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Relief of pruritus and decreases in plasma histamine concentrations during erythropoietin therapy in patients with uremia.

BACKGROUND: The pathophysiologic aspects of pruritus in patients with chronic renal insufficiency are poorly understood, and there is no universally effective treatment. The improvement of pruritus in several patients receiving erythropoietin therapy raised the possibility that erythropoietin affects uremic pruritus directly. METHODS: We undertook a 10-week placebo-controlled, double-blind, crossover study in a group of patients receiving hemodialysis who had severe pruritus, to investigate the effects of recombinant human erythropoietin on their pruritus and plasma histamine levels. Twenty patients with uremia, of whom 10 had severe pruritus and 10 did not, received erythropoietin (36 units per kilogram of body weight three times weekly) and placebo in random order, each for five weeks. The severity of pruritus was scored weekly, and plasma histamine levels were measured at the beginning and end of each five-week period. RESULTS: Eight of the 10 patients with pruritus had marked reductions in their pruritus scores during erythropoietin therapy. The mean (+/- SE) pruritus score decreased from 25 +/- 3 to 6 +/- 1 in these patients. The pruritus returned within one week after the discontinuation of therapy. The improvement was not related to the change in hemoglobin level. These eight patients were successfully treated again with low doses of erythropoietin (18 units per kilogram three times weekly), and the effect has persisted for six months. The patients with pruritus had elevated plasma histamine concentrations (20.7 +/- 2.7 nmol per liter), as compared with the patients without pruritus (4.2 +/- 0.6 nmol per liter; P less than 0.001) and normal subjects (2.1 +/- 0.2 nmol per liter; P less than 0.001). Therapy with erythropoietin induced a decrease in plasma histamine concentrations in both groups of patients with uremia, and recurrences of pruritus after the discontinuation of erythropoietin were accompanied by increases in plasma histamine concentrations. CONCLUSIONS: Erythropoietin therapy lowers plasma histamine concentrations in patients with uremia and can result in marked improvement of pruritus.

Double-Blind Method

Uremic pruritus and skin mast cells.

The number of mast cells in the skin was evaluated in 25 patients with end-stage renal failure on different treatment modality (conservative, hemodialysis and peritoneal dialysis). According to the presence of pruritus, uremic patients were divided into two groups: group A, 13 patients with diffuse pruritus, and group B, 12 patients without pruritus. Controls were 6 age- and sex-matched healthy subjects. In comparison with patients without pruritus, patients with pruritus had mainly degranulated, diffusely spread and more numerous mast cells in the skin; significantly higher levels of plasma middle molecular weight substances, serum histamine and PTH and significantly lower serum iron levels. However, no differences were noted in observed parameters between groups on different treatment modalities. Favorable therapeutic effects in patients with pruritus were achieved either with iron supplementation in those with hypoferremia or with antihistamines, mast cell membrane stabilizers and high-permeability membranes.

Humans

Stratum corneum changes in patients with senile pruritus.

BACKGROUND: Generalized pruritus in the elderly is a common and distressing problem; often there is no evidence of skin disease other than xerosis. OBJECTIVE: The aim of the study was to determine whether any abnormality could be detected in the structure and function of the skin of patients with generalized pruritus. METHODS: The skin of 13 elderly patients with generalized pruritus, without skin disease or any underlying cause, was contrasted with that of age- and sex-matched normal control subjects. RESULTS: The patients had clinically drier skin (mean visual analogue scale score 2.9 [standard deviation +/- 2.2], controls 0.52 [+/- 0.59], p = 0.002). The severity of the pruritus was related to the degree of xerosis (r = 0.66). The patients had decreased skin surface conductance (10.7 mumho [+/- 3.4], controls 16 mumho [+/- 5.3], p = 0.017), and increased intracorneal cohesion (240.5 g [+/- 88], controls 162.7 g [+/- 39.8], p = 0.001). The patients also had statistically significantly diminished parameters of skin surface contour. CONCLUSION: The findings of increased intracorneal cohesion and altered skin surface contour parameters suggest that elderly patients with generalized pruritus may have an acquired abnormality of keratinization.

Aged

Suppression of histamine-induced pruritus by hydroxyzine and various neuroleptics.

