirofluorobenzene (DNFB). Additionally, THC decreased ear swelling and reduced Gr-1+ granulocytes following DNFB administration. Mice deficient in FAAH, furthermore, displayed decreased allergic response. These findings support that CB1R/ CB2R activation reduces inflammation in ACD. A notable exception, acute administration of a CB2R antagonist initially diminished inflammatory response, suggesting that CB2R antagonism may initially reduce acute inflammation but later propagate it.³²

Further studies have similarly suggested a pro-inflammatory role of CB2R activation.^33,34 Following DNFB-induced ACD, mice deficient in CRB2 exhibited decreased ear swelling after 24 hours. Additionally, 2-AG activation of CB2R was associated with increase in ear weight in murine models and elevation of IL-8 and MCP-1 gene expression in human leukemia cell line HL-6.³³ Ueda et al.³⁴ further supported the pro-inflammatory activity of CB2R in mice.

Systemic Sclerosis

The therapeutic role of ECS has also been proposed for the management of systemic sclerosis.^35,36 Ajulemic acid (AjA), a synthetic analogue of THC, significantly prevented bleomycininduced dermal fibrosis and modestly reduced its progression in three independent murine models. Moreover, co-treatment of AjA and a selective PPAR-γ antagonist entirely reversed the antifibrotic effects, illustrating that AjA activates PPAR-γ to reduce and further prevent fibrosis. Given its tolerated therapeutic dose, AjA offers a potential treatment for systemic sclerosis.³⁷

In a randomized, placebo-controlled, double-blinded phase 2 clinical trial (NCT02465437) of 42 participants with diffuse cutaneous systemic sclerosis, lenabasum (AjA, JBT-101) significantly improved Combined Response Index Systemic Sclerosis (CRISS) scores by 33% in addition to the Modified Rodnan Skin Score, Systemic Sclerosis Skin Symptoms Questionnaire, and Health Assessment Questionnaire Disability Index.^38,39 While one participant withdrew from the study due to dizziness, lenabasum established an acceptable safety profile without severe adverse events secondary to the study drug.³⁹

Conclusion

These reports demonstrate the evident but complex role of cannabinoids and the endocannabinoid system in skin homeostasis and pathology. Clinical trials have supported the therapeutic role of cannabinoids in the management of acne vulgaris, pruritus, atopic dermatitis, and systemic sclerosis, as highlighted in Table 2.^{19,25,26,27,29,30,31,38,39} In vitro and in vivo studies have further indicated the potential therapeutic use of cannabinoids in skin cancer and allergic contact dermatitis.^10,14,32 While the majority of evidence emphasizes the anti-inflammatory, anti-neoplastic activity of ECS, pro-inflammatory and proneoplastic properties have been documented.^{13,17,21,32,33,34,36} Further investigation is imperative to understand the influence of the cannabinoid type, delivery method, and concentration on pro- and anti-inflammatory mediators in skin homeostasis to ultimately define the therapeutic role of cannabinoids in clinical dermatology.

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¹Department of Neuroscience and Medical Scientist Training Program, Baylor College of Medicine, Houston, TX, USA
²Department of Dermatology, Baylor College of Medicine, Houston, TX, USA

Conflict of interest:
The authors have no conflicts to disclose.

Abstract
Chronic pruritus remains a difficult condition to treat with many non-specific therapeutic options. Recent scientific discoveries have elucidated the physiology associated with pruritus. Combined with clinical and experimental trials with immune-modulatory agents, chronic pruritus now has novel treatment options with known mechanisms of action. This review goes over recent scientific progress in understanding the molecular mechanisms governing pruritus, the cross-talk between the immune and nervous systems that regulate itch, and central nervous pathways and projections affected by itch. In light of these recent discoveries, we briefly discuss a growing body of data from relevant clinical trials investigating immunomodulatory drugs targeting specific interleukin receptors (IL-4/13/31) and intracellular signaling (e.g., Janus kinase) pathways. We focus on the physiological processes that control this complex physical and emotional experience, as well as the role of newer drugs used to treat chronic itch.

Key Words:
chronic pruritus, neuro-immune interaction, dorsal root ganglion, IL-4, IL-13, IL-31, IL-4Ra, dupilumab, ruxolitinib, tofacitinib, nemolizumab, Janus kinase

Introduction

Chronic pruritus (CP) is a debilitating condition defined as itch lasting longer than 6 weeks.¹ Causes of CP include both dermatologic and non-dermatologic diseases leading to involvement of the entire body (generalized) or specific areas (localized).¹ Treatment methods are often trial-error based in order to determine an optimal regimen to reduce symptoms. Generally, CP can be divided into broad categories of origin: dermatologic (e.g., atopic dermatitis and psoriasis), systemic (e.g., chronic kidney disease and cholestasis), neuropathic (e.g., post-herpetic itch), or psychogenic (e.g., obsessive-compulsive disorder and drug use).² Importantly, non-dermatologic causes can also present with skin findings due to the itch-scratch cycles and, therefore, can be masked by dermatitis. While CP is often a feature of inflammatory skin diseases, it can also stem from idiopathic causes, which are not marked by inflammatory processes.³ Thus, the mechanisms of CP are multifaceted and numerous activating mediators of itch are known, including histamine and substance P.⁴ Ultimately, the physiology of itch sensation results in the activation of peripheral sensory neurons.

Neuronal Physiology of Itch

The sensation of itch is initially transmitted through unmyelinated C-nerve fibers in the dermis and epidermis.⁵ These nerve fibers can be activated by numerous molecules including those involved in acute itch sensation, such as substance P, proteinases, and histamine. Although antihistamines are effective in reducing itch from mast cell degranulation, they have little to no effect in CP.⁶ Additionally, not all C-nerve fibers that transmit itch are histamine responsive.⁷ Specifically, the only group of neurons that have thus far been identified as required for itch transmission are those expressing gastrin-releasing peptide receptor (GRPR).⁸

Recent work identified the central nervous system circuits that GRPR neurons utilize to transmit itch sensation to the brain in a mouse model.⁹ By utilizing retrograde neuronal labeling in combination with immediate early gene expression (c-fos) after inducing itch, Mu et al. identified the spinoparabrachial pathway to be activated by pruritus.⁹ Additionally, they identified direct monosynaptic connections between GRPR sensory neurons and projection neurons from the spinal cord to the parabrachial nucleus (PBN).⁹ Further, inhibition of these projections resulted in diminished scratching when mice were treated with histamine.⁹ Remaining work by Mu et al. focused on the PBN, a region of the brain stem implicated in arousal, thermoregulation, taste, and now itch.^10-12

The researchers identified that neurons in the PBN are activated by itch, and that modulation of these neurons could alter itch-induced scratching when administering pruritogens like histamine or chloroquine to mice.⁹ They also discovered that glutamatergic signaling in the PBN was required for itchinduced scratching.⁹ Genetic deletion of the vesicular glutamate transporter resulting in an inability to release glutamate by PBN neurons resulted in the loss of itch-induced scratching for six different pruritogens including the 1-fluoro-2,4-dinitrobenzene (DNFB) induced chronic itch model.⁹ Overall, this work identified the PBN as a key relay station for the central nervous system processing of itch and, moreover, elucidated a necessary role for local glutamatergic signaling for itch-induced scratching for both acute and chronic pruritus models. Understanding the neuronal circuit of itch aids in clarifying the physiology of non-dermatologic causes of itch and begins to uncover novel target cell-types for treatments. Future experiments should focus on the genetic expression pattern of these neurons to identify drug targets to modulate the neuronal activity of these itch-sensing neurons. Although brain region specific alteration of neurotransmission is not currently a viable option for the treatment of pruritus, novel therapies targeting the neuroimmune interaction have begun to be utilized in the treatment of CP.^13-17

One of the most common causes of CP is atopic dermatitis (AD) and the role of the immune system, particularly driven by type 2 T helper (Th2) cellular responses and cytokines. Specifically, interleukin (IL)-31 has been identified as a potent pruritogen, and IL-4 and IL-13 drive skin inflammation leading to AD like features and itch.^18,19 Work in the past year from Oetjen and colleagues has furthered our understanding of how these interleukins act specifically on neurons and co-opt downstream signaling mechanisms to mediate itch.³

Oetjen et al. identified expression of interleukin receptors (IL-4Ra, IL13Ra1, and IL31Ra) on both human and mouse dorsal root ganglion (DRG) neurons.³ It is important to note that both IL-4 and IL-13 bind to the IL-4Ra receptor. Utilizing intracellular calcium indicator dyes, their work demonstrated that both human and mice DRG neurons were directly activated by IL-4 and IL-13.³ Overall, DRG responsive neurons represented a small subset of histamine positive neurons and were mainly small diameter <18 um neurons.³ Interestingly, while DRG neurons were responsive to these interleukins, IL-4 and IL-13 were not acute pruritogens and did not potently induce itch-like behavior in rodents compared to IL-31.³ However, when paired with administration of acute pruritogens like histamine, IL-4 caused increased itching bouts compared with histamine alone.³ This evidence suggests that IL-4 and IL-13 could act to sensitize neurons and lower the threshold for itch.³

To test the necessity of IL-4 and IL-13 in the development of CP, the researchers genetically deleted the IL-4Ra receptor from DRG neurons. They subsequently discovered that in a calcipotriol mouse model of AD, both scratching behavior and histological changes due to dermatitis were ameliorated.³ They also identified Janus kinase (JAK) signaling as the downstream mediator of IL-4Ra signaling in DRG neurons similar to immune cells expressing the receptor. Loss of neuronal JAK signaling produced similar results as the loss of IL-4Ra receptor in mice.³ Most remarkably, however, was the discovery that in parallel to the genetic loss of JAK signaling, exogenous delivery of ruxolitinib, a JAK inhibitor, produced similar results, and was beneficial in reducing scratching in a non-inflammatory itch rodent model.³ Overall, their findings identified a novel neuro-immune system cross-talk, whereby interleukin activation of sensory neurons mediated itch through the JAK intracellular signaling cascade.

Immune-Modulatory Agents in Chronic Pruritus Associated Disorders

Using their basic science findings as rationale, Oetjen et al. set-up an experimental trial to explore if JAK signaling might be a novel therapeutic target in chronic idiopathic pruritus (CIP) patients with no overt signs of inflammation. In this short investigation, the researchers treated five CIP patients with oral tofacitinib, a JAK inhibitor, and found a significant reduction in their itching as quantified by a 0-10 numerical rating scale.³ This finding is summarized in Table 1.

Other recent clinical trials have also focused on specific immune modulators to treat moderate-to-severe AD in patients who have failed conventional topical treatments to alleviate their itch symptoms. These have included blockade of IL-4Ra receptor, JAK, or IL-31Ra receptor signaling.^13-17,20 Select clinical and experimental trials utilizing these drugs are presented in Table 1. Overall, there appears to be positive treatment responses to these treatments with minimal side effects. Dupilumab, an IL-4Ra receptor antagonist, has been the most studied, with large-scale clinical trials showing dose dependent improvements in symptoms. Based on the phase 2 trials, weekly subcutaneous 300 mg with topical glucocorticoids appears to elicit the best response, however, the measured outcomes used between trials are different and subject numbers vary greatly. Dupilumab was recently approved by the US Food and Drug Administration on March 28, 2017 for moderate-to-severe eczema (AD) at an initial dose of 600 mg (two 300 mg injections) followed by 300 mg injections every other week.²¹ Tofacitinib has also been assessed in clinical and experimental trials in both ointment and oral forms, and demonstrated signs of improvement in both AD and CIP. Although the oral tofacitinib trials are very small and neither placebo controlled nor blinded, they did show improvement of symptoms in both AD and CIP patients as measured by body surface involvement and itch cessation, respectively. Lastly, a recent trial published on nemolizumab, an IL-31Ra antagonist, reported a dose-dependent response in pruritus reduction.

Review of Key Messages

• Neuro-immune system interactions play a key role in CP.
• IL-4/IL-13 signaling through the IL-4Ra receptor on peripheral sensory neurons and downstream Janus kinase-signal transducer of activation (JAK-STAT) pathway signaling lowers the threshold for itch.
• Treatments targeting IL-31R, IL-4Ra, and intracellular JAK signaling for CP may in part induce clinical relief of itch through their action on peripheral sensory neurons.

