Chester Clinic

Pii: s0002-9343(02)01434-

Pruritic Dermatoses: Overview of Etiology and
Therapy
Ernest N. Charlesworth, MD, Vincent S. Beltrani, Sr., MD This review begins with a brief survey of the neuro-
physiology and neuroanatomy of pruritus, and goes
uli in only a limited number of ways. The sensa- on to describe the etiology of the major allergic and
tion of itching, or pruritus, is the most common nonallergic pruritic disorders. The etiology of pruri-
symptom of dermatologic conditions. In 1660, the Ger- tus often suggests the appropriate treatment. For
man physician Samuel Hafenreffer defined itching as an example, urticaria, which is primarily mediated by
"unpleasant sensation that provokes the desire to histamine, is amenable to treatment with H antihis-
tamines. Second-generation, nonsedating antihista-
scratch," and although this definition has been modified mines appear to be more effective than sedating
to correlate with current knowledge, it remains a reason- antihistamines, perhaps because of better compli-
able one.Pruritus is the subjective sensation of itching.
ance. Other systemic pharmacologic options may be
The types and causes are complex and not yet completely useful in nonhistamine-mediated disorders, for ex-
understood. Perhaps the unfortunate plight of the itching ample, immunomodulators for inflammation-induced
patient is best described in this brief poem by Julian Ver- pruritus or opiate antagonists for atopic dermatitis.
Nonpharmacologic measures, such as proper skin
care, and physical modalities, such as phototherapy
I itch, I itch, the whole day through or acupuncture, may also be helpful. Am J Med.
I also itch at night.
2002;113(9A):25S–33S. 2002 by Excerpta Medica, I try so hard to stop myself I'm looking such a sight.
To itch is not so nice you know, It really is deplorable But to scratch is really something That is often quite enjoyable.
The sensation of itch is the common factor in a multi- tude of diverse cutaneous disorders. Histamine is the pri-mary mediator of itching in some types of allergic disease,but multiple agents or mediators can provoke itching inboth allergic and nonallergic diseases.
This review provides a brief overview of the pathogen- esis of itching, describes the major itching skin disordersrelated to allergic and nonallergic disease, and includes adiscussion of nonpharmacologic and pharmacologictherapies.
WHAT CAUSES PRURITUS?
Diffuse itch is believed to be induced by specific, nonmy-elinated C-fiber stimulation, whereas itch that is localizedboth in space and time involves the A-␦ fibers.A com-plex plexus of nonmyelinated, dendritic processes are be-lieved to be present at the distal endings of these fibers,which terminate in the lower epidermis and possibly at From the Department of Allergy and Dermatology, Shannon Clinic, SanAngelo, Texas, and Department of Allergy and Clinical Immunology, the dermal– epidermal junction, where the "itch recep- University of Texas Medical School at Houston, Houston, Texas, USA tors," not yet morphologically identified, are presumed (ENC); and the Department of Dermatology, College of Physicians and to be located. These polymodal (responsive to mechani- Surgeons, Columbia University School of Medicine, New York, NewYork, USA (VSB).
cal, thermal, and chemical stimuli) nociceptors are found Requests for reprints should be addressed to Ernest N. Charlesworth, only in the skin, mucus membranes, and cornea.No MD, Shannon Clinic, Department of Dermatology and Allergy, 215 East other tissue experiences pruritus. It is now generally ac- College Avenue, San Angelo, Texas 76903. E-mail: [email protected].
cepted that the sensations of itch and pain are transmitted 2002 by Excerpta Medica, Inc.
All rights reserved.
A Symposium: Pruritic Dermatoses/Charlesworth and Beltrani, Sr.
Figure 1. Simplified diagram of the neuroanatomic pathways for pruritus. Dendritic itch receptors in the epidermis and dermo-
epidermal junction can be activated by (proinflammatory) pruritogenic mediators, which travel through the peripheral sensory
nonmyelinated C-fibers to the dorsal root ganglia to the dorsal roots and into the spinal cord. The spinothalamic relay axons cross to
the contralateral ventrolateral quadrant rostral to the level at which the sensory neurons enter the spinal cord. The C-fibers reach the
thalamus and hypothalamus by means of the reticular formation of the encephalic trunk to the cerebral cortex.
by separate C-fibers. The magnitude of itch can be mod- proteases, kinases, cytokines, leukotrienes, neuropep- ulated by changes in stimulus frequency, but the quality tides, leukotrienes, opioids, and endorphins.
of itch does not change into pain at high frequencies.
