Understanding Pruritus in Systemic Disease

Transcription

1 Vol. 21 No. 2 February 2001 Journal of Pain and Symptom Management 151 Review Article Understanding Pruritus in Systemic Disease Małgorzata Krajnik, MD and Zbigniew Zylicz, MD, PhD. Department of Palliative Medicine (M.K.), The Ludwik Rydygier University of Medical Sciences, Bydgoszcz, Poland, and Hospice Rozenheuvel (Z.Z.), Rozendaal, The Netherlands Abstract Many pruritic conditions do not originate in the skin, but are the result of systemic abnormality. Among the diseases that can cause pruritus are renal insufficiency, cholestasis, Hodgkin s lymphoma, polycythemia vera, solid tumors, and many others. Other pruritic conditions appear to be iatrogenic; opioid-induced pruritus may be the most important in palliative medicine. Successful treatment of the underlying condition usually relieves itch. But, with time, many diseases progress and treatment of the cause will be impossible. Topical treatments may be of limited value. Strategies involving systemic treatments include use of antidepressants, oral opioid antagonists, or cholestyramine. There is no one cure for all pruritic symptoms. Better understanding of mechanisms of pruritus may help develop better treatments. J Pain Symptom Manage 2001;21: U.S. Cancer Pain Relief Committee, Key Words Pruritus, itch, histamine, serotonin, central transmitters, systemic disorders Introduction Pruritus (lat. prurigo) or itch is one of the most puzzling symptoms in advanced systemic diseases. Although patients are lucky that severe pruritus is a rare symptom, this rarity results in limited knowledge about its mechanisms and treatment. The medical literature is full of anecdotes concerning pruritus, but contains only a few clinical trials and evidencebased data. Not infrequently, these trials involve very small numbers of patients. In this review, attention will be paid to pruritus due to systemic diseases. Many dermatologic causes of pruritus, although interesting, will be omitted here or discussed very briefly. Careful analysis and pooling of available data may result in new ideas about the etiology and treatment of this symptom. Address reprint requests to: Zbigniew Zylicz, MD, PhD Hospice Rozenheuvel, Rosendaalselaan 20, 6891 DD Rozendaal, The Netherlands. Accepted for publication: March 20, Neuroanatomy of Itch Pruritus represents a distinct sensation arising from the superficial layers of the skin, the mucous membranes (including the upper respiratory tract), and the conjunctivae. 1,2 The nerve endings responsible for itching are located close to the dermo-epidermal junction, more superficially than the nerve endings coding for pain. These nerve endings tend to cluster densely around the itch points. Itch impulses are conducted to the ipsilateral dorsal root ganglia, and synapse there with secondary neurons. Efferents from these neurons immediately cross over to the opposite anterolateral spinothalamic tract. They continue to the posterolateral ventral thalamic nucleus, and then pass through the internal capsule to the somatosensory cortex of the post-central gyrus. Anxiety, boredom, mental distraction, or competing cutaneous sensations may magnify or reduce the perceived pruritus. 3,4 Itch can also be initiated centrally by trauma, stroke, brain abscess, tumors, and multiple sclerosis. 5 U.S. Cancer Pain Relief Committee, /01/$ see front matter Published by Elsevier, New York, New York PII S (00)

2 152 Krajnik and Zylicz Vol. 21 No. 2 February 2001 Peripheral Itching Mediators Histamine Many substances have been proposed as cutaneous mediators of pruritus (Table 1). One of the best known is histamine, which reproducibly causes severe itching if applied to the superficially damaged skin or injected intradermally. If injected deeper, histamine produces pain. 1 Three subclasses of histamine receptors are recognized. Both H1 and H2 receptors have been characterized in the human skin, but only H1 seems to be directly involved in histamine-induced pruritus. 6 Recently described histamine H3 receptors behave as autoreceptors regulating release and biosynthesis of histamine in the central nerous system (CNS) and other tissues, including skin. 7,8 The H3 receptors may also form a link with other receptor systems, making the whole picture even more confusing. 9 The majority of histamine released in the skin originates from the dermal mast cells. Histamine is also released from skin blood vessels, eccrine glands, the area surrounding hair follicles, and circulating basophils. 1 Histamine itself may evoke release or formation of other mediators. In rats, histamine causes depolarization of SP/CGRP neurons via the H2 receptor, which would lead to release of these peptides in the peripheral tissue. 10 Two hours after histamine application, there was increased expression of Fos-like immunoreactivity in the rat dorsal horn neurons. This may be responsible for the increased synthesis of neuroactive substances involved in the transmission or modulation of pruritus by the dorsal horn neurons. When histamine is injected repeatedly at the same site, this response decreases and tachyphylaxis develops. This finding questions the role of histamine in chronic itch. 11 Serotonin Serotonin, acting directly on peripheral serotoninergic receptors, can induce itch. 12 Serotonin is a weaker pruritogen than histamine upon intradermal injection. 13 A mixture of serotonin and prostaglandins produced itch in patients with policythaemia vera (PV) and aspirin administered together with serotonin antagonists relieved this type of pruritus. 14,15 Serotonin acts on the C-fibers via 5-HT3 receptors, which appear to be involved in the pathophysiology of both pruritus and pain. Tropisetron, a potent selective 5-HT3 receptor antagonist, significantly reduced serotonin-induced itch, but did not have significant effect on histamineinduced itch and serotonin-induced alloknesis (itchy skin). 