Pruritus (itch) is a common symptom encountered by dermatologists and primary physicians. It is defined as an unpleasant sensation that provokes a desire to scratch. Scratching can be considered physiologically appropriate only when it helps to remove the noxious stimulus from the skin, such as in parasitosis. In most other circumstances, it causes a great deal of discomfort and distress to the person. Although itching is often seen as a minor social disability, it can be so severe and intractable as to completely incapacitate a person and present a diagnostic and therapeutic challenge to the physician.

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 may also produce itch. The itch sensation is received by unspecified free nerve endings in the skin.¹ The search to identify specific itch fibers in humans is ongoing.

Until recently pain and itch were thought to be transmitted along the same pathways. The theory was that low-intensity stimulation of unmyelinated C fibers resulted in itch, whereas high-intensity stimulation of these same fibers resulted in pain. This theory has been disputed because of the differences in the features of pain and itch: a) Pain produces a withdrawal response, whereas itch produces a desire to scratch, b) morphine relieves pain but makes itch worse, and c) itch and pain can be perceived independently at the same site.

Chemical Mediators of Itch
Histamine is synthesized and stored in the mast cells in the skin and is one of the most important mediators of itch. Histamine causes severe itching if applied close to the dermal-epidermal junction and is released in response to various injurious stimuli. It acts on the H1 receptors to produce itch and the symptomatic relief of itching by H1 antihistamines validates the involvement of histamine in causing this sensation in most inflammatory skin conditions.

Several other chemical substances have been implicated in the causation of itch (Table 1). 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. Prostaglandins do not have pruritic activity on their own but potentiate itching due to other mediators. Opioids have a central pruritic action and also act peripherally by augmenting histamine itch.

Central Itch Mechanism:

Patients with tumors and lesions of the central nervous system have been reported to have intractable pruritus.² The 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 CSF is hypothetical, but offers attractive possibilities for blocking and manipulating itch therapeutically.

Itching is associated with both 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 dermatological disorder and its treatment relieves the itch. Several skin diseases are associated with pruritus, some of which are listed in Table 2. Itching is such an important component of some disorders—eg, 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 present 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 may present as a pre-bullous pruritic phase for several months before the characteristic blisters appear.³

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. Over-bathing and contact allergy to topical therapies may lead to dermatitis. These findings should not be interpreted as the primary skin disorder.

Selected systemic conditions associated with itching are listed in Table 3. Several are potentially serious, and it can be dangerous to label a case of generalized pruritus as 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 presenting symptom and may pose diagnostic difficulties.

Systemic Diseases Associated With Pruritus:

Chronic Renal Disease
Itching is one of the most distressing symptoms seen in patients with chronic renal disease. The itching may be localized or generalized, is unassociated with a rash and is persistent and intractable. Dialysis may provide some relief but rarely improves itching significantly. Patients have dry skin but emollients do not give complete relief. Increased density of mast cells in the skin and increased histamine levels has been observed in some patients but antihistamine treatment is only partially helpful. 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.⁴ Other therapeutic modalities include ultraviolet B (UVB) phototherapy and oral activated charcoal. We have no experience with naltrexone and ondansetron which have also been tried.⁵ Renal transplantation is the definitive treatment.

Cholestasis
Pruritus is a common and early symptom in patients with cholestatic liver diseases such as primary biliary cirrhosis, primary sclerosing cholangitis, obstructive gallstone disease, and carcinoma of head of pancreas. Drug- and pregnancy-induced cholestasis can also cause severe pruritus, which is probably related to increased levels of bile salts and other related compounds. The levels of bile salts do not correlate with the severity of itching but measures to lower bile salt levels do provide some relief of itching.

Itching from cholestasis is usually generalized but worse on the hands and feet. There are no primary skin lesions; however, changes secondary to scratching may be pronounced. Other cutaneous signs may be present: jaundice and spider angiomas due to underlying liver disease and xanthelasma from hypercholesterolemia. Treatment with ion exchange resins, such as cholestyramine, probably acts by lowering levels of bile salts and other pruritogens. Altered central opioidergic neurotransmission is thought to be a contributing factor.⁶ Opioid antagonists such as naloxone have been found to be useful. Rifampicin has been shown to reduce pruritus in patients with primary biliary cirrhosis.⁷

Polycythemia Vera
Up to 50% of patients with polycythemia vera experience a severe prickly sensation after contact with water. This symptom, which commonly starts after a bath, is termed the bath-itch and it may precede the development of polycythemia vera by several years. Skin lesions are absent. Antihistamines are usually ineffective, but psoralen plus ultraviolet A (UVA) phototherapy has been helpful in some patients.

Iron Deficiency Anemia
The role of iron deficiency as a cause of pruritus is controversial. Patients with iron deficiency may experience pruritus on skin that appears normal, and patients with polycythemia vera and severe iron deficiency report improvement in pruritus after correction of the iron deficiency.⁸ However, a study of patients with iatrogenic iron deficiency did not report any pruritus in these patients.⁹ Thus, itching in iron-deficient patients may be due to other, unknown causes.