Both C- and A-␦ fibers conduct impulses at varying Injection of histamine results in the characteristic symp- speeds to the spinal cord by means of the dorsal nerve toms of acute urticaria: the "triple response" of Lewis roots of the spinal nerves. provides a simplified dissipating within 1 hour. Urticaria and pruritus that last illustration of the pathway of itch sensations mediated by ⬎1 hour are unlikely to be caused solely by histamine, and the typical triple response is never noted in other Although the peripheral and central mechanisms of pruritic dermatoses. Histamine generates itch through itch are not fully understood, both altered peripheral ex- citation and central disinhibition are involved. Local par- 1, but not H2, itch receptors.It is also believed to render the zone of surrounding skin abnor- oxysmal pruritus is believed to have a central origin. Cen- mally sensitive to other stimuli. Stimuli normally per- tral inhibition may be partially restored by scratching.
ceived as tactile, pressure, or temperature-change sensa- This phenomenon is the basis of the "gate-control" the- tions are instead perceived as itch, in a phenomenon ory, which suggests that scratching and vibration cause known as alloknesis.
neural impulses to travel on the larger A-fibers, inhibitingthe itch signals in the slower C-fibers.The A-fiber input Serotonin and the Prostaglandins
"closes the gate" to the C-fiber output.Endogenous en- Other chemical mediators of pruritus include serotonin, kephalins are also believed to act at the spinal level to which is weakly pruritogenic and inconsistently produces modulate the perception of itch. Scratching may abolish a painful itch when injected intradermally,and the itch by central inhibition rather than by fatigue of the prostaglandins (PGE1, PGE2, endoperoxidases), which peripheral sensory receptor.
are weak pruritogens by themselves, but which can mark-edly increase the itch response when given with serotonin ENDOGENOUS AGENTS THAT CAUSE
or with histamine.
Proteinases and Kinins
Although numerous substances are thought to cause pru- These substances have also been proposed as mediators of ritus,direct evidence exists only for a causal role of his- itch. The injection of trypsin or chymotrypsin produces tamine in the itching experienced by patients with urti- intense itch associated with the triple response of Lewis, caria or mastocytosis. Other agents that have been inves- an effect that is inhibited by antihistamines, suggesting tigated in pruritus include serotonin, prostaglandins, that histamine is the primary mediator. Administration December 16, 2002 THE AMERICAN JOURNAL OF MEDICINE威 Volume 113 (9A) A Symposium: Pruritic Dermatoses/Charlesworth and Beltrani, Sr.
of papain or kallikrein causes a painful pricking sensation Table 1. Allergic and Nonallergic Causes of Pruritus
that is not associated with the triple response and does not respond to antihistamines.However, if proteinases —Atopic dermatitis are mediators of pruritus, they probably function by damaging nerve terminals, which results in stimulation of itch fibers, rather than by inducing release of chemical —Endocrine diseases mediators of pruritus.
This family of agents, considered to constitute "hista- mine-releasing factor," have been proposed as mediators Diabetes mellitus of histamine-independent itching. However, except for —Metabolic diseases interleukin (IL)-2, which shows a rapid, mild prurito- Chronic renal failure genic effect,none has been shown to either induce or prevent pruritus. Interestingly, although the level of tu- Carcinoid syndrome mor necrosis factor (TNF)–␣ is elevated in many pruritic —Malignant diseases dermatoses, it does not induce pruritus when injected into the skin.
Polycythemia rubra vera —Autoimmune diseases These agents, which are end products of arachidonic acid Dermatitis herpetiformis metabolism, evoke inflammation, but not pruritus, when Linear IgA syndrome therapy is virtually useless for treating pruritus, there are Pruritus ani and pruritus scroti/vulvi several reports of some decrease in the itch of Sjo¨gren Neuropsychiatric causes syndrome with the use of zileuton, a 5-lipoxygenase in-hibitor, which suppresses the release of leukotrienes B4, IgA ⫽ immunoglobulin A.