Conclusion

Overall, with the recent scientific discoveries describing a novel neuro-immune interaction associated with chronic pruritus, we can hypothesize that the availability of new immune-modulatory treatments for regulating peripheral sensory neurons to alter itch sensation appears promising. Given the different roles of IL-4/ IL-13 to sensitize neurons to pruritogens, IL-31 acting as an acute pruritogen, and JAK as an intracellular signaling mechanism in neurons to transmit itch independent of inflammation, the next series of obvious clinical questions include the use of combination treatments to address these different aspects of itch sensation (Figure 1 and Table 1). Since most of the JAK studies have been off-label, stronger clinical trials that test the efficacy of these inhibitors with regard to chronic pruritus are warranted. With advances in understanding the pathogenesis of pruritus, including a central nervous system pathway for itch sensation, combined with concordant trials on drugs targeting receptors and their signaling pathways, we are poised to gain an even greater understanding of the underlying biologic mechanisms that may guide the development of new and more effective treatments for chronic pruritus.

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Key Words:
aging skin, comorbidity, itch, pruritus, xerosis

Pruritus is the most common skin complaint in patients over the age of 65 years.1,2 This often neglected symptom can have a profound impact on the quality of life in the elderly, especially through sleep deprivation. Given the multitude of variables that come with advanced age, the management of pruritus in the elderly poses a particular clinical challenge.

Pathophysiology

Pruritus in advanced age may result from a variety of etiologies. Xerosis (dry skin), which increases with age, is probably the most common cause of pruritus in the elderly.^3,4 As skin ages, the integumentary and vascular systems undergo atrophy, leading to suboptimal moisture retention. However, many elderly patients have pruritic skin without xerosis. Other skin changes in advanced aged patients that may contribute to itch include decreased skin surface lipids and clearance of transepidermally absorbed materials from the dermis, reduced sweat and sebum production, as well as diminished barrier repair.⁴

A decline of normal immune function that occurs with aging also produces a higher incidence of autoimmune skin disorders that can induce pruritus, such as bullous pemphigoid and postherpetic neuralgia. Additional factors may also play a role, such as age-related changes in nerve fibers and polypharmacy. Certain cutaneous and systemic disorders that are associated with pruritus are also more prevalent in advanced aged patients (as discussed below). However, in many instances, no apparent cause is found.

Clinical Features

A detailed history, review of systems, and physical examination are of prime importance in guiding antipruritic treatment of senescent skin. Once cutaneous and systemic causes of itch are excluded, idiopathic itch of the elderly may be considered. However, if an underlying cause is discovered, it should be addressed, as this frequently leads to symptomatic improvement. Certain pruritic cutaneous diseases are more prevalent in the elderly population, such as xerosis, nummular dermatitis, and seborrheic dermatitis. The later is especially common in patients with dementia and Parkinson’s disease. Systemic diseases that are associated with pruritus, such as chronic kidney disease, hepatic dysfunction, and endocrine disorders, are also more prevalent in the elderly. Notably, infectious etiologies of pruritus, including scabies and lice, may be more common in this age group especially within institutionalized care settings. In addition, medications frequently used in the elderly increase the possibility of drug-induced pruritus (e.g., aspirin, opioids, and angiotensin converting enzyme inhibitors). Another serious consideration in this cohort is that chronic pruritus may be a presenting sign of underlying malignancy (e.g., low grade lymphoma, multiple myeloma, and myleodysplastic syndromes), and thus, any case with a high index of suspicion necessitates a thorough work-up.⁵ Psychogenic and neuropathic disorders are also common causes in this age group.⁶

General Principles

The management of pruritus in the elderly poses a particular challenge. Physical and cognitive impairments may make application of topical treatments impossible and compliance an issue. Comorbid conditions, especially those involving the liver and kidney, as well as the frequent polypharmacy in this age group, confers a greater risk of adverse drug reactions. At present, there is no universally accepted therapy for itch. Instead, management of pruritus, especially in the elderly, requires an individualistically tailored approach with consideration of the patient’s general health, the severity of symptoms, and the adverse effects of available treatments. Some of the treatments discussed are unlicensed for use in pruritus and should be administered under a specialist setting.

There are a number of general measures that may be useful in the management of pruritus in the elderly, irrespective of the underlying cause (Table 1). Patient education is central to the management of pruritus.⁷ Identifying and removing aggravating factors are often the initial steps in effective treatment. Breaking the “itch-scratch” cycle is critical and patients should be informed of the increased cutaneous inflammation that scratching causes. Simple measures, such as keeping finger nails short, may help to interrupt this vicious cycle. The sensation of pruritus is often heightened by warmth, thus, where appropriate, measures such as tepid showering, wearing light clothing, and the use of air conditioning should be undertaken to keep the skin cool. Wherever possible, simple topical regimens are preferable in order to maximize compliance and limit potential adverse drug reactions.

Topical Treatments

Moisturizers, Emollients and Barrier Creams

Moisturizers, emollients, and barrier repair creams are the mainstay of pruritus treatment in the elderly, especially in cases associated with xerosis. These nonpharmacologic compounds reduce pruritus through improving barrier function by helping to prevent transepidermal water loss and possibly preventing the entry of irritants and other itch-causing agents. Topical therapies with a low pH may be especially useful in optimizing the skin barrier function through their maintenance of the normal acidic pH of the skin surface. In addition, low pH topical therapies may be of further benefit through their reduction in the activity of serine proteases, such as mast cell tryptase, which is known to activate protease-activating receptor 2 (PAR2) on skin nerve fibers. This notion stems from recent studies suggesting serine proteases, via PAR2 located on C fiber terminals, may play an important role in mediating pruritus.^8,9

Topical Corticosteroids

Topical corticosteroids do not directly exert antipruritic effects, instead their therapeutic benefits are derived from their anti-inflammatory properties. Therefore, they should only be used to provide relief of itching that is associated with inflammatory skin diseases, such as nummular dermatitis or psoriasis. Topical corticosteroids should not be used to treat generalized chronic itch or for prolonged periods. Of note, the elderly are particularly vulnerable to the adverse effects (especially skin thinning) from the excessive use of topical corticosteroids.¹⁰

Topical Immunomodulators

The topical calcineurin inhibitors, tacrolimus and pimecrolimus, have been shown to be effective in reducing pruritus in conditions such as chronic irritant hand dermatitis, seborrheic dermatitis, graft-versus-host disease, lichen sclerosis, anogenital pruritus, and prurigo nodularis.¹¹ The antipruritic effects of topical calcineurin inhibitors may be mediated via TRPV1, a member of the transient receptor potential (TRP) family of excitatory ion channels, located on nerve fibers. Although the recognized side-effects of these agents include transient burning and stinging sensations, they are particularly useful in the elderly as there is no associated risk of skin atrophy.

Menthol

Menthol, a naturally occurring cyclic terpene alcohol of plant origin, is frequently used as a topical antipruritic at concentrations of 1-3%. It has been shown that menthol elicits the same cooling sensation as low temperature through the TRPM8 receptor.¹² Both cooling the skin and menthol use result in the relief of experimentally induced itch, although the latter is not associated with a decrease in skin temperature. Of note, elderly patients who report a reduction in pruritus with cooling may especially benefit from topical therapies containing menthol.¹²

Capsaicin

Capsaicin has been reported to have a beneficial effect in chronic, localized pruritic disorders, particularly those of neuropathic origin, which are common in the elderly (e.g., postherpetic neuralgia, notalgia paresthetica, and brachioradial pruritus).^13,14 The TRPV1 receptor has recently been implicated in the pathogenesis of pruritus and may be the target through which capsaicin exerts its antipruritic effect.¹⁵ A recognized side-effect is an initial intense transient burning sensation at the application site, which may lead to poor compliance, particularly in the elderly.

Local Anesthetics

Pramoxine, a local anesthetic, reduces itch by interfering with transmission of impulses along sensory nerve fibers and has been shown to reduce pruritus in adult hemodialysis patients in a double-blinded study.¹⁶ Polidocanol is a non-ionicsurfactant with both local anesthetic properties and moisturizing effects. A combination of 5% urea and 3% polidocanol was found to significantly reduce pruritus in patients with atopic dermatitis, contact dermatitis, and psoriasis.¹⁷

Topical Salicylic Acid

Topical salicylic acid, a cyclooxygenase inhibitor, has been shown to significantly reduce pruritus in patients with lichen simplex chronicus, possibly due to their inhibitory effects on prostanoids.^18,19 Of note, oral salicylates do not relieve pruritus except in polycythemia vera.

Topical Cannabinoids

N-palmitoylethanolamine, a cannabinoid receptor CB2 agonist, has been incorporated into creams and shown to reduce pruritus reported in patients with atopic dermatitis, lichen simplex, prurigo nodularis, and chronic kidney disease-associated itching.^20-22

Systemic Treatments

Antihistamines

With the exception of chronic urticaria, antihistamines have little effect on conditions associated with pruritus. Sedating (first generation) antihistamines may have a role via their soporific effects on nocturnal pruritus, but in the elderly caution must be taken to avoid causing excessive drowsiness.²³

Antidepressants

The serotonin-norepinephrine re-uptake inhibitor (SNRI), mirtazapine, has been reported to relieve itch in patients with advanced cancers (e.g., leukemia and lymphoma, including cutaneous lymphoma), chronic kidney disease, and cholestasis.^24-26 Mirtazapine may also be especially useful for the treatment of nocturnal pruritus.²⁵ Additionally, selective serotonin re-uptake inhibitors (SSRIs) may have antipruritic effects. The SSRIs, paroxetine and fluvoxamine, have been shown to reduce chronic pruritus, with the most favorable responses seen in patients with pruritus due to atopic dermatitis, systemic lymphoma, and solid carcinoma; whilst sertraline has been shown to be an effective treatment for pruritus associated with chronic liver disease.^27,28

Although the antiprurituc mechanism of antidepressants is unclear, medications interfering with neuronal re-uptake of neurotransmitters, such as serotonin and norepinephrine, may act through the cerebral cortex to reduce the perception of pruritus.²⁹ Antidepressants may be particularly useful in elderly patients with psychogenic causes of pruritus. Of note, it may be prudent to start with lower doses of antidepressants in the elderly and then taper up cautiously to avoid the significant side-effects associated with these medications.

Opioid Agonists and Antagonists

An imbalance of the endogenous opioidergic system may have a role to play in the pathophysiology of pruritus. Itch is induced by both μ-opioid receptor agonists and κ-opioid receptor antagonists, while μ-receptor antagonists and κ-receptor agonists can reduce it. Studies have shown the antipuritic effects of μ-opioid receptor antagonists, such as naltrexone (in patients with cholestasis, end-stage renal disease, burns, and atopic dermatitis) and nalmefene (in patients with cholestasis, atopic dermatitis, and urticaria).^30-34

The κ-opioid receptor agonists, butorphanol and nalfurafine, appear to have an antipruritic effect in patients with chronic intractable itch and chronic kidney disease, respectively.^35,36 Due to the potential adverse effects associated with opioid agonists and antagonist, treatment is advisable under specialist supervision and at lower initial doses, especially in the elderly.

Neuroleptics

The neuroleptics, gabapentin and pregablin, are structural analogs of the neurotransmitter γ-aminobutyric acid (GABA). The exact mechanisms of their antipruritic effects are not clear, but they may be related to inhibition of central itch pathways. Neuroleptics may be particularly useful in the elderly for neuropathic pruritus related to conditions such as brachioradial pruritus, postherpetic neuralgia, and notalgia paresthetica.^6,14 Gabapentin has been shown to reduce pruritus in patients with chronic kidney disease and lymphoma, but treatment can actually worsen the itching in patients with cholestasis.^26,37 Of note, it has been suggested that using a lower dose of gabapentin with slow upward titration may reduce the risk of gabapentin-induced neurotoxicity and/or
coma in patients with reduced renal function, a problem that may be more prevalent in the elderly.³⁸ Additionally, treatment with pregabalin should not be stopped abruptly due to the risk of withdrawal symptoms.³⁹

Physical Treatment

Phototherapy

Ultraviolet A (UVA), broadband ultraviolet B (BB-UVB), and narrowband UVB (NB-UVB)-based phototherapies have been used for over three decades to treat various pruritic dermatoses. This mode of treatment may be particularly suitable in the elderly as it avoids the risk of adverse drug reactions (although the risk of phototoxicity is increased) and overcomes challenges such as physical and cognitive limitations that can lead to noncompliance.

