A case of generalized pruritus without rash

Clinical allergy–immunology rounds Supported by an unrestricted grant from Aventis Pharmaceuticals

A case of generalized pruritus without rash Thomas C Puchner Jr, MD* and Jordan N Fink, MD†

CHIEF COMPLAINT “Itching all over” HISTORY OF PRESENT ILLNESS The patient is a 31-year-old Caucasian female who presented to the Allergy and Asthma Center with a 7-month history of progressive pruritus without dermatitis. Seven months prior to her initial visit she noted localized pruritus on her elbows. No rash was noted, and the pruritus resolved after 5 days of treatment with an unknown cream. Five months prior she noted pruritus on her eyelids and feet which did not resolve with topical creams. She also found a “lump” on her right neck and felt fatigued. The patient saw her primary care physician who noted the neck mass and a possible enlarged spleen. A monospot was negative but she was told she probably had mononucleosis. Within a few weeks her fatigue resolved, however her pruritus progressed to include the rest of her body. Again, no rash or hives were noted. Two months prior to her clinic visit she again saw her primary care physician who did thyroid function studies which were normal. A repeat monospot was negative. When the patient presented to the Allergy Clinic she was having daily generalized pruritus which increased in the evenings. No rashes were noted by the patient. * Fellow-in-training, Allergy and Immunology Division, Medical College of Wisconsin, Milwaukee, Wisconsin. † Professor of Medicine and Pediatrics, Allergy and Immunology Division, Medical College of Wisconsin, Milwaukee, Wisconsin. Received for publication April 4, 2000. Accepted for publication in revised form May 26, 2000.

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She denied any new medications, soaps, detergents, or cosmetics. She related a 3-month history of a dry cough which she described as a “tickle.” She also noted rare instances of dyspnea. She perceived that her neck “lump” had decreased in size. There was no history of fever, chills, or night sweats. She had lost 14 pounds at the onset of her pruritus but recently her weight was stable. She had no atopic history. PAST MEDICAL HISTORY An ovarian cyst was removed in 1996. She also had a history of migraine headaches for which she used zolmitriptan three times per month. She was on no other medications. She had no medication or food allergies. FAMILY HISTORY Family history was negative for atopic disease, pruritus, or urticaria. SOCIAL HISTORY The patient was married, a nonsmoker, and worked as a psychologist in the public school system. There were no pets at home. PHYSICAL EXAM The patient looked well and was in no distress. Her head and neck exam was remarkable for a 1 1⁄2-cm firm mobile nontender right anterior cervical lymph node and a 2 1⁄2-cm mobile left cervical lymph node. No other adenopathy was appreciated. Oral exam was normal. Thyroid gland was normal. Lungs were clear, and the heart exam was normal. Abdomen was soft, nondistended, no masses or hepatomegaly were felt. Spleen tip was barely palpable. Extremities were only remarkable

for numerous excoriations on the distal legs and feet. No rash or hives were noted. LABORATORY CBC revealed a hemoglobin of 12.3 (12 to 16), MCV 75.8 (84 to 96), platelets of 501,000. The WBC was 9800 with 78% neutrophils, 6% lymphocytes, 10% monocytes, and 5% eosinophils. Sedimentation rate was elevated at 73. Basic chemistry, creatinine, and liver function tests (ALT, AST, Alk phos, bilirubin) were normal. Albumen was slightly depressed at 3.0 (3.2 to 5.5). HIV was nonreactive. QUESTIONS 1. What is causing the patient’s pruritus? 2. What is causing the patient’s cervical lymphadenopathy? 3. What is causing the patient’s splenomegaly? DIFFERENTIAL DIAGNOSIS Pruritus Pruritus was defined in 1660 by the German physician Samuel Hafenreffer as “an unpleasant sensation that provokes the desire to scratch.”1 Pruritus without rash or hives can be a perplexing clinical problem. Table 1 lists some of the causes of pruritus without rash. Generalized pruritus can be the initial manifestation of a systemic disease, especially chronic, progressive itch, and can precede the onset of the disease for months to years. Localized pruritus is infrequently associated with system disease,2– 4 although “extremely ferocious and persistent” pruritus of the nostrils has been stated as being pathognomonic of advanced central