This study evaluates the ability of hydroxyzine and various neuroleptics to suppress histamine-induced pruritus in ten volunteer subjects with the use of a double-blind crossover protocol. The itch threshold was determined in each volunteer by intradermal injection of gradually increasing concentrations of histamine. Volunteers were then given the study drugs and placebo at the same interval of time, under near identical conditions, and the itch threshold was determined. Thiothixene, hydroxyzine hydrochloride, chlorpromazine, thioridazine, and a lactose placebo were evaluated. Compared to other drugs, hydroxyzine alone was more effective in the suppression of histamine-induced itch. Consequently, hydrozyzine may be more effective in histamine-induced pruritus. The neuroleptic drugs used in this study do not significantly suppress histamine-induced pruritus, but they may be beneficial in nonhistamine-induced pruritus or psychogenic pruritus.

Adult

Cholestyramine in uraemic pruritus.

In a patient with longstanding severe uraemic pruritus who was undergoing chronic haemodialysis cholestyramine caused the pruritus to disappear completely within a few days. A four-week randomised controlled double-blind study was therefore performed in 10 other patients with uraemic pruritus who were on chronic haemodialysis. The pruritus improved considerably in four of the five treated patients, whereas only one of those treated with placebo experienced relief. The patient who had no relief while on cholestyramine showed a considerable improvement when the dose subsequently doubled. One of the five patients receiving cholestyramine experienced mild and easily reversible constipation, and another suffered nausea. Neither of these complications prevented the patients from continuing treatment. Cholestyramine seems to be useful in treating uraemic pruritus, although it is not known how it acts.

Cholestyramine Resin

Pruritus.

Pruritus is an important sign of localized or systemic disease and sometimes may be the only symptom of potentially fatal illness. Localized causes of pruritus include stasis dermatitis, atopic dermatitis, contact dermatitis, neurodermatitis and scabies. Generalized pruritus may be caused by environmental factors such as low humidity, skin diseases such as urticaria, or internal diseases such as biliary obstruction, renal failure, hematologic malignancy or acquired immunodeficiency syndrome. Therapy for pruritus depends on identification and treatment of the underlying cause. If no specific etiology is found, therapy is palliative. Avoidance of frequent bathing may be helpful, especially when xerosis plays a role. Topical emollients or short-term therapy with low-potency steroids may also be effective. Oral antihistamines provide nonspecific relief for many patients with intractable pruritus.

Baths

Cholinergic pruritus in a horse.

An 8-year-old gelding, with a 1-year history of intense pruritus only after exercise, was diagnosed as having cholinergic pruritus. Provocative testing, using exercise and hot-water baths to increase core body temperature, assisted in the diagnosis. Cholinergic pruritus in human beings is a variant of the more common syndrome, cholinergic urticaria, which is characterized by intense pruritus and pinpoint urticaria. With cholinergic pruritus, intense itching results without urticaria. Specific diagnostic laboratory tests have not been developed.

Animal Feed

Can proctological procedures resolve perianal pruritus and mycosis? A prospective study of 23 cases.

Twenty-three patients with pruritus ani associated with anal mycosis underwent primary treatment of a concurrent anal disorder. The anal disorders included haemorrhoids (n = 9), fissure (n = 8), anal spasm without fissure (n = 5), and occult mucosal prolapse (n = 1). Pretreatment investigation of faeces for parasites was negative. The glucosal tolerance test and white blood cell count were normal in all cases. Culture of skin smears from the perianal region was positive for Candida only in 16 patients, Dermatophytes only in 6 and a combination of both in 1 patient. Following the appropriate proctological procedure, pruritus resolved or markedly improved in 20 patients. The remaining three patients required antifungal treatment with econazole. Two of these, however, continued to complain of pruritus. It is suggested that in patients with pruritus ani associated with perianal mycosis, antimycotic therapy should be used only if fungal infection persists after treatment of the underlying proctological disease.

Adolescent

Pruritus: a practical approach.

Pruritus is usually caused by a primary disorder of the skin, but can also be caused by a systemic disease (Table 1). Some dermatologic conditions that cause pruritus can be inconspicuous or nonspecific (Table 2), while others are usually apparent on physical examination (Table 3). Classification of pruritus as localized (Fig. 1) vs. generalized (Fig. 3) can be helpful in arriving at a correct diagnosis. The history and physical examination are the most important diagnostic tools, though laboratory testing for systemic disease may be necessary. In refractory cases, one should consider occult systemic disease (such as malignancy), psychiatric disease (especially depression), and HIV infection. Subsequent referral to a dermatologist may be indicted. When treatment of the underlying cause of pruritus is not possible, antihistamines and topical agents (menthol, phenol, and/or pramoxine) can be helpful.