Conclusion

The multitude of variables that come with advanced age means that the management of pruritus in the elderly continues to pose a particular diagnostic and therapeutic challenge. Physical and cognitive limitations, multiple comorbid conditions, and polypharmacy are some aspects that can influence choice of treatment in this age group. Management of pruritus in the elderly must take an individualistically tailored approach with consideration of the patient’s general health, the severity of symptoms, and the adverse effects of treatment.

References

1. Beauregard S, Gilchrest BA. A survey of skin problems and skin care regimens in the elderly. Arch Dermatol 123(12):1638-43 (1987 Dec).
2. Norman RA. Xerosis and pruritus in the elderly: recognition and management. Dermatol Ther 16(3):254-9 (2003).
3. Fleischer AB, Jr. Pruritus in the elderly: management by senior dermatologists. J Am Acad Dermatol 28(4):603-9 (1993 Apr).
4. Ward JR, Bernhard JD. Willan’s itch and other causes of pruritus in the elderly. Int J Dermatol 44(4):267-73 (2005 Apr).
5. Wang H, Yosipovitch G. New insights into the pathophysiology and treatment of chronic itch in patients with end-stage renal disease, chronic liver disease, and lymphoma. Int J Dermatol 49(1):1-11 (2010 Jan).
6. Yosipovitch G, Samuel LS. Neuropathic and psychogenic itch. Dermatol Ther 21(1):32-41 (2008 Jan-Feb).
7. van Os-Medendorp H, Ros WJ, Eland-de Kok PC, et al. Effectiveness of the nursing programme ‘Coping with itch’: a randomized controlled study in adults with chronic pruritic skin disease. Br J Dermatol 156(6):1235-44 (2007 Jun).
8. Steinhoff M, Neisius U, Ikoma A, et al. Proteinase-activated receptor-2 mediates itch: a novel pathway for pruritus in human skin. J Neurosci 16;23(15):6176-80 (2003 Jul).
9. Yosipovitch G, Papoiu AD. What causes itch in atopic dermatitis? Curr Allergy Asthma Rep 8(4):306-11 (2008 Jul).
10. Dykes PJ, Marks R. An appraisal of the methods used in the assessment of atrophy from topical corticosteroids. Br J Dermatol 101(5):599-609 (1979 Nov).
11. Stander S, Schurmeyer-Horst F, Luger TA, et al. Treatment of pruritic diseases with topical calcineurin inhibitors. Ther Clin Risk Manag 2(2):213-8 (2006 Jun).
12. Patel T, Ishiuji Y, Yosipovitch G. Menthol: a refreshing look at this ancient compound. J Am Acad Dermatol 57(5):873-8 (2007 Nov).
13. Papoiu AD, Yosipovitch G. Topical capsaicin. The fire of a ‘hot’ medicine is reignited. Expert Opin Pharmacother 11(8):1359-71 (2010 Jun).
14. Wood GJ, Akiyama T, Carstens E, et al. An insatiable itch. J Pain 10(8):792-7 (2009 Aug).
15. Imamachi N, Park GH, Lee H, et al. TRPV1-expressing primary afferents generate behavioral responses to pruritogens via multiple mechanisms. Proc Natl Acad Sci U S A 106(27):11330-5 (2009 Jul 7).
16. Young TA, Patel TS, Camacho F, et al. A pramoxine-based anti-itch lotion is more effective than a control lotion for the treatment of uremic pruritus in adult hemodialysis patients. J Dermatolog Treat 20(2):76-81 (2009).
17. Freitag G, Hoppner T. Results of a postmarketing drug monitoring survey with a polidocanol-urea preparation for dry, itching skin. Curr Med Res Opin 13(9):529-37 (1997).
18. Yosipovitch G, Sugeng MW, Chan YH, et al. The effect of topically applied aspirin on localized circumscribed neurodermatitis. J Am Acad Dermatol 45(6):910-3 (2001 Dec).
19. Andoh T, Nishikawa Y, Yamaguchi-Miyamoto T, et al. Thromboxane A2 induces itch-associated responses through TP receptors in the skin in mice. J Invest Dermatol 127(8):2042-7 (2007 Aug).
20. Szepietowski JC, Szepietowski T, Reich A. Efficacy and tolerance of the cream containing structured physiological lipids with endocannabinoids in the treatment of uremic pruritus: a preliminary study. Acta Dermatovenerol Croat 13(2):97-103 (2005).
21. Eberlein B, Eicke C, Reinhardt HW, et al. Adjuvant treatment of atopic eczema: assessment of an emollient containing N-palmitoylethanolamine (ATOPA study). J Eur Acad Dermatol Venereol 22(1):73-82 (2008 Jan).
22. Stander S, Reinhardt HW, Luger TA. [Topical cannabinoid agonists. An effective new possibility for treating chronic pruritus]. Hautarzt 57(9):801-7 (2006 Sep).
23. Patel T, Ishiuji Y, Yosipovitch G. Nocturnal itch: why do we itch at night? Acta Derm Venereol 87(4):295-8 (2007).
24. Davis MP, Frandsen JL, Walsh D, et al. Mirtazapine for pruritus. J Pain Symptom Manage 25(3):288-91 (2003 Mar).
25. Hundley JL, Yosipovitch G. Mirtazapine for reducing nocturnal itch in patients with chronic pruritus: a pilot study. J Am Acad Dermatol 50(6):889-91 (2004 Jun).
26. Demierre MF, Taverna J. Mirtazapine and gabapentin for reducing pruritus in cutaneous T-cell lymphoma. J Am Acad Dermatol 55(3):543-4 (2006 Sep).
27. Stander S, Bockenholt B, Schurmeyer-Horst F, et al. 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 89(1):45-51 (2009).
28. Mayo MJ, Handem I, Saldana S, et al. Sertraline as a first-line treatment for cholestatic pruritus. Hepatology 45(3):666-74 (2007 Mar).
29. Stander S, Weisshaar E, Luger TA. Neurophysiological and neurochemical basis of modern pruritus treatment. Exp Dermatol 17(3):161-9 (208 Mar).
30. Bergasa NV, Alling DW, Talbot TL, et al. Oral nalmefene therapy reduces scratching activity due to the pruritus of cholestasis: a controlled study. J Am Acad Dermatol 41(3 Pt 1):431-4 (1999 Sep).
31. Monroe EW. Efficacy and safety of nalmefene in patients with severe pruritus caused by chronic urticaria and atopic dermatitis. J Am Acad Dermatol 21(1):135-6 (1989 Jul).
32. Patel T, Yosipovitch G. Therapy of pruritus. Expert Opin Pharmacother 11(10):1673-82 (2010 Jul).
33. Peer G, Kivity S, Agami O, et al. Randomised crossover trial of naltrexone in uraemic pruritus. Lancet 348(9041):1552-4 (1996 Dec 7).
34. Phan NQ, Bernhard JD, Luger TA, et al. Antipruritic treatment with systemic mu-opioid receptor antagonists: a review. J Am Acad Dermatol (2010 May 10). [Epub ahead of print].
35. Dawn AG, Yosipovitch G. Butorphanol for treatment of intractable pruritus. J Am Acad Dermatol 54(3):527-31 (2006 Mar).
36. Kumagai H, Ebata T, Takamori K, et al. Effect of a novel kappa-receptor agonist, nalfurafine hydrochloride, on severe itch in 337 haemodialysis patients: a phase III, randomized, double-blind, placebo-controlled study. Nephrol Dial Transplant 25(4):1251-7 (2010 Apr).
37. Bergasa NV, McGee M, Ginsburg IH, et al. Gabapentin in patients with the pruritus of cholestasis: a double-blind, randomized, placebo-controlled trial. Hepatology 44(5):1317-23 (2006 Nov).
38. Manenti L, Vaglio A. Gabapentin for uraemic pruritus. Nephrol Dial Transplant 20(6):1278-9 (2005 Jun).
39. Ehrchen J, Stander S. Pregabalin in the treatment of chronic pruritus. J Am Acad Dermatol 58(2 Suppl):S36-7 (2008 Feb).

ABSTRACT

Chronic kidney disease (CKD)-associated pruritus is a significant clinical symptom affecting more than 50% of patients on hemodialysis. Restricted by the availability of effective therapeutic options, the management of CKD-associated pruritus remains a treatment challenge. Evaluating research in this area is difficult, as most studies are not comparable due to differing methodologies and study designs, limited number of patients, and the lack of standardized measures. The most frequently used therapy is UVB phototherapy, eliciting favorable responses in most patients. Newer approaches, such as treatment with the µ-opiod-receptor antagonist, naltrexone, have yielded conflicting results. The use of the k-opioid-receptor-agonist, nalfurafine, appears to be partially effective in relieving CKD-associated pruritus, as shown by a meta-analysis of 2 clinical trials. Promising results have been obtained by treatment with the anticonvulsant gabapentin. CKD-associated pruritus is thought to be mediated by a proinflammatory state, which explains why immunomodulating drugs (e.g., thalidomide, tacrolimus, and pentoxiphylline) are effective in some patients. Treatment of CKD-associated pruritus should be undertaken according to individual benefit-risk ratio assessments.

Key Words:
chronic kidney disease, CKD, dialysis, itch, pruritus

Chronic kidney disease (CKD)-associated pruritus (also known as uremic pruritus) is a common, sometimes extremely distressing, and intractable symptom experienced by patients with advanced or end-stage renal disease.¹ CKD-associated pruritus affects approximately 50% of patients on regular hemodialysis;² although there is a paucity of concurring data, the rate of occurrence appears to be similar in those receiving peritoneal dialysis.³ The prevalence of CKD-associated pruritus may be underestimated by the nephrologists in charge because of the large variation in different populations and the inherent undulating pattern of pruritus in dialysis.⁴ Many attempts have been made to relieve this bothersome symptom in affected patients with limited success.

Pathogenesis

Although the pathophysiology is multifactorial and not well understood, there is increasing evidence that immune system dysfunction and an elevated proinflammatory pattern are involved in CKD-associated pruritus.⁵ A combination of factors appear to play an important role in its etiology.⁶

Therapeutic Options

Treatment options are limited in the management of CKD-associated pruritus. Therapeutic decision-making is further confounded when favorable findings from many reports (mostly uncontrolled trials or case series) are not validated by later studies. Herein, we present a focused review on the following therapies that have been tried with varying degrees of success:

• Topical treatments
• Systemic treatment with µ-receptor antagonists and k-agonists
• Gabapentin and anti-inflammatory agents
• Ultraviolet (UV) phototherapy

A stepwise approach (Figure 1) may be employed in therapeutic decision-making. With respect to risk-benefit assessments, the selection of treatment modality should be guided foremost by the agent exhibiting a better side-effect profile. If feasible in desperate cases, high-urgency renal transplantation may be considered for suitable patients, which almost always reliably resolves the pruritus.⁷

Topical Treatments

Tacrolimus Ointment

Topical treatment with tacrolimus can lead to complete or partial resolution of eczema and pruritus in atopic dermatitis.⁸ In a preliminary study we reported on 3 patients on peritoneal dialysis with severe CKD-associated pruritus, 1 of them showing severe scratch lesions. Patients applied tacrolimus 0.03% ointment twice daily to the most affected areas for a period of 7 days and were asked to score the intensity of itch by a visual analogue scale (VAS) 1 week prior, during the application, and 1 week thereafter. Treatment with tacrolimus ointment led to an almost complete resolution of pruritus in 2 of the patients, while a third subject experienced a reduction of VAS score from 7 to 3 in relation to the intensity of itch.⁹ In a proof of concept study, Kuypers et al. reported treating 25 patients with tacrolimus ointment for a period of 6 weeks with great success.¹⁰ Using the VAS scale, pruritus was reduced by 42.9% at the end of the treatment phase. However, a randomized, double-blind, vehicle-controlled study in 22 patients did not show the efficacy of tacrolimus ointment over vehicle in relieving CKD-associated pruritus.¹¹ Although, the effect of both the vehicle and the tacrolimus- containing ointment were significant (reducing pruritus to 80% of the initial values), the unexpected result could not be explained by the authors. No serious side-effects were observed. We believe that tacrolimus ointment is a safe and effective short-term treatment option for patients suffering from severe CKD-associated pruritus.

