Pruritus and Systemic Disease 

Updated: Mar 03, 2020
Author: David F Butler, MD; Chief Editor: William D James, MD 

Overview

Background

Pruritus is defined as an unpleasant sensation that provokes the desire to scratch. Certain systemic diseases have long been known to cause pruritus that ranges in intensity from a mild annoyance to an intractable, disabling condition. Generalized pruritus may be classified into the following categories on the basis of the underlying causative disease: renal pruritus, cholestatic pruritus, hematologic pruritus, endocrine pruritus, pruritus related to malignancy, and idiopathic generalized pruritus.

Pruritus, or itch, is most commonly associated with a primary skin disorder such as xerosis, atopic dermatitis, drug eruption, urticaria, psoriasis, arthropod assault, mastocytosis, dermatitis herpetiformis, or pemphigoid. However, when a primary skin condition cannot be identified as the cause of pruritus, then a systemic or neuropathic cause must be sought. Patients without signs of a primary skin condition should undergo a thorough evaluation of potential systemic causes of itching.

Pathophysiology

The sensation of pruritus is transmitted through slow-conducting unmyelinated C-polymodal and possibly type A delta nociceptive neurons with free nerve endings located near the dermoepidermal junction or in the epidermis. These neurons appear to be located more superficially and are more sensitive to pruritogenic substances than pain receptors. Activators of these nerves include histamine, neuropeptide substance P,[1] serotonin, bradykinin, proteases (eg, mast cell tryptase), and endothelin (which stimulates the release of nitric oxide). Impulses are transmitted from the dorsal root ganglion to the spinothalamic tract and eventually to the thalamus.[2]

Opioids are known to modulate the sensation of pruritus, both peripherally and centrally. Stimulation of opioid mu receptors accentuates pruritus, while stimulation of kappa receptors and blockage of mu receptors suppress pruritus.

In the mouse model that mimics atopic dermatitis in humans, the histamine (H4) receptor mediates both TH-2 inflammation and pruritus.[3] A variety of interleukins (ILs) and chemokines play a role in the pruritus of atopic dermatitis. IL-4 and IL-13, as well as TH2 chemokines CCL17, CCL22, and CCL26 play a pivotal role in the development of atopic dermatitis inflammation.[4] IL-33 induces IL-31, thereby promoting pruritus and scratching behavior.[5] IL-31 promotes growth, elongation, and branching of sensory nerves in atopic dermatitis.[6]

Renal pruritus

Renal pruritus can occur in patients with chronic renal failure (CRF) and is most often seen in patients receiving hemodialysis (HD). This term is synonymous with uremic pruritus; however, the condition is not due to elevated serum urea levels. The actual pruritogenic substance has yet to be identified. Pruritus is relatively absent in persons with acute renal failure; therefore, serum mediators other than urea and creatinine are implicated.

Other theories include elevated levels of circulating histamine in patients receiving HD. Researchers have found increased numbers of mast cells in various organ systems. However, antihistamines are, at best, marginal in the treatment of renal pruritus, suggesting other causative factors.

Parathyroid hormone (PTH) levels are commonly elevated in persons with CRF.[1] Dramatic relief of renal pruritus after subtotal parathyroidectomy has been described, and findings from 1 study confirmed previous case reports. However, other studies have shown no correlation between circulating PTH levels and the intensity of pruritus. Of note, a patient with a PTH-producing bronchogenic carcinoma was reported to have intractable pruritus as the presenting symptom.[7, 8, 9]

Elevated levels of divalent ions, such as calcium, magnesium, and phosphate, are thought to play a role. Marked improvement of pruritus resulting from low dialysate calcium and magnesium concentrations has been reported.[10, 11] Increased amounts of these ions are also seen in the skin of pruritic patients.

Decreased transepidermal elimination of pruritogenic substances, xerosis, elevated levels of serum bile acids, and increased epidermal vitamin A levels all may contribute to the condition. Elevated serum levels of serotonin are seen in patients with CRF. Serotonin is important in the transmission of pain and may be a contributing factor.

Pruritus in CRF also may be a possible manifestation of peripheral neuropathy.

Xerosis in uremic patients may worsen pruritus by reducing the threshold for itch.[12]

Proliferation of nonspecific enolase-positive sensory nerves in the epidermis has been documented in patients with uremia and may contribute; however, these results must be confirmed.

Opioid accumulation may contribute to itching in persons with CRF and overexpression and activation of opioid mu receptors. Mixed results with the use of opioid antagonists in the treatment of renal pruritus have led to conflicting opinions about the role of opioids.  A newer kappa-opioid receptor agonist, nalfurafine, has shown effectiveness in end-stage renal disease patients. Nalfurafine is only available for intravenous administration.[13, 14]

An immune hypothesis has also been suggested. In patients with CRF, a systemic inflammatory response involving overexpression of activated type 1 helper T lymphocytes (which secrete interleukin 2) may induce pruritus. UV-B, thalidomide, and tacrolimus all target mediators of this inflammation. Elevated ferritin and low transferrin and albumin levels have been correlated with the severity of pruritus.

Cholestatic pruritus

Cholestasis, or a decrease or arrest in the flow of bile, is associated with pruritus. The deposition of bile salts in the skin was thought to directly cause a pruritogenic effect, but this theory has been proven incorrect. In addition, indirect hyperbilirubinemia does not induce pruritus. Pruritus is more common with intraheptic cholestasis than extrahepatic cholestasis. 

