E. Weisshaar, MD and H. Gollnick, MD, PhD
Departments of Dermatology and Venereology, Otto-von-Guericke-University Magdeburg, Germany
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.
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
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 cholestatic4,5, 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 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 activity14,15. 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 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.
|Type Of Pruritus||Treatments Successfully Reported With Antipruritic Potency|
|Hematological Pruritus||Identification and treatment of the underlying hematological or myeloproliferative disease|
|Endocrine Pruritus||Identification and treatment of the underlying endocrine disorder and symptomatic treatment|
|Pruritus in Pregnancy||Identification and treatment of the underlying disease/ dermatosis and symptomatic treatment|
|Pruritus in HIV/AIDS||Identification and treatment of the underlying disease, antiviral agents|
|Pruritus in Malignancy||Removal or arrest of underlying carcinoma, no specific antipruritic agent|
|Drug-Induced Pruritus||Discontinue drug|
|Psychogenic Pruritus||Depending on cause, good results with doxepin 3 x 10 mg/day15|
|Aquagenic Pruritus||Antihistamines have partial relief19|
|Pruritus Sine Materia||Identification and treatment of the underlying dermatosis/systemic disease|
Table 2: Different types of pruritus and antipruritic drugs
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.
- Modified from Bernhard JD. Pruritis in skin diseases. In Bernhard JD: Itch – Mechanisms and management of pruritus. New York: McGraw-Hill p37–67 (1992).
- Bernhard JD. Itch-Mechanisms and management of pruritus. New York: McGraw- Hill p229–242 (1992).
- 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).
- 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).
- 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).
- 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).
- 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).
- Bernstein JE, Grinzi RA. Butorphanol-induced pruritus antagonized by naloxone. J Am Acad Dermatol 5(2):227–8 (1981 Aug).
- 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).
- 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).
- Schwörer H, Ramadori G. Treatment of pruritus: a new indication for serotonin type 3 receptor antagonists. Clin Investig 71(8):659–62 (1993 Aug).
- 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).
- 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).
- 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).
- 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).
- Bernstein JG. Handbook of drug therapy in psychiatry. 3rd ed. St. Louis, Missouri: Mosby Year Book Medical Publishers (1995).
- Ruzicka T, Assmann T, Homey B. Tacrolimus: the drug for the turn of the millennium? Arch Dermatol 135(5):574–80 (1999 May).
- 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).
- 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).
- Steinman HK, Greaves MW. Aquagenic pruritus. J Am Acad Dermatol 13(1):91–6 (1985 Jul).
- 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).
- Murphy M, Carmichael AJ. Renal itch. Clin Exp Dermatol 25(2):103–6 (2000 Mar).
- 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).