Gamma Linolenic Acid Ointment

In a recent study by Chen et al., a cream containing high concentrations of gamma linolenic acid (GLA), an essential fatty acid derived from certain plant seed oils, was tested on 17 patients with CKD-associated pruritus.¹² In this randomized, double-blind, placebo-controlled, crossover study patients were treated for 6 weeks, with a washout period of 2 weeks in between the 2 treatment phases. Paired analysis, using a VAS score ranging from 0 to 100, showed the intensity of pruritus was reduced from 75 to 30 following GLA treatment (p < 0.0001); whereas the median pruritus scores dropped from 72.5 to 67.5 after placebo treatment, which was a non-significant reduction. This investigation suggests that GLA can exert an improved antipruritic effect over vehicle and may serve as a useful adjunct in providing symptomatic relief.

µ-Opioid Receptor Antagonist

Naltrxone

A placebo-controlled, double-blind, crossover trial by Peer et al. showed that administration of oral naltrexone for 1 week led to an almost complete resolution of pruritus (as measured by VAS) in 15 patients with severe CKD-associated pruritus.¹³

Subsequently, we performed a placebo-controlled, double- blind, crossover study in 23 patients on either hemodialysis or peritoneal dialysis with persistent pruritus, who were previously unsuccessfully treated with other antipruritic therapies. Patients started with either a 4-week naltrexone regimen of 50mg per day or matched placebo. Sixteen of 23 patients completed the study. During the naltrexone phase, pruritus decreased by 29.2% according to VAS scoring and by 17.6% on a detailed questionnaire score. In comparison, during the placebo period, pruritus decreased by 16.9% according to VAS and by 22.3% as determined by the questionnaire score. The difference between naltrexone and the placebo treatments was not statistically significant.¹⁴

The findings of Peer et al.13 contrast the results of our study and cannot be explained by differences in patient compliance, naltrexone dose, or study design, as both studies were randomized, placebo-controlled, double-blind, crossover trials. However, the pathogenesis of uremic pruritus may be influenced by differences in the management of dialysis patients and regional disparities in lifestyle and dietary customs that are unique to certain parts of the world. Consequently, it may be possible that involvement of such additional pathogenetic factors have led to differences in both incidence of severe pruritus and naltrexone response.

k-Opioid Receptor Agonists

As k-opioid receptors primarily mediate antagonistic effects on µ-opioid-receptors and k-agonistic drugs seem to suppress morphine-induced itch, it is likely that activating these k-receptors may lead to alleviation of pruritus.¹⁵

Nalfurafine

A meta-analysis of 2 randomized, double-blind, placebo- controlled studies involving 144 patients showed that treatment with nalfurafine (a potent k-receptor agonist) can reduce itch in hemodialysis patients. Although statistical significance was shown, clinical efficacy was only modest in the treatment of uremic pruritus.¹⁶

Butorphanol

Butorphanol exhibits both k-agonistic and µ-antagonistic properties. It remains to be elucidated if this drug is effective in CKD-associated pruritus. Dwan et al. explored the use of intranasal butorphanol in 5 patients with intractable itch associated with various systemic or inflammatory skin diseases. Investigators reported rapid and marked improvements in itch.¹⁷ Study limitations included a small sample size and open-label design; consequently, further larger-scale, randomized, controlled trials are needed.

Other Systemic Treatments

Pentoxyfilline

In conceptualizing uremia as an inflammatory state and that CKD-associated pruritus results from this condition,⁴ we investigated the use of pentoxyfilline in 7 hemodialysis patients with CKD-associated pruritus who were recalcitrant to treatment with gabapentin or UVB-irradiation. Pentoxyfilline, a weak TNF-a inhibitor, was administered at 600mg 3 times a week (at the end of each dialysis session) for 4 weeks. In those patients who tolerated the drug, almost complete resolution of pruritus was experienced for at least 4 weeks, even after cessation of therapy. However, 4 patients discontinued therapy due to treatment-related side-effects.¹⁸

Figure 1: Therapeutic approach to CKD-associated pruritus
IPTH = intact parathyreoid hormone; Kt/V = urea clearance by dialysis

Thalidomide

Thalidomide, used as an immunomodulatory agent to treat graft-versus-host reactions or myeloma, suppresses TNF-a production, and can be effective in the treatment of CKD- associated pruritus.¹⁹ A placebo-controlled, randomized double-blind, crossover study of thalidomide for the treatment of refractory uremic pruritus demonstrated improvements in itch scores in approximately 55% of patients in both phases of the trial. In addition, it was speculated that the antipruritic action of thalidomide may result from a central depressant effect.²⁰

Gabapentin

Gabapentin, an anticonvulsant and gamma-aminobutyric acid agonist, has been shown to exert a pain-modulating effect on patients with diabetic neuropathy. Gunal et al., in a randomized, placebo-controlled trial involving 25 patients on hemodialysis with CKD-associated pruritus, reported that 300mg of oral gabapentin administered 3 times weekly is safe and effective in reducing the mean pruritus score (reduction of pruritus intensity, as measured by VAS, from 8.4 before treatment to 1.2 at the end of the 4-week study period).²¹ In another double-blind, controlled, crossover study, Razeghi et al. treated 34 patients with 100mg gabapentin orally 3 times a week.²² After 4 weeks of treatment, intensity of pruritus was reduced from 100 to 6.44, as measured by a VAS scale ranging from 0 to 100. As gabapentin appears to be well tolerated, it has the potential to become an important tool in the management of CKD-associated pruritus.

Ultraviolet (UV) Phototherapy

In the late 1970s, Gilchrest et al. reported on the effectiveness of sunburn-spectrum (UVB) phototherapy on patients with CKD-associated pruritus. Although patients receiving long-wave UVA radiation treatment did not improve, 9 of 10 subjects treated with UVB phototherapy showed a marked reduction in pruritus.²³ Subsequently, a series of studies explored the effectiveness of phototherapy in CKD- associated pruritus, especially radiation with broadband UVB. According to a meta-analysis by Tan et al., the most promising therapy for uremic itch is UVB radiation, whereas UVA does not appear to be effective.²⁴

Newer data suggest that less side-effects are associated with narrowband than with broadband UVB treatments.²⁵ The risks of skin malignancies following UVB irradiation and long-term topical immunosuppression are still matters of debate, especially in relation to immunocompromised patients suffering from advanced disease or in those scheduled to receive immunosuppressive treatment after renal transplantation.

Conclusion

The treatment of CKD-associated pruritus remains a frustrating endeavor and continues to present a significant therapeutic challenge for clinicians. Besides UVB phototherapy and gabapentin, immunomodulatory drugs and k-receptor agonists may be helpful in severe cases. A stepwise approach is suggested in choosing a therapeutic modality, and whenever possible, treatment should be initiated with the drug exhibiting the most favorable safety and efficacy profiles.

References

1. Mettang T, Fischer FP, Kuhlmann U. [Uremic pruritus. Pathophysiologic and therapeutic concepts]. Dtsch Med Wochenschr 121(33):1025-31 (1996 Aug).
2. Pisoni RL, Wikstrom B, Elder SJ, et al. Pruritus in haemodialysis patients: International results from the Dialysis Outcomes and Practice Patterns Study (DOPPS). Nephrol Dial Transplant 21(12):3495-505 (2006 Dec).
3. Tessari G, Dalle Vedove C, Loschiavo C, et al. The impact of pruritus on the quality of life of patients undergoing dialysis: a single centre cohort study. J Nephrol 22(2):241-8 (2009 Mar-Apr).
4. Weisshaar E, Matterne U, Mettang T. How do nephrologists in haemodialysis units consider the symptom of itch? Results of a survey in Germany. Nephrol Dial Transplant 24(4):1328-30 (2009 Apr).
5. Kimmel M, Alscher DM, Dunst R, et al. The role of micro- inflammation in the pathogenesis of uraemic pruritus in haemodialysis patients. Nephrol Dial Transplant 21(3):749-55 (2006 Mar).
6. Mettang T, Fritz P, Weber J, et al. Uremic pruritus in patients on hemodialysis or continuous ambulatory peritoneal dialysis (CAPD). The role of plasma histamine and skin mast cells. Clin Nephrol 34(3):136-41 (1990 Sep).
7. Altmeyer P, Kachel HG, Schafer G, et al. [Normalization of uremic skin changes following kidney transplantation]. Hautarzt 37(4):217-21 (1986 Apr).
8. Gianni LM, Sulli MM. Topical tacrolimus in the treatment of atopic dermatitis. Ann Pharmacother 35(7-8):943-6 (2001 Jul-Aug).
9. Pauli-Magnus C, Klumpp S, Alscher DM, et al. Short-term efficacy of tacrolimus ointment in severe uremic pruritus. Perit Dial Int 20(6):802-3 (2000 Nov-Dec).
10. Kuypers DR, Claes K, Evenepoel P, et al. A prospective proof of concept study of the efficacy of tacrolimus ointment on uraemic pruritus (UP) in patients on chronic dialysis therapy. Nephrol Dial Transplant 19(7):1895-901 (2004 Jul).
11. Duque MI, Yosipovitch G, Fleischer AB, Jr., et al. Lack of efficacy of tacrolimus ointment 0.1% for treatment of hemodialysis-related pruritus: a randomized, double-blind, vehicle-controlled study. J Am Acad Dermatol 52(3 Pt 1):519-21 (2005 Mar).
12. Chen YC, Chiu WT, Wu MS. Therapeutic effect of topical gamma-linolenic acid on refractory uremic pruritus. Am J Kidney Dis 48(1):69-76 (2006 Jul).
13. Peer G, Kivity S, Agami O, et al. Randomised crossover trial of naltrexone in uraemic pruritus. Lancet 348(9041):1552-4 (1996 Dec 7).
14. Pauli-Magnus C, Mikus G, Alscher DM, et al. Naltrexone does not relieve uremic pruritus: results of a randomized, double-blind, placebo-controlled crossover study. J Am Soc Nephrol 11(3):514-9 (2000 Mar).
15. Umeuchi H, Togashi Y, Honda T, et al. Involvement of central mu-opioid system in the scratching behavior in mice, and the suppression of it by the activation of kappa-opioid system. Eur J Pharmacol 477(1):29-35 (2003 Sep 5).
16. Wikstrom B, Gellert R, Ladefoged SD, et al. Kappa- opioid system in uremic pruritus: multicenter, randomized, double-blind, placebo-controlled clinical studies. J Am Soc Nephrol 16(12):3742-7 (2005 Dec).
17. Dawn AG, Yosipovitch G. Butorphanol for treatment of intractable pruritus. J Am Acad Dermatol 54(3):527-31 (2006 Mar).
18. Mettang T, Krumme B, Bohler J, et al. Pentoxifylline as treatment for uraemic pruritus–an addition to the weak armentarium for a common clinical symptom? Nephrol Dial Transplant 22(9):2727-8 (2007 Sep).
19. Silva SR, Viana PC, Lugon NV, et al. Thalidomide for the treatment of uremic pruritus: a crossover randomized double-blind trial. Nephron 67(3):270-3 (1994).
20. Daly BM, Shuster S. Antipruritic action of thalidomide. Acta Derm Venereol 80(1):24-5 (2000 Jan-Feb).
21. Gunal AI, Ozalp G, Yoldas TK, et al. Gabapentin therapy for pruritus in haemodialysis patients: a randomized, placebo-controlled, double-blind trial. Nephrol Dial Transplant 19(12):3137-9 (2004 Dec).
22. Razeghi E, Eskandari D, Ganji MR, et al. Gabapentin and uremic pruritus in hemodialysis patients. Ren Fail 31(2):85-90 (2009).
23. Gilchrest BA, Rowe JW, Brown RS, et al. Ultraviolet phototherapy of uremic pruritus. Long-term results and possible mechanism of action. Ann Intern Med 91(1):17-21 (1979 Jul).
24. Tan JK, Haberman HF, Coldman AJ. Identifying effective treatments for uremic pruritus. J Am Acad Dermatol 25(5 Pt 1):811-8 (1991 Nov).
25. Baldo A, Sammarco E, Plaitano R, et al. Narrowband (TL-01) ultraviolet B phototherapy for pruritus in polycythaemia vera. Br J Dermatol 147(5):979-81 (2002 Nov).

