Pruritus: A Practical Approach PETERJ. GRECO,MD, JACK ENDE, MD PRURITUS IS TROUBLESOMEto both patients and physicians. It is an extremely unpleasant sensation with numerous causes, for w h i c h treatment is often ineffective. Several case series 1-6 and n u m e r o u s review articles T M have focused primarily on the systemic diseases that can cause generalized pruritus (Table 1). However, patients w h o present to a primary care physician with pruritus most likely have a skin disorder rather than a systemic disease. The two purposes of this article are 1) to outline a practical diagnostic approach to the patient with pruritus and 2) to review the effectiveness of the various treatments available for pruritus.

PATHOPHYSIOLOGY OF ITCH Itch can be p r o d u c e d experimentally by numerous chemical stimuli, including histamine, proteolytic enzymes, and prostaglandins. 4~ Physical stimuli that can induce pruritus include electrical impulses and heat. 12 Some pruritogens act i n d e p e n d e n t l y of histamine, which in part explains w h y antihistamines often fail to relieve pruritus. No " i t c h r e c e p t o r " has been identified; the itch sensation is carried to the dorsal root ganglion bysmalldiameter, slowly conducting unmyelinated neurons known as C fibers. *t These fibers also transmit " s e c o n d p a i n " (the intense discomfort experienced, for example, a second or two after stubbing one's toe). Certain stimuli such as histamine or electrical current can produce either itch or pain, depending on the manner in w h i c h the stimulus is applied. Though transmitted by the same type of fibers, pain and itch are associated with different patterns o f electrical impulse within those fibers: painful stimuli induce continuous, highf r e q u e n c y impulses, while pruritic stimuli induce bursting, discontinuous impulses. 42 Thus, itch and pain are distinct sensory modalities. C fibers relay their impulses to the dorsal horn of the spinal cord, and synapse with both local interneurons and relay neurons that ascend to the reticular formation and the thalamus. 43 Inhibitory interneurons within the dorsal horn can be activated by peripheral and central stimuli and thereby modulate the sensation of pain (and, presumably, pruritus); these interneurons Receivedfrom the Divisionof General Internal Medicine, Hospital of the Universityof Pennsylvania, Philadelphia, Pennsylvania. Address correspondence and reprint requests to Dr. Greco: Division of General Medicine, MetroHealth Medical Center, 3395 Scranton Avenue, Cleveland, OH 44109.

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release endogenous opiates. Exogenous opiates ameliorate pain but induce pruritus. 22, 44 The pruritus of primary biliary cirrhosis has b e e n postulated to be a consequence of elevated plasma concentrations of the endogenous opiates methionine enkephalin and leucine enkephalin. 44, 45 The use of opiate antagonists as a treatment for pruritus is discussed in a later section of this article.

EVALUATION OF THE PATIENT WITH PRURITUS A rational approach to the patient with pruritus begins with the assumption that most such patients have a primary skin disorder, not a systemic disease. Thus, at the initial visit, the identification and treatment o f skin disorders should take p r e c e d e n c e over a search for systemic disease. Laboratory evaluation can safely be reserved for the patient in w h o m no skin disorder is apparent and w h o does not respond to treatment.

LOCALIZED PRURITUS Patients with pruritus may describe itching that is either generalized or localized to certain regions. In most cases, localized pruritus is due to a regional infection or dermatosis. By contrast, diffuse pruritus implies a dermatologic or systemic disorder affecting the entire skin surface. Clinicians should be aware, however, that even in diffuse pruritus some areas of the b o d y may be more symptomatic than others due to regional variations in cutaneous innervation, t e n d e n c y for irritation, or susceptibility to scratching. Thus, a patient suffering from a diffuse disease such as xerosis (dry skin) may report itching predominantly around the arm creases and u p p e r thighs. Other diffuse disorders may have predilections for certain areas. For example, urticaria preferentially affects pressure points, psoriasis the extensor surfaces, pityriasis rosea the back. Thus, the categorization of localized pruritus should be made only after questioning and examining the patient regarding symptoms and signs o f itching in other areas. The clinical approach to the patient with localized pruritus is best organized regionally. The differential diagnosis should include dermatoses that are localized to certain parts o f the b o d y and those that are diffuse but have a predilection for these sites. In the sections that follow the more c o m m o n conditions are described. Figure 1 provides a more c o m p l e t e listing o f pruritic dermatoses organized by body region.