Other theories implicate elevated venous histamine levels, retention of pruritogenic intermediates in bile salt synthesis, and high hepatic concentrations of bile salts resulting in hepatic injury and release of a pruritogenic substance. In support of the last point, rifampin and ursodeoxycholic acid decrease intrahepatic concentrations of bile salts and provide some relief of cholestatic pruritus.

One study has proposed that autotaxin, the enzyme that converts lysophosphatidylcholine into lysophosphatidic acid, may be a potential mediator of cholestatic pruritus.[15]

The accumulation of endogenous opioids, which modulate pruritus and increase opioidergic tone in the brain, is of recent interest because opioid antagonists have been shown to partially relieve cholestatic pruritus. In support of this theory, treatment with opioid antagonists may induce an opioid withdrawal–like syndrome.

Perhaps some combination of the pruritogenic substances mentioned above (ie, bile salts, histamine, opioids) induces cholestatic pruritus.

Hematologic pruritus

Iron is a critical factor in many enzymatic reactions. Although iron deficiency has not been proved to be a cause of pruritus, it may contribute to pruritus through a variety of metabolic paths. Patients with pruritus and iron deficiency may not be anemic; this observation suggests that pruritus may be related to iron and not hemoglobin.

Patients with polycythemia vera have increased numbers of circulating basophils and skin mast cells, which have been correlated with itching. The itch typically occurs during cooling after a hot shower. Mast cell prostaglandins and increased platelet degranulation, which lead to the release of serotonin and prostanoids, are thought to be important mediators of itching, along with iron deficiency, which may be a contributing factor. The fact that aspirin and paroxetine alleviate this form of pruritus suggests that serotonin from platelets may play a role. However, one study showed that the concentration of platelet serotonin was the same in polycythemic patients with and without pruritus.[16]

Endocrine pruritus

Hyperthyroidism has been associated with pruritus. Excess thyroid hormone may activate kinins from increased tissue metabolism or may reduce the itch threshold as a result of warmth and vasodilation.

Hypothyroidism is also implicated because pruritus is likely secondary to xerosis.

Diabetes mellitus is another possible cause, but cause and effect remain unproven. Metabolic abnormalities, autonomic dysfunction, anhydrosis, and diabetic neuropathy all may contribute.

Pruritus and malignancy

Numerous reports have linked pruritus to almost every type of malignancy. Release of toxins and the immune system have been suggested to play roles in malignancy-related pruritus.

Chronic pruritus without associated skin changes is a risk factor for having undiagnosed hematologic and biliary tract malignancies, but not other malignancies.[17]

In patients with Hodgkin disease, leukopeptidase and bradykinin appear to be the pruritogenic mediators released as an autoimmune response is mounted against malignant lymphoid cells.

Carcinoid syndrome may be associated with pruritus triggered by serotonin.

Cutaneous T-cell lymphoma may cause intractable pruritus and may have the cytokine interleukin 31 as a mediator of itching.[18]

Etiology

Renal pruritus occurs in patients with CRF, most often those receiving HD. The exact cause is not known, although toxic substances retained during HD, histamine, opioids, and neural proliferation have been postulated as potential causes.

The exact mechanism of cholestatic pruritus is not known. However, bile salts, histamine, opioids, and an unknown pruritogen from damaged hepatocytes are postulated as potential causes. Cholestatic pruritus is particularly common with cholestasis caused by primary biliary cirrhosis, primary sclerosing cholangitis, chronic hepatitis C, choledocholithiasis, obstructive carcinoma of the pancreas/biliary system, cholestasis of pregnancy, and end-stage liver disease of any cause. Drug-induced cholestasis may be caused by chlorpropamide, tolbutamide, phenothiazines, erythromycin, anabolic steroids, and oral contraceptives.

Hematologic pruritus may be seen in association with the following conditions:

  • Iron deficiency

  • Polycythemia rubra vera

  • Hypereosinophilic syndrome

  • Essential thrombocythemia

  • Myelodysplastic syndrome

Endocrine pruritus may be seen in association with the following disorders:

  • Hyperthyroidism

  • Hypothyroidism

  • Diabetes mellitus

  • Hyperparathyroidism

  • Hypoparathyroidism

The following malignancies are known to have the potential to cause itching:

  • Hodgkin disease

  • Non-Hodgkin lymphoma

  • Leukemias

  • Paraproteinemias and myeloma

  • Carcinoid syndrome

  • Sipple syndrome (multiple endocrine neoplasia)

  • Solid tumors, including GI malignancies, CNS tumors, and lung cancer
  • Cutaneous T-cell lymphoma

A variety of other systemic disorders are associated with pruritus, including the following:

  • Drug-induced pruritus without a rash

  • Mastocytosis

  • HIV infection and AIDS
  • Hepatitic C infection

  • Sarcoidosis

  • Eosinophilia-myalgia syndrome

  • Dermatomyositis

  • Scleroderma

  • Systemic lupus erythematosus

  • Sjögren syndrome

  • Neurofibromatosis

  • Hemochromatosis

  • Multiple sclerosis

  • Brain abscess

  • Parasitic infections, including those due to hookworms, pinworms, Trichinella spiralis (trichinosis), Gnathostoma spinigerum (gnathostomiasis), Giardia species, Ascaris species (ascariasis), or Onchocerca species (onchocerciasis)

  • Parvoviral infection

  • Leptospirosis

  • Chemical intoxication with mercury or diamino diphenylmethane

  • Primary cutaneous amyloidosis

  • Starvation

  • Fibromyalgia

  • Chronic fatigue syndrome

  • Dumping syndrome

  • Notalgia paresthetica

  • Adrenergic conditions (adrenergic pruritus)

  • Cholinergic conditions (cholinergic pruritus)

Epidemiology

Frequency

United States

Pruritus occurs in approximately 20% of adults. It is present in approximately 25% of patients with jaundice and in 50% of patients receiving renal dialysis.