¹Faculty of Medicine, University of Toronto, Toronto, ON, Canada
²Division of Dermatology, Sunnybrook Hospital, University of Toronto, Toronto, ON, Canada

ABSTRACT

There exists a multitude of medical conditions that cause intractable itch, or pruritus. The successful management of this symptom depends explicitly on establishing the underlying cause. Studies have shown that drugs not traditionally used in the treatment of cutaneous disorders, such as opiate receptor antagonists, antidepressants, and antiepileptics, can provide symptomatic relief of intractable itch. These novel antipruritic agents will be explored in this review.

Key Words:
Intractable itch, pruritus, opiate receptor antagonists, antidepressants, anticonvulsants, antihistamine, phototherapy, thalidomide

Itch, or pruritus, refers to an unpleasant sensation in the skin that provokes scratching. Arguably, all humans experience an itch at some point in their lives. One-fifth of the population is thought to suffer from some form of itch at any given moment.¹ The intensity of pruritus ranges from mild to severe, and can have a significant psychosocial impact on patients, by interfering with their sleep and daily activities. Itch is one of the most common symptoms associated with cutaneous disorders that require treatment from dermatologists.

Its management presents a treatment challenge, as many therapies are often tried to no avail.

Causation can sometimes be easily established, such as a primary dermatological disease (e.g., atopic dermatitis, psoriasis, urticaria), underlying renal or hepatic disease, or a drug-induced reaction (e.g., opiates). However, in many cases resolution of the symptom does not follow even after the etiology has been established; this is especially true for chronic disorders.
Tables 1 and 2 summarize dermatologic and systemic disorders that can cause intractable itch.

Pathophysiology

The neuropathways responsible for relaying pruritus to the brain are well-known. The itch sensation is carried to the brain by a dedicated subset of nociceptive C neurons. Like the pathways for pain and temperature, the message is relayed to the spinal cord, then crosses the midline and ascends via the lateral spinothalamic tract to the thalamus, and then finally travels to the cerebral cortex.

There are many peripheral mediators of pruritus, which include histamine, cytokines (IL-2), tryptase, substance P, serotonin, and opioid peptides. The most potent from this list is histamine, which is released by dermal mast cells via many triggers (i.e., IgE crosslinking, substance P, complement C5a). This biogenic amine acts mainly as a neurotransmitter and plays a major role in skin reactions associated with urticaria, urticaria pigmentosa, and insect bites. Its role in other skin diseases (e.g., atopic dermatitis) is debatable.

Traditional Topical Agents

Topical agents provide symptomatic relief. However, it must be stressed that successful management depends on establishing the underlying physiologic imbalance.

• Menthol 1%, compounded in an aqueous cream or in a moisturizer base, sensitizes thermal receptors to cold and is considered a safe remedy that has been used for centuries.
• Doxepin 5% cream is a topical tricyclic antidepressant that relieves pruritic symptoms associated with atopic dermatitis. Patients being treated with doxepin should be cautioned regarding adverse side-effects, such as systemic absorption and drowsiness.
• Capsaicin 0.025%-0.3% cream is derived from chili peppers, and triggers the release of substance P from C nociceptors, which desensitizes nerve fibers. Local irritation can result.
• Topical corticosteroids are only considered when there is a primary dermatosis, due to the potential for local side-effects (i.e., telangiectasia, atrophy, striae).
• Topical anesthetics are seldom used as they are associated with an increased risk of allergic sensitization.
• Other topical agents that may be of benefit include: moisturizers, oatmeal-based agents, calamine lotion, aloe and camphor.

Systemic Agents

Systemic agents are tried if there is a specific indication or if the more conservative measures are ineffective. Antihistamines are predominantly used for treating urticaria, but are otherwise rarely effective for itch. The first generation antihistamines are sedating, but are generally considered to be the most effective when compared with its subsequent counterparts. Due to its potential to affect performance, sedating antihistamines should be administered at night. The addition of successive generations (second or third) may be helpful for daytime relief as they are minimally sedating. Tranquilizers have been used, but they only serve to sedate the patient and do not directly address the pruritic symptoms.

Phototherapy

For patients who are unresponsive to traditional topical or systemic therapies, UV light (UVB or PUVA) may be an option. For example, UVB has been shown to be of benefit in the treatment of pruritus associated with chronic renal disease.² After 2 weeks of three treatments per week, improvement can be seen. If no improvement is detected following this treatment regimen, phototherapy should be reconsidered. Clinical experience seems to indicate that maintenance therapy is not required.

Novel Agents

In the past, if traditional agents were not effective, dermatologists had few other options. The emergence of a new understanding of the pathophysiology of itch has led to novel uses of existing therapies to treat pruritus, which include opiate receptor antagonists, antidepressants, and antiepileptics. The addition of these drugs to the dermatologist’s therapeutic arsenal provides options to patients who are inadequate responders to traditional agents. Table 3 provides a summary of these unconventional antipruritic agents.

Conclusions

Pruritus is a very common symptom that is associated with many dermatologic and systemic conditions, and can be challenging to treat. Conventional therapies such as topical agents and antihistamines are often not effective. Novel therapies such as opioid antagonists, antidepressants, and anticonvulsants are emerging as promising treatments for intractable itch.

References

1. Rea JN, Newhouse ML, Halil T. Skin disease in Lambeth. A community study of prevalence and use of medical care. Br J Prev Soc Med 30(2):107-14 (1976 Jun).
2. Seckin D, Demircay Z, Akin O. Generalized pruritus treated with narrowband UVB. Int J Dermatol 46(4):367-70 (2007 Apr).
3. Dunteman E, Karanikolas M, Filos KS. Transnasal butorphanol for the treatment of opioid-induced pruritus unresponsive to antihistamines. J Pain Symptom Manage 12(4):255-60 (1996 Oct).
4. Dawn AG, Yosipovitch G. Butorphanol for treatment of intractable pruritus. J Am Acad Dermatol 54(3):527-31 (2006 Mar).
5. Wolfhagen FH, Sternieri E, Hop WC, et al. Oral naltrexone treatment for cholestatic pruritus: a double-blind, placebo-controlled study. Gastroenterology 113(4):1264-9 (1997 Oct).
6. Metze D, Reimann S, Beissert S, et al. Efficacy and safety of naltrexone, an oral opiate receptor antagonist, in the treatment of pruritus in internal disease and dermatological diseases. J Am Acad Dermatol 41(4):533-9 (1999 Oct).
7. Bigliardi PL, Stammer H, Jost G, et al. Treatment of pruritus with topically applied opiate receptor antagonist. J Am Acad Dermatol 56(6):979-988 (2007 Jun).
8. Peer G, Kivity S, Agami O, et al. Randomised crossover trial of naltrexone in uraemic pruritus. Lancet 348(9041):1552-4 (1996 Dec 7).
9. Zylicz Z, Smits C, Krajnik M. Paroxetine for pruritus in advanced cancer. J Pain Symptom Manage 16(2):121-4 (1998 Aug).
10. Tefferi A, Fonseca R. Selective serotonin reuptake inhibitors are effective in the treatment of polycythemia vera-associated pruritus. Blood 99(7):2627 (2002 Apr 1).
11. Zylicz Z, Krajnik M, Sorge AA, et al. Paroxetine in the treatment of severe non-dermatological pruritus: a randomized, controlled trial. J Pain Symptom Manage 26(6):1105-12 (2003 Dec).
12. Browning J, Combes B, Mayo MJ. Long-term efficacy of sertraline as a treatment for cholestatic pruritus in patients with primary biliary cirrhosis. Am J Gastroenterol 98(12):2736-41 (2003 Dec).
13. Hundley JL, Yosipovitch G. Mirtazapine for reducing nocturnal itch in patients with chronic pruritus: a pilot study. J Am Acad Dermatol 50(6):889-91 (2004 Jun).
14. Davis MP, Frandsen JL, Walsh D, et al. Mirtazapine for pruritus. J Pain Symptom Manage 25(3):288-91 (2003 Mar).
15. Bueller HA, Bernhard JD, Dubroff LM. Gabapentin treatment for brachioradial pruritus. J Eur Acad Dermatol Venereol 13(3):227-8 (1999 Nov).
16. Winhoven SM, Coulson IH, Bottomley WW. Brachioradial pruritus: response to treatment with gabapentin. Br J Dermatol 150(4):786-7 (2004 Apr).
17. Taylor RS. Multiple sclerosis potpourri. Paroxysmal symptoms, seizures, fatigue, pregnancy, and more. Phys Med Rehabil Clin N Am 9(3):551-9 (1998 Aug).
18. Gunal AI, Ozalp G, Yoldas TK, et al. Gabapentin therapy for pruritus in haemodialysis patients: a randomized, placebo-controlled, double-blind trial. Nephrol Dial Transplant 19(12):3137-9 (2004 Dec).
19. Bergasa NV, McGee M, Ginsburg IH, et al. Gabapentin in patients with the pruritus of cholestasis: a double-blind, randomized, placebo-controlled trial. Hepatology 44(5):1317-23 (2006 Nov).
20. Alfadley A, Al-Hawasawi K, Thestrup-Pedersen K, et al. Treatment of prurigo nodularis with thalidomide: a case report and review of the literature. Int J Dermatol 42(5):372-5 (2003 May).
21. Daly BM, Shuster S. Antipruritic action of thalidomide. Acta Derm Venereol 80(1):24-5 (2000 Jan-Feb).

1. Michael DeGroote School of Medicine McMaster University
2. Dermatrials Research, Hamilton, ON, Canada

ABSTRACT

Pruritus, or itch, is a common sensation that causes a person to want to scratch. It is a complex process that may negatively impact quality of life and commonly occurs with skin disorders such as atopic dermatitis and urticaria. It could also be a symptom related to an underlying disease process such as cholestasis or hyperthyroidism, or simply be caused by dry skin, especially in the cold, winter months. Therapy is often aimed at eliminating the underlying cause first, followed by the management of the itchy sensation. Treatment may include prescription and over-the-counter (OTC) medications, herbal remedies, hydrotherapy, phototherapy, and ultraviolet therapy. This overview provides information regarding the various management and treatment options for pruritus.

Key Words:
pruritus, itch, urticaria

Pathophysiology of Pruritus

Pruritus is a complex process that involves the stimulation of free nerve endings found superficially in the skin. The sensation of pruritus is transmitted through the C-fibers in the skin to the dorsal horn of the spinal cord, and then, via the spinothalamic tract to the cerebral cortex for processing. Many chemicals have been found to be pruritogenic, therefore causing the itch sensation, including histamine, serotonin, cytokines, and opioids. There are six categories of pruritus: dermatologic, systemic, neurogenic, psychogenic, mixed, and other. Various treatment and management options exist depending on the category or cause.¹

Treatment

Treatment of pruritus can be categorized in several ways. A common method of grouping the various options is causative vs. symptomatic treatment. Causative treatment involves finding the underlying disorder and then correcting it, thereby eliminating the itch sensation. Symptomatic treatment involves substituting another sensation for the itch, using methods such as cooling, heating, or counter irritation (e.g., scratching). Symptomatic treatment can be used in addition to treating the underlying disease process in order to provide earlier relief. Most of the available treatment options are categorized under symptomatic therapy and management.

Prescription Medications

Prescription medications include topical and systemic antihistamines, corticosteroids, local anesthetics, and topical immunomodulators, among others. Some lower concentration preparations of these medications are available OTC.

