Pruritus: Etiology and patient evaluation

INTRODUCTION — Pruritus (itch) is a common symptom, rather than a specific disease entity, that occurs in a diverse range of skin diseases (table 1). Pruritus may also appear as a prominent feature of extracutaneous disorders, such as systemic, neurologic, and psychiatric diseases (table 2).

The pathogenesis and etiology of pruritus, as well as the evaluation of the patient with pruritus, will be reviewed here. The treatment of pruritus is discussed separately. (See "Pruritus: Therapies for localized pruritus".)

EPIDEMIOLOGY — Pruritus is a common symptom that is experienced by all human beings at some point during the course of life. The frequent occurrence of pruritus is supported by the results of epidemiologic studies. In a cross-sectional study (n = 11,730), chronic pruritus (pruritus persisting for more than six weeks) was reported in approximately 16 percent of German workers [1]. A separate study of almost 19,000 adults in Norway found a prevalence of chronic pruritus in the general population of approximately 8 percent [2].

DEMOGRAPHIC RISK FACTORS — Age, sex, and other demographic factors may influence risk for pruritus.

Advanced age — Pruritus is common in older adults. Dry skin (xerosis) is probably the most common cause of pruritus in this population; additional frequent causes for pruritus in older adults are neuropathic changes and immunosenescence (age-associated changes in the immune system). Pruritus in older adults may also result from causes of pruritus that also affect the general population, such as atopic dermatitis, other inflammatory skin diseases, scabies, and systemic diseases.

A study of 302 geriatric patients in nursing homes and geriatric outpatient centers in Mexico supports the high prevalence of chronic itch in the older adult population [3]. Among the patients, 25 percent had chronic itch, among whom 69 percent had xerosis and 28 percent had itch-related dermatoses (eg, stasis dermatitis, psoriasis, allergic contact dermatitis, lichen simplex chronicus). Certain comorbidities were associated with the presence of chronic itch, including diabetes mellitus and chronic venous insufficiency.

Idiopathic itch in older adults, sometimes inappropriately referred to as senile pruritus, presents a diagnostic and therapeutic challenge [4]. Age-related changes in nerve fibers and loss of input from pain fibers leading to central disinhibition of itch may play a role in otherwise unexplained pruritus [5].

Sex — Sex influences susceptibility to certain forms of pruritus. As an example, vulvar pruritus is a common symptom in females that can occur as a feature of a wide variety of cutaneous disorders [6]. Vulvar pruritus in prepubertal females often is secondary to irritant contact dermatitis, atopic dermatitis, psoriasis, or lichen sclerosus, though other disorders, such as pinworms or streptococcal infection, also may cause this symptom in children. Women of reproductive age with vulvar pruritus are most likely to have vulvovaginal candidiasis, allergic or irritant contact dermatitis, lichen simplex chronicus, psoriasis, or lichen sclerosus. Postmenopausal women are particularly susceptible to vaginal pruritus due to atrophic vulvovaginitis, lichen sclerosus, irritant contact dermatitis, or vulvar squamous cell carcinoma. Pruritic disorders specific to pregnancy may also occur in women. Vulvar dermatoses and pruritic dermatoses of pregnancy are reviewed separately. (See "Overview of vulvovaginal conditions in the prepubertal child" and "Vulvar lesions: Differential diagnosis of vesicles, bullae, erosions, and ulcers" and "Vulvar dermatitis" and "Vulvar lichen sclerosus" and "Vulvar lichen planus" and "Dermatoses of pregnancy" and "Vulvovaginitis in the prepubertal child: Clinical manifestations, diagnosis, and treatment".)

The possibility of other sex or gender differences in pruritus was explored in a retrospective study of 568 women and 469 men with chronic pruritus (pruritus persisting for more than six weeks) who were evaluated in a specialized itch clinic in Germany [7]. Statistically significant differences in the characteristics and morbidity of pruritus were detected. As examples, women were more likely to report sensations of stinging, warmth, or pain in association with itch, and men were more likely to have chronic pruritus resulting from dermatologic or systemic diseases. Additional studies are necessary to clarify the impact of sex and gender on the characteristics and symptomatology of pruritus.

Race or ethnicity — Race or ethnicity may influence susceptibility to itch due to variation of the prevalence of pruritic disorders among different populations [8,9]. Further study is necessary to clarify biologic factors that may lead to differences in the severity or perception of pruritus in different populations [10-12].

PATHOGENESIS — Although the neurologic pathways that lead to itch are not fully understood, it is generally accepted that transmission of signals along unmyelinated, histamine-sensitive, and non-histamine-sensitive peripheral C-nerve fibers (distinct from the C-nerve fibers that transmit pain) is involved. These fibers represent a minority (up to 5 percent) of C-nerve fibers in the body and are characterized by a slow conduction velocity and extensive terminal branching [13-18]. Histamine-sensitive fibers have an important role in transmission of acute itch and itch in urticaria, while non-histamine nerve fibers have a significant role in itch transmission of most types of chronic itch, possibly accounting for the poor response of many types of chronic itch to oral antihistamines.

