Pruritus

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[edit] Pruritus

Susan Tobey Denman

The skin is the largest organ in the human body, and the skin's most common symptom is itch. Thus pruritus presents a daily challenge to the clinician. Itch is defined as the unpleasant sensation that evokes the desire to scratch. Pruritus is present in every age group. It can be associated with many dermatologic, as well as systemic, diseases. Itch can also be generalized without an obvious etiology.

[edit] PATHOPHYSIOLOGY

Pruritus can be evoked by physical stimuli, such as a thin wire, electrical stimuli, and thermal heat, and chemical stimuli, such as histamine, serotonin, and substance P. Prostaglandins and dry skin, although not stimuli by themselves, both lower the threshold for evoking itch.

Itch receptors are free unmyelinated penicillate nociceptors in the epidermis.^[1] Unmyelinated C fibers carry the sensation of itch along the afferent pathway. These enter the dorsal horn of the spinal cord, synapse, cross the midline, and ascend in the spinothalamic tracts closely associated with pain fibers to the thalamus. Tertiary neurons ascend from the thalamus to higher centers that regulate the conscious perception of itch.

Central nervous system (CNS) factors can modulate our perception of itch by either amplifying or inhibiting the sensation. An example of inhibition is the effect of scratching an itch. Scratching demonstrates the concept of gating of sensory afferent activity. In this system, simultaneous firing of large-diameter myelinated fibers can presynaptically inhibit firing of smaller afferent fibers so that the sensations they usually evoke would be diminished in intensity or not perceived. Scratching stimulates firing of large-diameter myelinated A fibers that can presynaptically inhibit the firing of smaller afferent C fibers carrying itch. Psychologic factors, such as emotion and past experience, may also act on the gate-control system and modify the perception of itch.

An additional central influence on itch involves the enkephalins and opioid receptors in the CNS. When enkephalins bind to opioid receptors, they relieve pain and may cause itch.^[2] A pharmacologic example is the itching seen in more than 50% of patients who receive intraspinal or epidural morphine. When the opioid receptors are blocked by administration of a competitive antagonist, such as naloxone, itching is diminished or disappears. Parenteral naloxone has been used successfully in treating itching in cholestasis.^[2]

Histamine is the classic mediator of pruritus. Derived from mast cells, histamine acts on H₁ receptors to cause itch.^[3] But how histamine mediates itch in many dermatologic and general diseases is a paradox. Experimentally induced itching is always associated with wheal and flare, yet most clinical itch is not. Also, repeat injections of histamine at the same site results in tachyphylaxis. Antihistamines are often ineffective in relieving itch. An unknown cytokine has been proposed as mediator of itch in diseases such as atopic dermatitis.^[2] Supporting this is the antipruritic effect of cyclosporin A (a cytokine inhibitor) in atopic dermatitis, lichen planus, and mycosis fungoides. Substance P and serotonin also mediate itch. Peptides, such as bradykinin, vasoactive intestinal polypeptide (VIP), neurotensin, secretin, and substance P, are potent histamine releasers rather than primary mediators of itch. Prostaglandins modulate rather than cause itch. Prostaglandin E lowers the threshold for histamine-induced itch.^[2]

[edit] CLINICAL PRURITUS

Pruritus may be associated with numerous skin diseases (Box 89-1). Xerosis is the most common skin disease causing pruritus, particularly in the elderly. A careful history of bathing habits, use of emollients, whether patients experience concomitant burning and stinging, as well as physical examination showing increased skin markings with plates of scale and dryness, make this diagnosis.

Scabies can be difficult to find, especially in a fastidious patient. A single burrow on the heel of the foot is sometimes the only sign in these patients. If a patient has scabies, it should be possible to demonstrate a mite or eggs on skin scraping. Sometimes only part of a mite, such as a leg, will be found on skin scraping.

Atopic dermatitis is a very common, frustrating cause of severe itching. Often called the itch that rashes, patients report itching and scratching preceding the development of the rash characterized by eczematous dermatitis. Careful history usually elicits a personal or family atopic diathesis with allergies, hay fever, or asthma.