International

An underlying systemic disease is reported in 10-50% of patients who seek medical attention for pruritus.

The incidence of renal pruritus appears to be decreasing among patients receiving HD, most likely because of improvements in HD technique. Although previous data showed that as many as 85% of patients on HD are affected, new reports suggest the rate is 22-66%. Pruritus appears to affect up to 30% of patients with severe chronic renal insufficiency who are not undergoing dialysis.

The incidence of cholestatic pruritus depends on the underlying etiology. Approximately 60% of patients with primary biliary cirrhosis present with pruritus, and almost all develop pruritus at some point during the course of their disease.

Among patients with polycythemia vera, 48-70% of patients have aquagenic pruritus. Pruritus associated with iron deficiency is uncommon. Hyperthyroidism is the most common cause of endocrine pruritus. The rate is 4-11%, and the condition is especially prevalent in patients with untreated Graves disease. Pruritus is rare in patients with diabetes mellitus and hypothyroidism.

The rate of malignancy in patients presenting with generalized pruritus is less than 1-8%. Pruritus is commonly associated with Hodgkin disease and was once considered a B symptom of the disease. Approximately 35% of patients with Hodgkin disease have pruritus during their clinical course, whereas only approximately 10% have pruritus associated with non-Hodgkin lymphoma. Pruritus is a rare symptom of leukemia.

Sex

The sex of the patient does not seem to be associated with pruritus in systemic diseases.

Certain causes of cholestasis are more common in women than in men. These include primary biliary cirrhosis (90% of patients are women) and cholestasis of pregnancy. Primary biliary cirrhosis is thought to be an autoimmune disease that causes destruction of the small and medium bile ducts, leading to cholestasis. It most often occurs in women in the fourth or fifth decade of life, but it can occur in women as young as 20 years. Most patients initially present with fatigue and pruritus, and any women presenting with these symptoms should be suspected to have primary biliary cirrhosis. A positive antimitochondrial antibody finding has 98% specificity for the disease.

When an older man presents with generalized pruritus and iron deficiency but not anemia, the physician should consider the possibility of cancer, and routine screening tests (eg, fecal occult blood test, serum ferritin test, and urinalysis) may assist in diagnosing the cancer.

Age

Pruritus is more common in elderly people. Age is not related to the development of pruritus in systemic disease.

Prognosis

The prognosis is dependent on the underlying systemic illness that is causing the pruritus. 

Renal pruritus is an independent marker for mortality at 3 years for patients on hemodialysis. Patients with severe generalized pruritus and Hodgkin disease have a poor prognosis. Pruritus that recurs after treatment is useful in detecting recurrence of the cancer.

Many of the therapeutic modalities listed in the Treatment and Medication sections offer only symptomatic control. Only cure of the underlying condition results in complete resolution of pruritus. During treatment to relieve symptoms, every effort should be made to treat the underlying systemic disease.

Patient Education

Patients should be given a clear explanation of their disease and its relationship to pruritus. Patients should be taught how to manage xerosis because this condition may worsen pruritus. Instructions should include keeping the skin well moisturized and avoiding excessive bathing in hot water, low ambient humidity, use of alkaline soaps, and exposure to irritating fabrics. For severe cases, the patient can perform the soak and smear technique, which is the process of hydrating the skin for 20 minutes prior to bedtime, followed by the application of ointment to the wet skin.[19]

The following techniques have been found helpful in reducing pruritus in general:

  • Avoid hot showers or baths; use tepid water for bathing.
  • Use a mild, oilated soap or soap-free cleanser to bathe.
  • Apply a moisturizing lotion to the skin after bathing.
  • A camphor and menthol lotion is available over the counter (OTC) and may be applied several times a day to relieve itching.
  • A low-dose antihistamine like diphenhydramine is available OTC and may be taken several times a day for itching.

The itch-scratch cycle should be discussed, and patients should be encouraged to apply cool washcloths or gentle pressure to the areas and to resist the urge the scratch. Reduction or elimination of stressful factors should be discussed because stress appears to worsen itching.

Patients should be made aware that psychiatrists, social workers, and counselors are available to help them cope with the problems created by pruritus.

For patient education resources, please see the Skin Conditions & Beauty Center.

 

Presentation

History

Primary dermatologic disorders can cause pruritus, and these must be excluded before a systemic cause is considered. Therefore, a thorough history, including the onset, duration, severity, location, provoking factors, time relation, and relationship to activities such as bathing should be discussed with the patient who presents with pruritus.

A review of systems is needed to uncover signs and symptoms associated with systemic disease and to direct the physical examination and laboratory evaluation. A detailed drug history is required to exclude medications that can cause itching. A history of alcohol abuse may indicate chronic liver disease. A review of potential emotional stresses and mental health history may reveal a psychiatric cause.

Clues supporting a systemic cause include the insidious onset of generalized pruritus rather than an acute presentation.

Renal pruritus

Symptoms range from paroxysmal discomfort that may remit spontaneously to continuous itching that is present day and night. Approximately 46% of patients have pruritus on a daily basis, whereas 52% report it as appearing weekly or monthly. Pruritus is localized in 56% of patients and is most often seen on the back, abdomen, head, and shunt arms. The remaining patients usually present with generalized pruritus. The vertex of the scalp is a common site of pruritus, and excoriations may be present. Exacerbations are common at night and during or just after HD. The intensity may also increase during summer months.