13 Marked elevation in serotonin levels has been found in dialysed patients 16 and it has been suggested that serotonin may play an important role in pathogenesis of pruritus in uremia, lymphomas, PV, and cholestasis. Central Transmitters Endogenous opioids exert a regulatory action on pain and itching through the CNS. 1 However, the specific opioid antagonist naloxone may increase and decrease itching. Placebo-responders reported significantly greater itch after naloxone than placebo, and placebo non-responders reported less itch after naloxone. 17 This suggests that placebo response is highly dependent on endogenous opioids and naloxone may interfere with these effects. The endogenous opioids may also act peripherally. Intradermal injection of met-enkephalin or morphine potentiates histamine-evoked itching, and this effect was not influenced by naloxone. 18 Various CNS descending systems have been demonstrated to modulate itching. Some of these systems are opioid dependent, some are not. 2,16 Relationship Between Pain and Pruritus It has been speculated for a long time that widespread activation of nociceptive systems would mask the activity of itch-signalling pathways, and thus suppress itch and increase pain transmission. 18 There are some observations to support this hypothesis. Mild pain induced by scratching suppresses itching. Inhibiting pain by opioid administration may disinibit itch. 19 Afferent nerve fibers mediating itch are a subset of the large population of polymodal C-nociceptors, which are also known to mediate pain. They differ from other polymodal cutaneous nociceptors because they are particularly sensitive to histamine and other pruritogens, and they have their terminals in the superficial layers of the skin. These afferents project to a distinct subpopulation of the secondary neurons in the CNS. Itch is induced

3 Vol. 21 No. 2 February 2001 Understanding Pruritus In Systemic Disease 153 Table 1 Potential Chemical Mediators of Pruritus Amines: histamine, serotonin, dopamine, adrenaline, noradrenaline, melatonin Proteases: tryptases, chymases, carboxypeptidases, papain, kallikrein Neuropeptides: SP, CGRP, bradykinin, endothelin, neurokinin A & B, somatostatin, CRF, VIP, CCK, - & -MSH, neurotensin, bombesin, others Opioids: met-enkephalin, leu-enkephalin, -endorphin, morphine Eicosanoids: PGE2, PGH2, other PGs, LTB4, other LTs Growth factors Cytokines: IL-1 to IL-11, TNF- & TNF-, eosinophil products when only this population is excited. If a stimulus recruits more nociceptors, including also this subpopulation, more nociceptive dorsal horn neurons are activated to transmit pain, and itch may be blocked. Suppression of itching by concomitant painful stimulation of the same skin site may be explained by masking in a common pool of central processing neurons. Koppert et al. showed that histamine, which usually evokes itch, may evoke pain if the skin was pre-treated with bradykinin. 20 Bradykinin probably recruits more nociceptors for transmission of pain signals. These neurons will react to histamine as to pain stimulus. Table 2 Skin Diseases Associated with Pruritus 25 Xerosis Scabies Dermatitis herpetiformis Atopic dermatitis Lichen simplex chronicus Psoriasis Lichen planus Contact dermatitis Miliaria Drug reactions Insect bites Pruritic urticarial papules and plaques of pregnancy Pediculosis Urticaria Folliculitis Sunburn Polymorphous light eruption Bullous pemphigoid Pemphigus foliaceus Pityriasis rosea Fiberglass dermatitis Fungal infections Mycosis fungoides & Sezary syndrome Seborrheic dermatitis Psoriasis Why Are We Scratching? The purpose of itch may be seen as to provoke scratch, which in turn removes the pruritogen, a response likely to have originated when most pruritogens were parasites or insects. Classically, when scratching removes the superficial layers of the skin in which parasites live, the itching is replaced by pain and scratching stops. The sensation of itching is linked with the motor response of scratching via a spinal reflex and can be inhibited by cortical centers. 3 Scratching relieves itching for several minutes. Since the itching sensation is reinforced by facilitating circuits in the relay synapses in the spinal cord, the prolonged scratch-induced relief could be due to temporary disruption of these circuits. 1 Scratching is thought to stimulate large, fast conducting A-fibers adjacent to those conducting pruritus. The A-fibers synapse with the inhibitory interneurons and subsequently inhibit the C-fibers, thus reducing the pruritic sensation. This gate control system has been described by Wall. 21 Measuring Itching and Scratching To assess itch intensity, a 100-mm visual analogue scale is the most often used method. The patient indicates the intensity of pruritus on a line, with extremes from no pruritus at all to the worst pruritus you can imagine. 4 This method can easily be automated, allowing the analysis of a day-profile. 11 A numerical 0 10 scale also can be used. Usually, it is wise to Table 3 Laboratory Tests in Generalized Pruritus Complete blood count with differential leucocyte count Liver panel Renal panel Thyroid panel Chest radiograph Stool for occult blood Glucose HIV antibody (if risk factors are present)

4 154 Krajnik and Zylicz Vol. 21 No. 2 February 2001 record itching and scratching intensity on two separate visual analogue scales. More objective evaluation of scratching is based on recording hand movements during sleep. 2 Savin et al. 18,22 were the first to quantify scratching in human skin disease. They studied scratching patients in a sleep laboratory by monitoring several electrophysiological functions. It seems that there is an excellent correlation between the subjective sensation of itch and itch measured as nocturnal scratch in a large range of skin disease and itch due to systemic diseases. In some studies, a wireless scratch-radar with movement-sensitive system has been used. 23 It registers the rapid movements typical for scratching. Recently, an improved device with piezo-elements attached to fingernails has been developed. 