C4, D4, and E4.
opioid-induced pruritus. Evidence increasingly suggeststhat endogenous opioids (endorphins) may be involved Such agents as substance P, vasoactive intestinal polypep- in transmission of itch.
tide, and neurotensin A are abundant in the sensory neu-rons of the skin. Substance P and vasoactive intestinal polypeptide are the most potent histamine-liberatingagents in humans.Substance P induces the triple re- Atopic dermatitis (AD) and urticaria are allergic diseases sponse, suggesting that its effects are probably mediated in which pruritus is a predominant symptom. A multi- by histamine, which would be consistent with the obser- tude of nonallergic causes for pruritus also exist vation that the pruritic effects of substance P can be blocked by oral antihistamines. However, none of the peptides are directly pruritogenic, and it remains to be AD refers to the chronic, subacute, eczematous skin le- determined whether neuropeptides are responsible for sions characterized by an unrelenting itch. AD is gener- clinical pruritus.
ally defined as a chronically relapsing inflammatory skin Opioids and Endorphins
disease that frequently occurs in patients with a personal The role of these agents in the production of itch is un- or family history of asthma or allergic rhinitis.The dis- clear. Pruritus is the most common side effect of the in- order, which is increasing in frequency, has an estimated trathecal administration of opioids. Opioids can stimu- incidence of 10%.In contrast to other dermatologic late ␬- and ␦-receptors in the central nervous system disorders that are characterized by a primary lesion, e.g., and induce the release of histamine and other preformed psoriasis (papulosquamous lesions) or dermatitis herpe- mediators from mast cells.Interestingly, the various tiformis (DH; vesicular bullous lesions), AD lacks a pri- opioids differ in their capacity to release histamine, which mary skin lesion. Only the secondary cutaneous findings suggests that the mechanism is not immunologic.In the of excoriation, weeping, and lichenification, as well as pruritic dermatoses, opioids and endorphins have not pigmentary changes, are apparent. Hanifin and Rajka been conclusively implicated in the production of itch.
have defined the major and minor criteria for AD. Just as However, opioid antagonists, such as naloxone, naltrex- allergic rhinitis is characterized by sneezing and extrinsic one, ondansetron, and rifampicin, effectively control asthma is defined by wheezing, AD is characterized by December 16, 2002 THE AMERICAN JOURNAL OF MEDICINE威 Volume 113 (9A) 27S
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Table 2. Immune Abnormalities Present in Atopic Dermatitis
Urticaria
Urticaria is a common disorder of the skin characterized
Increased IgE synthesis by the transient appearance of elevated, erythematous le- Increased immediate skin-test reactivity to allergens sions that often have a pale center and that wax and wane, Increased basophil histamine release Impaired delayed-type hypersensitivity response moving from one site to another.Urticaria is typically Decreased CD8 suppressor/cytotoxic number and function markedly pruritic. Exceptions are urticarial vasculitis and Increased sIL-2 receptor levels delayed-pressure urticaria, which are characterized by Increased expression of CD23 on mononuclear cells pain or a burning sensation.
Increased production of IL-4 and IL-5 Histamine is the primary mediator for most types of Decreased production of IFN-␥ urticaria. Kaplan et alreported that 93% of patients CD ⫽ cluster of differentiation; IFN ⫽ interferon; IgE ⫽ immunoglob- with chronic urticaria clearly exhibited increased hista- ulin E; IL ⫽ interleukin; sIL ⫽ soluble interleukin.
mine release into skin blisters overlying lesions of urti-caria. In 4 of 5 patients with cold urticaria, levels of his-tamine were significantly elevated in skin blister fluid.
itching.Therefore, an AD-like syndrome but without An additional mechanism of chronic urticaria is the itching should lead one to consider other diagnoses. Be- production of an immunoglobulin (Ig) G autoantibody cause the onset of AD typically occurs at an early age, directed against the high-affinity ␣-subunit of the IgE new-onset pruritic eczematous dermatitis in an elderly receptor on mast cells and basophils.This may occur in adult is more likely to be caused by cutaneous T-cell lym- as many as 30% of patients with chronic idiopathic urti- phoma or another disorder.