Antihistamines

Itching occurs when histamine is released, causing redness, swelling, warmth, and consequently itchiness. Antihistamines, or H1 antagonists, act by blocking the histamines, and are the most widely used medications for this condition. They take approximately 15–30 minutes to be effective and can be short- or long-acting.²

Topical antihistamines are available in prescription as well as nonprescription forms. Camphor (Caladryl^®, Pfizer) is a common diphenhydramine preparation that has both antipruritic and anesthetic properties. This traditional therapy carries with it a small risk of contact dermatitis and allergic sensitization.³

Doxepin, a dibenzoxepin tricyclic compound, is a very active antihistamine that can be used for atopic dermatitis (AD) and also has a useful psychotherapeutic effect for pruritic patients. It acts by depressing cutaneous sensory receptors.⁴ The starting dose is 25–50mg, taken orally at bedtime. Doxepin cream 5% may be applied q.i.d. Some side-effects of this medication include drowsiness and localized burning or stinging, which are usually transient. Findings in a placebo-controlled, double-blind trial have confirmed the effectiveness of doxepin in the relief of pruritus caused by AD.⁵ In another study by Drake et al., topically applied doxepin was again found to be a safe and effective treatment for pruritus.5 Berberian et al. conducted a double-blind, controlled study that yielded similar results in which topical doxepin was added to topical hydrocortisone or topical triamcinolone resulting in a significantly faster and more substantial reduction in itching than corticosteroid alone, and a more prompt resolution of underlying AD.⁶

Hydroxyzine hydrochloride 25mg, po, t.i.d. or q.i.d., or diphenhydramine 25–50mg, po, may be given at bedtime when pruritus is usually at its worst.

Systemic antihistamines are effective in treating some, but not all causes of pruritus, for example, their role in treating AD is limited. They can provide some level of sedation, which may assist sleep, but may also carry with it the adverse effects of unwanted sedation and other anticholinergic properties such as dry mouth, gastrointestinal upset, stomach pain, nausea, and headache. This can be prevented by using nonsedating antihistamines such as fexofenadine (Allegra®, Aventis Pharmaceuticals).

Several low-sedating antihistamines have become available in the last decade. These newer antihistamines, such as loratadine (Claritin®, Schering Canada), block histamine receptors and prevent the activation of cells by histamine, thus preventing an allergic response. Unlike the traditional antihistamines, loratadine, desloratidine (Clarinex^®, Schering-Plough; Aerius^®, Schering Canada), and cetirizine (Zyrtec^®, Pfizer) do not cross the blood-brain barrier and, therefore, do not cause drowsiness. However, these medications have had limited success in the treatment of pruritus.4

Corticosteroids

Corticosteroid medications are derivatives of the natural hormones produced by the adrenal glands and have many functions including the control of inflammatory responses. Topical formulations are applied to the skin and typically used for localized pruritus such as dermatitis. Low potency preparations are available without a prescription. This class of medications has proven to be successful in the treatment of pruritus for many years by reducing skin inflammation, thus reducing the itching. Corticosteroids seldom alleviate generalized pruritus without dermatitis, but may rarely be helpful if used with lubricants in elderly patients with dry skin. Corticosteroid creams or ointments applied t.i.d. as maintenance therapy are most effective, especially for AD. Emollients, such as white petrolatum, hydrogenated vegetable oil, or hydrophilic petrolatum may be used as a supplement between corticosteroid applications to help hydrate the skin. Corticosteroids should not be used for prolonged periods because of the risk for skin atrophy.4

Oral corticosteroids, such as prednisone, should be considered a last resort, but if given, are best used in 1–2 week courses. Alternate-day use of this drug at 20–40mg every other morning may help to reduce side-effects.4

Local Anesthetics

Topical anesthetics work by directly interfering with the transmission of impulses along the sensory nerve fibers or by depressing cutaneous sensory receptors. Those drugs that interfere with transmission include benzocaine, diperodon, and lidocaine.⁷ Hercogova suggested that caine-based anesthetics should be avoided due to risk of sensitization, but lotions or creams containing 0.25% – 0.5% menthol can be useful.⁴

Pramoxine, another topical anesthetic, has a documented antipruritic effect and is most useful for mild-to-moderate pruritus. It may be combined with coolants, such as menthol, to increase its effectiveness.⁸ One study demonstrated that both the magnitude and duration of histamine-induced itch were reduced by pramoxine.⁹

Capsaicin, the active ingredient in cayenne and red pepper, owes its antipruritic properties to the desensitization of nociceptive nerve endings responsible for transmitting the itch sensation. It is useful at concentrations of 0.025–0.075% in localized intractable pruritus,¹⁰ but may cause localized burning and stinging which can limit its use and reduce compliance in patients. This irritation will subside with repeated use of the medication if the patient chooses to overcome the initial irritations.

⁸

Calcineurin Inhibitors

Topical calcineurin inhibitors pimecrolimus (Elidel^® Cream 1%, Novartis) and tacrolimus (Protopic^® Ointment, Astellas) possess anti-itch properties and, similar to corticosteroids, they reduce skin inflammation. However, they have a different mechanism of action and, thus, are not associated with the same adverse effects. Calcineurin inhibitors prevent T-cell activation, inhibit inflammatory cytokine release, and down-regulate high affinity immunoglobulin E receptor expression on the Langerhans’ cells.¹¹ They are second-line therapies indicated for short-term and non-continuous chronic treatment of mild-to-moderate AD in non-immunocompromised people ages 2 and older who have failed to respond adequately to other topical prescription treatments or when those treatments are not advisable.

Pimecrolimus is an ascomycin macrolactam. It shows activity not only against T-cell activation, but also against mast cells and pruritus. In a study of real-life usage by Lubbe et al., incorporation of 1% pimecrolimus cream into patients’ standard treatment regimen was well tolerated and improved AD in approximately two-thirds of patients.¹²

Tacrolimus is a macrolide lactone isolated from Streptomyces tsukubaensis. The release of cytokines, such as interleukins 4 and 5, are inhibited by this drug.¹³ A study by Drake, et al. demonstrated that topical tacrolimus ointment was associated with significant quality of life benefits in adult and pediatric patients with AD.¹⁴

There is concern about continuous long-term use of calcineurin inhibitors, because of the risk of cancer development. This is based on the FDA’s public health advisory regarding information from animal studies, as well as case reports in a small number of patients. The FDA has received reports of lymphoma and skin cancer in children and adults treated with these drugs, however it has not been clearly established whether the reported cancers are associated with direct use of these products.¹⁵ Based on these findings, we suggest caution in prescribing these drugs for long-term use. Application should be limited to areas of the skin affected by AD.

Calcineurin inhibitors are not indicated for use in children 4

Cholestyramine

Pruritus is a common and sometimes disabling manifestation of cholestasis. Cholestyramine is a nonabsorbable, basic polystyrene that serves as an anion exchange resin binding bile salts in the gut lumen. It is effective in a large proportion of cases of cholestasis-related pruritus. The resin depletes the serum bile salt pool, and has a greater affinity for dihydroxy bile salts than for trihydroxy bile salts. Cholestyramine also has complex effects on absorption of a variety of compounds other than bile salts, and it has been reported to improve pruritus in polycythemia rubra vera and uremia. Side-effects are mild, but common, and include constipation, fat malabsorption, and an unpleasant taste. These side-effects may make compliance an issue.¹⁶

Rifampicin

Rifampicin is an antibiotic that has also been shown to lower hepatocyte bile salt concentrations by competing for the uptake of these salts into the hepatocyte. In one study, pruritus disappeared in 11 of 14 subjects receiving rifampicin 600mg/day and three experienced partial improvement. 16

Naltrexone

Naltrexone, an opiate receptor antagonist, was studied in a randomized, double-blind, placebo-controlled trial to assess the antipruritic effects in patients with chronic cholestatic liver disease. The investigators found that oral naltrexone may be an effective and well-tolerated alternative for pruritus, refractory to regular antipruritic therapy. In this study, five of eight patients treated had considerably less itching.¹⁷ In another study, nine out of 20 patients receiving naltrexone had >50% improvement of pruritus. Side-effects in this study, including dizziness, nausea, vomiting, headache, drowsiness, dry mouth, and cramps, were transient and did not require specific treatment.¹⁸

Ultraviolet (UV) Light Therapy

UV phototherapy is used to treat various pruritic conditions including chronic renal failure; AD; HIV; aquagenic pruritus; solar, chronic, and idiopathic urticaria; urticaria pigmentosa; polycythemia vera; pruritic folliculitis of pregnancy; breast carcinoma skin infiltration; Hodgkin’s lymphoma; chronic liver disease; and acquired perforating dermatoses, among others. It is often undertaken after multiple attempts to treat stubborn itch, and can offer relief without many of the side-effects and risks of systemic medications. UV-based therapy utilizes UVB and UVA in both broadband and narrowband, as well as PUVA (psoralen UVA). Cost and side-effects can be a prohibitive factor for patients. Erythema is common in UVB, as is premature aging and photocarcinogenesis with both UVA and UVB. Side-effects associated with PUVA include redness, burning, headache, and nausea.^16,19

UVA, UVB, and PUVA light therapies have been especially useful in the treatment of pruritus in HIV patients, as well as in those patients with systemic mastocytosis and cutaneous T-cell lymphoma. It localizes the effect on the superficial nerve endings, sparing the remaining helper cells, and relieving the pruritus. Because of its more superficial penetration, UVB is believed to be safer than UVA. UVB also spares the remaining helper cells in HIV patients and may localize the effect on the superficial nerve endings, thus relieving pruritus. Systemic mastocytosis and cutaneous T-cell lymphoma also respond to UV therapy and because destruction of the proliferating CD4 clone is desirable, UVA is usually the preferred modality over UVB, although Millikan suggests that the relief of pruritus is more predictable with UVB than with UVA.3

Cutaneous Field Stimulation (CFS)

CFS, which electrically stimulates thin afferent fibers, including nocireceptive C-fibers, was reported to inhibit histamine-induced itching. The reduction in itching is accompanied by degeneration of the epidermal nerve fibers. In one open trial, localized itching responded to CFS treatment, and pruritus was reduced by 49% at the end of 5 weeks. Itch relapsed gradually after the discontinuation of CFS, which led the researchers to conclude that nerve fibers regenerated into the epidermis.20

Over-the-Counter Treatments

In addition to the nonprescription medications mentioned above, there are other OTC treatments that can be helpful for treating and managing pruritus. Moisturizing after a bath is extremely important, and emollients such as white petrolatum, or petrolatum depositing moisturizing body washes, and in-shower moisturizers (e.g., Olay^® Ribbons^®, Procter & Gamble; emulsifying ointment USP) can be helpful when applied while the skin is still wet.²¹

There is new evidence to show that moisturizers containing niacinamide and glycerin (e.g., Olay^® Quench^®, Procter & Gamble) not only hydrate the skin, but improve the skin’s resistance to external factors and improve the barrier function. Glycerin is required for moisturizers to work quickly and add moisture to the skin, but the niacinamide helps to sustain that benefit over a longer period of time.²¹

Alternative Therapies

Several alternatives to traditional treatment of pruritus have been proposed. Often these therapies can be used in conjunction with prescribed or OTC medications to relieve symptoms quickly. Compounds that have been found to be effective for pruritus by depressing cutaneous sensory receptors include menthol, camphor, and phenol.⁷ Some other alternative therapies that have been suggested include herbal remedies, nutritional therapy, reflex therapy, and hydrotherapy.³

Herbal Remedies

Several herbs have been proposed as corticosteroid-sparing agents and may provide a viable alternative to topical steroids and their side-effects. Oatmeal baths appear to be most useful because of its colloidal protein and high mucilaginous content. Other herbs have been suggested because of their high mucilage content as well, including flax, fenugreek, English plantain, hearts ease, marshmallow, mulberry, mullein, and slippery elm.3 More extensive research needs to be conducted regarding their possible use and effectiveness for the treatment of pruritus.

Tannins, also derived from herbs, may be helpful as well. The exact mechanism of action is unclear, but may perhaps be related to the coagulation of proteins in the skin. The most common tannin-containing herb is witch hazel, but others include oak bar, English walnut leaf, goldenrod, Labrador tea, lady’s mantel, lavender, and St. John’s wort.