24 These methods are especially useful for monitoring drug effectiveness. Some patients, however, do experience excruciating itch but refrain from scratch. For these patients the objective methods of scratch measurements are unsuitable. Evaluating the Patient with Pruritus Evaluating pruritus it is imperative to determine whether the patient s itching is related to primary dermatological or systemic disease, or is due to other causes. Usually, a thorough history and physical evaluation, including examination of the skin, lymph nodes, liver, and spleen, as well as pelvic and rectal areas, reveals the nature of disease. The acute onset of pruritus over several days is less suggestive of underlying systemic disease than is chronic generalized pruritus. Localized pruritus usually is not a consequence of systemic disease. Fixed, localized itching may be due to organic neurological disease analogous to painful neuropathies. Itching described by the patient as insects crawling over the skin may be psychogenic in origin. Itch which is migratory in timing and distribution may be secondary to malignancy (see below). Most patients are uncomfortable in bed because of the warmth and the minimal distractions. The absence of excoriation in the unreachable area of the midback strongly suggests that itching is not secondary to cutaneous eruptions and that systemic causes need to be considered. Itching is a frequent symptom of skin disease. In patients with inflammatory skin disease, it is generally assumed to be a response to one or more inflammatory mediators, including histamine, neuropeptides, or eicosanoids. There are some dermatoses that may be inconspicuous and difficult to recognize but are severely pruritic, like atopic dermatitis, bullous pemphigoid, contact dermatitis, dermatitis herpetiformis, fiberglass dermatitis, miliaria, pediculosis, scabies, urticaria, and xerosis (Table 2). Therefore, patients who present only with pruritus first should be examined to exclude these dermatoses, especially because they are readily treatable with local measures. Laboratory Evaluation (Table 3) The evaluation of the pruritic patient without skin manifestations should be directed at determining systemic causes. If the index of suspicion for systemic disease is low based on the history, review of systems, and physical examination, a 2-week trial of symptomatic therapy (see below) may be prescribed before proceeding to laboratory testing. 25 Systemic Disorders Associated with Pruritus Among all patients seeking medical attention for pruritus, the prevalence of underlying systemic disease has been reported to be 10 50%. 25,26 When itching is a manifestation of systemic disease, the cause may be also evident in the skin itself, as dry skin in hyperparathyroidism, warm and moist skin in thyrotoxicosis, or cutaneous candidiasis in diabetes mellitus (Tables 4 and 5). However, more often systemic diseases cause itching in healthy-looking skin. Specific Causes of Pruritus Chronic renal failure. Pruritus is a frequent symptom in end-stage renal disease and was first described as part of the uremic syndrome. Onequarter to one-third of uremic patients treated without dialysis exhibit uremic pruritus. 27 On maintenance hemodialysis, the incidence of uremic itching increases to 70 80%. 25 Pruritus is a feature of chronic, but not acute, renal failure. The etiology seems to depend on many factors, including dryness of the skin, secondary hyperparathyroidism, abnormal mast-cell proliferation in skin of patients on hemodialy-

5 Vol. 21 No. 2 February 2001 Understanding Pruritus In Systemic Disease 155 Table 4 Systemic Diseases Associated with Pruritus 139 Renal Chronic renal failure Hepatic Primary biliary cirrhosis Extrahepatic biliary obstruction Cholestasis of pregnancy Hepatits Oral contraceptives Drug ingestion Hematopoietic Polycythemia vera Hodgkin s disease Other lymphomas and leukemias Multiple myeloma Iron deficiency Mastocytosis Endocrine Hyperthyroidism Hypothyroidism Carcinoid syndrome Diabetes mellitus Miscellaneous Malignant neoplasms (carcinoma of breast, stomach, lung, CNS) AIDS Neurologic syndromes (multiple sclerosis) Opioid or other ingestion Psychosis Parasitic infestations Advanced age Table 5 The Most Common Causes of Pruritus in Palliative Care Senile pruritus Cholestasis Skin dermatoses (e.g., fungal infections) Lymphoproliferative disorders Drugs (e.g., systemic or spinal opioids) Other drugs (e.g., furosemide) Uremia Cancer (paraneoplastic) Psychogenic sis, and increased plasma histamine concentrations. Also, increased vitamin A levels in the skin, the proliferation of non-specific enolasepositive sensory nerve endings in the skin, peripheral neuropathy, increased levels of magnesium, phosphate, aluminium, and a circulating factor derived from the gastrointestinal tract and elevated levels of serotonin all seem to contribute to uremic pruritus. 25,27 Recent evidence supports the idea that uremic itching may be caused by accumulation of pruritogenic metabolites and not due to hypersensitivity reactions to the products from the dialysis equipment. 11 The role of the mast cells and histamine in chronic renal failure has been investigated. The plasma histamine concentrations proved to be about five times higher in patients with uremia and pruritus than in patients without uremia or pruritus. In most erythropoetintreated patients, pruritus improved within one week, probably due to the lowering of plasma histamine as a result of decreased production of histamine-releasing cytokines. 28 Because antihistamines lack any activity in this type of itch, the search for other mast cells or neutrophilderived mediators involved in pathogenesis of pruritus has continued. In addition to histamine, interleukins and leukotrienes are also known to be chemical mediators, which are secreted from mast cells and activate or induce chemotaxis of leukocytes. According to the observed high level of leukotriene B4, azelastin an inhibitor of its synthesis and inhibitor of leukotriene B4 receptors has been used successfully in the treatment of pruritus in hemodialysis patients. 29 In this study, there was no relationship between the leukotriene B4 activity decrease and improvement of pruritus, and azelastin also may have effects other than leukotriene inhibition. 