caria. Many of these patients develop a wheal and flare in The itch sensation in AD can be produced by a number response to a skin test with autologous serum, suggesting of different chemical mediators. Some of them serve as that a serum factor may induce histamine release from histamine liberators, although it would be naive to think cutaneous mast cells. There is also evidence that the his- that histamine is the sole or even the primary evoker of topathologic finding in these patients may resemble those the itch in this disease. In addition to an increase in the in patients with cutaneous late-phase responses to aller- presence of mediators that provoke itching, it is possible gen, with the observation of a polymorphous infiltrate that such patients have a decreased "itch threshold," consisting of eosinophils, neutrophils, and mononuclear which may be even more important in the pathophysiol- cells.Although classic antihistamines may show a ogy of AD than chemical mediators. The complexity of partial therapeutic effect in these patients, a strong argu- the perception of itching and the importance of the low- ment can be made for the use of newer nonsedating H1 ered itch threshold is underscored by the existence of antihistamines, which may demonstrate some anti-in- multiple environmental factors that contribute to AD, flammatory effects, such as inhibition of eosinophil mi- including exposure to woolen clothing, perspiration, and gration and synthesis and release of mast cell mediators, bacterial toxins; even psychological factors have been im- in addition to their H1-receptor actions.
Urticarial vasculitis is a small-vessel vasculitis in which Immunohistochemical staining of both acute and the morphology of the skin lesions resembles that of or- chronic lesions of AD shows lymphocytic infiltrates con- dinary urticaria, whereas the histopathologic features are sisting of cluster of differentiation (CD)3, CD4, and those of leukocytoclastic vasculitis. A skin biopsy is re- CD45RO memory T cells. Nearly all T-cell infiltrates in quired to confirm the diagnosis. Clinically, the lesions AD lesions express high levels of skin lymphocyte homing tend to persist in the same general areas beyond 24 hours receptor, cutaneous lymphocyte–associated antigen. The and may leave a purpuric stain on the skin.Extracuta- ability of the memory T cells to target the skin is further neous symptoms may occur and are often associated with enhanced by the presence of vascular cell adhesion mol- a decrease in serum complement. Musculoskeletal com- ecule–1, which acts as a vascular adhesion ligand for eo- plaints, such as arthralgias and arthritis, occur in 50% to sinophils. An abundance of major basic protein has been 75% of patients. Gastrointestinal symptoms, including detected in the dermis of patients with AD, representing abdominal pain, nausea, vomiting, and diarrhea, occur in the "footprints" of eosinophils in this inflammatory bat- approximately 17% to 30% of patients. Renal or pulmo- tle. Some of the immunoregulatory abnormalities found nary involvement may also appear as a late complication.
in AD are listed in It is clear that Th2 and Th1 Unlike the more common types of urticaria, urticarial cytokines contribute to the pathogenesis of the skin in- vasculitis involves more complex mechanisms than his- flammation in AD, but the exact pathogenesis of the itch- tamine release into the skin. This explains why antihista- ing remains unclear. The skin of patients with AD is in- mines, although useful for the control of pruritus in ur- herently pruritic; in no other dermatitis is the relation ticarial vasculitis, may not control the disease. Although between physical and emotional components interwoven histamine may play a role in the early phase of urticarial vasculitis, in later stages circulating antigen-antibody December 16, 2002 THE AMERICAN JOURNAL OF MEDICINE威 Volume 113 (9A) A Symposium: Pruritic Dermatoses/Charlesworth and Beltrani, Sr.
complexes form in the blood and are deposited in the iary obstruction, there is little or no correlation between vessel walls. Complement is activated by the classic path- serum concentrations of bile salts and the actual severity way, and C3a and C5a are generated, both of which are of itching. However, a role of bile salts in the skin cannot anaphylatoxins that contribute to the clinical lesions of be dismissed, because the application of bile salts to skin urticaria. These anaphylatoxins are capable of inducing blister bases in concentrations approaching those found skin mast cells to release histamine but also can set into clinically produces intense itching.Recent studies sug- motion the generation of multiple cytokines and chemo- gesting that opioid peptides may play a role in the pruri- kines that function as chemotactic factors, resulting in the tus of cholestasis have generated interest in the potential influx of neutrophils and eosinophils. The antibody iso- of opioid antagonists, such as naloxone and naltrexone, type in the immune complexes of urticarial vasculitis is as histamine-independent therapies for treating pruritic usually IgG or IgM. The antigen may be autologous or skin diseases.
exogenous from an infectious agent or a medication.