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Inguinal Pruritus Lichen simplex and psoriasis are c o m m o n causes of inguinal pruritus in men and women. Lichen simplex is described in a later section of this article; psoriasis is readily diagnosed by its clinical characteristics (erythematous papules and plaques with silvery scales). In men, pruritus in the inguinal area is due most commonly to dermatophyte (tinea) infections; occa-

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sionally it is due to contact dermatitis and pediculosis pubis, and rarely it is due to erythrasma. Scabies, psoriasis, and lichen simplex are c o m m o n causes of diffuse itching that can present primarily with inguinal pruritus. Tinea cruris usually results in bilateral, circinate, half-moon-shaped lesions starting in the crural folds, extending to the upper thighs and, rarely, to the external genitalia. The lesions are erythematous and scaling, often with central clearing. The scrotum is rarely in-

TABLE 1

Systemic DiseasesThat Cause Generalized Pruritus Condition

Reference(s)*

Carcinoma

Cormia 1965 zz

Chronic renal failure

Young et al. 197323

Drug abuse (noncholestatic) Alcohol Chloroquine Cocaine Heroin Morphine

Lyell 19723 Lyell 19723 Lyell 19723 Rathod et al. 1967 ~ Lyell 19723

Hematologic disorder Polycythemia vera

Lawrence eta]. 195325

Hodgkin's disease Non-Hodgkin's lymphoma Iron deficiency Hepatic cholestasis Drug-induced Anabolic steroids Cephalosporins Chlorpropamide Cimetidine Erythromycin estolate Gold NSAIDst Nicotinic acid Oral contraceptives Penicillin Phenothiazines Phenytoin Progestins Tolbutamide Pregnancy-related Primary biliary cirrhosis Hyperthyroidism Infection Giardia Helminths HIV*

Bluefarb 195926 Bluefarb 19592° Lewiecki 1976, 27 Vickers 1973 z8

Rarely the presenting symptom; not a feature of acute renal failure

"Pricking" quality; often associated with exposure to hot water Prognostic significance is unclear

Maddrey 1985 z9

Cunningham et al. 198930 Ahrens et al. 195031

Usually occurs in the third trimester; not always associated with jaundice Presenting symptom in around 50%

Caravati et al. 1969, ~2 Barrow and Bird 1966, 33 Barnes and Calnan 19743"

Occurs in 6% of patients with hyperthyroidism; sometimes associated with urticaria

Spaulding 1990, 3s Clyne and Eliopoulos 198936 Weller 19893~ Berger 1989 ~

Usually associated with urticaria Travel history Normal skin. papules, and folliculitis all have been described

Psychiatric disease Delusions of parasitosis Depression Neurotic excoriations

Comments

May manifest as numerous excoriations, lichen simplex chronicus (Fig. 2), or prurigo nodularis (Fig. 4) Lyell 19723 Sheehan-Dare et al, 199039 Fruensgaard 198440

*For complete reference citations, see the reference list. tNonsteroidal anti-inflammatory drugs. *Human immunodeficiency virus.

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GFeCO,Ende, PRURITUS

I Scalp I -Psoriasis .Seborrheic dermatitis

I Trunk I i ,Contact dermatitis (axillae,waistline) ,Erythrasma (axillae) ,Psoriasis

(periumbitica 0 ,Scabies .Seborrheic dermatitis .Urticaria

Patient with Localized Pruritus I I I I Anal region Inguinal region Hands I I I

.Candida • Contact dermatitis -Gonorrhea .Hemorrhoids .Pinworm

-Candida •Contact dermatitis .Erythrasma •Overuse of topical

.Psoriasis

.Pediculosis

•Tinea cruris

,Scabies •Tinea cruris

-Contact dermatitis •Scabies • Eczema

steroids

I Feet I ,Contact dermatitis ,Pitted keratolysis .,T nea pedis

I Legs ,Asteatotic eczema •Atopic dermatitis (popliteal fossae) ,Dermatitis herpetiformis (knees) • Lichen simplex (lateral malleoli) • Neurotic excoriations • Nummular eczema • Stasis dermatitis

FIGURE 1. Approachto the patient with localizedpruritus.