Contact dermatitis, either irritant or allergic, is a very common cause of itching. Irritant dermatitis is caused by a direct toxic effect of a substance on the skin, whereas allergic contact dermatitis is a type IV hypersensitivity reaction to substances such as fragrance, plants, preservatives, rubber products, dyes, and some topically applied medications (i.e., neomycin or diphenhydramine). Contact dermatitis begins as a local phenomenon, but when severe can become a generalized dermatitis, affecting areas of the skin that have never been in contact with the offending substance.

Dermatitis herpetiformis is a much rarer blistering disease, usually presenting with intense pruritus. Pruritus is usually the first symptom, and skin lesions include papules, wheals, and vesicles distributed symmetrically on the lumbosacral spine, elbows, and knees. The early vesicles are fragile and may be difficult to find intact.

Folliculitis often itches out of proportion to the clinically evident rash. The rash on the chest, back, or thighs consists of numerous small follicularly oriented pustules or papules.

Early bullous pemphigoid can present as pruritic urticarial patches that can be subtle and diagnosed on biopsy.

Lichen simplex chronicus is a secondary rather than primary skin lesion; it is thickened skin as a result of prolonged scratching or rubbing of an itchy area. The skin becomes thickened with exaggerated skin markings. This secondary finding can be present in patients with any of the listed dermatologic or systemic causes of itch.

[edit] SYSTEMIC DISEASES ASSOCIATED WITH PRURITUS

If no skin disease is evident, pruritus may be a symptom of one of the systemic diseases associated with pruritus (Box 89-2).

[edit] Uremic Pruritus

Itching in chronic renal failure is the most prevalent of all the systemic disorders listed in Table 89-2. A dramatic increase in the incidence of pruritus in chronic renal failure has occurred since the advent of hemodialysis: from 13% before the advent of dialysis in 1932 to 86% of dialysis patients at present. Currently, 25% of renal failure patients treated without dialysis complain of itching. The itch, often occurring in severe paroxysms, was generalized in 44% and localized in 56% of patients. Pruritus can be severe just before the patient's next dialysis, suggesting accumulation of pruritogenic metabolites; in other patients it is most severe during or immediately following dialysis and is often worse in summer.^[4]

Table 89-2 Pharmacologic Management of Pruritus in Cholestatic Jaundice

The pathophysiology of uremic pruritus is unclear. Many of the metabolic disturbances in uremia have been investigated. Secondary hyperparathyroidism with hypercalcemia, hyperphosphatemia, aluminum overload, mast cell proliferation in skin and elevated plasma histamine levels, atrophic sebaceous glands, atrophy of eccrine sweat glands, and microangiopathy are all present.^[5] Unknown cytokines have been proposed as causative agents.^[2]

Treatment with ultraviolet (UV) B or psoralen plus UVA (PUVA) has been successful with remissions of up to 18 months. The mechanism for UV effect on uremic pruritus is unknown but may be due to a systemic effect, since patients who receive this treatment to only half their body noticed a generalized improvement in their itch without localization to the treated side.

In addition to UV light, balneotherapy with polidocanol may be helpful if the patient is xerotic^[5]; antihistamines are of little value unless used in large soporific doses. Activated charcoal, 6 gm/day, has been effective. Topical capsaicin cream 0.0255% was shown to be effective in moderate and severe uremic pruritus. Capsaicin acts by depleting substance P from type C sensory nerves (Table 89-1).

Table 89-1 Management of Pruritus in Chronic Renal Failure

[edit] Cholestatic Liver Disease

Cholestatic liver disease is frequently associated with generalized pruritus. Pruritus can precede other signs and symptoms. It first appears in hands and feet and in areas of pressure and is worse at night. This itching can be very severe and is a serious clinical problem. Severe unrelieved itch in these patients can be an indication for liver transplantation.

Accumulation of bile acids in skin and plasma has been implicated in the pathogenesis of this pruritus because patients have high levels of bile acids in their skin and serum. Application of pure bile acids to the skin causes pruritus. Patients experience relief of itch when serum bile concentration is lowered by oral cholestyramine or external biliary drainage. The relationship of itch to bile salts is unclear, however, because not all patients with elevated serum bile acid levels itch and itching can subside without any decrease in bile salt levels.

