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Definition and etiology

Pruritus or itch is defined as an unpleasant sensation of the skin that provokes the urge to scratch. It is a characteristic feature of many skin diseases and an unusual sign of some systemic diseases.1, 2 Pruritus may be localized or generalized and can occur as an acute or chronic condition. Itching lasting more than 6 weeks is termed chronic pruritus.2Itching can be intractable and incapacitating, as well as a diagnostic and therapeutic challenge.

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Prevalence, risk factors, and natural history

Prevalence estimates, risk factors, and natural history exist for only a few specific disorders associated with itching and are mentioned in the discussion of those conditions.

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Pathophysiology

Peripheral Mechanisms

Physical Stimuli and Neural Pathways

Itch can be produced by mechanical (gentle touch, pressure, vibration, and wool), thermal and electrical stimuli such as transcutaneous or direct nerve stimulation. The sensation is received by free nerve endings in the skin and transmitted via unmyelinated C fibers and myelinated Aδ fibers to the central spinothalamic tracts.1, 2 Microneurography studies have demonstrated that itch and pain are transmitted by separate neural pathways.3, 4

Chemical Mediators

Histamine is one of the most important mediators of itch, although other chemical substances have also been implicated.3Some, such as neuropeptides, act by releasing histamine from mast cells, and itching caused by them responds to antihistamines. Others act independently; therefore antihistamines are not effective in some forms of pruritus. Opioids have a central pruritic action and also act peripherally by augmenting histamine itch.

Central Mechanism

Patients with tumors and lesions of the central nervous system have been reported to have intractable pruritus.1, 5-7Administration of opioids in epidural anesthesia can also lead to pruritus.

Etiology

Itching is associated with dermatologic and systemic causes, and it is important to determine whether there is an associated skin eruption. A characteristic rash usually establishes the diagnosis of a primary dermatologic disorder. Several skin diseases are associated with pruritus; some are listed in Box 1. Itching is an important component of some disorders (atopic eczema, dermatitis herpetiformis, lichen simplex chronicus, and nodular prurigo) and these conditions are rarely diagnosed in its absence. In conditions such as mild urticaria or aquagenic pruritus, the levels of histamine are sufficient for a sensory but not a vascular response, and there may be no skin findings. Bullous pemphigoid can manifest with a prebullous pruritic phase for several months before the characteristic blisters appear.8 An invisible form of mycosis fungoides can occur as pruritus without a rash and is diagnosed on biopsy.9

It is important to establish if pruritus preceded the appearance of a skin eruption. Severe itching leads to scratching that causes secondary skin changes of excoriation, lichenification, dryness, eczematization, and infection. Excessive bathing and contact allergy to topical therapies can lead to dermatitis. These findings should not be interpreted as the primary skin disorder.

Select systemic conditions associated with itching are listed in Box 2. Several are potentially serious, and it can be dangerous to label a case of generalized pruritus “nonspecific eczema” until these conditions are excluded. Pruritus of systemic disease is usually generalized, it may be the only manifesting symptom, and a specific rash is not present. Neurologic and psychiatric conditions associated with chronic pruritus are included in Box 2.

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Diagnosis

History

A detailed history is the single most important step toward diagnosing the cause of itching. This should include information on the onset, extent (generalized vs. localized), severity, type of itch, aggravating and alleviating factors, diurnal and seasonal variations, bathing, occupation, hobbies, medication history and allergies, and past medical and surgical history. Inquire about personal or family history of atopy (childhood eczema, allergic rhinitis, asthma), household and other contacts, pets, travel history, sexual history, and history of intravenous drug use (human immunodeficiency virus [HIV] or hepatitis C infection). If the patient has recently undergone surgery, ask if hydroxyethyl cellulose was used as a plasma expander, because this substance can be associated with intense generalized pruritus lasting for up to one year.

Review of Systems

A detailed history is important in chronic pruritus of unknown origin, including general health (fever, chills, weight loss); skin (pigmentation, sweating, asteatosis, plethora, and jaundice); hair (growth, texture, loss); nails (Beau's lines, onycholysis, color changes); eyes (exophthalmos, color changes); and endocrine, hematopoietic, gastrointestinal, genitourinary, neurologic, and mental status.5-7, 10

Physical Examination

The skin should be examined for evidence of any recognizable disorder. Scratching (causing excoriations) or rubbing (producing papules, nodules, and lichenified plaques) can lead to secondary changes that should not be interpreted as a primary skin disorder but can mimic one. Examination of the upper midback can help in this distinction, because it is relatively inaccessible and unavailable for scratching.

Look for evidence of parasitic infestation, especially scabies and lice. Examination of the skin, hair, and genitalia with surveillance scrapings can identify either disorder. Examination of clothing seams can identify body lice in the unkempt (vagabond's disease).