volved. Tight-fitting clothing, obesity, warm temperature, and prolonged exposure to moisture predispose toward this infection. Antifungal creams (such as 1% clotrimazole or 2% miconazole nitrate) or powders (such as tolnaftate) and measures to limit moisture are generally helpful, though recurrences are common. Inguinal pruritus in w o m e n is termed pruritus vulvae. Some patients with pruritus vulvae e x p e r i e n c e intense symptoms; scratching may be unavoidable, especially at night, resulting in lichenification (thickening o f the skin and increased p r o m i n e n c e of the normal skin markings) and scarring. In postmenopausal w o m e n pruritus vulvae is frequently due to estrogen deficiency and may respond to topical estrogen cream. Lubricants and gentle emollients may be helpful as well. Candidal vaginitis may incite vulvar pruritus and result in sustained itching as a result of lichenification; this disorder is readily diagnosed via examination of the vaginal discharge microscopically with potassium hydroxide. Lichen sclerosis et atrophicus is an uncommon disorder characterized by vulvar a n d / o r perianal papules and plaques that are white and atrophic. In addition to pruritus, this disorder can cause soreness, dysuria, and dyspareunia. Erythrasma, an intertriginous infection caused by a species of Corynebacterium, may be confused with tinea infections. Erythrasma is characterized by welldefined reddish-brown macules with fine scales; the borders are irregular but sharply demarcated. The diagnosis can be confirmed by the coral red appearance u n d e r a Wood's lamp; treatment with oral or topical erythromycin is effective, as are topical imidazoles. Infestation with the p u b i c louse (Phthiruspubis) is termed pediculosis pubis; this disorder causes itching in the inguinal area due to a delayed hypersensitivity reaction to the saliva of the causative organism; transmission is primarily sexual. The diagnosis can be made with a hand lens; either nits (eggs) or lice m a y b e seen. Lindane and p e r m e t h r i n are both effective. Contacts should be treated; treatment of fomites is probably unnecessary, however, because the organism cannot survive more than 48 hours off the human body.

Infestation with the body louse (Pediculus humanus corporis) is termed pediculosis corporis; this disorder also can involve the inguinal region. Symptoms may be so severe as to result in sleeplessness and irritability, h e n c e the phrase, "feeling lousy." Unlike pediculosis pubis, pediculosis corporis occurs primarily in persons with p o o r hygiene. As the body louse lives in the seams of clothing, the diagnosis is made by examining this area for lice and eggs. Boiling of infested clothing kills the organisms; treatment of contacts is unnecessary. Contact dermatitis can o c c u r in the inguinal area; not uncommonly, the inciting agent is an antifungal preparation used to treat a dermatophyte infection. In the acute stage, contact dermatitis presents with irregular, poorly outlined patches o f erythema and edema with surrounding vesicles and papules; lesions often e x u d e serum and form crusts. In chronic cases the skin can b e c o m e lichenified. The hallmark of contact dermatitis is the telltale linear or angular distribution suggesting an "outside job." Diagnosis can be confirmed by skin testing, but the clinician may find it easier simply to eliminate the suspected allergen and observe the patient. Initial treatment should include wet-to-dry dressings soaked with saline or Burow's solution, four times per day. Topical corticosteroids provide a useful adjunct therapy; high-potency steroids are safe if used briefly, but 1% hydrocortisone is the most potent agent that can safely be used chronically in intertriginous areas. Rarely are oral corticosteroids needed. Anal Pruritus

Similar to the genital region, the anal region is a site of numerous pruritic dermatoses. Chief among these are contact dermatitis, psoriasis, lichen planus, and various infections and infestations. In addition, the anal region may b e c o m e itchy for no apparent reason; this is termed pruritus ani. More c o m m o n in men than in women, pruritus ani may be precipitated by local factors such as soiling from diarrhea or mechanical irritation from rubbing or scratching. At times, a patient's t e n d e n c y to scratch may be so persistent and problem-

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atic as to suggest a psychoneurosis. Lichenification m a y b e c o m e p r o m i n e n t in pruritus ani. Infestations, psoriasis, and dermatophytoses should be excluded. Treatm e n t with t a l c u m or other drying p o w d e r s helps to prevent laceration and chafing. Tucks® pads are preferred for w i p i n g after b o w e l m o v e m e n t s because they tend to be less irritating and abrasive than toilet paper. 1% hydrocortisone can be used if infection has b e e n excluded.

Pruritic Legs W h e n patients present with pruritus localized to the legs, several diagnoses should be considered. Lichen s i m p l e x (Fig. 2) can o c c u r anywhere on the b o d y that the patient can reach, but is a particularly likely diagnosis w h e n the characteristic skin changes are f o u n d around the malleoli or lateral aspects of the shins m areas that can be r u b b e d r e p e a t e d l y w i t h the opposite foot. Older patients are also p r o n e to certain causes of itchy legs. These include n u m m u l a r eczema, w h i c h consists of coin-shaped groupings of vesicles and p a p u l e s that eventually form crusts and scales; the cause is unknown. The duration of these lesions is variable; most cases persist for weeks, though some may last for years. T r e a t m e n t is with topical corticosteroids; recurrences are c o m m o n . Older patients also are predisp o s e d to asteatotic eczema, particularly in the winter months w h e n their skin is m o r e p r o n e to dryness. Recognizable b y the characteristic diffuse fissuring and cracking of the skin, asteatotic eczema, also k n o w n as e c z e m a craquel~, responds to the same measures used for treatment of xerosis (described b e l o w ) . Stasis dermatitis often is a c c o m p a n i e d b y a mild itching; it is easily diagnosed by the edema, increased pigmentation, varicosities, and occasional ulceration. Topical steroids can be helpful, though p r o l o n g e d use of p o t e n t steroids can result in irreversible atrophy. Itchy dermatoses with a p r e d i l e c t i o n for the legs are s u m m a r i z e d in Figure 1.