30 Thalidomide, an effective treatment of leprosy, was found to alleviate pruritus in uremic patients with leprosy. This subsequently led studies on efficacy of this drug in uremic pruritus. This effect seemed to be related to its capacity to reduce tumor necrosis factor (TNF- ) synthesis by monocytes and its anti-inflammatory properties. 31 Like the observed antipruritic effect of erythropoetin, 28 this effect seems to be due to interference with cytokine production. Substance P is a candidate mediator of pruritus in peripheral nerve endings. Capsaicin depletes substance P from the C-nerve endings and inhibits itch transmission. Evidence from several studies supports the efficacy of topical capsaicin (applied as a 0.025% cream) in localized uremic pruritus. 32 Uremic pruritus is restricted to one or more areas of the body in approximately 70% of cases, and it seems to be rational and practical to use topical capsaicin in treating localized pruritus. The hypothesis that accumulation of a metabolite can cause itch in uremia has led to trials of chelating agents. 33,34 Oral charcoal (6 g daily) seems to be well tolerated and good results observed in some trials may support the

6 156 Krajnik and Zylicz Vol. 21 No. 2 February 2001 Table 6 General and Topical Measures (Modified from Twycross 137 ) Prevent boredom, anxiety, dry skin, heat Treat skin infections appropriately (fungal) Discontinue drugs that may cause pruritus (if possible) Eliminate common skin allergens (perfume, soap, neomycin preparations, antihistamine creams, alcohol containing skin preparations, wool wax alcohols (in lanolin), rubber, etc.) Apply cold application (ice, compress) Provide medicated baths (oatmeal, tar, baking soda) Apply lotions containing menthol (1/8 2%), phenol (1/8 2%), and camphor (0.1 3%) Apply tar compounds (liquor carbonis detergens 1 20%, pine tar 1 20%, ichthammol 1 20%) Apply emollients (lactic acid 3 12%) Apply anesthetics (benzocaine, lidocaine, pramoxine) Apply creams containing antihistamines or doxepin Apply capsaicin cream % for localized itches hypothesis that the uremic pruritogen may be present in the intestinal fluid or even be produced by the intestinal flora. 33 Vitamin A metabolism is altered in uremia, resulting in excess of epidermal retinol. 35 Charcoal, as well as UVB irradiation, may help to remove this pruritogen. 35,36 Stimulated by the findings in cholestatic pruritus (see below), oral naltrexone, the opioid antagonist, was given to uremic patients and found to relieve pruritus at a dose of 50 mg daily. 37 In some patients with chronic renal failure on dialysis, endorphin activity may be increased, and in such cases, naltrexone s beneficial effect on the pruritus probably results from competition with endogenous opioids for opioid receptors. Naltrexone also can relieve pruritus in patients with normal levels of endogenous opioids, and other mechanisms are thus possible. There is an abnormal pattern of cutaneous innervation in end-stage renal failure, and this has led to the neurogenic hypothesis of uremic pruritus. Neuron-specific, enolase-positive fibers may sprout throughout the epidermis in uremic patients, in contrast to healthy controls, in whom these nerve endings reached only the stratum basale. 38 Many patients on dialysis suffer from peripheral neuropathy and are prone to nerve damage. 39 Itch also may be manifestation of the uremic neuropathy. This, in turn, may explain the apparent efficacy of lidocaine in uremic pruritus. 40 However, this drug may be too toxic in uremic patients. Secondary hyperparathyroidism is another common problem in patients on dialysis. Dramatic relief of pruritus after subtotal parathyroidectomy has been reported. 40 However, no correlation between the intensity of pruritus and PTH activity has been found. 41 Increased serum levels of magnesium, calcium, and phosphate may be another candidates for uremic pruritogens. 27,42 Hypermagnesemia has been shown to correlate with itch. Magnesium may be involved in the pathogenesis of pruritus by neurogenic stimulation or by releasing histamine from mast cells. 43 Increased serum calcium and phosphate concentrations can lead to metastatic cutaneous calcification and stimulation of itch receptors. 27 Xerosis is present in 66 93% of patients with uremic pruritus. Administration of emollients for dry skin is useful for most patients. 25,27 Other trials of antipruritic treatment include neurotropin and cimetidine, but their role has not been established. 44,45 Ultimately, although some of these measures may help, only renal transplantation will guarantee a complete cure of the pruritus. In other cases, treatment of renal itch remains a clinical challenge. Hepatogenic pruritus. Pruritus occurs in approximately 20 25% of jaundiced patients, but is rare in those lacking cholestasis. 46 It affects 100% of patients with primary biliary cirrhosis (PBC) and is the initial symptom in almost half of the patients with this disease. 46 It may also precede jaundice in late pregnancy. Cholestatic pruritus complicates the use of oral contraceptives, phenothiazines, tolbutamide, anabolic steroids, and other drugs. Extrahepatic biliary obstruction of any cause is often associated with pruritus. In hepatic pruritus, patients have a typical post-inflammatory hyperpigmentation of the skin, which spares the midback and produces a characteristic butterfly configuration. 47 Bile acids have been strongly suspected as etiological factors, but do not correlate with the in-