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Table 1. Conditions Presenting as Pruritus Without Rash Condition Uremia Hemodialysis Cholestatis Chronic hepatitis (esp. C) Pregnancy Cutaneous malignancy (mycosis fungoides) Systemic malignancy Thyrotoxicosis Polycythemia vera AIDs Carcinoid syndromes Iron deficiency anemia Diabetes Mastocytosis Neurogenic Cerebral vascular accident Multiple sclerosis Cerebral abscess Jacob-Creutzfeldt disease Xerosis Cutaneous infections Scabies Fungal Solar Aquagenic Contact with pets (fleas) Psychogenic Medications

nervous system tumors.5,6 In contrast, pruritus which wakes the patient from sleep is suspicious for underlying disease.2 The presence of nocturnal pruritus has been stated to aid in distinguishing systemic disease pruritus from psychogenic pruritus. The sensations of pruritus and pain are transmitted by the small cutaneous unmyelinated C fibers. These fibers track to the thalamus via the spinothalamic track, which if severed will abolish pain and itch.7 At this time, a specific cerebral locus of pruritus has yet to be localized. Peripheral mediators that can stimulate C fibers and cause itch include histamine, trypsin, proteases, bradykinin, serotonin, substance P, and bile salts. Prostaglandins lower the threshold for itch and thus are thought to modulate rather than mediate pruritus.7 Morphine causes central modulation of pruritus.7 Pruritus without rash of greater than 3

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weeks duration without identifiable cause has been termed “pruritus of unknown origin.”2 The most common cause of generalized pruritus is xerosis, or dry skin. This is often seen in elderly and with excessive bathing or the use of harsh soaps. This scenario is more common in winter.2 Dermatographism can also present as generalized pruritus and should also be tested for by stroking the skin. A number of nonmalignant systemic illnesses have been associated with pruritus. Generalized pruritus may be associated with a systemic disease in 50% of patients.2 Pruritus without dermatologic findings has long been associated with uremia, although no single identifiable cause has been isolated to date. Hemodialysis patients often have increased pruritus just preceding or during hemodialysis. Conditions that result in cholestasis can also result in pruritus, even in the absence of jaundice. The pathogenesis of pruritus in cholestasis is not clear, and bile salts do not appear to be the sole cause. Hepatic conditions that result in cholestasis and itch without rash include chronic hepatitis (especially hepatitis C), primary and secondary biliary cirrhosis, sclerosing cholangitis, and common bile duct obstruction—particularly if caused by cancer of the bile duct or pancreas. Table 2 lists drugs such as estrogens, birth control pills, captopril, anabolic steroids, phenothiazines, trimethoprim/sulfamethoxazole, erythromycin, and alloupurinol that can cause cholestasis and therefore present as pruritus without

rash.2,4 Thus kidney and liver function tests should be a part of the laboratory evaluation of a patient with unexplained generalized pruritus. Pruritus associated with change in temperature such as after a warm bath (often termed “bath pruritus”) is seen in polycythemia vera. The pruritus is often described as “prickly” and is a presenting symptom in 14% to 52% of patients with polycythemia vera.6 Cyclical pruritus may occur with menses.2 Pruritus has also been noted in pregnancy. Itching associated with weight loss, tachycardia, hyperhidrosis, and tremors suggests hyperthyroidism, and a thyroid stimulating hormone level is recommended in this clinical presentation. Other nonmalignant systemic diseases that can be associated with pruritus include diabetes (often localized to the scalp and genitalia)2,8, iron deficiency anemia, AIDS, and some neurogenic causes such as cerebral vascular accident, multiple sclerosis, cerebral abscess, and Jacob-Creutzfeldt disease.4 A number of malignancies have been associated with generalized pruritus. The most frequently mentioned is Hodgkin’s disease. Hodgkin’s disease should be suspected when pruritus presents in the context of night sweats, weight loss, lymphadenopathy, and splenomegaly. The pruritus may precede the other clinical findings by several months.2 Other hematologic malignancies which may present with pruritus include nonHodgkin’s lymphomas (3% of cases) and leukemias. Mycosis fungoides (cutaneous T cell lymphoma) also has an unquestioned