Signal transmission in nerves may be stimulated by the action of a variety of neural mediators on sensory nerve endings in the epidermis, dermal-epidermal junction, and other sites. Mediators that have been identified as potential peripheral or central contributors to pruritus include histamine, proteases, cathepsins, gastrin-releasing peptide, opioids, substance P, nerve growth factor, interleukins, and prostaglandins and their respective receptors [19-21]. Of these, the identification of Mas-related G protein-coupled receptors (an itch-specific population of neurons) represents a major advance in understanding chronic itch. These receptors are key for transmission of nonhistaminergic itch [22].

The itch-transmitting primary afferent C neurons synapse with secondary transmission neurons that cross over to the contralateral spinothalamic tract and ascend to the thalamus. The itch stimulus then travels to the cerebral cortex, where multiple sites in the brain are activated, including those involved in sensory function, motor function, and emotion [16,23,24]. This suggests that there is no single area primarily responsible for processing this stimulus, a factor that may contribute to the multidimensional psychologic and physical aspects of pruritus.

Both scratching and rubbing skin inhibit the sensation of pruritus by stimulating inhibitory local circuits in the spinal cord and brain [25,26]; scratching also stimulates pain receptors, which inhibits the sensation of itch. The inhibitory interneurons can be activated by both peripheral and central stimuli, and they release endogenous opiates [15]. Additionally, central sensitization for itching may occur in patients with chronic pruritus such that noxious stimuli are perceived as itch rather than pain [23,27].

CLASSIFICATION — Pruritus is often categorized according to its duration, clinical manifestations, or etiology.

Acute versus chronic — Acute pruritus is defined as pruritus lasting less than six weeks; the term chronic pruritus refers to symptoms of longer duration [28,29]. Chronic pruritus is often difficult to manage and can be debilitating; therapies that provide transient relief usually do not address the underlying causes of chronic pruritus.

Clinical manifestations or cause — A two-tier classification system for pruritus has been proposed by a panel of experts from the International Forum for the Study of Itch [28]. The first tier allows the classification of pruritus when the diagnosis is unknown and consists of three groups:

●Group I – pruritus on diseased (inflamed) skin

●Group II – pruritus on nondiseased (noninflamed skin), such as pruritus related to end-stage kidney disease, cholestatic pruritus, or neuropathic pruritus

●Group III – pruritus presenting with severe, chronic, secondary scratch lesions, such as prurigo nodules associated with end-stage kidney disease or excoriations secondary to severe itch in patients with systemic disease-related pruritus or neuropathic pruritus

A skin biopsy may be useful for the evaluation of patients in group I, as it may assist in identifying a primary skin disease. Skin biopsy generally is not useful in patients in groups II or III.

When the origin of pruritus is known, pruritus can be divided into the following categories:

●Dermatologic – This group contains pruritus resulting from skin disorders. Examples include xerosis, atopic dermatitis, psoriasis, urticaria, and cutaneous infections. This group accounts for almost all disorders in group I. (See 'Dermatologic disorders' below.)

●Systemic – Systemic causes of pruritus consist of disorders that affect other organ systems, such as chronic renal failure, liver disease, hematologic or lymphoproliferative disorders, and malignancy. Drug-induced pruritus is also included in this category. (See 'Systemic disorders' below.)

●Neurologic – This group includes pruritus related to disorders of the peripheral or central nervous system. Examples include notalgia paresthetica, brachioradial pruritus, and multiple sclerosis. (See 'Neurologic disorders (neuropathic itch)' below.)

●Psychogenic – Examples of psychiatric disorders in which patients may complain of pruritus include depression, anxiety, psychogenic excoriation, and delusional infestation (also called delusional parasitosis).

●Mixed – Pruritus attributed to more than one cause is placed in this category.

POTENTIAL CAUSES

Dermatologic disorders — Numerous dermatologic disorders present with pruritus, most of which are characterized by the presence of visible skin inflammation (table 1). Examples of disorders that may present with pruritus are provided below.

Xerosis — Pruritus related to xerosis is characterized by itching in areas of dry, scaly skin (picture 1). Xerosis is a common cause of pruritus in older adults [30]. Symptoms often occur on the lower extremities. Severe xerosis may also precipitate the development of pruritic, eczematous dermatitis. Risk factors for xerosis include advanced age, frequent bathing, and ambient high temperatures with relatively low humidity, such as the environment produced by home heating in the winter [31]. (See "Pruritus: Therapies for generalized pruritus", section on 'Xerosis (dry skin)'.)