Anal Canal

Subhypnotic doses of propofol relieve pruritus induced by epidural and intrathecal morphine.

We investigated the efficacy of subhypnotic doses of propofol for spinal morphine-induced pruritus in a prospective, randomized, double-blind, placebo-controlled study. Fifty patients, ASA physical status 1-3, with spinal morphine-induced pruritus were allocated to receive either 1 ml propofol (10 mg) or 1 ml placebo (Intralipid) intravenously after gynecologic, orthopedic, thoracic, or gastrointestinal surgery. In the absence of a positive response, a second drug treatment was given 5 min later. The persistence of pruritus 5 min after the second treatment dose was considered a treatment failure. All failures then received, in an open fashion, a supplementary dose of propofol (10 mg) and were reevaluated 5 min later. Both groups were well matched. The success rate was significantly greater in the propofol group (84%) than in the placebo (16%) group (P less than 0.05). Ninety percent of the treatment failures in the placebo group were successfully treated by a supplementary dose of 10 mg propofol. Eight percent of the patients (4% in each group) were resistant to all treatments, including naloxone 0.08 mg intravenously. Three patients had a slight increase in sedation in the propofol group versus none in control (not significant). The beneficial effect of treatment was longer than 60 min in 85% of patients in the propofol group and in 100% of the controls (not significant). These results suggest that propofol in a subhypnotic dose is an efficient drug treatment for spinal morphine-induced pruritus. At the dose administered (10 mg), side effects were rare and minor.

Adult

Pruritus in polycythemia vera: treatment with aspirin and possibility of platelet involvement.

The characteristic temperature-dependent pruritus in polycythemia vera (PV) is described. The triggering factor seems to be a sudden decrease in skin temperature, e.g. after a hot bath or shower. The sudden onset and limited duration of the pruritus might suggest an activation or release of some humoral factor(s). In a controlled study we showed that aspirin alleviates this particular pruritus. Therefore, the possibility of prostaglandin and platelet involvement was considered. It was found that substances such as PGE2 and serotonin, produced and released by platelets, could elicit pruritus in healthy volunteers when injected intradermally and that PGE2 enhanced the cutaneous responses to serotonin. Studies of platelet aggregation did not reveal any abnormalitites in the PV patients but ADP was shown to sensitize platelets to adrenaline-induced aggregation in vitro. Although not proven the following hypothesis is suggested: a combination of ADP, emerging from erythrocytes, and catecholamines released from adrenergic vasoconstrictor nerves when the skin is cooled down, might stimulate platelets to aggregation in skin vessels and to production and release of pruritogenic factors.

Adult

Pruritus as a manifestation of systemic disorders.

A significant internal disorder is present in only a limited number of patients with essential pruritus. The mechanisms for the production of pruritus in these disorders are poorly understood and frequently are unrelated to liberation of histamine. Proteolytic enzymes in lymphoproliferative disorders, bile acids in obstructive hepatobiliary disease, parathyroid hormone in chronic renal failure, and prostaglandins and kinins are but a few of the chemicals that may ultimately be responsible for the development of pruritus in these and other purely cutaneous disorders. Patients with essential pruritus should have a comprehensive physical and laboratory evaluation, but psychologic, environmental, and other factors must be considered when thorough clinical evaluation is unrewarding. Treatment should be directed towards elimination of the underlying alteration, control of the additional factors, and alleviation of the symptom.

Biliary Tract Diseases

Suppression of histamine-induced pruritus by three antihistaminic drugs.

A double-blind crossover study of inhibition of histamine-induced pruritus by three commonly prescribed antihistamines was conducted on 28 normal subjects. Drugs used included diphenhydramine HCl (Benadryl), cyproheptadine (Periactin), hydroxyzine HCl (Atarax), and a lactose placebo in identical capsules. Intradermal histamine dose-response thresholds of pruritus were obtained before and after pretreatment with the three antihistamines and placebo in each subject. Analysis of data revealed a fivefold increase above baseline of the histamine dose required to produce pruritus following both cyproheptadine and placebo. This compared to a tenfold increase following diphenhydramine and a 750-fold increase following hydroxyzine HCl. The most common side effect was drowsiness, which occurred with all three drugs.

Adolescent

Relief of uremic pruritus with ultraviolet phototherapy.