Cholestatic pruritus

Cholestatic pruritus is characterized by an intermittent, mild, and insidious onset that may be generalized or localized. Pruritus is typically worse on the hands and feet and in areas under tight-fitting clothing. Pruritus and fatigue are commonly the presenting symptoms of patients with primary biliary cirrhosis. Associated symptoms of inflammatory bowel disease may be present in patients with primary sclerosing cholangitis.

Hematologic pruritus

Although hematologic pruritus related to iron deficiency remains controversial, the pattern that has been described is most often generalized; however, it may be localized, especially to the perianal and vulvar regions. Patients with polycythemia vera may have aquagenic pruritus (after a hot bath or shower) with a prickly sensation, but this is not specific. Aquagenic pruritus may occur within minutes of contact with water. However, it may precede the development of the disease by several years. Patients may report headache, visual disturbances, weight loss, night sweats, and vertigo. Other symptoms include redness, warmth, and pain (erythromelalgia) of the digits.

Endocrine pruritus

In most patients, endocrine pruritus is generalized and associated with symptoms of the underlying disease process (eg, hyperthyroidism vs hypothyroidism). Pruritus associated with diabetes mellitus is another controversial association. The described pruritus is often localized to the vulva or anus and usually is due to candidal or dermatophytic infection. However, unrelenting pruritus of the scalp is reported in association with diabetes mellitus.

Pruritus and malignancy

The symptoms of pruritus may differ in patients with lymphoma compared with symptoms in patients with carcinoma. Pruritus due to carcinoma results in moderate-to-severe itching with changes in intensity and location over the course of the disease. Common sites are the extensor surfaces of the upper extremities and the anterior surfaces of the lower legs. Pruritus of the nostrils has been associated with brain tumors.

Pruritus due to lymphoma may precede the diagnosis by 5 years. It is most common in patients with Hodgkin disease (nodular sclerosing subtype). The pruritus is described as intolerable, continuous, and severe and is accompanied by a burning sensation. It may begin on the lower extremities and progress to the whole body. If localized, the pruritus is commonly present in the areas drained by the lymphatics affected in the disease process.

Leukemic pruritus is usually generalized at onset and is less severe than that related to lymphoma.

Physical Examination

Physical examination assists in differentiating between systemic causes of pruritus and primary dermatologic conditions. When systemic disease underlies pruritus, patients may have normal-appearing skin or secondary lesions, such as excoriations, prurigo nodules or papules, lichen simplex chronicus, or signs of a secondary bacterial infection. Patients may have the butterfly sign, which is an area of relative hypopigmentation or normal skin on the middle of the back in combination with areas of postinflammatory hyperpigmentation in locations accessible to the patient's hands. Other signs of systemic disease are as follows:

  • Renal pruritus: Diffuse xerosis and half-and-half nails may be seen. The patient may have signs of peripheral neuropathy and uremia.

  • Cholestatic pruritus: Signs of liver disease include jaundice, spider angiomata, Dupuytren contractures, white nails, gynecomastia in men, xanthelasma, splenomegaly, and ascites.

  • Endocrine pruritus: Patients with hypothyroidism have brittle nails and dry, course skin and hair. Patients with hyperthyroidism may have warm, smooth, and fine skin. They may also have chronic urticaria and angioedema. Other signs are fever, tachycardia, exophthalmos (associated with Grave disease), and atrial fibrillation.

  • Hematologic pruritus: Patients with iron deficiency may have pallor if they have anemia; they might also have glossitis and angular cheilitis. Polycythemia vera may result in a ruddy complexion around the lips, cheeks, nose, and ears, along with hypertension and splenomegaly.

  • Pruritus and malignancy: Patients with Hodgkin disease may have ill-defined hyperpigmentation of the skin, ichthyosis, nontender lymphadenopathy, and splenomegaly.

Complications

Debilitating sleep deprivation and suicidal ideation may occur in patients with severe pruritus. Women with untreated intrahepatic cholestasis of pregnancy that begins before 33 weeks of gestation have increased rates of preterm deliveries and stillbirths. Other complications of pruritus include lichen simplex chronicus, prurigo nodules, and excoriations (which can become secondarily infected).

 

DDx

Diagnostic Considerations

The primary causes of pruritus are as follows:

 

Workup

Laboratory Studies

When a primary dermatologic condition is excluded and a systemic cause is suspected, certain laboratory tests may aid diagnosis. If suspicion is low concerning a systemic disease, a 2-week trial of therapy with oilated soap for bathing, emollients for after the bath, and oral antihistamines may be attempted. If this fails, a laboratory evaluation is indicated.

The following screening laboratory tests are recommended:

  • CBC count with differential: This test assists in uncovering polycythemia vera, in which the hemoglobin level, hematocrit value, WBC count (including absolute neutrophil count; see the Absolute Neutrophil Count calculator), and platelet count are elevated. Abnormalities are also seen in persons with hematologic malignancies. Patients with iron deficiency may have microcytosis and low hemoglobin levels. However, those with pruritus and iron deficiency may not be anemic; tests of and serum iron, ferritin, and total iron-binding capacity may be ordered to confirm or exclude the diagnosis.

  • Serum creatinine and blood urea nitrogen values: Persons with CRF have elevated levels.

  • Serum alkaline phosphatase and bilirubin, direct and indirect: Elevated levels may suggest cholestasis. If elevated, antimitochondrial antibody and serum anti–hepatitis C tests may be ordered to confirm primary biliary cirrhosis and hepatitis C, respectively, if these are suspected. Other tests may be needed to confirm other causes of cholestasis. A positive antimitochondrial antibody finding has 98% specificity for primary biliary cirrhosis.