Eczematous dermatitis — Eczematous dermatitis may manifest as inflammatory patches or plaques. Common causes include atopic dermatitis and contact dermatitis:

●Atopic dermatitis – Pruritus is the hallmark symptom of atopic dermatitis, a chronic, pruritic, inflammatory skin disorder that presents with erythematous or hyperpigmented papules or plaques. Skin involvement often reflects a characteristic distribution (eg, flexural surfaces in older children and adults; face, scalp, and extensor surfaces in infants (picture 2)). The onset of atopic dermatitis is often in childhood, and affected individuals frequently have a family history of allergic disease and other associated features (table 3). Alloknesis, a phenomenon in which a normally innocuous stimulus (eg, sweating, contact with wool) induces itch, is a prominent feature [32]. A vicious itch-scratch cycle, in which injury to the skin from scratching stimulates pruritus, can also occur in atopic dermatitis. (See "Atopic dermatitis (eczema): Pathogenesis, clinical manifestations, and diagnosis".)

●Contact dermatitis – Contact dermatitis refers to any dermatitis arising from contact between a substance and the skin. The dermatitis may be allergic or irritant induced. In allergic contact dermatitis, the trigger induces an immune response, while in irritant contact dermatitis, the trigger itself directly damages the skin (picture 3A-B). (See "Clinical features and diagnosis of allergic contact dermatitis" and "Irritant contact dermatitis in adults" and "Contact dermatitis in children".)

Urticaria — Urticaria, or hives, is a common, intensely pruritic acute or chronic disorder that presents with transient, erythematous, edematous plaques (welts or wheals), often with central pallor (picture 4). Individual plaques may enlarge or coalesce with other plaques and typically disappear over a few hours. Urticaria may result from allergy, physical insults, or systemic disorders. (See "New-onset urticaria".)

Papulosquamous disorders — Pruritus is a common feature of multiple papulosquamous disorders, such as psoriasis, lichen planus, pityriasis rubra pilaris, and others [33]. In psoriasis, there tends to be a cyclical quality to the symptoms, with the majority of pruritus occurring at night (picture 5). Furthermore, pruritus is not restricted to the area of the psoriatic plaque, often being generalized and poorly responsive to conventional antipruritics [34]. (See "Psoriasis: Epidemiology, clinical manifestations, and diagnosis".)

Infections and infestations — Cutaneous infections and infestations are common causes of pruritus in children and adults. Common infectious causes include dermatophyte infections (eg, tinea cruris, tinea pedis, tinea capitis), which typically manifest as scaly patches or plaques (picture 6A-D), and folliculitis, which presents with follicularly based inflamed papules and pustules (picture 7). (See "Dermatophyte (tinea) infections" and "Infectious folliculitis".)

Common cutaneous infestations with pruritus as a prominent feature include scabies mite infestation and pediculosis capitis, corporis, or pubis. Pruritus in scabies is due to a delayed hypersensitivity response to the mite proteins. Pruritus in pediculosis is caused by a delayed hypersensitivity reaction to saliva of the louse.

Scabies is associated with severe pruritus that usually worsens in the evening and night and can continue for several weeks after the mites are eradicated [35]. Affected patients may exhibit small, often excoriated papules and/or mite burrows, most often in intertriginous areas, such as the neck, axillae, genitals, and finger webs (picture 8A-B). Dermoscopy or skin scrapings can be used to identify the mite. Pruritus secondary to pediculosis may also be intense. In pediculosis, lice and louse eggs can be seen on hair shafts or clothing (picture 9A-C). (See "Scabies: Epidemiology, clinical features, and diagnosis" and "Pediculosis capitis" and "Pediculosis pubis and pediculosis ciliaris" and "Pediculosis corporis".)

Pruritus may also result from other arthropod bites. (See "Insect and other arthropod bites".)

Secondary skin disorders — Scratching or rubbing of pruritic skin leads to changes in the appearance of the skin in conditions such as lichen simplex chronicus and prurigo nodularis.

Lichen simplex chronicus describes the development of lichenified plaques (thickened skin with accentuated skin markings) and excoriations from excessive scratching of intensely pruritic skin, and is often noted in the setting of atopic dermatitis, neuropathic forms of pruritus, or psychopathology (picture 10) [36]. Common sites of involvement include the scalp, neck, extensor forearms, scrotum, and lower legs.

Prurigo nodularis is an uncommon disorder characterized by the development of multiple firm, pruritic nodules in a symmetric distribution (picture 11). Prurigo nodularis occurs in the setting of chronic pruritus, often in patients with a history of atopic dermatitis. (See "Prurigo nodularis".)

Scars — Burn scars are common in both children and adults and are associated with significant pruritus [37]. (See "Management of burn wound pain and itching".)

Keloids are often associated with pruritus at the periphery of the keloid (picture 12). This finding may result from entrapment of small nerve fibers [38]. (See "Keloids and hypertrophic scars".)

Other — Pruritus is a characteristic feature of autoimmune blistering diseases, such as bullous pemphigoid and dermatitis herpetiformis, as well as multiple other disorders, such as cutaneous mastocytosis.