Other possible herbs that may be advantageous include chamomile, which has shown to be equivalent to low concentrations of hydrocortisone, aloe vera, and capsaicin.3 Some side-effects may include irritant or allergic contact dermatitis. Some herbals can be toxic if ingested as well. Some of the oldest group of medications used to soothe and cool pruritic skin is menthol and camphor, which are both considered low risk and safe to use topically. ^3,4

Nutritional Therapy

Nutritional therapy, despite not being sufficiently researched as a monotherapy for pruritus, may be helpful in combination with other anti-itch treatments. Vitamins D and E, and linolenic acid have shown some efficacy in the treatment of psoriasis and atopic eczema.³

Reflex Therapy, Acupuncture, and Hydrotherapy

While they are not traditionally used, reflex therapy, acupuncture, and hydrotherapy are three treatments that may be beneficial as adjunctive therapy, however further research is needed. There is little research available regarding the effectiveness of reflex therapy and hydrotherapy. These options may be considered in difficult-to-treat patients where traditional approaches have been unsuccessful. Acupuncture is based on the gate theory of neurotransmission, however it is infrequently used in the Western world, and therefore has insufficient evidence to fully support its use. ³

Management

The management of symptoms is paramount in the treatment of pruritus. Patients should be educated regarding the self-care aspects of this condition. Eliminating the use of irritating or tight clothing is recommended, as well as maintaining a cool environment. Patients should avoid the frequent use of soap, topical irritants in clothing, dry environments, and vasodilators such as caffeine, alcohol, and hot water. Patients should be advised to take brief, tepid or lukewarm baths using mild cleansers with a low pH. Soap film should be rinsed off completely and skin should be patted lightly, followed by the generous application of a moisturizing lotion or cream.^4,7,22

Conclusion

Pruritus is a common complaint, but one that can often be a challenge to treat. It can be a major quality of life issue for patients, so it is important that both the underlying disease and associated symptoms are treated as quickly and effectively as possible. Health teaching regarding the prevention and management of pruritus should be included in the overall treatment of the cause and symptoms.

References

1. Heymann WR. Itch. J Am Acad Dermatol 54(4):705-6 (2006 Apr).
2. DermNet NZ. Pruritus (itch). URL: http://www.dermnetnz.org/systemic/itch.html. Last accessed 2006 Dec 28.
3. Millikan LE. Alternative therapy in pruritus. Dermatol Ther 16(2):175-80 (2003).
4. Hercogova J. Topical anti-itch therapy. Dermatol Ther 18(4):341-3 (2005 Jul-Aug).
5. Drake L, Cohen L, Gillies R, et al. Pharmakinetics of doxepin in subjects with pruritic atopic dermatitis. J Am Acad Dermatol 41(2):209-14 (1999 Aug).
6. Berberian BJ, Breneman DL, Drake LA, et al. The addition of topical doxepin to corticosteroid therapy: an improved treatment regimen for atopic dermatitis. Int J Dermatol 38(2):145-8 (1999 Feb).
7. Beers MH, Berkow R, editors. The Merck Manual of Diagnosis and Therapy, 17th Ed. New Jersey: John Wiley & Sons (1999).
8. Yosipovitch G, Hundley JL. Practical guidelines for relief of itch. Dermatology Nurs 16(4):325-8 (2004 Aug).
9. Yosipovitch G, Maibach HI. Effect of topical pramoxine on experimentally induced pruritus in humans. J Am Acad Dermatol 37(2 Pt 1):278-80 (1997 Aug).
10. Yosipovitch G, Greaves MW, Schmelz M. Itch. Lancet 361(9358):690-4 (2003 Feb).
11. Hanifin JM, Pallor AS, Eichenfield L, et al. Efficacy and safety of tacrolimus ointment treatment for up to 4 years in patients with atopic dermatitis. J Am Acad Dermatol 53(2 Suppl 2):S186-94 (2005 Aug).
12. Lubbe J, Friedlander SF, Cribier B, et al. Safety, efficacy, and dosage of 1% pimecrolimus cream for the treatment of atopic dermatitis in daily practice. Am J Clin Dermatol 7(2):121-31 (2006).
13. Kawashima M, QOL Research Forum for Patients with Atopic Dermatitis. Quality of life in patients with atopic dermatitis: impact of tacrolimus ointment. Int J Dermatol 45(6):731-6 (2006 Jun).
14. Drake L, Prendergast M, Maher R, et al. The impact of tacrolimus ointment on health-related quality of life of adult and pediatric patients with atopic dermatitis. J Am Acad Dermatol 44(1 Suppl):S65-72 (2001 Jan).
15. FDA Public Health Advisory: Elidel (pimecrolimus) cream and Protopic (tacrolimus) ointment.
16. Khandelwal M, Malet PF. Pruritis associated with cholestasis: a review of pathogenesis and management. Dig Dis Sci 39(1):1-8 (1994 Jan).
17. Wolfhagen, FH, Sternieri E, Hop WC, Vitale G, Bertolotti M, Van Buuren HR. Oral naltrexone treatment for cholestatic pruritus: a double-blind, placebo-controlled study. Gastroenterology 113(4):1264-9 (1997 Oct).
18. Terg R, Coronel E, Sorda J, Munoz AE, Findor J. Efficacy and safety of oral naltrexone treatment for pruritus of cholestasis: a crossover, double-blind, placebo-controlled study. J Hepatol 37(6):717-22 (2002 Dec).
19. Rivard J, Lim HW. Ultraviolet phototherapy for pruritus. Dermatol Ther 18(4):344-54 (2005 Jul-Aug).
20. Wallengren J, Sundler F. Cutaneous field stimulation in the treatment of severe itch. Arch Dermatol 137(10):1323-5 (2001 Oct).
21. Vender R. The management of itchy skin. Skin Therapy Lett – Pharm Ed 1(2):1-3 (2006 Sep-Oct).
22. Moses S. Pruritus. Am Fam Physician 68(6):1135-42 (2003 Sep).

ABSTRACT

Dryness and itching in the vulvovaginal area is an increasing problem as our female population ages and becomes menopausal. This dryness and itching is often the result of estrogen deficiency, and there are typically two types of treatment: Specific Therapy (or hormone replacement therapy), and Nonspecific Therapy. Dermatologists should be able to sort out the causes of the itching and irritation, and understand the approaches to therapy.

Key Words:
vulva, vagina, pruritus, estrogen

Dermatologists are not consulted regularly for vulvovaginal problems, but as our aging female population moves into menopause, more and more patients will be complaining of vulvovaginal itching and dryness. Those patients who already have skin conditions affecting their vulvar areas will be more susceptible to irritation and exacerbation of their skin conditions, which include inverse psoriasis, atopic and “sensitive” skin, genital lichen sclerosus, and lichen planus. Dermatologists should be able to sort out the causes of the itching and irritation, and understand the approaches to therapy.

Vulvovaginal Dryness and Itching

Vulvovaginal dryness and itching most commonly occur when there is an absence of estrogen stimulation. Estrogen is needed for the structural and functional integrity of the vagina and the introitus. Without estrogen, the first symptom is dryness. Typically, perimenopausal women develop this dryness long before hot flashes and menstrual cessation. The vagina begins to feel like “sandpaper” and may be accompanied by itching. Signs of this atrophic vulvovaginitis develop slowly and insidiously.

Perimenopause usually starts about 5-7 years before the last menstrual period, but can occur prematurely in the late twenties or thirties.¹ Relative atrophy can also develop postpartum with lactation and with the use of some birth control pills. Onset may be abrupt postsurgery or after chemotherapy.² Tamoxifen, an anti-estrogen used for treatment of breast cancer and malignant melanomas, can cause menopausal symptoms by blocking the estrogen effect in reproductive women. In postmenopausal women, it has an agonistic estrogen-like action.

Along with the dryness and itching, the other complaints of estrogen deficiency, e.g., hot flashes, insomnia, decreased libido, and psychological and cognitive changes eventually occur. Closer to the time of actual menstrual cessation, vaginal atrophic changes may increase to induce marked dyspareunia and urinary incontinence.

Poorly estrogenized vulvovaginal tissue thins, and then loses its normal vaginal secretions and normal flora. The result is an increased susceptibility to trauma from friction or chemical irritants, and to bacterial overgrowth, should it become irritated. Petechiae, telangiectasia, fissuring, and even a purulent discharge may develop. Initially there is vulval itching and then burning.

Estrogen Deficiency in Children

The effects of estrogen deficiency are often overlooked in young girls. In infancy, their genitalia are protected by maternally derived estrogen, but after the first two years of life, they are relatively estrogen deficient. There is relative atrophy, as well as a lack of the normal labial development, which become protective factors for the genital area. However, this atrophic, hypoestrogenic tissue is susceptible to irritants from urine, feces, cleansers and topical products and is susceptible to bacterial overgrowth like in an adult. One of the most common gynecological problems in children is vulvovaginitis. Many of the products used for cleansing and topical relief may just add insult to injury, creating more “contact” (usually of the primary irritant type) dermatitis.³

The Hypoestrogenized Vulva

On examination of the hypoestrogenized vulva, the vulvar trigone (the area of the vulva below the clitoris around the inside of the labia minora and around the hymenal ring) looks atrophic, pale and dry. The vaginal epithelium is dry, light pink to white, thin, and smooth due to loss of rugae. With increased severity, the vulva can show erythema, petechiae, telangiectasia, fissuring and erosion, and the open erosions may even produce a chronic purulent discharge. The pH is elevated at 6.0 – 7.0. The area around the vulva may be secondarily irritated with varying degrees of dryness, scaling and even painful fissures.⁴

Treatment

Treatment is divided into Nonspecific Therapy (i.e., addressing all the general factors that irritate the skin and any underlying conditions that may be further complicating management) and Specific Therapy (i.e., hormone replacement therapy).

Nonspecific Therapy

For Nonspecific Therapy, all irritating soaps and hygiene products should be discontinued along with sanitary pads, and hot constrictive synthetic clothing. Unfortunately, in addition to experiencing dryness, itchiness and irritation in the vulvovaginal area, menopausal women are also often incontinent. This is a major problem in older patients, and a very embarrassing problem that most women try to hide. They wear pads all day and consequently their vulvar area is chronically damp. Unfortunately, this “diaper dermatitis” is often missed. Patients do not volunteer such information and hide the pads during examinations. Heavy patients often wear constrictive clothing, which further complicates the problem. Because of the combination of urinary incontinence, heat, perspiration and odor, they use irritating cleansing products, “deodorants”, and wipes. It is important to take the time to obtain a full history of the products that your patients are using.

Encourage patients to use loose ventilated cotton type clothing as much as possible, avoiding pantyhose and girdles. Nonirritating cleansers like Cetaphil® lotion (Galderma) should be used to gently cleanse the area. Disposable wipes or feminine deodorant products should be discouraged. For cleansing and soothing irritation, recommend a sitz bath for 5-10 minutes, 2-3 times daily with Burow’s solution, mixing 1/2-1 packet of Domeboro® (Bayer) or Buro-Sol® (Stiefel) in 500ml water. A hand-held showerhead is invaluable for cleansing and rinsing the genital area.

If the skin is dry and cracked, use plain petrolatum or even light mineral or olive oil after the soak and while the skin is still damp. If there is mild to moderately severe pruritus and irritation, then topical l% hydrocortisone in petrolatum or triamcinolone 0.l% ointment may be necessary. Secondary infection from bacteria and yeast may require treatment, and any underlying dermatological condition must be treated. If the patient is not responding, patch testing may be necessary. If incontinence is a major problem, the patient should be referred to a urologist or gynecological urologist for pelvic floor management.

Table 1: Two types of therapy recommended for treatment of atrophic vulvovaginitis.

Specific Therapy

Specific Therapy utilizes hormone replacement. However, estrogen replacement can be a confusing and complicated process, because there are many products and regimens available. Adequate estrogen levels can be achieved by taking the hormone orally, vaginally, or by a transdermal route. However, the oral or transdermal routes may not be adequate for the vagina, and a vaginal cream could still be necessary. The oral dose of estrogen needed is individualized, and can be given continuously or in a cyclic fashion, with or without the progestin. If the uterus is present, a progestin must be given to protect the vaginal lining from excess estrogen stimulation. The systemic estrogens available are estradiol, conjugated estrogen and estropipate. Recently there has been controversy about which progestational agent is safer or more effective. The two progestins are medroxyprogesterone acetate and micronized progesterone. Pure micronized progesterone is felt to be safer and more effective.