  • Thyrotropin and thyroxine: The results assist in ruling out hypothyroidism and hyperthyroidism.

  • Fasting glucose value, if prompted by signs or symptoms

  • Stool for occult blood in patients aged 40 years or older: A positive result suggests possible malignancy in the GI tract.

  • HIV antibody test, if risk factors are present

  • Skin biopsy for routine pathology and immunofluorescence to exclude subacute occult autoimmune conditions such as pemphigoid and dermatitis herpetiformis

Imaging Studies

In patients with Hodgkin disease, chest radiography may help in detecting lymphadenopathy in the mediastinum. If cholestasis is present, abdominal ultrasonography may be performed to evaluate the biliary tract.

Other Tests

When the results of initial laboratory screening are negative and when the physician still suspects a systemic cause, tests of the following may be ordered:

  • Serum protein electrophoresis

  • Stool for ova and parasites

  • Stool for occult blood (may reveal source for anemia)

  • Urine for hydroxy indole acetic acid (5-HIAA) and mast cell metabolites

Negative findings from the initial evaluation do not necessarily exclude systemic disease, and follow-up screening may be repeated every 3-6 months if clinical suspicion continues.

Procedures

Endoscopic retrograde cholangiopancreatography should be performed when primary sclerosing cholangitis, choledocholithiasis, or obstructive malignancy is suspected.

Skin biopsy for direct immunofluorescence and special stains may help exclude a primary dermatologic condition, such as dermatitis herpetiformis or bullous pemphigoid (ie, pruritic pemphigoid), or confirm a systemic cause, such as in mastocytosis.

Histologic Findings

Because skin lesions are most likely secondary to scratching, biopsy reveals nonspecific findings. Histologic features may include a hyperkeratotic epidermis with acanthosis and parakeratosis and elongation of the rete ridges. A perivascular lymphoid infiltrate may be present.

 

Treatment

Medical Care

 

The treatment for pruritus of systemic disease varies depending on the underlying etiology. New therapies are based on advances in the understanding of the mechanisms that cause pruritus. However, without eradication of the underlying systemic disease, treatment is often palliative at best and can be frustrating for both the patient and physician.

Certain therapies, such as antihistamines and emollients, offer marginal benefit. Nevertheless, they should be tried because of their low cost and potential for providing relief. Sedating antihistamines may be effective in patients with nocturnal pruritus. Although antihistamines are partially effective in treating pruritus due to systemic disease, the effect is usually marginal and the relief is unsatisfactory. Doxepin, a tricyclic antidepressant (TCA) with antihistaminic properties, at dosages of 25-50 mg at bedtime may be quite helpful. Mirtazapine at 15-30 mg at bedtime has also been used to treat pruritus.[20, 21]

Gabapentin taken orally has demonstrated effectiveness in neurogenic pruritus and more recently has demonstrated effectiveness in uremic, hematologic, and idiopathic pruritus.[22]

Aprepitant, an anti-nausea neurokinin receptor 1 antagonist, has been showed to be highly effective in reducing pruritus in a group of patients with various skin disorders. Patients with atopic dermatitis and prurigo nodularis seemed to respond best.[23]

Renal pruritus

Treatment can be physical, topical, or systemic.

Physical therapy with UV-B therapy is a treatment of choice. Patients have reported months of remission after 6-8 treatments. UV-B reduces cutaneous phosphorus, decreases the number of dermal mast cells, and reduces epidermal vitamin A levels. However, some concern has been expressed that broad-band UV-B treatment might possibly increase the risk of nonmelanoma skin cancer. Narrow-band U-VB seems less likely to do so. One study from Scotland failed to demonstrate an increased risk of skin cancer in patients receiving narrow-band UV-B therapy.[24]

Topical therapy is especially helpful in cases of localized pruritus.

Capsaicin 0.025% cream is effective for localized pruritus due to CRF, as has been shown in double-blinded, placebo-controlled studies.

Topical application of a eutectic mixture of local anesthetics (eg, EMLA cream) before capsaicin treatment may reduce the burning sensation associated with capsaicin.[25]

Tacrolimus 0.03% ointment has shown promising results for localized renal pruritus in a prospective study, but randomized placebo-controlled studies are needed. Tacrolimus is a calcineurin inhibitor, it decreases the differentiation of type 1 helper T lymphocytes, and it reduces the production of interleukin 2.[26]

Topical gamma linolenic acid appears promising.[27] Topical gabapentin cream (3-6%) has been reported to help vulvodynia and could potentially be used to treat localized areas of neurogenic pruritus such as pruritus vulvae, pruritus scroti, and notalgia paresthetica.[28]

Systemic therapy includes UV-B and activated charcoal, which are first-line treatments, along with ensuring effective dialysis.[12, 29, 30, 31, 32, 33] Narrow-band UV-B is particularly effective. Oral activated charcoal is inexpensive, effective, and well tolerated; therefore, it is considered a reasonable treatment when UV therapy has failed. Activated charcoal is thought to prevent the absorption of an unknown pruritogen.

Cholestyramine is not as effective and is associated with adverse effects, such as acidosis.

Efficient dialysis is helpful. Pruritus tends to become severe with insufficient dialysis.[34]

Thalidomide has been reported as effective but should be used with caution because of its adverse-effect profile.[35] However, in the authors' experience, thalidomide is a valuable tool in cases unresponsive to conventional therapy.