Most patients with bullous pemphigoid develop eczematous or urticarial plaques and bullae, although a subset initially present with pruritus in the absence of primary skin lesions (picture 13A-B) [39]. Dermatitis herpetiformis is associated with gluten sensitivity and presents with intensely pruritic inflammatory papules and vesicles on sites such as the forearms, knees, scalp, and buttocks (picture 14). A skin biopsy and direct immunofluorescence studies are necessary to confirm a diagnosis of autoimmune blistering disease. (See "Clinical features and diagnosis of bullous pemphigoid and mucous membrane pemphigoid" and "Dermatitis herpetiformis".)

Pruritus is a frequent symptom in patients with cutaneous involvement in mastocytosis. In mastocytosis, pruritus is induced by exposure to triggers for mast cell mediator release. When necessary, a skin biopsy can confirm the diagnosis. (See "Mastocytosis (cutaneous and systemic) in adults: Epidemiology, pathogenesis, clinical manifestations, and diagnosis" and "Mastocytosis (cutaneous and systemic) in adults: Epidemiology, pathogenesis, clinical manifestations, and diagnosis", section on 'Signs and symptoms'.)

Systemic disorders — Pruritus caused by systemic disease typically presents without a primary skin eruption. Secondary skin lesions related to scratching and rubbing, such as lichenified plaques, excoriations, and prurigo nodules, are often present. (See 'Secondary skin disorders' above.)

A variety of systemic diseases, including malignancy, should be considered when a patient presents with generalized pruritus without any dermatologic manifestations (table 2). Select disorders are reviewed below.

Renal disease — Uremic pruritus is common among hemodialysis and peritoneal dialysis patients and remains one of the most common and potentially disabling symptoms of end-stage kidney disease [40]. Patients typically complain of pruritus, which is often generalized but may be most prominent on the back [41-43]. Many patients experience worsening of symptoms in the evening and night. Pruritus may also be exacerbated during and at the conclusion of dialysis [41,44]. A single cause of uremic pruritus has not been identified; multiple factors may contribute. (See "Uremic pruritus".)

Liver disease — Cholestatic pruritus, which occurs due to the impaired secretion of bile, is a common symptom in certain forms of liver disease. It is typically generalized and often begins with an acral distribution involving the palms and soles, areas that are uncommon sites for pruritus in other systemic diseases. Symptoms later become more generalized [45].

Examples of associated conditions include primary biliary cholangitis, intrahepatic cholestasis of pregnancy, sclerosing cholangitis, viral hepatitis, drug-induced cholestasis, as well as cases of obstructive jaundice. Pruritus is a common presenting symptom of primary biliary cholangitis and occurs at some point in almost all patients [46]. (See "Clinical manifestations, diagnosis, and prognosis of primary biliary cholangitis (primary biliary cirrhosis)" and "Intrahepatic cholestasis of pregnancy".)

The mechanism of cholestatic pruritus has not been clearly elucidated. Patients with cholestatic pruritus have elevated plasma opioid levels, which conceivably could contribute to itch [45]. In addition, the enzyme autotaxin and its substrate lysophosphatidic acid have been proposed as potential mediators in cholestatic itch [45,47]. Interaction between bilirubin and peripheral itch sensory neurons through Mas-related G-protein-coupled receptors has also been proposed as a mechanism for itch [48]. (See "Pruritus associated with cholestasis".)

Endocrine disease — Pruritus may occur in association with thyroid disease and diabetes:

●Thyroid disorders – Generalized pruritus is seen commonly in patients with thyrotoxicosis, particularly in Graves' disease [46,49]. Possible mechanisms include reduction of the itch threshold mediated by vasodilation, as well as activation of kinin pathways secondary to an increased metabolic rate. Hypothyroidism is less frequently associated with itch and is associated with skin xerosis [46]. (See "Overview of the clinical manifestations of hyperthyroidism in adults" and "Clinical manifestations of hypothyroidism".)

●Diabetes – Generalized itching does not appear to occur at increased frequency in diabetic patients [50]. However, pruritus due to disorders associated with diabetes, including dermatophyte infections, xerosis, diabetic neuropathy, and cutaneous Candida infections, may occur [46]. In particular, diabetic neuropathy may account for otherwise unexplained pruritus localized to the lower extremities, scalp, or trunk [51,52]. Pruritus vulvae has been associated with poorly controlled diabetes [50]. (See "Screening for diabetic polyneuropathy".)

Malignancy — Generalized pruritus may be the presenting sign of hematologic malignancies; however, the association is not as strong in solid tumors. Pruritus occasionally presents years before the malignancy becomes clinically detectable. Pruritus may also occur as a feature of paraneoplastic skin diseases, such as eruptive seborrheic keratosis, malignant acanthosis nigricans, dermatomyositis, and erythroderma [53,54]. (See "Cutaneous manifestations of internal malignancy", section on 'Sign of Leser-Trélat' and "Cutaneous manifestations of internal malignancy", section on 'Acanthosis nigricans' and "Clinical manifestations of dermatomyositis and polymyositis in adults" and "Grover's disease (transient and persistent acantholytic dermatosis)".)