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hyperhidrosis; there is controversy as to the causative agent. This condition causes shallow pits in the stratum c o r n e u m on the ball of the foot. Treatment is directed at avoiding excessive moisture; topical e r y t h r o m y c i n and imidazoles are effective.

GENERALIZED PRURITUS Some patients c o m p l a i n of diffuse itching, not localized to any particular region of the body. Because of the n u m e r o u s possible causes of generalized pruritus, a systematic a p p r o a c h is necessary. The history m a y provide useful clues. Itching in other family m e m b e r s suggests scabies or infestation with a nonscabies mite f r o m a pet; n e w soaps or detergents suggest an allergic or irritant dermatitis. Onset or worsening in the winter is typical of xerosis (dry skin). O c c u r r e n c e during or just after bathing is characteristic of aquagenic pruritus, a condition of u n k n o w n cause that is characterized b y normal skin and diffuse pruritus on e x p o s u r e to water. In the elderly, this entity is due primarily to xerosis, 46 w h i l e in y o u n g e r patients it is usually idiopathic; occasionally, p o l y c y t h e m i a vera is the cause. The a p p r o a c h to the patient w i t h generalized pruritus is based on w h e t h e r there is an obvious skin abnormality on physical examination (Fig. 3); in practice, this distinction can be difficult 3 for two reasons. First, itching invariably leads to scratching, and in some patients the resulting secondary skin changes can domi-

P r u r i t i c Feet

Tinea pedis (athlete's foot) is the most c o m m o n cause of itchy feet. With a curious p r e d i l e c t i o n for the space b e t w e e n the fourth and fifth toes, tinea pedis is easily recognizable by the whitish scaling and maceration that form b e t w e e n the digits. T r e a t m e n t w i t h antifungal creams and p o w d e r s usually is successful but recurrences are c o m m o n and necessitate r e p e a t e d courses of therapy. Contact dermatitis often is found on the feet and can be confused with tinea pedis, particularly if the toes are involved. The differentiation can be made b y noting that the interdigital spaces are spared in contact dermatitis while these areas are typically involved in tinea pedis. Microscopic examination for fungi may be necessary. Pitted keratolysis is a pruritic, m a l o d o r o u s foot infection that occurs in persons w i t h

FIGURE 2. Lichensimplex chronicus: note the skin thickening and increased prominence of the normal skin markings (lichenification). (Reproduced with permission from Fitzpatrick TB, EisenAZ, Wolff K, Freedberg I, Austen KF. Dermatology in general medicine, 3rd edition. Copyright 1987, McGraw-Hill, Inc.)

Greco, EiTde, PRURITUS

344 Patient with Generalized Pruritus I

I Normal skin or excoriations I Consider diagnoses in table 2 U If none seems obvious, treat for xerosis

I Skin lesions other than excoriations I Consider diagnoses in table 3 U If none seems obvious, evaluate for scabies

If no response, evaluate lot systemic disease

If evaluation negative,consider skin biopsy or dermatology reterral

If evaluation negative,consider scabies, HIV, psychiatricdiagnoses

a vesicular disorder, may present without vesicles because of excoriation of the intensely pruritic lesions. 49 Finally, urticaria, though usually apparent on the basis of a careful history, may be inapparent at the time of physical examination because of the transient nature of the lesions. Table 2 provides a more c o m p l e t e list of the pruritic dermatologic conditions that may be inconspicuous, while Table 3 lists the pruritic dermatologic conditions that are usually readily apparent on physical examination. In addition to looking for lesions, an important

FIGURE 3. Approach to the patient with generalized pruritus.

nate the clinical presentation. The consequences of scratching can range from simple linear excoriations to more substantial changes such as lichen simplex (Fig. 2) or prurigo nodularis (Fig. 4); the more severe changes are particularly p r o m i n e n t in patients with neurodermatitis. Second, a n u m b e r o f primary dermatologic conditions can present initially with minimal or no physical findings. Aquagenic pruritus, for example, is by definition associated with no primary skin lesions. Xerosis may be missed on casual inspection; on closer examination using tangential lighting, however, fine scaling and cracking of the epidermis are visible. 47 Scabies is often inapparent in patients with good hygiene3; a significant n u m b e r of patients present with fewer than ten lesions. 48 Dermatitis herpetiformis, classically

FIGURE 4. Prurigo nodularis. (Photograph courtesy of David J. Margolis, MD.)