Endocrine Disorders
Patients with thyrotoxicosis can present with intractable generalized pruritus. Itching may be due to increased skin blood flow, which increases the skin temperature and decreases the itch threshold. Patients with thyrotoxicosis and mucocutaneous candidiasis may present with localized itching in the genital area. Myxedema causes severe itching due to dryness of skin.

Although diabetes mellitus itself probably does not cause generalized pruritus, a number of diabetics complain of itching. These patients may present with anogenital itching due to mucocutaneous candidiasis. Intractable localized pruritus of the scalp occurs due to diabetic neuropathy.¹⁰

Pruritus in Malignancy
The strongest association of pruritus and malignancy is with Hodgkin's disease.¹¹ Itching may precede Hodgkin's disease, and the intensity correlates with the severity of the disease. Itching is present more on the legs and the lower half of the body, is described as burning in quality, and is usually more intense at night. Generalized pruritus has also been described in patients with leukemia, but is less intense than in Hodgkin's disease. The association between solid visceral tumors and pruritus is less clear, though pruritus has been reported in patients with cancers of the lung, colon, breast, uterus and prostate. The pruritus frequently remits when the malignancy is treated and reappears with relapse of the disease.

Pruritus is a feature of the premycotic phase of mycosis fungoides (cutaneous T-cell lymphoma). The pruritus may be severe early in the course of the disease even though the cutaneous lesions are insignificant. Pruritus may precede the onset of cutaneous T-cell lymphoma by several years.

Pruritus In Human Immunodeficiency Virus Disease
Patients with human immunodeficiency virus disease (HIV) are prone to develop several skin diseases that are associated with itching. Scabies, pediculosis, candidiasis, drug eruptions and seborrhoeic dermatitis are a few of the conditions that may present with severe itching. Patients with HIV can also develop a generalized intensely pruritic, papular eruption due to eosinophilic folliculitis, a disorder which is often resistant to topical steroids; dapsone and ultraviolet B phototherapy have been found to be useful in such cases.

Aquagenic Pruritus
Aquagenic pruritus is an intense pricking sensation that develops after contact with water at any temperature or a sudden drop in the temperature of the skin. The itching usually occurs immediately after a shower or a bath and lasts 30 to 60 minutes. A family history may be present in one-third of the cases. It is a chronic and severe condition, and the patients may be wrongly labeled as psychoneurotic. Symptoms are similar to those seen in patients with polycythemia vera, which should be excluded in these patients. The response to antihistamines is not satisfactory, although blood histamine levels are elevated.

Atopic Eczema
Pruritus is a hallmark of atopic eczema, which is characterized by typical distribution of skin lesions and a chronic relapsing course. A personal or family history of atopic diseases can usually be elicited. Various immunologic and functional skin disturbances, like dryness and altered sweating, are implicated in the pathogenesis. The primary event is itching; skin lesions are secondary to scratching and rubbing. The lesions are on the extensor aspect in the infantile phase but later involve the flexural aspect of the elbow, knees, wrists, ankles and neck. Itching in atopics is precipitated by undressing, dry skin, contact with wool, and flushing.

Aging and Pruritus
Persistent and generalized itching is experienced by almost 50% of persons in the seventh decade of life. In most cases it is due to excessive dryness of the skin due to failure of the skin to retain water. An overheated, dry environment may contribute to dryness, leading to fine scaling and cracking of skin. Applying generous amounts of emollients, like soft, white paraffin, as well as correcting the temperature and humidity, is often helpful. However, it is also important to rule out other causes of pruritus. A primary skin condition like scabies or pre-bullous pemphigoid should be considered. The patient should be screened for an underlying systemic disease such as renal, hepatic, or endocrine disorder and for drug hypersensitivity. Screening for an underlying malignancy should be done according to any localizing symptoms, keeping economic considerations in mind.¹²

Pruritus In Pregnancy
Pruritus in pregnancy may be nonspecific due to any skin condition, but there are other pruritic conditions unique to pregnancy. Herpes gestationis is a rare, autoimmune disorder characterized by intensely pruritic urticarial lesions on the trunk that progress to vesicobullous eruptions. The condition presents during the second or third trimester and regresses spontaneously after delivery. It has a tendency to recur in subsequent pregnancies. Another condition that presents as severely itchy papules and hives late in pregnancy is termed pruritic urticarial papules and plaques of pregnancy. This condition does not progress to bullous disease, remits after delivery, and recurrences are uncommon. Cholestasis in pregnancy may also present as pruritus; jaundice may or may not be present.

Psychogenic Pruritus
Pruritus should be labeled as psychogenic only when cutaneous and systemic causes have been ruled out. Psychogenic itching can present as generalized pruritus with extensive excoriations. Other patients develop pruritus that is localized usually to the perianal or perineal areas. In these cases, threadworm, candidiasis and other inflammatory and neoplastic causes should be excluded. Parasitophobia can be recognized by the person's description of the illness and presentation of the material perceived as parasites. Patients require psychiatric advice and antidepressant and anxiolytic drugs like doxepin and hydroxyzine.

