The treatment for pruritus of systemic disease varies depending on the underlying etiology. New therapies are based on advances in the understanding of the mechanisms that cause pruritus. However, without eradication of the underlying systemic disease, treatment is often palliative at best and can be frustrating for both the patient and physician.
Certain therapies, such as antihistamines and emollients, offer marginal benefit. Nevertheless, they should be tried because of their low cost and potential for providing relief. Sedating antihistamines may be effective in patients with nocturnal pruritus. Although antihistamines are partially effective in treating pruritus due to systemic disease, the effect is usually marginal and the relief is unsatisfactory. Doxepin, a tricyclic antidepressant (TCA) with antihistaminic properties, at dosages of 25-50 mg at bedtime may be quite helpful. Mirtazapine at 15-30 mg at bedtime has also been used to treat pruritus. [17, 18]
Gabapentin taken orally has demonstrated effectiveness in neurogenic pruritus and more recently has demonstrated effectiveness in uremic, hematologic, and idiopathic pruritus. 
Aprepitant, an anti-nausea neurokinin receptor 1 antagonist, has been showed to be highly effective in reducing pruritus in a group of patients with various skin disorders. Patients with atopic dermatitis and prurigo nodularis seemed to respond best. 
Treatment can be physical, topical, or systemic.
Physical therapy with UV-B therapy is a treatment of choice. Patients have reported months of remission after 6-8 treatments. UV-B reduces cutaneous phosphorus, decreases the number of dermal mast cells, and reduces epidermal vitamin A levels. However, some concern has been expressed that broad-band UV-B treatment might possibly increase the risk of nonmelanoma skin cancer. Narrow-band U-VB seems less likely to do so. One study from Scotland failed to demonstrate an increased risk of skin cancer in patients receiving narrow-band UV-B therapy. 
Topical therapy is especially helpful in cases of localized pruritus.
Capsaicin 0.025% cream is effective for localized pruritus due to CRF, as has been shown in double-blinded, placebo-controlled studies.
Topical application of a eutectic mixture of local anesthetics (eg, EMLA cream) before capsaicin treatment may reduce the burning sensation associated with capsaicin. 
Tacrolimus 0.03% ointment has shown promising results for localized renal pruritus in a prospective study, but randomized placebo-controlled studies are needed. Tacrolimus is a calcineurin inhibitor, it decreases the differentiation of type 1 helper T lymphocytes, and it reduces the production of interleukin 2. 
Topical gamma linolenic acid appears promising.  Topical gabapentin cream (3-6%) has been reported to help vulvodynia and could potentially be used to treat localized areas of neurogenic pruritus such as pruritus vulvae, pruritus scroti, and notalgia paresthetica. 
Systemic therapy includes UV-B and activated charcoal, which are first-line treatments, along with ensuring effective dialysis. [26, 27, 28, 29, 30, 9] Narrow-band UV-B is particularly effective. Oral activated charcoal is inexpensive, effective, and well tolerated; therefore, it is considered a reasonable treatment when UV therapy has failed. Activated charcoal is thought to prevent the absorption of an unknown pruritogen.
Cholestyramine is not as effective and is associated with adverse effects, such as acidosis.
Efficient dialysis is helpful. Pruritus tends to become severe with insufficient dialysis. 
Thalidomide has been reported as effective but should be used with caution because of its adverse-effect profile.  However, in the authors' experience, thalidomide is a valuable tool in cases unresponsive to conventional therapy.
Erythropoietin has been studied, [35, 36] and one double-blinded, placebo-controlled study showed marked benefit in patients receiving small doses for up to 6 months. However, this effect could not be confirmed.
Other systemic therapies include nicergoline and free fatty acids (eg, those in primrose oil); these have shown positive results in reducing renal pruritus. Gabapentin has been shown to be effective in the treatment of chronic uremic pruritus, but it has been shown to worsen cholestatic pruritus.  Butorphanol, an opioid that displays mu antagonism and kappa agonism, has been shown to relieve uremic pruritus.  A newer kappa-opioid receptor agonist, nalfurafine, has been shown to be effective in significantly reducing pruritus in hemodialysis patients when compared to a placebo in a large, double-blinded, randomly controlled study. [10, 11]
A double-blinded controlled study in Iran demonstrated that oral zinc sulfate (440 mg daily) significantly reduced pruritus in a group of patients undergoing hemodialysis for renal insufficiency. 