TABLE 2

Pruritic Dermatologic Conditions That May Be Inconspicuous or That May Cause a Nonspeciflc Eruption* Condition

Clues to Diagnosis

Aquagenic pruritus

Symptoms occur during or after exposure to water at any temperature

Atopic dermatitis

History of asthma, hay fever; elevated serum IgE

Bullous pemphigoid

Skin biopsy with immunofluorescence

Contact dermatitis

Exposure to a new chemical or household product; angular or linear distribution; may require patch testing

Dermatitis herpetiformis

Intense burning prior to appearance of lesions; skin biopsy with immunofluorescence

Fiberglass dermatitis

Can occur in household contacts of those with industrial exposure

Insect bites

Agricultural work, gardening, pets

Miliaria (prickly heat)

Fever or hot environment; occlusive clothing

Pediculosis corporis (body lice)

Lice and eggs in the seams of patient's clothing

Scabies

Pruritus in household contacts; epidemics occur in long-term care facilities (see Table 4 for diagnosis and treatment)

Urticaria (hives)

History of wheals in association with pruritus; dermatographism may be present even when wheals are not

Xerosis (dry skin)

Common in winter and with exposure to air conditioning; higher prevalence in the elderly

* Based on information obtained from Gilchrest 1982. 8

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part of the physical examination is to test for dermatographism; this physical finding is assessed by stroking the skin firmly with a blunt object and watching for the appearance of urticaria over the next few minutes. Other important signs to be sought on general physical examination are those indicative of an underlying systemic disease such as hyperthyroidism, liver disease, anemia, or lymphoma.

INITIAL TREATMENT OF THE PATIENT WITH GENERALIZED PRURITUS On the basis of the history and physical examination, the cause of pruritus may be apparent and appropriate treatment can be provided. If, on the other hand, the history is unrevealing and the examination reveals normal skin or only excoriations, a likely diagnosis is xerosis and the patient should be given a two-week trial of empiric therapy. This includes reducing the freq u e n c y and duration of bathing (e.g., no more than a five-minute shower in warm water one to three times per week); using a mild soap (such as Dove ®, Basis,® or Neutrogena ®) and restricting its use to the intertriginous areas; and using an emollient (such as Eucerin® Cream or Sarna® lotion) immediately after bathing (before the skin is c o m p l e t e l y dry) and as often as desired. Adjunctive measures include the use of a humidifier and avoidance of wool clothing directly against the skin. ~7 Since bathing habits may be difficult to change, the patient should be given specific written instructions. Bath oil in the water has been r e c o m m e n d e d for

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patients w h o take baths, but the resulting slipperiness may increase the risk of slipping and falling. If the physical examination reveals nonspecific papules or nodules, one should consider the diagnoses listed in Table 2. Patients with scabies usually have burrows, w h i c h are linear or S-shaped raised lesions 3 to 5 mm in length; these are found most c o m m o n l y on the sides of the fingers, on the volar surfaces of the wrists, and in the groin. Scabies can, however, present with only diffuse papules; these represent an i m m u n e response to the scabies mite Sarcoptes scabiei. Even if no burrows can be found, any lesions that are present should be evaluated for the presence o f scabies as described in Table 4. Figure 5 shows the microscopic appearance of scabies eggs and the adult mite. If scabies is fOund, both the patient and all household and sexual contacts should be treated simultaneously; this can be accomplished with a single application of either 5 % p e r m e t h r i n cream (Elimite ®) or 1% lindane lotion (Kwell®). Permethrin and lindane appear to have equal efficacies. 4a Some authorities are n o w r e c o m m e n d i n g p e r m e t h r i n as the first-line agent for scabies, s° It is extremely important to warn patients that residual itching is c o m m o n for several weeks after treatment and that this does not necessarily indicate treatment failure. Aggressive treatment of fomites is not necessary because the scabies mite cannot survive for more than a few days off the human body; patients can simply wash their bedsheets and any clothing they will be wearing in the next five days. ~1

TABLE 3 Pruritic Dermatologic Conditions That Are Usually Apparent on Physical Examination* Condition

Clues to Diagnosis

Drug reactions

Exposure to new agent in the past two weeks

Folliculitis

Lesions are centered on hair follicles

Fungal infections

Examination of scrapings from lesion with KOH test

Lichen planus

Small, flat-topped polygonal papules with Wickham's striae (delicate white lines); mucous membrane involvement