History (Including Signs and Symptoms):

A detailed history is the single most important step towards diagnosing the cause of itching. There are a number of historical axioms; exceptions occasionally exist.

Onset
Inflammatory skin conditions usually have an acute onset, whereas underlying systemic disorders are usually associated with chronic (weeks to months), progressive pruritus.

Extent (Generalized vs Localized)
Systemic diseases usually present with generalized pruritus. However, remember the possibility of systemic disease in patients with localized itching; diabetics may occasionally present with intractable localized pruritus of the scalp.

Severity
Although the perception of itching severity varies from person to person, itching that awakens someone from sleep is less likely to be psychogenic.

Quality
Patients with dermatitis herpetiformis may describe their itching as burning in quality, whereas it is often a pricking sensation in aquagenic pruritus and polycythemia.

Diurnal and Seasonal Variation
Most patients with itching, but especially those with scabies, are worse in the evening when relaxing or later at night due to the warmth of the bed. Pruritus due to xerosis and atopic eczema is often worse in the winter due to low relative humidity and increased transepidermal water loss.

Bathing
In addition to itching in polycythemia vera and aquagenic pruritus that occurs after bathing, frequent hot baths and excessive use of soap aggravate pruritus by causing dry skin.

Other Aggravating Factors
Exercise, clothing contact (touch), skin cooling, air and topical preparations may aggravate itching.

Occupation and Hobbies
Exposure to chemicals at work or home may cause irritant or allergic contact dermatitis and should be suspected, especially if there is a temporal relation.

Medication History
A detailed inquiry of prescription, over-the-counter (including herbals), topical, office sample, and recreational drugs is important, especially in undiagnosed cases of itching. Selected drugs associated with itching include those causing cholestasis (eg, chlorpropamide, phenothiazines, erythromycin estolate, oral contraceptives, captopril, and trimethoprim-sulfamethoxazole), antimalarials, opiates, salicylates and quinidine.

Medication Allergy
Look for drugs that are chemically related to the patient's list of drug allergies. An example involving systemic drugs includes administration of sulfonamide-based diuretics in patients with sulfonamide antibiotic allergy. Topical allergies preclude systemic administration of chemically related drugs. Examples include avoiding systemic doxepin and aminophylline in those with topical doxepin and ethylenediamine allergies, respectively.

Other History
Inquire about personal or family history of atopy (childhood eczema, allergic rhinitis and asthma), household and other contacts, pets, travel and sexual history (HIV disease).

Prior Diagnoses
Always listen to the patients and other physicians' theories of possible causes.

Dermographism and Physical Urticaria
These disorders are associated with itching including diminutive variants that may cause itching without a rash.

Duration
According to Kantor and Bernhard,¹³ itching lasting for greater than 3 weeks without an identifiable cause is pruritus of undetermined origin (PUO). PUO and those patients with non-specific rashes present the greatest diagnostic challenges.

Review of Systems
A complete detailed inquiry is especially important in PUO, 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.¹³ In one follow-up study 4(9%) of 44 patients with generalized pruritus were found to have systemic disease.¹³

Physical Examination
(Including Cutaneous and Other Signs):

The skin should be examined thoroughly for evidence of any recognizable disorder. Scratching (causing excoriations) or rubbing (producing papules, nodules, and lichenified plaques) may lead to secondary changes that should not be interpreted as a primary skin disorder but may mimic them. Examination of the upper midback may help in this distinction, as 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 may identify either disorder. Direct, reflected light may identify nits of pubic and head lice. Examination of clothing seams may identify body lice in the unkempt (vagabond's disease). Look for other cutaneous signs mentioned above 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.

Investigations:

A preliminary panel of laboratory investigations has been suggested (Table 4) for patients with generalized pruritus (pruritus of unknown origin; PUO) and nonlocalizing illness clinically.¹⁴

Other laboratory and imaging studies and endoscopy (Table 4) are performed when localizing signs are present. Histopathological 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 may show immune deposits in early cases of pemphigoid.

Patients with PUO should be followed with periodic reevaluation for as long as the symptoms persist, since an underlying disorder may manifest later.

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 PUO. Although difficult to implement in patients with atopic dermatitis, the importance of breaking the itch-scratch cycle should be clearly explained as scratching leads to more itching. Cool compresses and cool baths may help relieve the itch. Warmth aggravates itch, so a cool environment at 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 (Table 5). Pinching or gently massaging the affected area may help temporarily.

Pruritus due to dry skin, especially in the elderly, responds to emollients such as petrolatum. 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 used only when there are signs of cutaneous inflammation. Topical tacrolimus can be prescribed 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 may work better. Tricyclic antidepressants such as doxepin have antihistamine activity in addition to central effects and are useful in chronic, severe pruritic states. Ultraviolet 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 like 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) (Table 5).

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