Although bile salts are not directly responsible for pruritus, treatment with cholestyramine that binds bile salts is effective in reducing itch in cholestatic disease. In addition to bile salts, cholestyramine binds other substances in the intestine that may be the basis for its effectiveness, since it has also been used successfully in uremic patients and in polycythemia vera. Patients who do not tolerate cholestyramine can be given colestipol hydrochloride (Colestid), another ion exchange resin that is less constipating.

Naloxone, an opiate receptor antagonist, given intravenously, improved pruritus in a double-blind, placebo- controlled trial of 20 patients with chronic cholestatic liver disease.^[2] This suggests that central opiate receptors and enkephalins may mediate itch in cholestasis.

Odansetron, which blocks 5HT receptors, has also been shown to improve itching of cholestasis, suggesting that serotonin is involved in the itch (Table 89-2).

[edit] Hematologic Disorders Associated With Pruritus

An estimated 14% to 52% of patients with polycythemia vera (PCV) have pruritus. Pruritus triggered by a sudden decrease in temperature is considered a highly diagnostic symptom, especially when it occurs as a patient emerges from a warm bath and begins to cool off. The itch is pricking in quality and lasts for minutes or hours. In one study, two-thirds of patients with uncontrolled PCV had elevated plasma and urine histamine levels. Unfortunately, antihistamines are not usually successful. Two controlled studies suggest that antiserotonin agents relieve pruritus in PCV.^[6]

Iron deficiency can be associated with pruritus and may relate to underlying malignancy. Prolonged generalized pruritus is frequently experienced before the diagnosis of Hodgkin's disease is made.

Aquagenic pruritus is intense distressing itching after water contact without visible skin changes. There is an age range of 17 to 81 years, with a mean age of 40.5 years. It is more common in males and has a mean duration of 6.1 years.

A subset of aquagenic pruritus is aquagenic pruritus of the elderly, which happens after prolonged immersion in warm water when the patient dries off. This usually begins after age 60; 75% are women. Treatment of xerosis is key to management.

[edit] Patient Evaluation

To evaluate the itching patient, a careful history and physical examination of the entire body is important. In patients who have no visible rash, an unexplained adenopathy or organomegaly can indicate an occult malignancy.

If the physical examination is negative, symptomatic treatment for 2 weeks should be initiated. Patients will need specific instructions for bathing. They should bathe no more than once a day, use warm not hot water, and use of a mild soap, such as Dove unscented or Cetaphil, sparingly. They should pat their skin dry and use adequate amounts of emollients. A midpotency steroid cream can be applied to moist skin with emollient overlay twice daily.

If emollients alone are unsuccessful, antihistamines can be added to the regime. H₁ blockers, such as hydroxyzine, can be added. If patients do not respond to this empirical treatment, screening laboratory studies should be done to rule out systemic disease causing itch (see Box 89-2). If laboratory studies are negative and the patient has skin lesions, a skin biopsy should be done. If present, biopsy an early primary lesion. If no primary lesions are present, a biopsy of perilesional skin or skin near an area that has been scratched can be helpful in bullous pemphigoid or dermatitis herpetiformis.

If itch persists in spite of a thorough evaluation and conservative therapy, a multisystem therapeutic approach may be helpful. If patients have a localized area of itching or lichenification, a midstrength topical steroid applied with the Schotz regimen can be used. A nonsteroid alternative is tar emulsion; care should be taken to apply in the direction of hair growth (to prevent folliculitis). An unna boot can be used on localized area of itch to protect the area from scratching and reduce lichenification. Patients should be encouraged to continue emollients. Patients should avoid heat, dress coolly, and take warm not hot showers. Other antihistamines can be used. Doxepin has the advantage of a long-lasting therapeutic result. Because doxepin is variably absorbed, serum level, obtained 12 hours after the last dose, will help ensure that the patient has an adequate dose. Nonsedating antihistamines are not usually helpful. Pimozide may be used for opiate receptor antagonist effect. A transcutaneous electrical nerve stimulation (TENS) unit may help, via sensory gating mechanism, in some patients.

Patients who have persistent generalized pruritus should be regularly reevaluated with repeat screening laboratory tests, since itching can be the early presenting sign of occult malignancy.

[edit] REFERENCES