The most common malignancies associated with pruritus include Hodgkin lymphoma, non-Hodgkin lymphoma, mycosis fungoides, polycythemia vera, leukemias, plasma cell dyscrasias, and gastric carcinoid tumors (see "Cutaneous manifestations of internal malignancy"):

●Hodgkin lymphoma – Itching as a primary symptom is commonly seen in patients with Hodgkin lymphoma, developing in approximately 30 percent of cases [49]. In some patients, pruritus precedes the clinical presentation of lymphoma by up to five years and, therefore, can be regarded as a paraneoplastic sign [46,53]. Itching is often located on the lower extremities and is occasionally accompanied with ichthyosiform skin changes. Pruritus related to Hodgkin lymphoma is often more severe in older patients and patients with more advanced disease. Symptoms may be aggravated at night [45,53]. (See "Clinical presentation and diagnosis of classic Hodgkin lymphoma in adults".)

●Polycythemia vera – Aquagenic pruritus (water-induced itching) may occur in up to two-thirds of patients with polycythemia vera [55]. Patients frequently complain of intractable itching within minutes after contact with water. Alternatively, stinging, tingling, or burning sensations occur. The chest, back, medial upper arms, and anterior legs are common sites of involvement [55]. Aquagenic pruritus may precede a diagnosis of polycythemia vera by several years or more. The condition has also been associated with other diseases, including myelodysplastic disorders and T cell lymphomas. (See "Clinical manifestations and diagnosis of polycythemia vera", section on 'Pruritus'.)

●Mycosis fungoides – Pruritus is a frequent manifestation of mycosis fungoides (cutaneous T cell lymphoma). The erythrodermic form of mycosis fungoides, Sézary syndrome, and folliculotropic mycosis fungoides are often extremely pruritic. There are case reports of pruritus preceding the onset of skin findings by several years [56]. (See "Clinical manifestations, pathologic features, and diagnosis of mycosis fungoides".)

●Other hematologic malignancies – Patients with non-Hodgkin lymphoma may present with pruritus, but there are limited epidemiologic data on the prevalence of this symptom. Other hematologic malignancies linked to chronic pruritus include leukemia, most commonly chronic lymphocytic leukemia, as well as multiple myeloma [46,53]. (See "Clinical presentation and initial evaluation of non-Hodgkin lymphoma" and "Clinical features and diagnosis of chronic lymphocytic leukemia/small lymphocytic lymphoma" and "Multiple myeloma: Clinical features, laboratory manifestations, and diagnosis".)

●Gastric carcinoid – In contrast to the usually nonpruritic intermittent cutaneous flushing associated with intestinal carcinoids, the intermittent "histamine" flush associated with atypical gastric carcinoids tends to be pruritic. (See "Clinical features of carcinoid syndrome", section on 'Gastric NET variant syndrome'.)

Patients who do not have evidence of malignancy at the time of a diagnosis of pruritus may have a slightly increased risk for a future diagnosis of malignancy [57,58]. As an example, in a population-based cohort study that used electronic medical records of 8744 patients with chronic pruritus and 31,580 patients without chronic pruritus from the United Kingdom to compare the five-year risk for new malignancy in these populations, patients with chronic pruritus demonstrated increased risk for hematologic malignancy (adjusted hazard ratio 2.02, 95% CI 1.48-2.75) and bile duct carcinoma (adjusted hazard ratio 3.73, 95% CI 1.55-8.97), but not for other types of cancer [57]. A nationwide Danish cohort study that examined the relationship between a pruritus diagnosis (duration unspecified) and subsequent cancer found increased risk for hematologic malignancies as well as several other types of cancer [58].

Infections — Various systemic infections may be associated with pruritus. For example, pruritus is a common feature of primary varicella-zoster virus infection (chicken pox). (See "Clinical features of varicella-zoster virus infection: Chickenpox".)

Pruritus is also common in patients with HIV infection and can have a significant negative effect on quality of life in this population [59,60]. A study of 303 HIV-infected patients in Spain found a point prevalence of pruritus of 31 percent [59]. In addition, chronic pruritus was reported by 45 percent of 201 HIV-infected patients in a study in the United States [60]. The majority of patients in both studies were receiving antiretroviral therapy.

Pruritus in the setting of HIV infection may occur as a result of primary skin disorders that are common in HIV-infected individuals (eg, xerosis, seborrheic dermatitis, and dermatophyte infections) or as a result of less common HIV-associated skin disorders, such as eosinophilic folliculitis. HIV-associated eosinophilic folliculitis is an intensely pruritic condition associated with advanced HIV disease. It is characterized by a perifollicular papular eruption that involves the upper trunk, limbs, and face (picture 15) [61]. Pruritic papular eruption is another pruritic, papular skin disorder that may occur in the setting of HIV. (See "HIV-associated eosinophilic folliculitis" and "HIV-associated eosinophilic folliculitis", section on 'Differential diagnosis'.)