Table 2. Medications Associated with Pruritus Without Rash Caused by Cholestasis Estrogens Captopril Erythromycin Allopurinol Anabolic steroids Birth control pills Trimethoprim Phenothiazines

Caused by Mast Cell Degranulation Opiates

Caused by Unknown Mechanism Antimalarias Aspirin Quinidine NSAIDs

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association with pruritus which is usually associated with skin manifestations but has preceded the disease by as long as 10 years.6 Solid tumors of the gastrointestinal tract, lung, ovary, and prostate may be associated with generalized itch without rash, although some authors question whether the association is more anecdotal rather than true cause and effect. A complete physical exam is appropriate for persistent generalized pruritus without skin manifestations, but extensive cancer screening is controversial and not recommended by some experts at this time.6,9 A complete blood count and chest x-ray (to evaluate for hilar adenopathy) are indicated when the clinical presentation is suspicious for either lymphoma or leukemia. Several miscellaneous causes of pruritus should be mentioned. Table 2 lists additional medications that can cause pruritus in the absence of rash or urticaria. Aspirin, NSAIDs, quinidine, and antimalarials have all been noted to cause pruritus without rash.2,4 Itching can also precede the development of a rash or hives from the medication. Opiates probably cause pruritus through direct mast cell degranulation.4 Aquagenic pruritus is an uncommon but well recognized condition in which exposure to any type of water including seawater at any temperature can result in pruritus.10 The cause is unknown, and may precede the development of aquagenic urticaria.2 In fact, some authors state “anything that can cause urticaria may also cause itching without a rash.”2 Thus, the evaluation of pruritus of unknown origin may be the same as that of chronic urticaria. Because polycythemia vera can also present as pruritus with water exposure, a complete blood count should be done in patients being evaluated for aquagenic pruritus. Aquagenic pruritus is also described as a “prickly” sensation similar to polycythemia vera.2,11 Brachioradial pruritus is a recurrent solar pruritus that occurs on sun-exposed areas, particularly on the lateral aspects of the arms. It is more common in temperate climates and responds to topical capsaicin.12

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Scabies should be suspected when pruritus affects several members of a household— especially if the genitalia are involved. Scabies can present as generalized pruritus with the only skin findings noted in the genital area.4 The history of a patient with pruritus should include questions about pets and occupation. Contact with pets infected with fleas could be an underreported cause of pruritus.2 Numerous occupational exposures to irritants or chemicals can cause itching without rash. Finally, if there are no findings of systemic disease, psychogenic pruritus may be considered, but this should be a diagnosis of exclusion, and patients with persistent pruritus should be followed at regular intervals and checked for systemic disease. Depression and anxiety can be a result of chronic itching and should not be assumed to be the primary cause. Cervical Lymphadenopathy The presence of palpable cervical lymph nodes less than 1 cm in diameter is not uncommon in young adults. An exact size limit cannot be stated as to what defines an abnormal lymph node. The presence of lymphadenopathy must be reviewed in the context of other clinical features of the patient and the characteristics of the node. For example, infected lymph nodes are often tender due to rapid enlargement of the node with resultant capsular stretching; they are occasionally fluctuant, matted together, and the overlying skin may be inflamed and tender. Carcinomatous nodes are usually hard, nontender, and may be fixed to underlying tissues. Lymphomatous nodes are firm and rubbery, mobile, and nontender. The anatomic location of the enlarged lymph nodes also plays an important role in determining the etiology of the adenopathy. Causes of bilateral cervical lymph node enlargement include local infections of the head, neck, sinuses, ears, scalp, and throat— especially tonsillitis and pharyngitis caused by viruses, mycoplasma, or bacteria. Mononucleosis syndromes