Topical replacement therapy includes estriol, conjugated estrogen and estradiol in various forms. Hormone replacement therapy is contraindicated in the presence of:

• estrogen-dependent malignancies
• breast cancer
• thromboembolic disease (The onset may be abrupt
  postsurgery or after chemotherapy)
• undiagnosed vaginal bleeding
• endometriosis
• hypertriglyceridemia
• pregnancy

For those who cannot use hormone replacement therapy, a vaginal lubricant or moisturizer should be considered, such as Replens® (Shire Pharmaceuticals) that will last up to 72 hours. They can be very effective postpartum, during lactation and in premenopausal women.^5,6,7

References

1. McLean JM. Anatomy and physiology of the vulva. In: Ridley CM and Neill SM, editors. The Vulva. Oxford: Blackwell Science (1999) pp.58-59.
2. Kaufman RH, Faro S. Miscellaneous vaginal disorders. In: Kaufman RH and Faro S, editors. Benign Diseases of the Vulva and Vagina. St. Louis: Mosby (1994) pp.367-71.
3. Williams TS, Callen JP, Owen LG. Vulvar disorders in the prepubertal female. Pediatr Ann 15(8):588-605 (1986 Aug).
4. Pincus SH. Vulvar dermatoses and pruritus vulvae. Dermatol Clin 10(2):297-308 (1992 Apr).
5. Margesson LJ. Normal Anatomy of the Vulva. In: Fisher BK, Margesson LJ, editors. Genital Skin Disorders: Diagnosis and Treatment. St. Louis: Mosby (1998) pp.104-7.
6. Lynch PJ, Edwards L. Genital Dermatology. Baltimore:Churchill Livingston (1995) pp.93-95.
7. Willett WC, Colditz G, Stampfer M. Postmenopausal estrogens – opposed, unopposed, or none of the above. JAMA 283(4):534-5 (2000 Jan).

TPP – Canada Institutes Changes to Clinical Trial Regulations

TPP – Canada announced that as of September 1, 2001, some new clinical trial regulations will become effective, resulting in important and long awaited changes in both the clinical trial review and conduct in Canada. These changes include:

• Some Phase I protocols (e.g., bioequivalence, or trials involving healthy volunteers) will have an internal target review time of seven calendar days.
• Following submission of an Investigational New Drug application (IND), the waiting period will be 30 days instead of 60 days.
• Only qualified investigators (i.e., physicians or dentists who are licensed to practice) can undertake clinical trials.
• Prior to starting a clinical trial, the sponsor must supply the names of all Ethics Review Boards and their conclusions
• Clinical trial sites in Canada will be open to TPP inspection and review.
• All clinical trials must be conducted following Good Clinical Practice standards, even trials not requiring an IND.

These changes will have a major impact on how clinical trials will be carried out in the future.

ABSTRACT
Despite the predominance of itch as a leading and distressing symptom in most of the dermatological and several systemic diseases, there is relatively little progress in understanding its pathophysiology. This is most likely the main reason for the limited number of satisfactory anti-itch treatments and the fact that even today various therapies have empirical but not evidence-based character. There are no specific antipruritic drugs on the market, but there are a high number of case reports and experimental investigations describing medications with antipruritic potency. It is therefore the aim of this article to briefly review the major systemic antipruritic drugs and give a short overview on the different types of pruritus and their possible systemic therapy.

Key Words:
itch, pruritus, systemic antipruritic drugs

Itching is a sensation that, if sufficiently strong, will provoke scratching or the desire to scratch. It is a frequent and distressing symptom of various dermatological (see Table 1) and systemic diseases (see Table 2). It can also occur in some patients without any skin symptoms. Knowledge has accumulated about the initiation of itch by external stimuli, but the neuronal substrate in the skin has not been completely identified. This has fortunately changed to some degree since a group of histamine-sensitive Cfibers were recently identified, which probably represent the afferent units that mediate itch sensations². Histamine, derived from mast cells, is the best known pruritogen. It induces different degrees of itching when applied in different concentrations into the skin. In most dermatological and systemic diseases, except urticaria, histamine is not the main mediator. There are other proinflammatory mediators to consider such as substance P, proteases, interleukin-2, acetylcholine, vasoactive intestinal peptide (VIP) and opioid peptides. The different types of pruritus (see Table 2) have different etiological factors, which in most cases have not yet been clarified. As well, the mechanisms of excitatory and inhibitory processing in the central nervous system are not defined.

Drugs With Antipruritic Potency Antihistamines

Histamine acts as a neuromediator via three receptors: H1 receptors, which are located in the brain and the central nervous system, H₂ receptors, which mediate the secretion of gastric acid and other hormones, and H₃ receptors, which are involved in vasodilation and vasoconstriction of blood vessels. Classic sedating antihistamines, the newer nonsedating antihistamines, and tricyclic antidepressants can be used to block pruritis caused by histamine. Tricyclic antidepressants will be discussed separately.

Antihistamines are one of the most widely used medications in the world. They are helpful for treating diseases in which histamine plays a central role such as urticaria. But in most pruritic disorders they have only sedative and placebo effects³. Exception should be made, however, for antihistamines such as cetirizine that show an additional inhibitory effect on eosinophils. These play an important role in mediator release in a variety of allergic disorders and atopic eczema. Due to the limited and controversial antipruritic effect of antihistamines within the great variety of itching dermatoses, and the large number of papers on antihistamines, this will not be discussed here in further detail. In particular, evidence based studies fullfilling Cochrane’s criteria in atopic dermatitis have never been performed.

Table 1: Some dermatological disorders associated with pruritus¹

Opiate Antagonists

Severe itching can follow epidural and intraspinal analgesia. This is due to the presence of µ-opioid receptors in the central nervous system, and can be antagonized by naloxone. Opiate antagonists have also shown some antipruritic potency in etiologically different types of pruritus such as cholestatic^4,5, uremic⁶, butorphanol-induced⁷, histamine-induced⁸ pruritus and in itching associated with urticaria and atopic dermatitis⁹.

Serotonin Receptor Antagonists

Since 1993, several reports have been published on the improvement of cholestatic¹⁰, uremic¹⁰ and opioid-induced¹¹ pruritus by ondansetron, a serotonin (5HT3) receptor antagonist. Under experimental conditions this antipruritic potency could not be verified¹². Further investigations showed that tropisetron, another 5-HT₃ receptor antagonist, has some antipruritic potency in mast cell depleted skin¹³.

Tricyclic Antidepressants

Tricyclic antidepressants bind to H₁ receptors with a high degree of affinity, and to a lesser extent to H₂ receptors. Doxepin has demonstrated antihistaminergic, antimuscarinic, antiserotonergic, anti-alpha-adrenergic and sedative activity^14,15. Tricyclic antidepressants may also have some effects on neurogenic and psychogenic itching. Oral doxepin proved to reduce itching in patients suffering from chronic idiopathic urticaria. Due to its pharmacokinetic profile doxepin can be applied topically, reducing systemic adverse effects such as drowsiness, dryness of the mouth and eyes, and constipation¹⁵.

Tacrolimus (FK 506)

Tacrolimus is a macrolide immunosuppressive agent, which suppresses the T-cell mediated immune response. It mediates pruritus via the modulation and suppression of T-cell invasion, and the release of mediators that can provoke pruritus. Systemic administration of tacrolimus (FK 506) is effective for the treatment of psoriasis, Behcet’s disease, pyoderma gangraenosum and Crohn’s disease¹⁶. A topical formulation of tacrolimus (Protopic/Fujisawa) is undergoing regulatory evaluation in the US and Canada for use in atopic dermatitis and other inflammatory dermatoses¹⁶.

Ascomycin

Ascomycin derivatives represent a new class of compounds with immunomodulating properties. SDZ ASM 981 is the first ascomycin macrolactam derivative to be developed for the treatment of inflammatory skin diseases, especially atopic dermatitis¹⁷. It selectively inhibits the release of inflammatory cytokines. This derivative can only penetrate damaged skin. To our knowledge there are no data on its systemic effects in pruritus and pruritic skin diseases.

Table 2: Different types of pruritus and antipruritic drugs

Other

Immunosuppressives such as corticosteroids and cyclosporine may have an itch-relieving effect in atopic dermatitis and cutaneous T-cell lymphoma. However, they are not antipruritic drugs, because the antipruritc action is secondary to the result of their anti-inflammatory activity.

References

1. Modified from Bernhard JD. Pruritis in skin diseases. In Bernhard JD: Itch – Mechanisms and management of pruritus. New York: McGraw-Hill p37–67 (1992).
2. Bernhard JD. Itch-Mechanisms and management of pruritus. New York: McGraw- Hill p229–242 (1992).
3. Schmelz M, Schmidt R, Bickel A, Handwerker HO, Torebjörk HE. Specific Creceptors for itch in human skin. J Neurosci 17(20):8003–8 (1997 Oct).
4. Nolen TM. Sedative effects of antihistamines: safety, performance, learning and quality of life. Clin Ther 19(1):39–55;discussion 2–3 (1997 Jan–Feb).
5. Bergasa NV, Talbot TL, Alling DW, et al. A controlled trial of naloxone infusions for the pruritus of chronic cholestasis. Gastroenterology 102(2):544–9 (1992 Feb).
6. Bergasa NV, Alling DW, Talbot TL, Wells MC, Jones EA. Oral nalmefene therapy reduces scratching activity due to the pruritus of cholestasis: a controlled study. J Am Acad Dermatol 41(3 Pt 1):431–4 (1999 Sept).
7. Peer G, Kivity S, Agami O, Fireman E, Silverberg D, Blum M, Iaina A. Randomised crossover trial of naltrexone in uraemic pruritus. Lancet 348(9041):1552–4 (1996 Dec).
8. Bernstein JE, Grinzi RA. Butorphanol-induced pruritus antagonized by naloxone. J Am Acad Dermatol 5(2):227–8 (1981 Aug).
9. Heyer G, Dotzer M, Diepgen TL, Handwerker HO. Opiate and H1 antagonist effects on histamine induced pruritus and alloknesis. Pain 73(2):239–43 (1997 Nov).
10. Metze D, Reimann S, Beissert S, Luger T. Efficacy and safety of naltrexone, an oral opiate receptor antagonist, in the treatment of pruritus in internal and dermatological diseases. J Am Acad Dermatol 41:533–9 (1999).
11. Schwörer H, Ramadori G. Treatment of pruritus: a new indication for serotonin type 3 receptor antagonists. Clin Investig 71(8):659–62 (1993 Aug).
12. Larijani GE, Goldberg ME, Rogers KH. Treatment of opioid-induced pruritus with ondansetron: report of four patients. Pharmacotherapy 16(5):958–60 (1996 Sep–Oct).
13. Weisshaar E, Ziethen B, Gollnick H. Can a serotonin type 3 (5-HT3) receptor antagonist reduce experimentally-induced itch? Inflamm Res 46(10):412–6 (1997 Oct).
14. Weisshaar E, Ziethen B, Rohl FW, Gollnick H. The antipruritic effect of a 5-HT3 receptor antagonist (tropisetron) is dependent on mast cell depletion – an experimental study. Exp Dermatol 8(4):254–60 (1999 Aug).
15. Figueirado A, Fontes Ribeiro CA, Goncalo M. Mechanisms of action of doxepin in the treatment of chronic urticaria. Fundam Clin Pharm 4:147–158 (1990).
16. Bernstein JG. Handbook of drug therapy in psychiatry. 3rd ed. St. Louis, Missouri: Mosby Year Book Medical Publishers (1995).
17. Ruzicka T, Assmann T, Homey B. Tacrolimus: the drug for the turn of the millennium? Arch Dermatol 135(5):574–80 (1999 May).
18. Van Leent EJ, Gräber M, Thurston M, Wagenaar A, Spuls PI, Bos JD. Effectiveness of the ascomycin macrolactam SDZ ASM 981 in the topical treatment of atopic dermatitis. Arch Dermatol 134(7):805–9 (1998 Jul).
19. De Marchi SD, Cecchin E, Villalta D, Sepiacci G, Santini G, Bartoli E. Relief of pruritus and decreases in plasma histamine concentrations during erythropoietin therapy in patients with uremia. N Engl J Med 326(15): 969–74 (1992 Apr).
20. Steinman HK, Greaves MW. Aquagenic pruritus. J Am Acad Dermatol 13(1):91–6 (1985 Jul).
21. Berth-Jones J, Graham-Brown RA. Cholinergic pruritus, erythema and urticaria: a disease spectrum responding to danazol. Br J Dermatol 121(2):235–7 (1989 Aug).
22. Murphy M, Carmichael AJ. Renal itch. Clin Exp Dermatol 25(2):103–6 (2000 Mar).
23. Zuberbier T, Munzberger C, Haustein U, et al. Double-blind crossover study of high-dose cetirizine in cholinergic urticaria. Dermatology 193(4):324–7 (1996).