7 Vol. 21 No. 2 February 2001 Understanding Pruritus In Systemic Disease 157 tensity of pruritus. 48 In spite of this, lowering plasma bile acids with cholestyramine may be effective. This compound could remove other pruritogens together with bile salts. Given these observations, many theories have been posted to explain hepatic pruritis. 46,49 Theories of hepatic itch include not only retained bile salts, but accumulation of a pruritogenic intermediary in bile salt synthesis pathways; bile salt toxicity to hepatocyte membranes with release of an unidentified pruritogen; histaminemediated itch from activation of mast cells by unidentified activators; and centrally acting pruritogenic endogenous opioids accumulating as a result of hepatocyte secretory failure. 50 To counteract the activity of accumulated endogenous opioids that stimulate and upregulate opioid receptors, opioid antagonists have been tried, with apparent success However, upregulated opioid receptors abruptly inhibited by naltrexone may be responsible for considerable side effects that are best characterized as opioid abstinence syndrome. Therefore, it is interesting that a partial agonist, buprenorphine, which effectively blocks opioid receptors and only partially stimulates them, acts probably as a competitive inhibitor to endogenous opioids, without evoking abstinence symptoms. As a result, it may reduce itch. In one trial, this treatment was found effective in two out of five patients. 51,53 Similar observation was done by us using codeine in a young patient with PBC. 54 Codeine 60 mg a day was able to reduce severe itch to nearly zero, within several hours. Codeine may serve as a competitive inhibitor in comparison to endogenous opioids. Tolerance development may be a problem, however, as the endogenous opioid activity probably does not decrease. Recent evidence also suggests that serotonin mayb be an important mediator. The specific 5-HT3 antagonists have been found to be successful in treatment of cholestatic pruritus. 55,56 Among the other therapies described to be successful in cholestatic pruritus, propofol, 57 rifampicin, 58,59 and UVB 60 deserve attention. These results, although promising, have not been confirmed in clinical trials. Stenting of the bile duct is the only recognized method for pruritus relief in extrahepatic cholestasis. This method is so effective that there are only a few patients who may be candidates for clinical trials with new antipruritic drugs. Hematopoietic disorders. Polycythemia vera. Approximately 30 50% of patients with polycythaemia vera (PV) suffer from temperature-induced itching, which may precede development of disease by several years. 61 Successful treatment of PV usually relieves pruritus. 62 Correction of venesection-induced iron deficiency may also give relief, but it may be at the expense of exacerbating the PV. Due to the observation that aspirin alleviates this particular form of pruritus, the role of platelet serotonin and prostaglandins has been suggested. 14 However, the concentration of platelet serotonin was similar in patients with PV with and without pruritus and no functional abnormalities of platelets were found. Pruritus in PV appears to be somehow associated with the raised histamine concentrations in blood and urine, but antihistamines are generally ineffective. There have been some reports on effectiveness of cimetidine, but its role is not yet established. 61 Cyproheptadine was the only antihistamine to be effective in decreasing pruritus, but it is also a strong antagonist of serotonin. 63 Pizotifen, a potent antihistaminic and antiserotoninergic drug prescribed for migraine prophylaxis, had also antipruritic effect in PV. 15 Cholestyramine is effective in the treatment of pruritus in PV, probably not due to extraction of bile salts. 63,64 Hodgkin s disease. As a primary, so-called B symptom, itch is seen in about 30% of patients with Hodgkin s disease. 65 It may precede the onset of the disease by as long as 5 years. 66 It is often worse at night and starts in the legs and later engages the whole body. Generalized pruritus tends to occur more often in the nodular sclerosis type of Hodgkin s disease with mediastinal mass. 65 In localized disease, pruritus tends to occur in the area drained by the lymphatic vessels invaded by the disease. Generalized pruritus was considered to be a B symptom of Hodgkin s disease from 1965 until 1971, but following several studies showing that itching had a negligible impact on survival, it was replaced by weight loss. 65 More recent reports, however, suggest that patients with Hodgkin s lymphoma and mycosis fungoides suffering from severe pruritus did less well than stagematched non-pruritic patients. 67 Based on these and other studies, severe pruritus was superior to night sweats for identifying patients who require more aggressive therapy in Hodgkin s disease.

8 158 Krajnik and Zylicz Vol. 21 No. 2 February 2001 Table 7 Summary of Drug Therapy in Systemic Pruritus Indication Drug Dose Comments Cholestatic, uremic or opioid-induced pruritus Ondansetron 4 8 mg IV followed by 4 mg P.O. q8h Cholestatic and uremic pruritus Naltrexone Initially 25 mg q24h, if no adverse effects increase the dose to 25 mg q8 12h. Very expensive. May produce constipation. Therapy evidenced by several controlled trials. 55,91,134,135,140 Naltrexone antagonizes effect of natural opioids. It may cause serious abstinence syndrome. 37,51,138 Generalized pruritus in terminal disease Paroxetine mg, q24h Nausea and vomiting may be troublesome. Add 5-HT3 antagonists or mirtazapine in the first days. The effect often fades for the unknown reasons after 6 12 weeks. Evidence from a double- blind trial not yet published. 133 Uremic pruritus Charcoal 6 g q8h 33,141 Uremic, localized pruritus, notalgia Capsaicin % cream, q8h 32,113,118 paresthetica Lymphoproliferative disorders, policythemia Cimetidine 200 mg q6h 45,61,73 vera, uremia Lymphoproliferative disorders Prednisolone Start with mg, taper No references available the dose in several weeks. Policythemia vera Aspirin 500 mg q8 24h Evidenced in controlled clinical trial. 14 When scratching and sleeplessness is a problem Hydroxyzine mg q8h Use it before night, to induce better night rest. Probably very mild specific effect on itching. 22,142 Chronic urticaria Doxepin mg q8h Is effective in treating patients with urticaria and coldand heat-urticaria. 132 The early phase of mycosis fungoides is characterized by the presence of a chronic non-specific dermatitis and frequently pruritus. 66 Although generalized pruritus is not usually seen in the absence of cutaneous manifestations, it may precede the disease for as long as ten years. Mycosis fungoides should thus be suspected in any patient with dermatitis and severe pruritus. Other hematological malignancies. The incidence and significance of pruritus in other lymphomas and leukaemia are unknown, but it has been reported in approximately 3% of patients with non-hodgkin s lymphoma. 