Pruritus may also be associated with systemic disease in patients with HIV infection (eg, lymphoma, chronic renal disease, or hepatic disease) or may present as a manifestation of early HIV infection [62].

Systemic rheumatic disease — Itch is a common symptom of dermatomyositis, systemic sclerosis (scleroderma), and primary Sjögren's syndrome (P-SS) [63-69]. The pathophysiology of chronic itch in systemic rheumatic diseases is not well understood; however, P-SS is highly associated with skin xerosis. (See "Cutaneous dermatomyositis in adults: Overview and initial management", section on 'Impact on quality of life' and "Clinical manifestations of Sjögren's syndrome: Extraglandular disease" and "Clinical manifestations and diagnosis of systemic sclerosis (scleroderma) in adults".)

Patients with dermatomyositis frequently experience intense pruritus that impairs their ability to sleep and affects their quality of life. An increase in interleukin-31 (a cytokine linked to pruritus) in the skin has been detected in patients with pruritus related to dermatomyositis [70].

Drug reactions — The mechanisms through which drugs induce itch vary. As examples, pruritus may result from drug-induced skin dryness, such as may occur with systemic retinoid therapy, or as an associated feature of drug-induced phototoxicity, such as may follow doxycycline therapy.

In addition, pruritus without an associated skin eruption is a side effect of numerous medications (table 4). Pruritus frequently accompanies the use of opiates, particularly when intrathecally or epidurally administered [71]. Pruritus also has been reported as a side effect of a number of molecularly targeted and immunotherapeutic antineoplastic agents, including inhibitors of epidermal growth factor, tyrosine kinase, BRAF, MEK, programmed cell death receptor 1 (PD-1), programmed cell death ligand 1 (PD-L1), and cytotoxic T lymphocyte-associated protein 4 (CTLA-4) [72-76]. Drug-induced cholestasis may also induce pruritus [77,78]. (See "Prevention and management of side effects in patients receiving opioids for chronic pain", section on 'Pruritus' and "Cutaneous adverse events of molecularly targeted therapy and other biologic agents used for cancer therapy" and "Toxicities associated with immune checkpoint inhibitors".)

Neurologic disorders (neuropathic itch) — Neurologic dysfunction results in the development of itch in multiple disorders, including brachioradial pruritus, notalgia paresthetica, postherpetic neuralgia, and other disorders.

Brachioradial pruritus — Brachioradial pruritus presents with localized pruritus involving the proximal dorsolateral forearm. Symptoms may be intermittent, unilateral or bilateral, and in some cases may extend to the upper arm, shoulder, neck, or upper trunk [79]. Symptomatic relief often occurs with application of ice to the affected area (the "ice-pack sign"), a finding that may assist with diagnosis [80,81].

The pathogenesis of brachioradial pruritus is not well understood. Current theories suggest cervical nerve root impingement at the levels of C5 to C8 as a predisposing factor and solar radiation as an exacerbating factor [82-84]. Rarely, brachioradial pruritus is associated with spinal tumors; in such cases, motor or neurologic deficits usually are present [85,86].

The relationship between brachioradial pruritus and cervical spine disorders was evaluated in a retrospective study of 111 patients with brachioradial pruritus [81]. Cervical spine abnormalities (primarily degenerative joint disease) were detected in 42 of 45 patients (93 percent) who underwent radiologic imaging of the cervical spine. The relevance of these findings was unclear given that only 8 of 31 patients (26 percent) referred to neurologists for evaluation were thought to have radiculopathy or peripheral neuropathy as a contributor to their symptoms.

Support for sun exposure as a contributing factor stems from the observation that affected individuals are often fair-skinned, middle-aged adults who live in sunny climates and frequently engage in outdoor leisure activities. Moreover, the condition frequently worsens during the summer months [81].

Additional study is necessary to determine the pathogenic mechanism of brachioradial pruritus. It is unclear whether routine radiologic evaluation of the cervical spine is of value. We typically reserve radiologic imaging and referral to neurology for patients with other neurologic symptoms. Radiologic imaging also may be performed for further evaluation in treatment-refractory cases [81]. The treatment of brachioradial pruritus is reviewed separately. (See "Pruritus: Therapies for localized pruritus", section on 'Brachioradial pruritus'.)

Notalgia paresthetica — Like brachioradial pruritus, notalgia paresthetica is characterized by localized pruritus and appears to be of neurologic origin. The current view on etiology is that the itch is due to nerve entrapment of the posterior rami of spinal nerves that arise from T2 to T6 [87].

The symptoms are unilateral and involve skin medial to the scapular border on the mid or upper back. Cutaneous changes secondary to scratching or rubbing the skin (such as hyperpigmentation) are the only visible findings (picture 16). Secondary amyloid deposition may be detected in skin biopsies. (See "Pruritus: Therapies for localized pruritus", section on 'Notalgia paresthetica'.)