A complete physical examination to look for other cutaneous signs mentioned in the “Review of Systems” section is essential. Pelvic and rectal examination as well as examination of the lymph nodes, liver, and spleen is important.5-7, 10

Investigations

In some cases, the diagnosis is apparent from the history, physical examination, or bedside studies (such as a scabies preparation). When the diagnosis is not apparent, laboratory studies may be indicated.

In general, the laboratory investigation should be directed by the findings of the history and physical examination. In a patient with no pertinent findings, a reasonable initial screen consists of complete blood count, complete metabolic panel, hepatitis C antibodies, TSH, and chest x-ray. Based on the initial results and the course of the pruritus, further testing may be indicated (Box 3).

Histopathologic examination of the skin lesions may be required. In pruritus without a rash, a biopsy specimen for direct immunofluorescence from normal-appearing skin might show immune deposits in early cases of pemphigoid or findings diagnostic of mycosis fungoides in routine histopathology.

Patients with chronic idiopathic pruritus should be followed with periodic re-evaluation if the symptoms persist, because an underlying disorder can manifest later.5-7, 10

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Treatment

General Concepts and Topical and Systemic Treatments

Identifying and treating the underlying cause is the most effective therapy for pruritus. Symptomatic treatment should be prescribed while the primary condition is being treated. Cool compresses and cool baths might help relieve the itch; a cool environment in the home and workplace also helps. Cooling lotions with calamine, pramoxine, or menthol and camphor are helpful (Box 4).

Pruritus due to dry skin, especially in the elderly, responds to generous amounts of emollients such as petrolatum and white paraffin, as well as correcting the temperature and humidity. Patients should avoid frequent and hot baths and excessive use of soap, which further dries the skin. Topical corticosteroids should not be prescribed indiscriminately but should be used only if there are signs of cutaneous inflammation. Topical tacrolimus may be prescribed for limited use in patients with atopic dermatitis. Topical capsaicin may be useful in chronic localized pruritus such as notalgia paresthetica.

H1-receptor antihistamines are the drugs of choice for urticaria. The newer nonsedating antihistamines are less effective in atopic dermatitis; the older sedating antihistamines might work better. Tricyclic antidepressants such as doxepin have antihistamine activity in addition to central effects and are useful in chronic, severe pruritus. Gabapentin, buspirone, and selective serotonin reuptake inhibitors (SSRIs) may be considered in select patients. Ultraviolet (UV) B phototherapy is very effective in uremic pruritus and may be helpful in patients with prurigo nodularis, atopic dermatitis, HIV infection, and aquagenic pruritus. Opioid-receptor antagonists, such as naloxone, have occasionally been used for intractable pruritus of renal and cholestatic diseases. Other measures that have been tried for chronic pruritus are acupuncture and transcutaneous electrical nerve stimulation (TENS) (see Box 4).

Aggressive treatment of the eczema may be the only way to control the pruritus in patients with atopic dermatitis. Limited use of systemic corticosteroids as well as other systemic immunosuppressives may be needed to treat the eczema.1, 10

Treatment of Specific Disorders

Chronic Renal Disease

Other than general treatments as mentioned earlier, mild disease might respond to UVB phototherapy and erythropoietin. Second-line treatments include oral activated charcoal, cholestyramine, and the opioid antagonist naltrexone. Third-line therapies include thalidomide and parathyroidectomy.1, 10

Dialysis can provide some relief but rarely improves itching significantly. Parathyroid hormone levels have been found to be increased and have been implicated as a cause. These patients experience relief of pruritus after parathyroidectomy.6Renal transplantation is the definitive treatment.1, 10

Cholestatic Disease

Ion-exchange resins, such as cholestyramine, probably act by lowering levels of bile salts and other pruritogens. Altered central opioidergic neurotransmission is believed to be a contributing factor, 12 and opioid antagonists such as naloxone and naltrexone have been found useful.13 Second-line therapies include rifampicin, which has been shown to reduce pruritus in patients with primary biliary cirrhosis, 14 ursodeoxycholic acid, SSRIs, and S-adenosylmethionine. Third-line treatment includes UVB phototherapy, extracorporeal albumin dialysis, plasmapheresis, and dronabinol, a cannabinoid.1, 10

Polycythemia Rubra Vera

Antihistamines are usually ineffective, but psoralen plus ultraviolet A (PUVA) phototherapy has been helpful in some patients. Aspirin has been reported effective, and a trial showed SSRIs to be effective.1, 10

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Summary

• Pruritus or itch is a characteristic feature of many skin diseases and an unusual sign of some systemic diseases.
• The presence of skin changes does not exclude the possibility of an underlying systemic cause of the pruritus.
• The absence of a rash does not automatically mean that the underlying cause of the itching is a systemic disease.
• Dermatologic and internal medicine evaluations, including laboratory tests, skin biopsy, and radiographic studies as dictated by history and physical findings, should be considered for patients with generalized pruritus lasting longer than 6 weeks.
• Identifying and treating the underlying cause are the most effective therapies for pruritus.

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