caused by cytomegalovirus, EpsteinBarr virus, or toxoplasmosis, Kawasaki’s disease in children, and tuberculosis can all cause bilateral cervical node enlargement.13,14 Head and neck infections causing unilateral cervical adenopathy include tonsillar abscesses, dental abscesses, and salivary adenitis. Unilateral cervical lymphadenopathy can also result from metastatic disease of head and neck tumors as well as lymphomas. Clinical features that suggest that lymph node enlargement needs to be pursued include patient age and the presence of constitutional symptoms. Lymphadenopathy in patients less than 30 years old is due to a benign cause in 80% of the cases, whereas over age 30 the cause is benign in only 40% of cases.14 Fevers, chills, and diaphoresis suggest an infectious etiology, while night sweats and weight loss suggest malignancy or HIV infection. Occupations or hobbies the result in frequent trauma, especially to an extremity, can also result in localized lymph node enlargement. The decision to observe and follow lymphadenopathy rather than biopsy can be difficult. It is suggested that biopsy be performed after no more than 1 to 2 months of observation if the physician remains suspicious that the node is abnormal.13 Slap et al retrospectively reviewed the clinical features of 123 patients aged 9 to 25 who had diagnostic lymph node biopsies. Lymph node size ⬎2 cm on physical examination or an abnormal chest xray were findings that suggested an etiology requiring biopsy, whereas recent otolaryngologic disease with enlarge cervical nodes was strong evidence against the presence of a disease requiring biopsy.13,15 A search for generalized lymph node enlargement as well as for hepatosplenomegaly should be performed if suspicious cervical lymph nodes are palpated. Splenomegaly The spleen is the largest lymphoid organ in the body. A palpable spleen is almost always an abnormal physical finding as long as it is in the correct

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anatomical position, although some experienced physicians may palpate a spleen in 1% of healthy adults. A normal sized spleen is approximately 12 cm long and 7 cm wide,16 weighs 130 to 150 grams, has a blood volume of 300 mL,17 and lies obliquely in the abdomen parallel to the 10th rib. When the spleen enlarges, its lower pole moves anteriorly, inferiorly, and to the right.14 Mild splenomegaly may be difficult to appreciate on a physical exam, especially if the patient is obese. Computed tomography, abdominal ultrasound, or technecium 99m liver-spleen nuclear scanning can be used to confirm the presence of splenomegaly. Evaluation of a patient with splenomegaly should include evaluation of the peripheral blood, a bone marrow aspirate, as well as liver function tests and a chest x-ray. The severity of splenomegaly depends on the disease. Mechanisms that can result in splenomegaly include the following: (1) increased immune response with proliferation of splenic lymphoid cells (eg, systemic lupus erythematosis, rheumatoid arthritis, or infections such as subacute bacterial endocarditis), (2) focal or generalized infiltration by neoplastic cells (lymphoma, leukemia, metastatic carcinoma), granulomas (tuberculosis, sarcoidosis), or amyloidosis, (3) extramedullary hematopoesis associated with various myeloproliferative disease, (4) proliferation of phagocytes (infections) or histiocytes (storage diseases), (5) vascular congestion (cirrhosis, splenic vein thrombosis, congestive heart failure) or pooling of red blood cells and/or granulocytes (sequestration).14,16,17 Some causes of mild-to-moderate splenomegaly are listed in Table 3. The most common cause of transient moderate splenomegaly is a systemic infection.14 The infectious cause can be viral (viral hepatitis, Epstein-Barr, cytomegalovirus, and HIV), toxoplasmosis, bacterial (subacute bacterial endocarditis), tuberculosis, brucellosis, malaria, and other less common infections. Infections usually result in mildto-moderate splenic enlargement. Other causes of mild splenomegaly in-

