Chronic Pruritus in the Absence of Specific Skin Disease: An Update on Pathophysiology, Diagnosis, and Therapy

Nicoletta Cassano; Gianpaolo Tessari; Gino A. Vena; Giampiero Girolomoni

Disclosures

Am J Clin Dermatol. 2010;11(6):399-411. 

In This Article

General Considerations in the Treatment of Pruritus

Removal of the causative agent, whenever possible, and appropriate treatment of the underlying disease is essential. Skin care measures to alleviate skin dryness such as use of moisturizers, reduction in frequency of bathing, humidification of dry indoor environments, prevention of excessive sweating, and avoidance of hot baths, soap, and irritant fabrics are generally recommended.[21] In particular, the skin of elderly people benefits from regular use of emollients.[21,22] Improper use of topical medications (e.g. corticosteroids for prolonged periods, possible sensitizing agents such as topical antihistamines and anesthetics) must be avoided.

Targeting Pruritus Elicitation in the Skin

Dermatologic itch must be managed through treatment of the specific skin disorder or skin changes. Irresistible episodes of pruritus can be controlled by application of cold compresses and wet dressings with topical corticosteroids.[78] Topical antipruritics such as camphor, menthol, oatmeal baths, and polidocanol arecommonly used, but evidence fromRCTsis lacking.

Oral antihistamines are frequently prescribed in the case of any pruritic condition, sometimes as an ex juvantibus criterion. Sedative and/or anti-inflammatory qualities of certain H1 receptor antagonists are thought to be useful to control itch. However, with the exception of urticaria and mastocytosis, the role of antihistamines for the management of other pruritic disorders is still controversial.[79,80] Nevertheless, a recent retrospective analysis of 67 patients with chronic pruritic dermatoses or chronic pruritus of unknown origin has shown good antipruritic effects with high-dosage nonsedating H1 receptor antagonists, used as monotherapy or in combination.[81]

Phototherapy with various UV sources, especially UVB, is widely used in patients with chronic pruritus. It has a wide antiinflammatory cutaneous activity, and can offer relief without many of the adverse effects and risks of systemic medications. Its efficacy has been demonstrated in some RCTs.[40,41,82,83]

Some itchy conditions (e.g. notalgia paresthetica, prurigo nodularis, aquagenic pruritus, and also uremic pruritus) may respond to topical capsaicin, a substance binding to the TRPV1 receptor. TRPV1 receptors are nonselective heat-activated cation channels, located in theCNS and in cutaneous nerve fibers. They are involved in the transmission and modulation of itch. Capsaicin induces desensitization of nerve fibers, inhibition of neuropeptide accumulation, and suppression of painful and pruritic sensations.[84] Topical calcineurin inhibitors (tacrolimus and pimecrolimus), which are approved for treatment of atopic dermatitis, have been found to bind to TRPVl on cutaneous nerve fibers, and to cause an initial release of substance P and calcitonin gene-related peptide from primary afferent nerve fibers.[84] This effect explains the transient burning occurring during the first days of treatment. Topical calcineurin inhibitors are useful for treating the pruritus associated with some dermatoses, such as atopic dermatitis.

Thalidomide, which can be useful in the treatment of prurigo nodularis, actinic prurigo, as well as uremic pruritus, acts as an immunomodulatory drug, a tumor necrosis factor-α inhibitor, and also a peripheral and central nerve depressant, but has an unfavorable safety profile.[39]

Novel approaches to dermatologic itch, which deserve further evaluation, are H4 receptor antagonists,[80] topically applied opioid receptor antagonists,[85] and cannabinoid receptor agonists such as palmitoylethanolamide, stearoylethanolamide, and stearoylisopropylamide.[86]

The treatment of prurigo nodularis is particularly challenging. Phototherapy (UVB, oral PUVA) has been proven to be effective and safe in a RCT, but the need for regular sessions of therapy is impractical for many patients.[83] No RCTs are available with any other drug, including emollients, corticosteroids, topical capsaicin, topical tacrolimus, cyclosporine (ciclosporin), thalidomide, naltrexone, antidepressants, and oral retinoids.[18] Results are variable, but long-term combinations and rotational treatments can be effective.

Targeting Pruritus Elicitation in the CNS

Gabapentin, carbamazepine, and derivatives, commonly used as antiepileptic drugs, are capable of blocking the neuropathic afferent pathway and therefore may be helpful in neuropathic itch. Gabapentin was also recently proven to be well tolerated and effective in the treatment of uremic pruritus and various pruritic disorders.[37,87] Its mechanism of action is unclear and has been hypothesized to be both central and peripheral. Gabapentin and pregabalin inhibit release of calcitonin gene-related peptide from primary afferent neurons through an increase of GABA in the spinal cord.[87] Compared with gabapentin, pregabalin is characterized by a more rapid response, but evidence from RCTs in the treatment of pruritus is lacking.[88]

Opioid receptor antagonists, such as naloxone and naltrexone, have an important influence on the neurogenic component of itch by inhibiting itch transmission. Systemically administered opioid receptor antagonists showed antipruritic effects not only in hepatogenic pruritus, but also in hydroxyethyl starchinduced pruritus and various pruritic skin diseases, such as atopic dermatitis, cutaneous lymphoma, and prurigo nodularis.[89,90] However, adverse effects and costs lead to considering these drugs as a second-line approach to chronic pruritus. Butorphanol possesses both κ-agonist activity and μ-antagonist activity, and has been successfully used in small case series of patients with intractable pruritus.[91]

Antidepressants directly influence central pruritus perception by as-yet unknown mechanisms. It is speculated that they interfere in the neuronal reuptake of neurotransmitters, such as serotonin and norepinephrine, and thereby reduce pruritus perception. Accordingly, tricyclic (e.g. amitriptyline, clomipramine, doxepin) and tetracyclic (e.g. mirtazapine) antidepressants have been employed with some success in chronic pruritus and prurigo nodularis.[18,92,93] Doxepin and mirtazapine have additional antihistaminic effects. The selective serotonin reuptake inhibitor paroxetine was reported to have antipruritic effects in polycythaemia vera, psychogenic pruritus, paraneoplastic pruritus, and idiopathic pruritus in a small RCT.[94]A recent open-label study supports the usefulness and good tolerability of paroxetine and fluvoxamine in patients with chronic pruritus.[95] Paroxetine may produce a variety of cutaneous and noncutaneous adverse effects requiring adequate monitoring of the patient.[96]

A list of the most frequently used systemic therapies for pruritus, other than antihistamines, is given in table VII .

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