66 It is more commonly seen in lymphocytic than in granulocytic leukemia and is more frequent in chronic rather than in acute disease. A large study of 125 patients with generalized pruritus followed for up to 6 years did not show a significant overall increase of malignant neoplasms except for lymphomas, which did occur with a higher than expected frequency. 68 A search for occult malignancy in a patient with pruritus should be therefore limited to lymphoproliferative disorders. 66 Pruritus has been reported as a rare initial symptom in multiple myeloma, Waldenstrom s macroglobulinemia, and some benign gammopathies. 69 Histamine has been suggested as a mediator for pruritus associated with lymphoproliferative diseases. It may be released from basophils, the number of which is usually increased. In these disorders, the activity of histidine decarboxylase, which is responsible for production of histamine, is elevated in abnormal cells. 70 In Hodgkin s disease, it has been suggested that an autoimmune response to lymphoid cells may cause the release of pruritogens, like leukopeptidases and bradykinins. 65 The eosinophilia seen in the pleomorphic infiltrate of Hodgkin s disease also may be linked to histamine release, and a possible role for high serum levels of IgE is underlined. 71 Specific cutaneous deposits of IgE occur in 10 20% of

9 Vol. 21 No. 2 February 2001 Understanding Pruritus In Systemic Disease 159 patients with lymphoma or leukemia. With the exception of uncommon cutaneous nodular lesions in Hodgkin s disease, which are usually pruritic, the lesions in leukemia or other lymphomas are usually asymptomatic; they may produce a burning sensation or be painful, but they rarely itch. The presence of specific skin lesions is believed to be a poor prognostic sign. 71 In mycosis fungoides, pruritus appears to be associated with the degree of histologic epidermotropism by the neoplastic and inflammatory cell infiltrate. This is seen mostly in the early stages. Thus, the release of pruritogenic mediators close to the naked dermo-epidermal nerve endings may lead to pruritus. Others propose that pruritus in mycosis fungoides might be due to the release of leukopeptidases and cellular products created by host resistance to the malignant cells. 72 In the Sezary syndrome, the pruritus may be due to the production or release of soluble T-cell lymphokines, such as interleukin-2 (IL-2). 72 Treatment of pruritus in the presence of Hodgkin s disease is best accomplished by treating the lymphoma. If this fails, there is no standard therapy. Cimetidine has been shown to be more effective in this kind of itching. 73 This may suggest that the pruritogens in Hodgkin s disease may be different, or that H2 activity may simply cause itching in Hodgkin s disease but not in other conditions. Older anecdotal observations reveal that prednisolone and other corticosteroids may be effective in the treatment of this type of pruritus. Iron deficiency. Iron deficiency, with or without anemia, has been reported as a rare cause of generalized pruritus. 74 In men, iron deficiency is mostly related to alcoholism or cancer. Generalized pruritus with iron deficiency, particularly in the elderly male, is a reason for alert. Simple screening procedures like serum ferritin, fecal occult blood, and urinalysis should be done as soon as possible. The pathogenesis of pruritus may be a result of psychological and epithelial changes, which may predispose to itch. Iron is necessary for activity of many enzymes. Alterations in their function may lead to the metabolic disturbances and itching. Pruritus due to iron deficiency responds to iron, which should be continued until the iron stores are back to normal. Endocrine disorders. Pruritus occurs in 4 11% of patients with thyrotoxicosis, especially with long-lasting, untreated Graves disease. 75 Theories on how excess of thyroid hormones may lead to itching range from activation of kinins due to increased tissue metabolism to reduction in the itch threshold due to warmth and vasodilatation. Urticaria and pruritus, or urticaria alone, also can be seen in hyperthyroidism. Chronic urticaria and angioedema can be the presenting sign of underlying autoimmune thyroid disease, even in the euthyroid state. 76 Among patients with chronic urticaria, the incidence of thyroid autoimmune disease was reported as approximately 12%. 76 Rarely, pruritus accompanies hypothyroidism, probably due to the xerosis which is seen in 80 90% of patients. This itching responds to emollients and treatment with thyroid hormone. In diabetes mellitus, pruritus often is localized around the vulva or anus and is due to Candida albicans or dermatophyte infection. 77 Generalized pruritus is probably very rare. 78 It is not clear whether metabolic abnormalities due to renal failure, autonomic dysfunction with anhidrosis, or diabetic neuropathy, are responsible for this phenomenon. Solid tumors. Infrequently, generalized pruritus precedes the emergence of cancer. More often, it occurs as a consequence of the disease, as in cholestasis due to the carcinoma of the pancreas. As a paraneoplastic symptom, it has been reported in patients with malignant tumors of breast, stomach, lung, prostate, uterus, colon, nasopharynx, and others. 79 Pruritus due to carcinoma usually differs from the pruritis encountered in lymphoma. Itching associated with carcinoma may be generalized or localized; if localized, it is usually experienced on the pretibial areas, inner aspects of the thighs, upper thorax, shoulders, and the extensor surfaces of the upper extremities. Its intensity may change over time and the skin is free from visible lesions. In some advanced brain tumors, itching is characteristically restricted to the nostrils, with paroxysmal facial itch being associated with brainstem glioma. 80 Pruritus of the nostrils is usually severe and persistent, and the patient has to scratch even during sleep. Pruritus disappears rapidly when the cancer is successfully treated; the reappearance may herald tumor recurrence. Tumors may induce localized itch probably through invasion of the fourth ventricle.