Postherpetic neuralgia — Between 30 and 58 percent of patients with postherpetic neuralgia experience pruritus at the site of herpes zoster [88,89]. Symptoms may be most likely to occur in following eruptions on the head, face, or neck [88]. Pruritus also may occur in association with acute herpes zoster. (See "Pruritus: Therapies for localized pruritus", section on 'Postherpetic itch'.)

Multiple sclerosis — Infrequently, patients with multiple sclerosis experience recurrent and severe episodes of generalized pruritus [90]. Symptoms have been attributed to activation of artificial synapses in areas of demyelination [46]. (See "Manifestations of multiple sclerosis in adults", section on 'Sensory symptoms'.)

Other — Pruritus may be a symptom of small fiber neuropathies (disorders of small nerve fibers associated with autonomic and sensory symptoms) [91]. Small fiber neuropathies may be idiopathic or associated with other diseases (eg, diabetes, infection, autoimmune disorders, Fabry disease, etc). In addition, neuropathic itch can occur as a result cerebrovascular accidents, trigeminal trophic syndrome [92], or Creutzfeldt-Jakob disease [93,94].

Chronic pruritus of unknown origin — Chronic pruritus of unknown origin (CPUO) is chronic pruritus in individuals who present with chronic itch in the absence of an identifiable etiology [95]. Although not restricted to older adults, CPUO includes patients with pruritus considered secondary to advanced age, a condition also referred to as "pruritus of the elderly." As understanding of the etiologies of CPUO expands, the scope of this diagnosis will likely become narrower.

Psychogenic itch — General or localized pruritus can occur in the setting of psychiatric illnesses or somatoform disorders [96]. In a series of 100 psychiatric inpatients, the prevalence of generalized pruritus was 42 percent [97]:

●Psychogenic excoriation – Psychogenic excoriation (also known as neurotic excoriation) is a disorder in which individuals excessively pick and scratch normal skin. Affected patients typically complain of significant pruritus. On physical examination, scattered, linear, crusted lesions may be present anywhere on the body within reach of the patient, although they are most often confined to the extremities [98]. (See "Skin picking (excoriation) disorder and related disorders".)

Psychologic stress may be associated with the development of symptoms [99]. In one study of 68 patients with psychogenic excoriation, 90 percent described a conflict or stressor preceding the onset of the condition [100]. Increased rates of psychiatric diseases, particularly mood and anxiety disorders, have also been identified in patients with this disorder [101]. As an example, a case-control study (n = 100) found that the prevalence of self-reported depression or bipolar disorder was significantly greater among patients with psychogenic excoriation than among controls (42 versus 18 percent and 12 versus 0 percent, respectively) [102].

Delusional infestation is a separate psychiatric disorder characterized by the patient's false belief that he or she is suffering from a parasitic infection. Patients often complain of pruritus. Delusional infestation is discussed in greater detail separately. (See "Delusional infestation: Epidemiology, clinical presentation, assessment and diagnosis".)

Due to the increased prevalence of psychopathology among patients with otherwise unexplained pruritus, clinicians should consider the possibility of an underlying psychiatric disorder in such patients.

●Drug use – Individuals with substance use disorders involving opioids, cocaine, or amphetamines often complain of itch and scratching. (See "Opioid use disorder: Epidemiology, pharmacology, clinical manifestations, course, screening, assessment, and diagnosis" and "Cocaine use disorder in adults: Epidemiology, clinical features, and diagnosis" and "Methamphetamine use disorder: Epidemiology, clinical features, and diagnosis".)

●Other factors – Psychologic factors might affect the severity of pruritus in individuals with pruritus unrelated to a psychologic disorder. A study that explored the impact of emotional states on pruritus found that sensitivity to pruritus was greater during exposure to a film that was intended to elicit negative emotions than to a film that was intended to elicit positive emotions [103]. Further studies are necessary to clarify the impact of emotional states on pruritus.

Itching, like yawning, may be contagious, causing people to feel an urge to scratch after they see another person scratching. This seems more common in patients who suffer from chronic itch [104,105].

EVALUATION — A key component of patient evaluation is the determination of the presence or absence of primary skin lesions. The presence of primary skin lesions suggests a dermatologic disorder. In patients who present without skin lesions or with only secondary skin lesions (eg, excoriations, hyperpigmentation, or lichenification), the possibility of systemic, neurologic, or psychogenic causes of itch must be considered [29]. Inquiries regarding the location (generalized or localized), temporal nature, and exacerbating and alleviating factors for pruritus can also offer clues for diagnosis.

An algorithm describing the approach to the evaluation of patients with pruritus is provided (algorithm 1).

Pruritus with primary skin lesions — The majority of patients who present to outpatient medical clinics with pruritus will have an obvious primary skin disorder that explains their symptoms. The evaluation of such patients involves the identification of the cause of the skin eruption. A skin biopsy or other diagnostic tests (eg, potassium hydroxide preparation for cutaneous fungal infections) may be useful for diagnosis when the etiology is unclear. (See "Approach to the clinical dermatologic diagnosis".)