Cholestyramine is the first-line therapy, followed by rifampin and opioid antagonists. Ondansetron may also be tried. Cholestyramine has only been show effective in a few randomized studies, but this drug is thought to be helpful in relieving pruritus. Because of its low cost, it should be tried before more expensive treatments are considered.
Opioid antagonists, including naloxone, may relieve pruritus, but intravenous administration limits its use outside the hospital setting. Oral naltrexone is also effective. [42, 43, 44, 45] Oral nalmefene has been tested and is effective but may only be available in intravenous form.  To prevent opioid withdrawal syndrome, low starting doses should be used. These drugs should not be used in patients in need of palliative opioid treatment. Butorphanol, which antagonizes the mu receptor but agonizes the kappa receptor, has been shown to be effective in suppressing cholestatic pruritus. 
Ursodeoxycholic acid and S-adenosyl-L-methionine have both been reported to decrease pruritus in women with cholestasis of pregnancy, but ursodeoxycholic acid may improve fetal outcomes and biochemical serum markers. [47, 48]
Ondansetron has limited effectiveness and, because it relieves opioid-induced pruritus, it appears to affect opioid pathways.
Stanozolol relieves pruritus; however, it worsens cholestasis and is not recommended.
Removal of the offending agent should be initiated in patients with drug-induced cholestasis.
Other therapies that may be effective are thalidomide, infused propofol, serotonin-selective reuptake inhibitors, UV-B, phenobarbital, dronabinol, and bright-light therapy indirectly reflected toward the eyes.
Iron deficiency responds to treatment with iron, which should be continued until ferritin levels are normalized. Correction of iron deficiency in persons with polycythemia vera may decrease the pruritus but worsen the polycythemia vera.
Patients with pruritus due to polycythemia vera may benefit from aspirin, which is considered the first-line therapy. Cimetidine, danazol, cholestyramine, UV-B light therapy, and psoralen with UV-A therapy have all been shown to help. [51, 52]
Interferon-alfa may provide relief, but its adverse effects may decrease compliance. 
Treatment with paroxetine at 20 mg/d has been shown to be effective, but further clinical trials are needed.
One patient with severe pruritus due to Hodgkin disease responded dramatically to thalidomide at 200 mg by mouth at night. 
The pruritus of hypothyroidism is secondary to xerosis and should be treated with emollients and thyroid hormone replacement. Pruritus secondary to hyperthyroidism improves with the correction of thyroid function.
Topical cannabinoid agonist creams have been shown to relieve pruritus associated with certain chronic dermatoses. Treating the underlying disorder is the mainstay of therapy for controlling pruritus. Corticosteroids with palliative chemotherapy in late-stage Hodgkin disease often provide relief.
Nonspecific treatments for intractable pruritus, such as UV-B light therapy, cholestyramine, naloxone, and activated charcoal, should be considered. Paroxetine relieves itch in patients with advanced cancer; however, the effect usually lasts only 4-6 weeks.
Successful transplantation is the only definitive treatment for renal pruritus. When pruritus is associated with obstructive malignancy of the biliary tract or other obstructive causes (eg, primary sclerosing cholangitis), placing a stent to relieve the obstruction also treats the pruritus. Liver transplantation may be considered in patients who have pruritus associated with nonmalignant cholestasis that does not respond to medical therapy.
Consultation with the following specialists may be helpful:
Dermatologist: Always consult a dermatologist to rule out any primary cause of pruritus and to discuss UV-B or psoralen UV-A light therapy when it is considered in the treatment plan.
Gastroenterologist: A gastroenterologist should evaluate any patient with liver or biliary tract disease.
Hematologist/oncologist: These specialists should always be involved in the care of patients with pruritus due to hematologic or malignant causes.
Endocrinologist: Patients with endocrine pruritus should be evaluated for treatment of their thyroid disease, which often cures their itch.
Surgeon and/or transplant surgeon: Patients with CRF or chronic liver disease may need to be evaluated for kidney or liver transplantation, respectively. A surgeon should always be consulted in cases of malignant cholestasis.
A low-protein diet may help decrease pruritus in persons with CRF.
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