Mycosis fungoides

Lymphadenopathy; can mimic benign dermatoses such as eczema but does not respond to usual therapy

Pemphigus foliaceus

Superficial crusting and scaling; Nikolsky's sign (dislodging of the epidermis with lateral finger pressure on lesions)

Pityriasis rosea

Finely scaling oval plaques that follow the skin cleavage lines; a "herald patch" precedesthe generalized eruption

Pruritic and urticarial papules and plaques of pregnancy

Can occur at any time in pregnancy; usually resolves with delivery

Psoriasis

Large erythematous plaques with mica-like scale; Auspitz sign (blunt scraping of scale reveals punctate bleeding)

Sunburn

Exposure history

* Based on information obtained from Denman 1986.12

Greco, Ende, F~uRrrus

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TABLE 4 Diagnosis and Treatment of Scabies* Diagnosis 1. Vigorously scrape any suspicious lesions with a No. 15 scalpel blade. A drop of mineral oil on the blade will prevent the material from falling away. 2. Collect material on a slide and apply more oil and a coverslip. Examine under low power for adult organisms, eggs, nymphs, or scybala (Fig. 5). Treatment 1. Scabicides are prescribed for the patient and all sexual or household contacts. • 1% lindane cream or lotion (Kwell®): apply to dry skin over the entire body from the neck down (include scalp in children); leave on for 8 - 1 2 hours then wash off. Some authorities recommend a second treatment 48 hours later. Contraindicated in children less than 2 years of age and in pregnant women.

or • 5 % permethrin cream (Elimite®): apply in an identical fashion. 2. Patients should be warned that persistent pruritus after treatment is common and only rarely is a sign of treatment failure. 3. Clothing and bed linen that will be used in the next five days should be laundered in warm or hot water. *Based on information obtained from Elgart 1990. s~

FOLLOW-UP EVALUATION Patients empirically treated for xerosis w h o have c o m p l i e d with the r e c o m m e n d e d measures but have not e x p e r i e n c e d relief should be asked to return for a second visit. The history should focus on clues to the presence of one of the dermatologic diagnoses outlined in Table 2, and the patient should again be q u e s t i o n e d carefully a b o u t s y m p t o m s of the systemic diseases outlined in Table 1. Patients w i t h pets should have t h e m e x a m i n e d by a veterinarian for fleas or mites: in one study, half of 101 patients with u n e x p l a i n e d pruritus w e r e c u r e d after their pets had b e e n treated for docum e n t e d flea or mite infestations, s2 A c o m p l e t e physical examination should again be p e r f o r m e d , w i t h particu-

FIGURE S. Scabies mite (upper/eft) and eggs (lower right). (Reproduced with permission from Fitzpatrick TB, Polano MK, Suurmond D. Color atlas and synopsis of dermatology. Copyright 1983, McGraw-Hill, Inc.)

lar attention paid to any n e w lesions that may have developed. Any n e w p a p u l e s or nodules f o u n d should be evaluated for the p r e s e n c e of scabies as previously described. If the cause o f pruritus is still not a p p a r e n t and there has b e e n no relief w i t h nonspecific measures, an evaluation for systemic disease is warranted. Many authors s, ~2, ~3, 18, 20 r e c o m m e n d a chest x-ray, a c o m p l e t e b l o o d c o u n t w i t h differential, liver function tests, b l o o d urea nitrogen assay, creatinine assay, and thyroid function tests. Others r e c o m m e n d in addition s e r u m glucose assay, urinalysis, testing of the stool for ova and parasites, m e a s u r e m e n t s of iron and iron-binding capacity, testing of the stool for occult blood, and s e r u m protein electrophoresis. The k n o w n association b e t w e e n pruritus and occult malignancy 1' 3,22 is of c o n c e r n in the patient w i t h u n e x p l a i n e d pruritus, but data suggest that malignancy is a relatively u n c o m m o n cause of pruritus. Six case series v6 described 384 patients w h o had b e e n referred to dermatologists for generalized pruritus. Excluding six patients for w h o m underlying malignancies had already b e e n diagnosed prior to their referrals, the prevalence of malignancy in this highly selected p o p u l a t i o n was 6.3% ( 2 4 / 3 7 8 ) . This included nine definite cases and one p r o b a b l e case of carcinoma, four definite cases and one s u s p e c t e d case of non-Hodgkin's l y m p h o m a , three cases of Hodgkin's disease, three cases of polycythemia vera, two cases of suspected mycosis fungoides, and one case of s u s p e c t e d myeloma. T w o of these studies~, 6 described longitudinal follow-up after the initial evaluation. In one study, all of 39 patients initially free of malignancy w e r e free of malignancy after 1 to 6.5 years of follow-up. 5 In the o t h e r study, four of 118 such patients w e r e s u b s e q u e n t l y diagnosed with a malignancy after 6 years of follow-up (three lung cancers and o n e renal cell carcinoma) 6 Thus, the likelihood of detecting a malignancy even a m o n g patients referred to a dermatologist is relatively small, and the s u b s e q u e n t

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incidence appears to be less than 1% per year. Investigation for malignancy can probably be limited to a chest x-ray and any additional tests that are suggested by history and physical examination.