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Table 3. Causes of Mild-to-Moderate Splenomegaly Disease Subacute bacterial endocarditis Mononucleosis syndromes Amyloidosis Sarcoidosis Polycythemia vera Pernicious anemia Iron deficiency anemia Cirrhosis with portal hypertension Congestive heart failure Lymphoma Hemangioma Splenic cysts Splenic abscess Splenic hematoma Trauma Collagen vascular diseases Systemic lupus erythematosis Rheumatoid arthritis (Felty’s syndrome) Serum sickness Immune thrombocytopenic purpura

clude congestive heart failure, rheumatoid arthritis, and systemic lupus erythematosis. Moderate splenomegaly can be seen with hepatic cirrhosis, lymphomas, splenic abscesses, hematomas, infarcts from sickling or emboli, sarcoidosis, and amyloidosis. Massive splenomegaly occurs in leukemias, sarcoidosis, storage diseases such as Gaucher’s and Niemann Pick diseases, and occasionally with splenic or portal vein obstruction. The differential diagnosis of patients who present with fever, lymphadenopathy, rash, arthralgia and splenomegaly includes infectious mononucleosis, sarcoidosis, lymphomas, collagen vascular diseases, or serum sickness.16 Hypersplenism defines any clinical condition that results from exaggerated splenic phagocytosis of erythrocytes, granulocytes, and/or platelets. The mechanism could be from cellular sequestration due to abnormal splenic blood flow and/or sludging, or by production of antibodies directed against one or more cell lines which results in the cells being readily phagocytized by splenic macrophages. The spleen can sequester up to 90% of the platelet pool or 45% of the red blood cell pool.14 The diagnostic criteria for hy-

persplenism include the following: (1) splenomegaly, (2) cytopenia of one or more cell lines, (3) normal or hyperplastic cellularity of the deficient cell line(s) in the marrow, (4) correction by splenectomy.14 Many of the causes of splenomegaly listed in Table 3 can result in hypersplenism, thus the treatment of the hypersplenic state depends on the underlying cause. If that cause cannot be corrected, splenectomy might be indicated. Splenectomy may be indicated as part of the treatment of a disease or to alleviate the consequences of hypersplenism (eg, thrombocytopenia). Splenic trauma is the most common indication for splenectomy16,17 including inadvertent splenic trauma at the time of operation for other abdominal conditions. Other diseases in which splenectomy may be indicated include immune thrombocytopenic purpura, cytopenias associated with anemias (eg, autoimmune hemolytic anemia), leukemias (especially hairy cell and chronic lymphocytic), storage diseases (Gaucher’s), rheumatoid arthritis (Felty’s syndrome), or HIV disease with thrombocytopenia.14,17 Primary tumors of the spleen are extremely rare. In the past, splenectomy was frequently done in Hodgkin’s disease as part of a staging laprotomy, however, splenectomy is rarely done today because of the risk of overwhelming post-splenectomy infections.17 CLINICAL COURSE Based on the patient’s adenopathy, weight loss, splenomegaly, and lymphopenia, malignancy—specifically lymphoma—was suspected. A computed tomography scan of the chest, abdomen, and pelvis was ordered and a lymph node biopsy was arranged for the following day. Her CT scan revealed extensive bulky mediastinal adenopathy thought consistent with lymphoma, numerous abnormal neck nodes, mild splenomegaly, and numerous small pericaval and periaortic nodes in her abdomen. The node biopsy revealed nodular sclerosing Hodgkin’s disease. The patient was referred to a hematologist. Gallium scan