Pruritus is not uncommon in endocrine disorders. Gen- Although there is no evidence that cutaneous mastocyto- eralized itching may be a presenting symptom of thyro- sis is an allergic skin disease, the systemic release of mast toxicosis, possibly related, in part, to an increase in blood cell– derived histamine causes generalized itching, in- flow to the skin. Hypothyroidism may also be associated creased vasopermeability, bronchoconstriction, urti- with itching, which is aggravated by the dryness of the caria, and even gastric hypersecretion. Clinical syn- skin typical of this condition. Although generalized pru- dromes of mastocytosis range from localized cutaneous ritus is not a feature of diabetes mellitus, localized itching involvement to mast cell leukemia, all of which are char- secondary to candidiasis is very common.
acterized by the excess production of mast cell mediators,with histamine being the primary culprit.
Urticaria pigmentosa is perhaps the most common The possibility of an underlying malignant disease should presentation of mastocytosis in both children and adults.
be considered in the middle-aged or elderly patient who The lesions of urticaria pigmentosa are usually erythem- presents with generalized pruritus. An expensive workup atous brownish plaques that urticate when stroked or is usually not justified, and the evaluation should be rubbed (Darier sign). Itching may be intense and is some- guided by a detailed history and physical examination.
times triggered by cutaneous trauma, friction, tempera- Lymphoma is the most likely associated neoplasm, with ture, alcohol ingestion, and certain drugs (e.g., codeine).
Hodgkin disease the most likely lymphoma. Patients withpolycythemia vera report a most unusual water-induced itching that is worse on the lower extremities.Interest- Patients with pruritus unrelated to allergic disease may ingly, such itching may precede the development of poly- exhibit a variety of underlying causal medical conditions, cythemia by several years. A similar symptom has been among them chronic renal disease, primary biliary cir- reported in association with hypereosinophilic syndrome rhosis, endocrine disorders, and malignant disease.
and myelodysplasia syndrome.
Chronic Renal Disease
About 50% of patients with chronic renal disease have DH is an intensely pruritic papular vesicular disorder as- pruritus, as do an estimated 80% of patients on chronic sociated with a gluten-sensitive enteropathy similar to renal dialysis. Mechanisms include xerosis, hyperpara- that seen with celiac disease. Pruritus is the primary thyroidism, iron deficiency, neuropathy, and possibly symptom, although some patients may experience burn- cholestasis.Rarely are antihistamines effective in sup- ing. Lesions are distributed symmetrically over the exten- pressing itching in these patients, even though plasma sor surfaces of the elbows, knees, and buttocks. DH is an histamine levels are elevated in uremia, and skin mast autoimmune disorder in which serum IgA and IgG anti- cells are increased in chronic renal disease.Treatment reticulin antibodies are found in many patients. Granular includes dietary restrictions and phosphate-binding ther- deposits of IgA are seen in the papillary dermis.These apy, as well as hydration therapy for xerosis. Although deposits lead to activation of the alternative complement antihistamines may offer some relief, ultraviolet B or pso- pathway, resulting in an influx of neutrophils and eosin- ralen plus ultraviolet A are common treatments.
ophils, which ultimately contributes to blister formation.
Primary Biliary Cirrhosis
Persons with certain human leukocyte antigen (HLA) an- Itching precedes the appearance of jaundice in 50% of tigens, including HLA-B8 and HLA-DR3, appear to be patients with primary biliary cirrhosis, which occurs al- predisposed to develop DH. Oral dapsone (diaminodi- most exclusively in women ⬎30 years old. Although pru- phenyl sulfone) or sulfapyridine relieves symptoms ritus may develop in many disorders associated with bil- within a few days.
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Linear IgA Dermatosis and Chronic Bullous
Table 3. Treatment of Pruritic Skin Disorders
Disease of Childhood
Identify and treat the provocative factors Linear IgA dermatosis (LAD) and chronic bullous disease Provide patient education on proper skin care of childhood (CBDC) are heterogeneous syndromes in Short, cool showers or 20- to 30-minute tepid baths which patients present with annular or grouped papules, Limit mild soap use to intertriginous areas only vesicles, and bullae. Like DH, the lesions of LAD and Lubricate frequently, especially after bathing CBDC are distributed symmetrically over the extensor Humidify ambient environment (in winter) surfaces of the elbows, knees, and buttocks. Unlike DH, Avoid contact irritants (e.g., wool, hairy pets, cleansers, these diseases are not associated with a gluten-sensitive enteropathy. CBDC is more common in children ⬍5 Topical antipruritics may offer short-term relief Camphor/menthol preparations (Sarna lotion*) years, with a slight predominance in girls. Like DH, Crotamiton (Eurax†) CBDC and LAD are strongly associated with the presence of the HLA-B8 haplotype, and immunofluorescence of perilesional skin shows a homogeneous band of IgA along Pramoxine HCI (Prax‡) the dermal– epidermal junction. In adults with LAD, Capsaicin cream51—especially for well-localized itches there is an association with lymphoid and nonlymphoid Eutectic anesthetics—especially for well-localized itches malignancies. Like DH, LAD responds to dapsone or sul- Topical doxepin53—may be suitable for small areas of fapyridine but not to a gluten-free diet. CBDC is usually a self-limited disease that tends to remit spontaneously within 2 years but may require treatment with dapsone or —Topical: corticosteroids,54 macrolides TREATMENT OF PRURITUS
Cholestyramine56: for renal failure, cholestasis, and The therapeutic objective in pruritis is its cessation.