TREATMENT The most widely used agents for pruritus are the Hi-antagonists. At the doses usually e m p l o y e d in clinical practice, hydroxyzine is more effective than diphenhydramine, cyproheptadine (a histamine and serotonin antagonist), and placebo in the relief of experimental (histamine-induced) pruritus. 53 However, the levels of effectiveness of these agents for clinical pruritus have been more difficult to demonstrate. One of the earliest double-blind studies of antipruritic agents showed neither cyproheptadine nor trimeprazine (a phenothiazine with antihistaminic properties) to be better than placebo for 46 patients with various pruritic dermatoses, s4 In a more recent study, hydroxyzine was superior to cyproheptadine in relieving pruritus in children with atopic dermatitis, s5 Clemastine, however, was no better than placebo for the subjective relief of pruritus in patients w h o had atopic dermatitis. 56 Doxepin is a substantially more potent Hi-antagonist than either diphenhydramine or hydroxyzine, 57 and is clinically m u c h more effective and less sedating than diphenhydramine for pruritus due to idiopathic urticaria. 5s In topical form it is more effective than vehicle alone for relief of eczema-associated pruritus, 59 but is not available commercially in this form. It m a y b e a good choice for patients with neurotic excoriations, in doses of 10 to 25 mg, tid. 6° Several nonsedating antihistamines have recently b e c o m e available; data are conflicting, however, regarding their effectiveness for pruritus. Since pruritus worsens considerably at night for most patients, the sedating agents might be e x p e c t e d to be superior. Indeed, in one study terfenadine and astemizole were less effective than trimeprazine and nitrazepam (a benzodiazepine) in the prevention of nocturnal scratching in patients with atopic dermatitis. 61 In two other studlesS6, 62 terfenadine was no better than placebo in relieving the pruritus of atopic dermatitis. In a fourth study 63 the experimental nonsedating HI-antagonist LN2974 was no better than placebo in reducing itch and scratching for ten subjects who had atopic dermatitis. In other studies, however, nonsedating histamine antagonists have b e e n shown to be effective for pruritus. In one, both terfenadine and acrivastine (another nonsedating Hi-antagonist) were superior to placebo in relieving itch in patients with atopic dermatitis. 64 In another, terfenadine was superior to chlorpheniramine and placebo in patients with pruritus due to primary biliary cirrhosis. 65 These seemingly contradictory find-

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ings are probably related to the different patient populations studied, differing agents and dosages employed, and differing methods of measuring therapeutic efficacy. In our view the modest potential benefit of nonsedating histamine antagonists must be balanced against their high cost. Given that pruritus typically is most severe at night, prescription of a sedating agent such as hydroxyzine before bedtime is probably the most rational and least costly choice of an antihistamine for pruritus. Opiate antagonists have been demonstrated to be effective against certain forms of pruritus. Naloxone (a parenteral narcotic antagonist) inhibits histamineinduced itch66; several uncontrolled observations suggest that this agent is clinically effective against pruritus caused by several conditions. 67-69 In a controlled study, naloxone was more effective than placebo in relieving pruritus induced by epidural morphine. 7° In another, nalmefene (an oral opiate antagonist) was more effective than placebo in relieving pruritus in patients with chronic urticaria or atopic dermatitis. 7t In a third study, nalmefene p r o d u c e d sustained (six months) relief for nine patients with primary biliary cirrhosis whose pruritus had been refractory to standard treatment. Although this agent was associated with a severe narcotic-withdrawal syndrome on initiation of treatment, these symptoms resolved over a period of several days and did not interfere with long-term compliance. 45 In the United States, the only oral opiate antagonist that is currently available is nahrexone; this agent has not been evaluated for its effect on pruritus, though it is structurally similar to naloxone and nalmefene. Topical p h e n o l (0.5%) and menthol (0.25%) have been used for many years to treat pruritus; both are present in Sarna lotion or can be added to petrolatum or Eucerin cream by a pharmacist. These agents p r o d u c e a cooling sensation, w h i c h some patients find beneficial; controlled studies of their efficacy, however, are sparse. In one study, none of 57 various topical agents (including p h e n o l and menthol) was effective in relieving histamine-induced experimental pruritus72; the authors of that report, however, cited a report that did show menthol and phenol to be partially effective in the relief of experimental (histamine-induced) pruritus. Pramoxine is a topical anesthetic that is marketed for the relief of pruritus and is available in several formulations. In one study it was more effective than 1% hydrocortisone for patients with various pruritic dermatoses, while causing allergic reactions less frequently than did other topical anesthetics. 73 Numerous other agents have been reported to be effective against pruritus in uncontrolled observations. It should be noted, however, that the placebo effect is strong in the treatment of pruritus: in a study that evaluated four different placebo agents, two-thirds o f patients responded to at least one of the pills. 54