Occasionally, the skin findings in patients with primary skin disorders are subtle [29]. Xerosis may not be apparent unless the skin is inspected closely, when fine scaling and epidermal cracking may be visible [106]. Scabies may not be obvious in patients in whom there are few lesions, and urticaria, due to its transient nature, often can be missed [98]. A careful physical examination and patient history can be helpful in these scenarios.

Generalized pruritus without primary skin lesions — A detailed patient history is particularly important in patients with generalized pruritus who lack primary skin lesions, as the differential diagnosis for this presentation is broad and includes disorders that are associated with significant morbidity [29]. In addition to details regarding the nature of pruritus, the following components of the patient history may be useful for diagnosis:

●History of thyroid disorders, liver disease, renal disease, HIV infection, or malignancy

●Presence of constitutional symptoms (eg, fever, weight loss, night sweats)

●Medication history

●Travel history

●Psychiatric and substance abuse history

●Pruritus in other household members (suggests scabies without identifiable skin lesions)

In the absence of primary skin findings, the physical examination should focus on looking for evidence of systemic disease. Findings of conjunctival pallor, thyromegaly, splenomegaly, or stigmata of liver disease should be sought out. Lymph nodes should be palpated for signs of lymphadenopathy.

The initial evaluation generally should not include an extensive laboratory investigation for underlying systemic disease. Our typical initial evaluation includes:

●Complete blood count with differential to evaluate for evidence of malignancy, myeloproliferative disease, or iron deficiency

●Serum bilirubin, transaminases, and alkaline phosphatase to evaluate for evidence of liver disease

●Thyroid-stimulating hormone to evaluate for evidence of a thyroid disorder

●Blood urea nitrogen and creatinine to evaluate for renal disease

●Chest radiograph to evaluate for evidence of adenopathy

Additional laboratory tests are based upon the patient history and suspicion for an underlying disorder. Examples include HIV testing, immunofluorescence studies and enzyme-linked immunosorbent assay to detect bullous pemphigoid, stool examination for ova and parasites, hepatitis B and C serologies, and serum protein electrophoresis and immunoelectrophoresis (if a plasma cell dyscrasia is suspected).

While the cause of pruritus is being investigated, gentle skin care to minimize skin dryness (eg, use of emollients and mild cleansers) may be helpful, as skin dryness may exacerbate pruritus regardless of the underlying cause [29]. Topical antipruritic agents (eg, pramoxine) and avoidance of triggering factors (eg, excessive heat) may also be of value. (See "Pruritus: Therapies for generalized pruritus", section on 'Xerosis (dry skin)'.)

Patients in whom an underlying cause of pruritus is not identified should be reevaluated periodically for an underlying cause; however, the best protocol for reevaluation is unclear. During the first year of symptoms, we typically reassess these patients every four to six months, with less frequent reassessment thereafter. A review of systems and physical examination should be performed at the time of reassessment. Although basic laboratory tests assessing for hematologic, liver, and thyroid abnormalities also are often repeated, the value of this approach is unconfirmed. Alternatively, the findings of the review of systems and physical examination may be used to guide the selection of laboratory tests or studies.

Localized pruritus without primary skin lesions — Localized pruritus in the absence of a skin eruption suggests the possibility of neuropathic or psychogenic itch. In particular, associated symptoms of burning sensations, pain, or sensory loss may occur in patients with neuropathic disease. (See 'Neurologic disorders (neuropathic itch)' above.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Pruritus".)

SUMMARY AND RECOMMENDATIONS

●Epidemiology and pathogenesis – Pruritus is a common disorder. The pathogenic mechanisms that lead to the sensation of pruritus are not fully understood but are thought to involve the transmission of signals from peripheral C-nerve fibers to neurons in the spinal cord and brain. A variety of neural mediators may be involved in this process. (See 'Epidemiology' above and 'Pathogenesis' above.)

●Classification – Pruritic disorders can be classified as dermatologic, systemic, neurologic, or psychogenic causes of pruritus. Dermatologic disorders typically present with skin findings that indicate the presence of a primary skin disorder (table 1). Secondary signs of pruritus, such as excoriations, skin lichenification, and skin hyperpigmentation, may also be present. (See 'Classification' above and 'Dermatologic disorders' above.)

Multiple systemic disorders, some of which are associated with significant morbidity, may present with symptoms of pruritus (table 2). Pruritus may be the initial sign of disease in patients with hematologic malignancies. Pruritus related to solid tumors is uncommon. (See 'Systemic disorders' above.)

●Patient evaluation – A key component of the evaluation of patients with pruritus is the assessment of whether a primary skin disorder is present. Primary skin lesions are subtle in some skin disorders. If primary skin lesions are identified, but the diagnosis remains uncertain, a skin biopsy can be used to assist with diagnosis. (See 'Evaluation' above.)

The possibility of a systemic disorder should be considered in patients with generalized pruritus and no evidence for primary skin lesions. Along with a careful patient history and physical examination, select laboratory studies can be useful for obtaining a diagnosis. (See 'Evaluation' above.)