Regarding opioid antagonists, studies of oral naltrexone have shown mixed results, with efficacy only in a small subset of patients.[36, 37]

Difelikefalin, a peripherally restricted selective kappa opioid receptor agonist, was shown to cause significant reduction in itch intensity and improved itch-related quality of life as compared with those receiving placebo in a group of hemodialysis patients.[38]

Erythropoietin has been studied,[39, 40] and one double-blinded, placebo-controlled study showed marked benefit in patients receiving small doses for up to 6 months. However, this effect could not be confirmed.

Other systemic therapies include nicergoline and free fatty acids (eg, those in primrose oil); these have shown positive results in reducing renal pruritus. Gabapentin has been shown to be effective in the treatment of chronic uremic pruritus, but it has been shown to worsen cholestatic pruritus.[41] Butorphanol, an opioid that displays mu antagonism and kappa agonism, has been shown to relieve uremic pruritus.[42] A newer kappa-opioid receptor agonist, nalfurafine, has been shown to be effective in significantly reducing pruritus in hemodialysis patients when compared to a placebo in a large, double-blinded, randomly controlled study.[13, 14]

A double-blinded controlled study in Iran demonstrated that oral zinc sulfate (440 mg daily) significantly reduced pruritus in a group of patients undergoing hemodialysis for renal insufficiency.[43]

Cholestatic pruritus

Cholestyramine is the first-line therapy, followed by rifampin and opioid antagonists. Ondansetron may also be tried. Cholestyramine has only been show effective in a few randomized studies, but this drug is thought to be helpful in relieving pruritus. Because of its low cost, it should be tried before more expensive treatments are considered.

Rifampin, a hepatic enzyme inducer, is effective for pruritus of cholestasis. Caution should be used in patients with preexisting liver disease because of possible hepatotoxicity.[44, 45]

Opioid antagonists, including naloxone, may relieve pruritus, but intravenous administration limits its use outside the hospital setting. Oral naltrexone is also effective.[46, 47, 48, 49] Oral nalmefene has been tested and is effective but may only be available in intravenous form.[50] To prevent opioid withdrawal syndrome, low starting doses should be used. These drugs should not be used in patients in need of palliative opioid treatment. Butorphanol, which antagonizes the mu receptor but agonizes the kappa receptor, has been shown to be effective in suppressing cholestatic pruritus.[42]

Ursodeoxycholic acid and S-adenosyl-L-methionine have both been reported to decrease pruritus in women with cholestasis of pregnancy, but ursodeoxycholic acid may improve fetal outcomes and biochemical serum markers.[51, 52]

Extracorporeal albumin dialysis may be considered when severe pruritus is refractory to other therapies.[53, 54]

Ondansetron has limited effectiveness and, because it relieves opioid-induced pruritus, it appears to affect opioid pathways.

Stanozolol relieves pruritus; however, it worsens cholestasis and is not recommended.

Removal of the offending agent should be initiated in patients with drug-induced cholestasis.

Other therapies that may be effective are thalidomide, infused propofol, serotonin-selective reuptake inhibitors, UV-B, phenobarbital, dronabinol, and bright-light therapy indirectly reflected toward the eyes.

Hematologic pruritus

Iron deficiency responds to treatment with iron, which should be continued until ferritin levels are normalized. Correction of iron deficiency in persons with polycythemia vera may decrease the pruritus but worsen the polycythemia vera.

Patients with pruritus due to polycythemia vera may benefit from aspirin, which is considered the first-line therapy. Cimetidine, danazol, cholestyramine, UV-B light therapy, and psoralen with UV-A therapy have all been shown to help.[55, 56]

Interferon-alfa may provide relief, but its adverse effects may decrease compliance.[57]

Treatment with paroxetine at 20 mg/d has been shown to be effective, but further clinical trials are needed.

One patient with severe pruritus due to Hodgkin disease responded dramatically to thalidomide at 200 mg by mouth at night.[58]

Endocrine pruritus

The pruritus of hypothyroidism is secondary to xerosis and should be treated with emollients and thyroid hormone replacement. Pruritus secondary to hyperthyroidism improves with the correction of thyroid function.

Nonspecific treatments

Topical cannabinoid agonist creams have been shown to relieve pruritus associated with certain chronic dermatoses. Treating the underlying disorder is the mainstay of therapy for controlling pruritus. Corticosteroids with palliative chemotherapy in late-stage Hodgkin disease often provide relief.

Nonspecific treatments for intractable pruritus, such as UV-B light therapy, cholestyramine, naloxone, and activated charcoal, should be considered. Paroxetine relieves itch in patients with advanced cancer; however, the effect usually lasts only 4-6 weeks.

Surgical Care

Successful transplantation is the only definitive treatment for renal pruritus. When pruritus is associated with obstructive malignancy of the biliary tract or other obstructive causes (eg, primary sclerosing cholangitis), placing a stent to relieve the obstruction also treats the pruritus. Liver transplantation may be considered in patients who have pruritus associated with nonmalignant cholestasis that does not respond to medical therapy.

Consultations

Consultation with the following specialists may be helpful:

  • Dermatologist: Always consult a dermatologist to rule out any primary cause of pruritus and to discuss UV-B or psoralen UV-A light therapy when it is considered in the treatment plan.

  • Gastroenterologist: A gastroenterologist should evaluate any patient with liver or biliary tract disease.

  • Hematologist/oncologist: These specialists should always be involved in the care of patients with pruritus due to hematologic or malignant causes.

  • Endocrinologist: Patients with endocrine pruritus should be evaluated for treatment of their thyroid disease, which often cures their itch.