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showed uptake in the supraclavicular regions as well as the mediastinum but no uptake below the diaphragm. She was staged as IIB Hodgkin’s disease. The patient had 6 cycles of chemotherapy. After her first cycle the adenopathy, cough, pruritus, and fatigue resolved. A follow-up chest x-ray revealed complete resolution of her mediastinal adenopathy. She received consolidative radiotherapy to her supraclavicular, cervical, and mediastinal regions and currently is in complete remission. She is thought to have a good prognosis. HODGKIN’S DISEASE AND PRURITUS Pruritus occurs in approximately 10% of Hodgkin’s disease (HD) patients at the time of diagnosis,18 superficial neck adenopathy in 50% to 60%,13,18 and splenomegaly in 10%.13 Pruritus may precede the clinical manifestations of HD by as long as 5 years.6 Itch has been described in HD as early as 1965.19 In the 1970s, the clinical significance of pruritus as a prognostic indicator in HD was heavily debated. The Ann Arbor conference on HD in 1971 attached no independent prognostic importance to the presence of pruritus. However, Feiner et al questioned this in 1978 when they noted 6 HD patients who presented with pruritus had more aggressive disease.20 Alexander echoed that impression and felt pruritus had a “prognostic index of major importance.”21 Gobbi et al evaluated 635 patients with HD. Twelve percent of those staged with mild (class A) disease had pruritus only, and these patients had a worse clinical course and prognosis.22 Currently in the staging of HD, systemic symptoms that carry a poor prognosis are designated by the suffix B and include fever, night sweats, and loss of greater than 10% of body weight.18 Thus while the presence of pruritus in HD seems universally accepted, the prognostic significance is still under debate. The presence of lymphadenopathy is a hallmark of HD; in a small percent of patients, the nodes can become tender after alcohol consumption. Splenectomy and staging laprotomy are rarely

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done as previously mentioned because of the risk of post-splenectomy sepsis. MALIGNANCY AND PRURITUS The association between pruritus and two malignancies—Hodgkin’s disease and mycosis fungoides—seems unquestioned. However, the relationship between pruritus and other malignancies is controversial. In 1966 Rajka diagnosed or “suspected” malignancy in 9 out of 34 (26%) patients who had severe and prolonged pruritus (2 had HD).23 Vickers reported on malignancy in 12 of 76 patients (16%) with pruritus, although the cancers weren’t specified and were only typed as “neoplasia or reticulosis.”24 Other investigators have not found increased risk of malignancy in patients with generalized pruritus. Lyell reported on a 3 year prospective study of 74 patients with pruritus and found malignancy in only 2 (3%).25 Beare prospectively evaluated 43 patients with pruritus without rash and found malignancy in 3 (7%; one lymphoma).26 Kantor and Lookingbill retrospectively evaluated by questionnaire 44 patients with generalized pruritus. After 6.5 years of follow-up, malignancy was diagnosed in 5 (11%), however 2 of these had cancer diagnosed before the evaluation.27 Rantuccio followed 447 patients with idiopathic pruritus observed for 18 years and found cancer in 3 (1 with HD).28 Finally, Paul et al followed 125 patients with generalized pruritus for 6 years and found malignancy in 7

(6%).9 This cancer incidence did not differ significantly from the value expected in the general population, although 2 of the 7 cancers were lymphomas which was a significantly higher than predicted incidence. The authors concluded that “no significant overall increase of malignant neoplasms is to be expected in patients with generalized pruritus” and that extensive cancer screening and follow-up was unwarranted in these patients.9 Lober also agreed that “one cannot conclude, based upon previous studies, that generalized pruritus is statistically significantly associated with the presence of cancer.”6 Cancer and generalized pruritus both increase in incidence with advanced age. Study selection criteria can bias the patients entered into trials and therefore the symptoms they might present with. The relationship between generalized pruritus and malignancy other than HD needs further study to clarify if any causal association truly exists. It would seem clinically prudent, however, to follow patients who present with generalized, progressive pruritus with regular examinations. TREATMENT OF PRURITUS Treatment of generalized pruritus includes practical recommendations on skin care and hydration, local and systemic agents, and a few nonpharmacologic treatments. Table 4 lists some of the local and systemic agents. There is difficulty in evaluating the efficacy of

