AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

Pruritus, or itch, 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.

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, 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. Opioids are known to modulate the sensation of pruritus, both peripherally and centrally.

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. 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. 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.

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. 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.

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.

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.

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.

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.

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.

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.

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.

Mortality/Morbidity

Pruritus causes significant morbidity. Some conditions that cause systemic pruritus appear to be associated with an increased mortality rate.

• In patients receiving HD, renal pruritus is an independent marker for mortality at 3 years.
• Patients with severe, generalized pruritus associated with Hodgkin disease have significantly shorter survival than those with mild or no pruritus.

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.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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

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, 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.

Causes

• 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
• A variety of other systemic disorders are associated with pruritus, including the following:
• • Drug-induced pruritus without a rash
  • Mastocytosis
  • HIV infection and AIDS
  • 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)

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Xerosis

Scabies: Multiple excoriated papules are present with fine wavy and linear lines overlying erythematous papules. The linear light or skin-colored lines are burrows and are the primary skin finding in persons with scabies. Scabies may be difficult to diagnose because patients may present with pruritus and subtle skin findings.

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab 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), 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

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
  • 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

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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.

• 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, UV-B treatment increases the risk of nonmelanoma skin cancer.
  • 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.
    • 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.
    • Topical gamma linolenic acid appears promising.
  • Systemic therapy includes UV-B and activated charcoal, which are first-line treatments, along with ensuring effective dialysis. 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.
    • Thalidomide has been reported as effective but should be used with caution because of its adverse-effect profile. 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.
    • Erythropoietin has been studied, 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.
    • Butorphanol, an opioid that displays mu antagonism and kappa agonism, has been shown to relieve uremic pruritus.
• 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.
  • Opioid antagonists, including naloxone, may relieve pruritus, but intravenous administration limits its use outside the hospital setting. Oral naltrexone is also effective. Oral nalmefene has been tested and is effective but may only be available in intravenous form. 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.
  • 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.
  • Extracorporeal albumin dialysis may be considered when severe pruritus is refractory to other therapies.
  • 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.
  • Interferon-alfa may provide relief, but its adverse effects may decrease compliance.
  • Treatment with paroxetine at 20 mg/d has been shown to be effective, but further clinical trials are needed.
• 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.
• Chronic vaginal pruritus and lichen sclerosis et atrophicus: When these conditions cause pruritus of the vaginal area, treatment with topical pimecrolimus cream has been effective.
• 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

• 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

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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

Drug Category: Detoxifying agents

These agents are used to treat renal pruritus.

Drug Category: Topical agents

Topical agents are used to treat localized renal pruritus.

Drug Category: Immunomodulatory agents

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

Drug Category: Bile Acid Lowering Agents

These agents are used to treat cholestatic pruritus.

Drug Name	Ursodeoxycholic acid/ursodiol (Actigall, Urso 250, Urso Forte)
Description	Hydrophilic bile acid that alters hydrophilicity and distribution of total bile acids and increases excretion of hydrophobic bile acids. Decreases damage to hepatocyte membrane by decreasing uptake of hydrophobic bile acids at terminal ileum (and likely in hepatocytes). First-line treatment for patients with intrahepatic cholestasis of pregnancy; normalizes laboratory values and decreases morbidity and mortality to the fetus by reducing exposure to bile acids.
Adult Dose	10-16 mg/kg/d until delivery
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity (bile acids); intolerance
Interactions	Bile-sequestering agents (eg, cholestyramine) and aluminum-based antacids may interfere with action
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Adverse events may include GI discomfort, including diarrhea

Drug Category: Hepatic enzyme inducing agents

These agents are used to treat cholestatic pruritus.

Drug Category: Opioid antagonist agents

These agents are used to treat cholestatic pruritus.

Drug Name	Naltrexone (ReVia, Vivitrol)
Description	Naltrexone may also be considered if patients with cholestatic pruritus do not respond to cholestyramine and rifampin. Naltrexone can be administered PO and has a longer half-life than naloxone.
Adult Dose	Initial: 12.5 mg PO qd (cut 50-mg pill) with or without previous naloxone infusion Maintenance: 25-250 mg/d
Pediatric Dose	Not established in patients with cholestatic pruritus
Contraindications	Documented hypersensitivity; acute hepatitis; liver failure
Interactions	Inhibits effects of opiates; coadministration with yohimbine may increase symptoms of anxiety or nervousness
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Caution in hepatic impairment (metabolites may accumulate, decrease dose); hepatotoxicity may occur (check serum hepatic panels periodically during treatment); opioid withdrawal–like symptoms may occur but should improve within days of continued treatment (low-dose infusion with naloxone for 24 h may prevent these adverse effects); pruritus may recur during therapy due to up-regulation of opioid receptors (prevented by interrupting treatment 2 d/wk) Adverse effects include thromboembolic disorder, depression, hypersensitivity disorder, and eosinophilic pneumonia

Drug Category: Anti-inflammatory agents

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

Drug Category: Antidepressant agents

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

Drug Category: Analgesic opioid agents

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

Drug Category: Immunosuppressant agents

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

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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).

Prognosis

• Renal pruritus is an independent marker for mortality at 3 years for patients on HD.
• 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.
• 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 excellent patient education resources, please see eMedicine's Skin, Hair, and Nails Center.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Most cases of psychogenic pruritus are clinically evident, and patients benefit from referral to a psychiatrist.
• • Failure to detect a systemic cause of pruritus could be considered negligence.
  • Thorough laboratory evaluation of patients with diffuse pruritus but without clinical evidence of a primary skin disorder is mandatory even if patients appear to have only psychiatric abnormalities.
• If no systemic cause of pruritus is detected with laboratory evaluation, repeat evaluation should occur every 6 months.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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