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INTRACTABLE PRURITUS For the patient with pruritus for w h i c h no cause has been found and for w h o m none o f the above measures has proved satisfactory, several diagnostic possibilities should receive particular attention. Among patients referred to a dermatologist because of pruritus, the diagnoses that are most frequently "almost missed" are scabies, dermatitis herpetiformis, and fiberglass dermatitis. 3 Empiric treatment for scabies can be problematic because persistent itching (for several weeks) is not u n c o m m o n even after successful treatment; in addition, 1 0 - 15% of patients fail to respond to a single application of lindane or permethrin.4S Dermatitis herpetiformis is most reliably diagnosed by biopsy of normal skin using direct immunofluorescence, w h i c h shows granular deposition of IgA in the dermal papillary tips. ~9 Thus, referral to a dermatologist for skin biopsy may be worthwhile in difficult cases. In patients at high risk for malignancy (such as the elderly or patients previously treated for cancer), a more thorough evaluation for cancer should be considered. Human immunodeficiency virus (HIV) serologic testing may be warranted, since pruritus has b e e n described as one of the presenting symptoms of H1V infection. 38 Psychiatric disease should also be considered as a possible cause of unexplained pruritus. Such a diagnosis, however, should be made on the basis of positive features rather than simply on the basis o f exclusion. Neurotic excoriations are scattered crusting lesions that can be present anywhere the patient can reach. In one controlled study, however, patients with neurotic excoriations most often had lesions confined to the extremities. 4° Importantly, patients often acknowledged that they sometimes scratched even w h e n they did not truly itch. In addition, most patients were found on formal psychiatric examination to have a depressed or dysphoric mood. Finally, in this study 60% of patients suspected that their diseases could be of a psychogenic nature, and 90% described a serious conflict or stress that had p r e c e d e d the onset of the dermatosis. 4° Treatments that have been reported to be effective for patients with neurotic excoriations include behavioral therapy 74 and psychotherapy. 4° Major depression is also associated with generalized pruritus. In one study, patients referred to a dermatology clinic for evaluation of generalized pruritus or chronic urticaria were administered the Beck Depression Inventory (BDI) and the State-Trait Anxiety Inventory (STAI) and were compared with age- and gender-matched control patients. Thirty-two percent of the patients with generalized pruritus had BDI scores above 14 (indicative of depression), as c o m p a r e d with 13% of the controls. By contrast, patients with chronic urticaria did not differ significantly from the controls on the BDI scores, and neither patient group differed from the controls in their STAI scores. 39 Thus, symp-

toms of depression should be sought in patients with unexplained pruritus. An antidepressant with antihistaminic properties (such as d o x e p i n ) may be a good choice for such patients. For those patients w h o continue to itch despite extensive evaluation and appropriate treatment, periodic reevaluation is required. It is fruitless to tell patients who itch not to scratch. Patients can, however, be instructed to rub with the palm of the hand (rather than the fingernails) over a wide area of skin; this t e c h n i q u e is more effective than scratching and is less likely to induce excoriations or other skin changes. 7~ Compliance with this r e c o m m e n d a t i o n can be enhanced by instructing patients to keep their fingernails short.

SUMMARY Pruritus is usually caused by a primary disorder of the skin, but can also be caused by a systemic disease (Table 1). Some dermatologic conditions that cause pruritus can be inconspicuous or nonspecific (Table 2), while others are usually apparent on physical examination (Table 3). Classification of pruritus as localized (Fig. 1) vs. generalized (Fig. 3) can be helpful in arriving at a correct diagnosis. The history and physical examination are the most important diagnostic tools, though laboratory testing for systemic disease may be necessary. In refractory cases, one should consider occult systemic disease (such as malignancy), psychiatric disease (especially depression), and HIV infection. Subsequent referral to a dermatologist may be indicted. When treatment of the underlying cause of pruritus is not possible, antihistamines and topical agents (menthol, phenol, a n d / o r pramoxine) can be helpful. The authors gratefully acknowledge David J. Margolis, MD, for his helpful comments on the manuscript.

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