Definition and cause

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. Chronic pruritus is defined as itching lasting longer than 6 weeks. ² Itching can be severe, intractable, and incapacitating, and it can present a diagnostic and therapeutic challenge to even the most experienced physician.

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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 diverse mechanical stimuli such as gentle touch, pressure, vibration, and wool fibers. Thermal and electrical stimuli such as transcutaneous or direct nerve stimulation can also produce itch. The itch sensation is received by free nerve endings in the skin and transmitted via unmyelinated C fibers and myelinated Ad 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 synthesized and stored in the mast cells in the skin and is one of the most important mediators of itch. Several other chemical substances have been implicated in the causation of itch. ³ Some of these mediators, such as the neuropeptides, act by releasing histamine from mast cells, and therefore itching caused by them responds to antihistamines, whereas others act as independent pruritogens. This explains why 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. ^1,5–7 Administration of opioids in epidural anesthesia can also lead to pruritus. The presence of a central itch center that responds to pruritogens in the blood and the cerebrospinal fluid is hypothetical, but it offers attractive possibilities for blocking and manipulating itch therapeutically.

Causes

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 and its treatment relieves the itch. Several skin diseases are associated with pruritus, some of which are listed in Box 1. Itching is such an important component of some disorders—for example, atopic eczema, dermatitis herpetiformis, lichen simplex chronicus, and nodular prurigo—that a diagnosis of these conditions is rarely made in its absence. Dermatologic diseases can also occur without a rash in conditions such as mild urticaria or aquagenic pruritus, where the levels of histamine are sufficient for a sensory but not a vascular response. Bullous pemphigoid can manifest with a prebullous pruritic phase for several months before the characteristic blisters appear. ⁸ There is also an invisible form of mycosis fungoides that can occur as pruritus without a rash, but it demonstrates diagnostic features of mycosis fungoides on skin biopsy. ⁹

It is also important to establish if pruritus preceded the appearance of a skin eruption. Severe itching leads to vigorous 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, and a specific rash is not present. Pruritus may be the only manifesting symptom and can pose diagnostic difficulties. Neurologic and psychiatric conditions associated with chronic pruritus are included in Box 2.

A new classification scheme for pruritus focuses on clinical signs and distinguishes between diseases with and without primary or secondary skin lesions. They include three groups of conditions: pruritus on diseased or inflamed skin (with underlying conditions listed in Box 1), pruritus on primarily normal or noninflamed skin (with underlying conditions listed in Box 2), and pruritus occurring with severe chronic secondary scratch lesions, such as prurigo nodularis (with underlying conditions listed in Boxes 1 and 2). Diagnostic procedures for all three groups include skin biopsy and laboratory and radiologic investigation, if necessary, which are adapted to the patient's history and preexisting diseases.

It is important to remember that the presence of skin changes does not exclude the possibility of an underlying systemic cause, and the absence of a rash does not automatically mean that the underlying cause is a systemic disease. There might also be mixed causes of chronic pruritus from overlapping and coexistence of several diseases, and in some instances the cause is undetermined. ¹

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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, it is important to find out 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. Always listen to the patients and other physicians' theories of possible causes.

Review of Systems

A complete detailed inquiry is especially 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 thoroughly 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 to the hands 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. Direct, reflected light can identify nits of pubic and head lice. Examination of clothing seams can identify body lice in the unkempt (vagabond's disease).

Look for other cutaneous signs mentioned in the “Review of Systems” section. A complete physical examination is essential, including pelvic and rectal examinations. Enlargement of the lymph nodes, liver, and spleen are important to identify. ^5–7,10

Investigations

In some cases, no laboratory studies are necessary, because the diagnosis will be 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. However, in a patient with no pertinent findings on history and physical examination to direct the investigation, a reasonable initial screen consists of complete blood count, blood urea nitrogen, creatinine, aspartate transaminase, alanine aminotransferase, alkaline phosphatase, bilirubin, hepatitis C antibodies, thyroid-stimulating hormone, 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 to establish or substantiate the clinical diagnosis. 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 fugoides.

Patients with chronic idiopathic pruritus for longer than 6 weeks should be followed with periodic re-evaluation for as long as 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 and in cases of chronic pruritus of unknown origin. Although breaking the itch-scratch cycle is difficult to implement in patients with atopic dermatitis, the importance of breaking the itch-scratch cycle should be clearly explained because scratching leads to more itching. Cool compresses and cool baths might help relieve the itch. Warmth aggravates itch, so a cool environment in the home and workplace helps. Light clothing, light bedclothes, and a cool shower before bedtime keep the person comfortable at night. Cooling lotions with calamine, pramoxine, or menthol and camphor are helpful (Box 4). Pinching or gently massaging the affected area can help temporarily.

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 they should be used only when there are signs of cutaneous inflammation. Topical tacrolimus can 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 pruritic states. Trials of gabapentin, buspirone, and selective serotonin reuptake inhibitors (SSRIs) are reasonable to consider in select patients. Ultraviolet (UV) B phototherapy is very effective in uremic pruritus and may be helpful in other forms of pruritus associated with prurigo nodularis, atopic dermatitis, HIV disease, 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).

More aggressive treatment of the underlying atopic eczema may be the only way to control the pruritus. Additional measures include very limited use of systemic corticosteroids, other immunosuppressives, and even biologics to treat the eczema. ^1,10

Treatment of Specific Disorders

Chronic Renal Disease

Treatment with emollients, topicals including pramoxine, topical corticosteroids, and sedating antihistamines may be helpful in mild cases. Other first-line therapies include 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 also been found to be increased, and this has been implicated as a cause of pruritus. Patients with increased levels of parathyroid hormone who undergo parathyroidectomy experience relief of pruritus. ⁶ Aromatherapy was shown to have benefit for patients undergoing hemodialysis in a recent study. Renal transplantation is the definitive treatment. ^1,10

Cholestatic Disease

In addition to general topical and systemic supportive therapies, another treatment is ion exchange resins, such as cholestyramine, which probably acts 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

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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Suggested Readings

• Alonso-Llamazares , Rogers RS , Oursler JR , Calobrisi SD. Bullous pemphigoid presenting as generalized pruritus: Observation in six patients. Int J Dermatol. 37: 1998; 507-514.
• Bernhard JD. Pruritus in skin disease. 37-67.
• Greaves M. Mediators of pruritus. 85-94.
• Hagermark O, Wahlgren C. Treatment of itch. Semin Dermatol. 14: 1995; 320-325.
• Kantor GR, Bernhard J. Investigation of the pruritic patient in daily practice. Semin Dermatol.. 14: 1995; 290-296.
• Pujol RM, Gallardo F , Llistosella E. Invisible mycosis fungoides: A diagnostic challenge. J Am Acad Dermatol. 47: 2002; S167-S171.
• Ständer S, Steinhoff M , Schmelz M. Neurophysiology of pruritus: cutaneous elicitation of itch. Arch Dermatol. 139: 2003; 1463-1470.
• Ständer S, Weisshaar E , Mettang T. Clinical Classification of itch: A position paper of the International Forum for the Study of Itch. Acta Derm Venereol. 87: 2007; 291-294.
• Ward JR, Bernhard JD. Pruritus. 533-537.
• Zirwas MJ, Seraly MP. Pruritus of unknown origin: A retrospective study. J Am Acad Dermatol. 45: 2001; 892-896.