10 160 Krajnik and Zylicz Vol. 21 No. 2 February 2001 If itching is localized, it is unlikely to be related to malignancy. However, there are some exceptions. Pruritus vulvae has been reported in patients with carcinoma of the cervix. Pruritus ani may accompany rectal or sigmoid cancer, and prostate cancer may manifest by persistent itching at the scrotal and perineal region. The pathophysiology of pruritus in malignant disease is not known. One of the oldest hypotheses suggests an allergic reaction of the host to tumor specific antigens. 80,88 In 1942, Urbach believed that products of cancer tissues could activate histamine, with resultant widespread urticaria. 81 However, studies disclosed that cancer patients were subnormally sensitive to histamine-induced itching, and antihistamines were not effective. 82 It has also been suggested that itch may result from toxic products of necrotic tumor cells entering the systemic circulation or may be a sign of immune response prompted by microscopic cutaneous implants of the tumor. In some cases, pruritus may be due to the non-specific debilitating effects of the carcinoma on the patient, which make the skin more susceptible to external irritants. Opioid-induced pruritus. Pruritus is a well-known adverse effect of opioid administration. The incidence is low, approximately 1%, after systemic administration, and increases to 20 90% in patients receiving spinal opioids. 3,83 The obstetric patient seems to be more susceptible to pruritus, probably due to the interaction of estrogen with opioid receptors. 84,85 Eyelid pruritus has been reported after intravenous morphine. 86 Opioids release histamine from mast cells, but this does not appear to be a mechanism of itching. Pruritus due to spinal opioids is usually limited to the face, neck or upper thorax; the facial areas innervated by the trigeminal nerve are at highest risk. With spinal opioids, a segmental distribution of itching spreading rostrally from the level of injection is frequently observed, suggesting that it is likely due to cephalad spread of the opioids in the cerebrospinal fluid and subsequent interaction with the trigeminal nucleus and nerve roots. 83 Studies with monkeys and mice given different opioids into the medullary dorsal horn support the hypothesis that the medullary dorsal horn is a site that mediates opioid-induced facial-scratching behavior. 87,88 The itch may be blocked by the addition of the local anesthetic bupivacaine to the spinal opioid. 89 Apart from stimulation of central itch centers, morphine may activate serotoninergic pathways. It is suggested from an animal study that morphine may produce part of its analgesic effect through the release of serotonin. 90 Thus, the inhibition of serotonin receptors may block neuronal activity and attenuate pruritus. Ondansetron, a specific 5-HT3 antagonist, successfully relieved pruritus associated with intrathecal morphine, 91,92 apparently without jeopardizing spinal analgesia. Another hypothesis that attempts to explain spinal opioid-induced itch is that opioid antagonism of the inhibitory transmitters glycine and GABA may be responsible for the itch. 83 This also considers segmental itch after spinal opioids as a manifestation of local excitation by opioids within the spinal cord. Pruritus due to spinal opioid administration is difficult to treat. Antihistamines are of limited use. Antagonists are effective, but for obvious reasons impractical. 89 It has been suggested that nalbuphine, a mixed agonist-antagonist drug with -partial agonist and -agonist properties, may reverse pruritus, even more effectively than naloxone, without compromising analgesia. 93 Similarly, intranasal butorphanol reduced spinal opioid-induced pruritus without reversing the analgesic effects of opioid therapy. 94 Butorphanol is a potent 1 and 1 receptor agonist and a weak 2 receptor agonist. Because it has higher affinity for the 2 receptor than fentanyl and morphine, it may function as a competitive antagonist when given with other opioids. Probably activation of 2 receptor is responsible for side effects of spinal opioids. Further clinical studies with butorphanol are needed to support this hypothesis. Although confusing, butorphanol alone also is able to induce pruritus which can be reversed by naloxone. 95 Propofol given in subhypnotic dose has a success rate of 80% in relieving pruritus induced by epidural morphine for 3 6 hours when given as a bolus without affecting analgesia. 57 Given the marked depressive effect of propofol on dorsal horn neurons, it is postulated that antipruritic action may be due to the inhibition of dorsal horn transmission. Some problems concerning opioid-induced itch are not yet clear. If systemic opioid agonists reach CNS in sufficient concentrations to produce analgesia, they also are reaching medullary dorsal horn, and would be expected to

11 Vol. 21 No. 2 February 2001 Understanding Pruritus In Systemic Disease 161 produce pruritus. The discrepancy between the incidence of itch after systemic and spinal opioids is unexplained. Based on their study with monkeys, Thomas et al. proposed that morphine has also anti-pruritogenic activity at nonmedullary dorsal horn locus that inhibits the ability of the medullary dorsal horn-administered morphine to induce pruritus and scratching. 96 Thus, the etiology of itch caused by systemic or spinal opioids may be different, which is in agreement with the observation that H1 blocking agents are much more effective against pruritus caused by systemic than by spinal morphine. 97 The itching due to systemic morphine is generalized, while pruritus due to spinal opioids has typically segmental distribution. Morphine induces urticarial wheal and flare reactions when injected intradermally in clinically used doses. 98 The urticaria is presumed to be the result of histamine release from mast cells. Intradermal morphine injection may be even used as a positive skin test control in skin testing for allergy. Development of urticaria along the vein into which morphine is administered also may be observed occasionally. Histamine plasma levels may increase after intravenous administration of morphine, but not after fentanyl. 98 Contrary to this, plasma histamine levels are not elevated following epidural morphine administration. 99 Failure of naloxone to prevent histamine release suggests that this mechanism does not involve an opioid receptor. 100 Recent evidence indicates that morphine induces histamine release via opioidindependent G-protein activation. 100 In the treatment of morphine-induced itch, opioid rotation to, for example, hydromorphone, may be tried. 101 Rectal administration of diclofenac significantly reduces the incidence and severity of postoperative morphine-induced pruritus. 102 Neurogenic pruritus. Some types of neuropathies may be experienced by the patients as localized or focal pruritus. This is known in multiple sclerosis where severe paroxysmal pruritus is due to activation of artificial synapses between axons in the demyelinated areas of CNS. 103 In such cases anti-epileptics seem to be effective, as they may be in pain due to neuropathy. Unilateral cerebral lesions such as cerebral tumors, strokes, or abscesses can be associated with pruritus, probably due to effects on the descending pathways which modulate pruritus. 