Table 4. Drugs Used to Treat Generalized Pruritus Systemic Agents Antihistamines Opioid antagonists Naloxone Naltrexone Corticosteroids Propofol (subhypnotic doses) Doxepin Ondansetron Aspirin (in polycythemia vera) For cholestatic pruritus Cholestyramine Ursodeoxycholic acid Methotrexate

Topical Agents Coolants, eg, menthol Corticosteroids Doxepin Capsaicin ointment Anesthetics EMLA Pramoxine

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antipruritic agents because of placebo effects of up to 50%.4 In some instances, as in this case study, treatment of the underlying disease cures the itch. Practical measures to treat generalized pruritus without rash are similar to those recommended in atopic dermatitis and include daily use of vaseline and other moisturizing ointments to maintain skin hydration, avoiding low humidity conditions in home or at work that could result is excessive dryness of the skin, avoiding wool and other clothing that can act as irritants to the skin, using unscented soaps and detergents when bathing and washing clothing, showering with lukewarm rather than hot water (hot water increases histamine release), avoiding excessive heat exposure, and taking a 10 minute bath daily to rehydrate the skin.4 A number of topical treatments have been used to treat generalized pruritus. These include topical coolants like menthol, which causes a cool sensation of the skin that interferes with the sensation of itching.4,29 Topical anesthetics such as EMLA (a combination of lignocaine and prilocaine) and pramoxine30 may be effective. Topical diphenhydramine is not effective, however topical doxepin might help.4 Potent fluorinated topical corticosteroids are efficacious for short-term treatment, but extended application over large areas of the body is not recommended due to the possibility of developing systemic steroid side effects. Topical capsaicin ointment blocks the C nerve fibers that transmit pain and itch. It has been shown to be effective in some cases of generalized pruritus,4 however its use is limited by a burning sensation that occurs frequently (up to 30%) in the initial period of treatment. EMLA applied prior to capsaicin use can diminish this sensation.4 Oral antihistamines remain the first drug of choice to treat generalized pruritus.31 First generation antihistamines are limited by their well known side effect of sedation, although this may be a desirable effect if there is insom-

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nia associated with the pruritus and the antihistamine is taken at bedtime. Second generation antihistamines are preferred due to their limited incidence of sedation, and all are effective in treating generalized pruritus. The opioid antagonists naloxone and naltrexone have recently received significant attention for the treatment of generalized pruritus. Epidural opioids can cause generalized itch, and the coadministration of an opioid antagonist can block the itch.4 Naloxone and naltrexone work in a histamine-independent manner via antagonism of central opiate receptors that modify itch.32 Naltrexone has been shown to decrease the pruritus associated with uremia.33 Metze et al evaluated naltrexone in 50 patients with pruritus of varying etiologies. “A significant therapeutic response” was achieved in 35 of the 50 patients within 1 week.32 Unfortunately, in some patients naltrexone has also caused pruritus.34 Serotonin activates C fibers, and therefore serotonin antagonists have been used to treat pruritus.4,31 Ondansetron has been shown to help in cholestatic pruritus.35 Cholestyramine is generally regarded as the first drug of choice to treat cholestatic pruritus. Other drugs that have shown some efficacy in cholestatic pruritus include ursodeoxycholic acid and methotrexate.36 Aspirin has been demonstrated to be effective in alleviating the itch associated with polycythemia vera,4 but it is not effective for other causes of generalized pruritus. Subhypnotic doses of intravenous propofol, a hypnotic used in anesthesiology, have been shown to be effective in itch associated with spinal morphine use and in cholestasis.4,31,37 Finally, a few nonpharmacologic treatments have helped treat certain causes of pruritus. Ultraviolet light (A and B) has been shown to be beneficial in uremic pruritus, although it can also cause pruritus.4,38 Transcutaneous electronic nerve stimulation (TENS) has also been shown to diminish pruritus in a few case studies.39

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