Achievement of this goal can be difficult, and treatments Opiate antagonists: for atopic dermatitis,57 cholestasis are as diverse as the causes ().Therapy Oral cromolyn59: for systemic mast cell disease should focus on the elimination of a definable trigger.
Pruritus should always be considered as symptomatic of an underlying problem. However, too often the provoc- ative factor is unidentifiable or not curable. Symptomatic treatment is then the only option.
Histamine-induced pruritus, which is always accom- panied by a wheal and flare response, is amenable to treat- ment with H1 antihistamines, which effectively inhibit activation of the H 1 receptors. Such agents prevent, to varying degrees, but do not reverse, the responses medi- Fujisawa Pharmaceuticals Co., Ltd., Osaka, Japan.
ated by histamine alone. The best results are attained ‡ Ferndale Laboratories, Inc., Ferndale, MI.
when the antihistamine is administered "around-the-clock," not simply taken as needed. Maximum benefitoften requires the administration of doses higher than Antihistamine efficacy is assessed in terms of the those recommended. Doenicke et alfound that cur- agent's ability to inhibit the triple response of Lewisand rently recommended regimens do not adequately prevent the effects of histamine and suggest that additional doses 1 receptors in vitro.When antihistamines are administered to patients with urticaria, the itching after 4 hours may be needed to achieve an adequate ther- often disappears before the clearance of the wheals and apeutic response. Flushing is the first symptom to re- flares, as observed clinically by the author (VSB). Second- spond to antihistamine therapy. Flushing syndromes generation, nonsedating antihistamines seem to be more show a better response when both H1 and H2 antagonists effective than sedating antihistamines because they are are administered.
associated with better compliance.
The choice of antihistamine is based on its effective- ness, frequency of administration, and side-effect profile.
Comparative Studies with Newer and Older
The dose of the H 1 antagonist should be increased to tolerance, and adding an antihistamine from another H1-receptor antagonists are widely used to treat allergic group has been shown to be more helpful than increasing skin diseases characterized by pruritus, including urti- the dose of a single agent.
caria and atopic dermatitis. These agents prevent pruritus December 16, 2002 THE AMERICAN JOURNAL OF MEDICINE威 Volume 113 (9A) by acting on the H 1 receptors on the small, branching unmyelinated C-fibers in the skin.Thus, the distribu- The sensation of itching, or pruritus, is the most common tion of the antihistamine into the skin to produce cuta- symptom of dermatologic conditions. The types and neous H1 blockade would be important to its antipruritic causes of pruritus are complex and varied. Although his- tamine is the primary mediator of itch in some allergic Not surprisingly, comparative studies on antihista- disorders, such as urticaria, there are multiple potential mine distribution in the skin are rare. In 1 such study, mediators of itch in both allergic and nonallergic disor- Simons et alin Canada compared the extent of fexofen- ders. The selection of therapy is facilitated when the eti- adine and diphenhydramine distribution in the skin con- ology of an itching disorder is known. For example, his- comitantly with the H1-receptor antagonist activity. The tamine-induced itching generally responds to H results of this double-blind, prospective, randomized tamines, whereas tacrolimus may be useful in such T-cell parallel-group study, comparing a newer nonsedating diseases as AD. The challenge is to identify the cause of antihistamine with a classic sedating antihistamine, the symptom and to select the treatment that fits that showed that fexofenadine given orally penetrated the skin (obtained by punch biopsy), and suppressed whealing, toa significantly greater extent than diphenhydraminegiven orally.
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