  • Surgeon and/or transplant surgeon: Patients with CRF or chronic liver disease may need to be evaluated for kidney or liver transplantation, respectively. A surgeon should always be consulted in cases of malignant cholestasis.

Diet

A low-protein diet may help decrease pruritus in persons with CRF.

 

Medication

Medication Summary

The goals of pharmacotherapy are to reduce morbidity and prevent complications.

Detoxifying agents

Class Summary

These agents are used to treat renal pruritus.

Activated charcoal (Charcodote)

Activated charcoal is the drug of choice for the initial treatment of renal pruritus. Its mechanism of action is unknown, but it is thought to bind an unknown pruritogen. Sorbitol and flavoring are added to some forms to enhance palatability.

Topical agents

Class Summary

Topical agents are used to treat localized renal pruritus.

Capsaicin topical

Capsaicin is derived from plants of the Solanaceae family. It may render skin and joints insensitive to pain and pruritus by depleting substance P in peripheral sensory neurons, decreasing the transmission of sensation. If is for localized pruritus only.

Immunomodulatory agents

Class Summary

Immunomodulatory agents are used to treat recalcitrant renal or cholestatic pruritus.

Thalidomide (Thalomid)

Thalidomide is thought to decrease T helper cells while inhibiting the production of TNF-alpha, which may induce itching. It has a strong central depressant effect that may decrease pruritus. Because of adverse events, attempt other treatments first.

Bile Acid Lowering Agents

Class Summary

These agents are used to treat cholestatic pruritus.

Cholestyramine (Prevalite, Questran)

Cholestyramine is an anion-exchange resin that binds bile acids in the GI tract, interrupting their enterohepatic circulation; it is primarily used to lower cholesterol. Patients must have adequate bile flow for the drug to be effective. Consider this therapy early in cases of hepatic cholestasis because it is inexpensive and may provide relief (within 1-3 wk). Pruritus returns within weeks of discontinuation.

Ursodeoxycholic acid/ursodiol (Actigall, Urso 250, Urso Forte)

Ursodeoxycholic acid/ursodiol is a hydrophilic bile acid that alters the hydrophilicity and distribution of total bile acids and increases the excretion of hydrophobic bile acids. It decreases damage to the hepatocyte membrane by decreasing the uptake of hydrophobic bile acids at the terminal ileum (and likely in hepatocytes). Ursodeoxycholic acid/ursodiol is first-line treatment for patients with intrahepatic cholestasis of pregnancy; it normalizes laboratory values and decreases morbidity and mortality to the fetus by reducing exposure to bile acids.

Hepatic enzyme inducing agents

Class Summary

These agents are used to treat cholestatic pruritus.

Rifampin (Rifadin)

Rifampin is traditionally used as an antibiotic with the known mechanism of action of inhibiting RNA synthesis in bacteria. It also inhibits the reuptake of hepatic bile acid and induces hepatic mixed-function oxidases, which may detoxify hepatic bile acids. Consider this drug when a course of cholestyramine fails.

Opioid antagonist agents

Class Summary

These agents are used to treat cholestatic pruritus.

Naloxone (Narcan)

Naloxone is an opioid antagonist and is given intravenously; therefore, it should only be used in emergency treatment of exacerbations of cholestatic pruritus in a hospital setting. A low-dose infusion may be used for 24 hours before oral naltrexone or nalmefene to avoid opioid withdrawal syndrome (sometimes seen in patients given oral opioid antagonists).

Naltrexone (ReVia, Vivitrol)

Naltrexone may also be considered if patients with cholestatic pruritus do not respond to cholestyramine and rifampin. Naltrexone can be administered orally and has a longer half-life than naloxone.

Anti-inflammatory agents

Class Summary

Anti-inflammatory agents are used to treat polycythemia rubra vera.

Aspirin (Anacin, Ascriptin, Bayer Aspirin, Bayer Buffered Aspirin)

Aspirin appears to decrease platelet degranulation of serotonin and prostaglandins, which contribute to pruritus. It is first-line treatment for symptomatic control of pruritus related to polycythemia vera. Relief may last 12-24 hours.

Antidepressant agents

Class Summary

These drugs are used to treat generalized pruritus in patients with advanced cancer or polycythemia vera.

Mirtazapine (Remeron, Remeron SolTab)

Mirtazapine is a relatively new antidepressant and is not as widely used as sertraline. It exhibits both noradrenergic and serotonergic activity. In cases of depression associated with severe insomnia and anxiety, mirtazapine has been shown to be superior to other SSRI drugs.

Paroxetine (Paxil, Paxil CR)

Paroxetine is a potent selective inhibitor of neuronal serotonin reuptake. Its mechanism of relieving pruritus is unknown. Effects occur within a few days but may last only 4-6 weeks.

Doxepin (Sinequan, Adapin)

Doxepin is a TCA that has potent H1-blocking activity, making it quite useful for urticaria. However, it has very potent sedative and anticholinergic effects. It can be quite effective if used at bedtime because the sedative effects can help a patient with pruritus sleep.

Analgesic opioid agents

Class Summary

Agents with central analgesic action may be useful. May alter perception and response to varied stimuli.

Butorphanol (Stadol)

Butorphanol is a mixed agonist-antagonist narcotic with central analgesic effects for moderate to severe pain. It causes less smooth muscle spasm and respiratory depression than morphine or meperidine. Weigh the advantages against the increased cost of butorphanol.

Immunosuppressant agents

Class Summary

These agents may prevent release of inflammatory cytokines from mast cells.