We studied the effect of ultraviolet-light phototherapy on severe persistent pruritus in 18 adult patients on hemodialysis. Patients were randomly assigned to one of two light sources. The experimental group received conventional sunburn-spectrum light in gradually increasing doses. The control group received time-matched exposures to long-wave ultraviolet light. All patients received eight exposures to the entire skin surface over a four-week treatment period. Nine of 10 patients in the sunburn-spectrum group reported marked decrease in pruritus as opposed to two of eight in the placebo group (P less than 0.01). of those responding to sunburn-spectrum light, improvement usually occurred two to three weeks into treatment. Mild sunburn, noted by some patients in this group, was the only side effect. The response to phototherapy was unaffected by the presence of secondary hyperparathyroidism. Ultraviolet phototherapy is a safe, convenient, inexpensive and effective treatment for uremic pruritus.

Adult

Relief of pruritus as an early sign of spinal cord compression in Hodgkin's disease.

In a patient with advanced Hodgkin's disease (HD) associated with generalized pruritus, an unexpected relief of itching was found to be an early sign of spinal cord compression. Following irradiation of an extradural mass at the Th II level, itching recurred. Although the mechanisms bringing about itching in HD are unknown, the relief and recurrence of the symptom in our patient are in line with a peripheral origin of pruritus in the disease. Spontaneous relief of pruritus in HD despite other signs of active disease should prompt a neurological examination, since early recognition and treatment of spinal cord compression in lymphoma are important to avoid residual neurological disability.

Adult

Ultraviolet phototherapy of uremic pruritus.

Repeated exposure to mid-range ultraviolet light (UVB) can dramatically relieve the pruritus associated with uremia. The efficacy of UVB phototherapy in uremic pruritus has been established in a controlled trial; experience with 38 patients suggests that 80 to 90% of those receiving 6 to 8 exposures respond favorably within the treatment period (2 to 5 weeks). Treatment frequency appears not to influence the remission rate, although patients on more intensive schedules experience relief sooner than those treated once weekly. Remissions are long-lasting in many patients, sometimes longer than 2 years. Patients with recurrent pruritus respond to phototherapy at least as well as previously untreated patients and tend to improve more rapidly. UVB phototherapy appears to exert its beneficial effect systemically rather than locally, but its mechanism of action is otherwise unknown.

Adult

Treatment of pruritus in cholestasis of pregnancy with a new anion exchange resin (Secholex).

Anion exchange resins form a non-absorbable complex with bile acids in the intestine, thus removing bile acids from the enterohepatic circulation and facilitating bile acid excretion in the faeces. A new bile acid sequestrant (PDX chloride, Secholex) was evaluated for the relief of pruritus in cholestasis of pregnancy (CP) in 31 women. CP was verified by the presence of the abnormal lipoprotein X in serum and the clinical series was divided into two degrees of severity, pruritus gravidarum (PG) and hepatosis of pregnancy (HP) based on liver function tests. Eleven of 31 women discontinued treatment because of gastro-intestinal side effects. Of the 20 women continuing the study for more than one week, all with a milder form of cholestasis, PG (n=8), experienced relief of pruritus, while some relief was obtained in 75% of the women with HP. After up to 4 weeks administration of Secholex, no obvious interference with fat absorption was evident judging from the serum lecithin content of linoleic and arachidonic acids. A reduction in serum folic acid might indicate an interaction in folic acid absorption. An expected reduction in serum cholesterol levels which are characteristically increased in CP, was not achieved by the administration of Secholex.

Anion Exchange Resins

Ultraviolet phototherapy of uremic pruritus. Long-term results and possible mechanism of action.

The beneficial effect of sunburn-spectrum ultraviolet (UVB) phototherapy on uremic pruritus was studied. Seven patients were treated twice weekly for 4 weeks with UVB to one half of the body and placebo phototherapy to the other half. All patients noted generalized improvement without localization of benefit to the UVB side, suggesting a systemic effect of UVB. A comparison of three schedules varying from one to three treatments weekly showed that the percentage of patients responding was not influenced by frequency of UVB exposure, although patients treated more intensively improved faster. In three patients, improvement was delayed until 2 weeks after completion of a course of six treatments over 2 weeks, indicating a delayed onset of benefit in at least some patients. Overall 32 of 38 patients improved after a course of six or eight UVB exposures. Pruritus has recurred in 15 patients after a mean remission of 3 months. Sixteen patients are known to remain in remission for a mean of at least 10.6 months after the first or second course of treatment. The present evidence indicates a systemic mechanism of action for the long-lasting relief of uremic pruritus afforded by UVB phototherapy.

Adult