Pathophysiology of Itch and New Treatments

Ulrike Raap; Sonja Ständer; Martin Metz

Disclosures

Curr Opin Allergy Clin Immunol. 2011;11(5):420-427. 

In This Article

Stepwise Approach for the Therapy of Itch

An important factor in itch is dry skin. Thus, a moisturizing therapy should be initiated. A wide array of medications (e.g. β-blockers, allopurinol) and psychogenic factors but also hot spices, alcohol, and hot beverages can intensify the sensation of itch, which should be avoided accordingly and are included in the first step of therapy for itch (Table 2).[51]

Local Therapies for the Stepwise Approach to Treat Itch

Lesions caused by scratching should be treated with classic dermatological therapies [e.g. emollients, topical corticosteroids, short-term relief with polidocanol, urea, menthol as first step therapy (Table 2)]. The second step of therapy includes the treatment of the cause of itch (Table 2). During the third step of therapy chronic localized lesions from scratching (e.g. lichen simplex, prurigo nodularis) are treated, for example with capsaicin cream[51] (Table 2). Further, calcineurin inhibitors including tacrolimus and pimecrolimus are included in the third step of itch therapy as shown in atopic dermatitis, prurigo, chronic-irritant hand eczema and genital pruritus[52] (Table 2). Topical cannabinoid agonists may also be used for the treatment of itch as shown in patients with atopic dermatitis[53] (Table 2).

Many patients require a combination of systemic and topical therapies due to itch and secondary scratch lesions. Whole-body phototherapies with UV-A or UV-B light are included in the third step of therapy (Table 2) and can be used separately or in combination. UV-therapy can be helpful in patients with contraindications to systemic agents, for example in itch during late-term pregnancy, in the elderly patient and in patients in whom other antipruritic therapies have failed. However, UV-light therapy is not recommended for patients using calcineurin inhibitors.

Systemic Application of Drugs for the Stepwise Approach to Treat Itch

The newer and nonsedating H1-antihistamines are a popular treatment option in chronic pruritus due to their good efficacy, low costs and lowside-effects. They are included in the fist step of therapy of itch (Table 2). In patients with chronic urticaria an updosing of nonsedating antihistamines up to four-fold had been recommended by an international panel of experts as shown in the latest guideline of the European Academy of Allergy and Clinical Immunology.[54] This may also account for other itchy skin diseases. Because modern antihistamines may, at least in higher dosages, also be able to reduce the extent of degranulation and release of other pruritogenic medicators by mast cells, this may further enhance the antipruritic effect of antihistamines.[55]

Most other currently employed systemic approaches of treating itch target the central nervous system. For example, in clinical practice, anticonvulsants including gabapentin and pregabalin have been shown to be effective in the treatment of itch that are included in the third step for the therapy of itch[56] (Table 2). The exact mechanism of action for these drugs, however, is not yet clarified.

Another third step therapy include antipruritic drugs including agonists or antagonists of the opioid system (Table 2). Naltrexone, for example is an oral opioid receptor antagonist with a long-lasting, selective blockade of μ-opiate receptors. Naltrexone has been shown to be partially effective in relieving itch in case series and controlled trials of patients with chronic kidney diseases and in various dermatological diseases.[57•] Based on the assumption that opioid-induced itch is mediated by activation of μ-opioid receptors and can be suppressed by activation of κ-opioid receptors, it was thought that κ-agonists may be an effective treatment for itch. This is supported by the finding that the κ-receptor agonist nalfurafine effectively reduced itch in treatment refractory hemodialysis patients.[58•]

Various antidepressants have long been used in the treatment of chronic itch and are included in the third step of therapy (Table 2). For example, the antipruritic effectiveness of the selective serotonin reuptake inhibitors paroxetine and sertaline has been documented in controlled studies and case reports of patients with polycythemica vera, somatoform pruritus, paraneoplastic pruritus, and cholestatic pruritus.[59]

Mirtazapine, a tetracyclic antidepressant with additional H1 antihistaminic and serotonergic effects has successfully demonstrated an antipruritic effect in idiopathic pruritus, cholestasis, uremia, and neoplasm-induced pruritus.[60] Furthermore, the tricyclic antidepressant doxepin can be used topically and systemically for its additive antihistaminic and anticholinergic effects in pruritus.[61]

The exact mechanisms underlying the documented antipruritic effects of the described drugs are not entirely clear. One important aspect, especially for the tricyclic and tetracyclic antidepressants, may be the known antihistaminergic effect of these drugs. Furthermore, central nervous effects of serotonin are thought to have a regulatory action on the itch-related transmission.[61]

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