104,105 The itching is usually contralateral to the cerebral lesion and may be accompanied by other sensory abnormalities. Localized pruritus of the midback, called notalgia paresthetica, may be a form of peripheral neuropathy involving the second through sixth thoracic nerves. 106 This rare clinical entity was first described by Astwazaturow in 1934 and is characterized by focal, intense itching on a patch of the skin of the medial scapular border. 107 Capsaicin has been reported to be effective in relieving itch in notalgia paresthetica, which suggests the role of neuropeptides in its pathophysiology. 108 Postherpetic neuralgia can occasionally manifest as localized pruritus. 109 Pruritus may respond to gabapentin, similar to pain. 110 Aquagenic pruritus. Aquagenic pruritus is characterized by intense itching, sometimes accompanied by a burning or stinging sensation after contact with water, regardless of temperature, without any cutaneous alterations and skin or systemic disease. 111 It may be an isolated symptom or accompany different proliferative disorders, like PV. The discomfort appears 1 5 minutes after exposure to water and lasts for minutes. The pathogenesis is unknown, but the increased degranulation of mast cells has been demonstrated after the contact with water and the release of acetylcholine. 111 However, histamine does not seem to play a key role, and both H1 and H2 antagonists are not always effective in prevention or treatment. Topical scopolamine inhibits pruritus after contact with water, but it is useless with generalized itching. Increased cutaneous fibrinolytic activity has been demonstrated both before and after the contact with water. 112 The effectiveness of topical capsaicin treatment suggests that substance P and other neuropeptides released from cutaneous nerve fibers play a key role in mediating itch in aquagenic pruritus. 113 PUVA treatment may be helpful in aquagenic pruritus, probably by leading to the reduction of responsiveness of cutaneous sensory nerves, similar to that observed after topical capsaicin. 114 Aspirin together with a serotonin antagonist have relieved aquagenic pruritus accompanying PV, but may increase the risk of gastrointestinal hemorrhage. 14,15 The addition of baking soda to the bath water to raise the ph to 8 may be helpful, but at least 0.5 kg is needed for an average bath. 114

12 162 Krajnik and Zylicz Vol. 21 No. 2 February 2001 Iatrogenic pruritus. Apart from opioids, other drugs like aspirin, may cause pruritus as a manifestation of allergic reaction, mostly with rash. Some drugs lead to pruritus by a mechanism involving cholestasis or hepatotoxicity. Hydroxyurea has been reported to cause severe pruritus during treatment of PV. 115 Hydroxyethyl starch administration has been reported to cause long-lasting itching. 116 Psolaren plus long-wave ultraviolet light (PUVA) therapy produced a distressing pruritic or painful sensation referred to as PUVAitch or -pain in 20 25% of patients; this was probably due to photoallergy and/or phototoxicity. 117 It may begin during or after the treatment and may be localized (more often) or generalized. The itch may cause significant morbidity. Although PUVA-itch has been treated successfully with capsaicin, 118 it is notoriously unresponsive to treatment and lasts, on average, 2 months. The cause of PUVA-itch appears to be related to the substance P release from terminal nerve endings by UV light. Other mechanisms may also be responsible for drug-induced pruritus without rash. These may involve neuropeptide-related effects, augmented pharmacological actions (captopril), immunologic hypersensitivity, other toxic effects, and other idiosyncratic mechanisms. 119 Itching in HIV disease. Pruritus has been described as a presenting sign of AIDS, 120 and may be important in early diagnosis. Pruritus may occur with or without a primary dermatosis. Patients with HIV-related disease may develop any condition associated with pruritus, ranging from infections and infestations to systemic diseases. There is a high prevalence (92%) of skin diseases in HIV-positive patients, especially seborrheic dermatitis, candidiasis and xerosis. 121 A pruritic papular eruption in AIDS patients is closely correlated with general immunosuppression, 122 and eosinophilia and elevation in serum IgE (with pruritus) has been associated with some cutaneous diseases (eosinophilic folliculitis, atopic dermatitis, prurigo nodularis). 123 The eosinophilia presumably represents an allergic response to an unidentified stimulus, which is primarily confined to the skin. 25 Basophils and mast cells from HIV-infected patients demonstrate enhanced degranulation with release of pruritogenic components. Patients with itching AIDS-related skin diseases showed abnormal levels of several cytokines, suggesting their involvement in pruritogenesis. 124 A recent study suggests that therapy- resistant, intractable pruritus accompanied by hypereosinophilia may be used to define a subset of HIV-seropositive individuals showing prototypic hyperactivation of humoral immunity; 125 these patients have a high HIV viral load. Peripheral neuropathy may also be an important cause of pruritus in HIV-infected patients. Infection of peripheral nerves by HIV could lead to direct stimulation of pathways associated with pruritus or to release of substance P. In addition, the epidermis is commonly abnormal, which enhances the effects of irritants and allergens. 126 Senile pruritus. Persistent and widespread itching is experienced by at least 50% of those in the seventh decade of life or beyond. In women, itching may be part of the postmenopausal syndrome. In most instances, generalized pruritus is a result of xerosis and skin atrophy, 127 but in many cases there is no good explanation for this symptom. So called senile pruritus may be the result of age-associated degeneration in peripheral nerve endings. 70 The patient must be encouraged to apply emollients, and ambient temperature and humidity should be modified. Hormone replacement therapy is usually sufficient to control postmenopausal pruritus. Psychogenic pruritus. Non-specific psychological states, such as anxiety, fatigue, or stress, may exacerbate itching. Stress due to uncontrollable situations may impact on the course of pruritic dermatoses. Coping styles may help predict whether or not pruritus would be exacerbated by mental stress. Psychogenic pruritus has been most frequently associated with the depressive disorders. Especially in older patients, itch may be a depressive equivalent; affected patients may deny feelings of depression. In depression, dopamine and serotonin are pruritic mediators and elevated CSF levels of certain endogenous opioids have been demonstrated. Feelings of helplessness and hopelessness are associated with the secretion of serotonin, dopamine and opioids, and with pruritus. 128 Pruritus may also accompany anxiety or represent a hysterical conversion reaction, as it has been reported in a school epidemic. 129 Psychotic patients occasionally suffer from gener-