Systemic Drugs With Antipruritic Potency

E. Weisshaar, MD and H. Gollnick, MD, PhD
Departments of Dermatology and Venereology, Otto-von-Guericke-University Magdeburg, Germany

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.

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