Pathophysiology of Itch and New Treatments

Abstract and Introduction

Abstract

Purpose of review: Itch represents one of the most bothersome symptoms in allergic disorders and numerous dermatological and systemic diseases. Chronic itch has a dramatic impact on the quality of life. The pathophysiology of itch is diverse and involves a complex network of cutaneous and neuronal cells. Thus, we highlight the current pathophysiological aspects of itch together with new treatment options.
Recent findings: Apart from histamine, several mediators and receptors including the neurotrophins nerve growth factor (NGF), brain-derived neurotrophic factor, neurokinins/neuropeptides such as substance P, gastrin-releasing peptide, cytokines such as interleukin-31, autotaxin and the histamine H4 receptor have been identified for playing a role in the pathophysiology of itch. In the skin, tissue resident cells such as keratinocytes, mast cells and cells of the inflammatory infiltrate including lymphocytes and eosinophils have been described to interact with neuronal cells, for example via the release of neurotrophins, neuropeptides and cytokines, adding novel regulatory pathways for the modulation of itch. Accordingly, promising treatment strategies such as the neurokinin-1 receptor antagonist aprepitant have been introduced for a successful management of itch.
Summary: In this review, we highlight novel key players in the pathophysiology of itch with subsequent introduction of promising, novel and experimental treatment strategies.

Introduction

Itch represents one of the most bothersome symptoms, which almost everyone has experienced once in the lifetime. According to the International Forum for the Study of Itch, itch is defined as being chronic if it persists for 6 weeks or longer.^[1] Chronic itch can occur in all ages. However, children may be less affected because they also display a significantly lower number of comorbidities, which are known to evoke itch. Itch triggers the desire to scratch. Next to pain, itch may serve as an alarm system for the skin in order to remove possibly damaging or harming substances quickly by the triggering of scratch. Thus, acute itch fulfils an essential part of the innate defence mechanism of the body. However, chronic itch – especially when present for years – lost this function.

In the skin, many factors contribute to the induction, exacerbation and inhibition of itch. For example, physical stimuli such as cold and heat modulate the perception of itch; painful heat and cold can significantly diminish itch, whereas moderate cold intensifies it.^[2] Mechanical factors such as rubbing or scratching the skin can briefly suppress itch by activating nerve fibers that selectively activate and deactivate certain areas of the central nervous system.^[3]

Itch is mediated via free nerve endings of nonmyelinated C-type nerve fibres that are located at the dermoepidermal junction and within the epidermis. There is a subpopulation of itch-specific nonmyelinated C nerve fibres that respond only to histamine. Interestingly, there is also evidence of histamine-independent itch-specific fibers in the skin.^[4] In this regard, specific G protein-coupled receptors, which mediate chloroquine-induced itch have been identified in peripheral sensory neurons.^[5] These neurons also respond to other itch inducing signals including capsaicin. Further, spinal neurons express the gastrin-releasing peptide receptor, which has previously been shown to be importantly involved in the transmission of itch, indicating that receptor expressing neurons may be itch-specific.^[6]

Another key element for the transmission of itch are neurokinin-1 receptor expressing skin nerves and dorsal horn neurons as shown recently in a rat model, indicating that the neurokinin/neuropeptide substance P may play a role as a spinal transmitter for itch.^[7••]

Chronic itch is a major diagnostic and therapeutic problem and can have a profound impact on the patients' quality of life.^[8•] Itch can occur in patients suffering from numerous different diseases, for example inflammatory skin diseases, metabolic disorders, liver and kidney diseases, or lymphoproliferative and myeloproliferative disorders. The underlying causes and the mechanisms of itch are diverse and only partly understood. A better understanding of the pathophysiology of itch will support the diagnosis and treatment options for patients with chronic itch.

Cite this: Pathophysiology of Itch and New Treatments - Medscape - Oct 01, 2011.

Table 1. Stepwise graduated diagnostic assessment of patients with chronic pruritus (modified according to the AWMF-German Guidelines)
History	Onset and course of pruritus, presence and onset of skin lesions, known systemic and dermatological diseases and allergies, predisposition for atopic dermatitis, medical history, drug intake, family history
Clinical examination	basic: Physical examination including lymph nodes, skin examination, dermographism in-depth: Internal, neurologic, psychosomatic, gynecologic/urologic consult
Laboratory investigation	basic: Electrolytes, erythrocyte sedimentation rate, blood count, differential blood count, total protein, protein electrophoresis, iron metabolism, blood glucose, uric acid, urea, creatinine, liver transaminases, bilirubin, alcalic phosphatase, hepatitis serology, thyroid function test, total IgE serum level, PSA, urine status, fecal-occult-blood test in-depth: For example: level of folic acid, zinc, vitamin B12, antimitochondrial antibodies, immunoglobins, indirect immunofluorescence, antibodies against thyroid gland, parathyroid hormone level, parathormon, porphyrine, bone marrow investigation
Diagnostic procedures	Skin biopsy (histology, direct immunofluorescence) in case of presence of skin lesions, which could not have been classified upon clinical criteria, and performance of an additional skin biopsy, helicobacter pylori 13C urea breath test, lactose deficiency H2-exhalation test, endoscopy/biopsy
Imaging	basic: Chest radiograph, ultrasound abdomen in-depth: CT-scan or MRI-scan especially for tumor detection and in case of neuropathic pruritus, ultrasound lymph nodes

CT, computed tomography; IgE, immunoglobulin E; PSA, prostate specfic antigen.

Table 2. Stepwise approach for the symptomatic treatment of itch
	Therapy
First step	Moisturizing therapy Avoidance of triggering factors Initial symptomatic therapy: Nonsedating H1 antihistamines (sometimes updosing needed) Topical corticosteroids
Second step	Symptomatic therapy according to the cause of itch
Third step	In case of unclear cause and nonresponse during the second step: Symptomatic topical and/or systemic therapy including, for example capsaicin, calcineurininhibitors, cannabinoidagonists, naltrexone, gabapentin, UV-therapy, immunsuppressives (cyclosporine), antidrepressants
	Clinical studies in special centres
Supporting therapy during each step	Treating the cause (multidisciplinary)
	Basic therapy In case of sleeping disturbances: sedating H1 antihistamines, tranquilizer, trizyclic antidpressives or neuroleptics Psychosomatic consultation, for example trainings in case of automatic scratching habbits In case of erosive scratching lesions: disincentive therapies (e.g. Lavasept)local administration of steroids

Adapted from [51]

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