Pimecrolimus (Elidel)

Pimecrolimus is the first nonsteroid cream approved in United States for mild-to-moderate atopic dermatitis. It is derived from ascomycin, a natural substance produced by the fungus Streptomyces hygroscopicus var ascomyceticus. It selectively inhibits the production and release of inflammatory cytokines from activated T cells by binding to the cytosolic immunophilin receptor macrophilin-12. The resulting complex inhibits phosphatase calcineurin, thus blocking T-cell activation and cytokine release. Cutaneous atrophy has not been observed in clinical trials, a potential advantage over topical corticosteroids. Pimecrolimus is indicated only after other treatment options have failed. Use short-term and for intermittent use only.

 

Questions & Answers

Overview

What is pruritus and how is it classified?

Which dermatologic conditions cause pruritus?

How is the sensation of pruritus transmitted?

What modulates the sensation of pruritus?

Who is at increased risk for renal pruritus?

What is the role of antihistamines in the treatment of renal pruritus?

What is the pathogenesis of renal pruritus?

What is a possible CNS manifestation of renal pruritus?

What may worsen renal pruritus?

What is the role of enolase-positive sensory nerves in the pathogenesis of renal pruritus?

What is the role of opioids in the pathogenesis of renal pruritus?

What is the immune hypothesis of the pathogenesis of renal pruritus?

What is cholestatic pruritus?

What is the role of iron deficiency in the pathogenesis of hematologic pruritus?

What is the role of polycythemia vera in the pathogenesis of hematologic pruritus?

What is the role of hyperthyroidism in the pathogenesis of endocrine pruritus?

What is the role of hypothyroidism in the pathophysiology of endocrine pruritus?

What is the role of diabetes mellitus in the pathogenesis of endocrine pruritus?

What is the role of malignancy in the pathogenesis of pruritus?

What causes renal pruritus?

What causes cholestatic pruritus?

Which conditions may cause hematologic pruritus?

Which disorders may cause endocrine pruritus?

Which malignancies may cause pruritus?

Which systemic disorders may cause pruritus?

What is the prevalence of pruritus in the US?

What is the global prevalence of pruritus?

How does the prevalence of pruritus vary by sex?

How does the prevalence of pruritus vary by age?

What is the prognosis of pruritus?

What is the prognosis of renal pruritus?

How is pruritus cured?

What education about pruritus should patients receive?

What are treatment options for reducing pruritus symptoms?

What is the itch-scratch cycle managed?

Presentation

Which dermatologic disorders should be excluded before considering a systemic cause of pruritus?

How is a systematic disease etiology of pruritus diagnosed?

What are the signs and symptoms of renal pruritus?

What are the signs and symptoms of cholestatic pruritus?

What are the signs and symptoms of hematologic pruritus?

What are the signs and symptoms of endocrine pruritus?

How do the symptoms of pruritus vary among different malignancies?

How are dermatologic causes of pruritus differentiated from systematic causes in the physical exam?

Which physical findings suggest a systemic cause of pruritus?

What are complications of pruritus?

DDX

What are the primary dermatologic causes of pruritus?

Workup

What is the role of lab testing in the diagnosis of systemic causes of pruritus?

Which lab tests may be performed in the workup of systemic pruritus?

What is the role of imaging studies in the workup of systemic pruritus?

Which additional lab tests may be performed when initial findings are negative but a systemic cause of pruritus is still suspected?

What is the role of endoscopic retrograde cholangiopancreatography in the diagnosis of cholestatic pruritus?

What is the role of skin biopsy in the workup of pruritus?

Which histologic findings suggest a systemic cause of pruritus?

Treatment

What are the treatment options for pruritus of systemic diseases?

What are the treatment options for renal pruritus?

What is the role of topical therapy for renal pruritus?

What systemic therapy is used in the treatment of renal pruritus?

What is the role of dialysis in the treatment of renal pruritus?

What is the efficacy of thalidomide as a treatment for renal pruritus?

What is the efficacy of oral opioid antagonists as a treatment for renal pruritus?

What is the efficacy of erythropoietin for the treatment of renal pruritus?

Which medications may be used to treat renal pruritus?

What is the efficacy of oral zinc sulfate for the treatment of renal pruritus?

What are the treatment options for cholestatic pruritus?

What are the treatment options for hematologic pruritus?

What are the treatment options for endocrine pruritus?

What are general treatment options for treating pruritus of systemic diseases?

What is the role of surgery in the treatment of pruritus of systemic disease?

Which specialist consultations may be helpful for the treatment of pruritus of systemic disease?

Which dietary restrictions may be useful in the treatment of renal pruritus?

Medications

What are the goals of drug therapy for pruritus of systemic disease?

Which medications in the drug class Immunosuppressant agents are used in the treatment of Pruritus and Systemic Disease?

Which medications in the drug class Analgesic opioid agents are used in the treatment of Pruritus and Systemic Disease?

Which medications in the drug class Antidepressant agents are used in the treatment of Pruritus and Systemic Disease?

Which medications in the drug class Anti-inflammatory agents are used in the treatment of Pruritus and Systemic Disease?

Which medications in the drug class Opioid antagonist agents are used in the treatment of Pruritus and Systemic Disease?

Which medications in the drug class Hepatic enzyme inducing agents are used in the treatment of Pruritus and Systemic Disease?

Which medications in the drug class Bile Acid Lowering Agents are used in the treatment of Pruritus and Systemic Disease?

Which medications in the drug class Immunomodulatory agents are used in the treatment of Pruritus and Systemic Disease?

Which medications in the drug class Topical agents are used in the treatment of Pruritus and Systemic Disease?

Which medications in the drug class Detoxifying agents are used in the treatment of Pruritus and Systemic Disease?