**6. Systemic Treatments**

#### **6.1. Opioid Antagonists**

Endogenous opioids have been implicated in the genesis of the pruritus associated with cholestasis [110,111]. One study demonstrated the effect of naltrexone 50 mg/day for a week in 15 dialyzed patients with severe UP in a randomized cross-over trial, and the results indicated that short-term amelioration of UP was found and attributed to the inhibition of basophil histamine release. Only mild upper gastrointestinal tract symptoms were found to be the side effects [112]. Opioid antagonists should therefore be considered for patients with severe and persistent UP [2].

More recently, another perspective was elaborated on regarding the use of a κ-agonist, for κreceptor stimulation inhibits µ-receptor effects both peripherally and centrally and hence might inhibit itching induced by substance P [64]. A meta-analysis approach was used to assess the efficacy of nalfurafine, which is a κ-agonist, in two randomized placebo-controlled clinical studies. Nalfurafine was administered intravenously postdialysis over 2-4 weeks, and the results were encouraging, as improvements in the worst itching, itching intensity and sleep disturbances were noted in the nalfurafine group, with significant *p* values [113]. In addition, the evaluation of adverse events demonstrated that nalfurafine was well tolerated.

### **6.2. Erythropoietin**

De Marchi *et al*. studied the effect of erythropoietin in dialysis patients with elevated plasma histamine levels in a placebo-controlled, double-blind, crossover study. They found that erythropoietin improved UP and decreased plasma histamine concentrations. Further, they found that it can result in marked improvement of UP and that recurrence of pruritus occurred after discontinuation of erythropoietin [114]. However, this effect was not related to the change in hemoglobin levels [115].

#### **6.3. Serotonin Antagonists**

Serotonin has been suggested as a possible mediator of cholestasis and UP. One study indicated that ondansetron, a selective inhibitor of serotonin type 3 receptors, at 4 mg twice a day for approximately 3 months can significantly reduce the severity of UP in peritoneal dialysis patients with moderate to severe pruritus [116]. This treatment was well tolerated and showed no significant side effects. However, the study by Ashmore *et al*. failed to show any significant change in the pruritus scores in patients treated with ondansetron in comparison with the placebo group [117].

#### **6.4. Gabapentin**

Gabapentin, a γ-aminobutyric acid analog, is a potent anticonvulsant drug that was has been clearly demonstrated as effective in the treatment of neuropathic pain, especially diabetic neuropathy. Considering that neuropathic pain and pruritus share common pathogenic mechanisms, gabapentin, which is usually used to treat neuropathic pain, emerged as another possibility in the arsenal of treatment for severe UP resistant to other therapies [64]. Recent, limited data suggest that gabapentin is a promising drug in treating UP, given its efficacy and its safety [13,91,118]. In a randomized, placebo-controlled, double-blind study, 25 patients were treated with gabapentin versus a placebo for 4 weeks; the treatment was then reversed, and the mean pruritus score dropped significantly. No patient dropped out due to adverse events from gabapentin [119]. Regarding its pharmacokinetics, gabapentin is eliminated primarily through the kidney, and it is removed by hemodialysis. It has a significantly longer half-life in patients on hemodialysis than in those with normal kidney function, and thus, these patients need lower doses at less frequent intervals [64]. The recommended dose for hemo‐ dialysis patients is 200- 300 mg after each hemodialysis session, with somnolence, dizziness and fatigue being the most commonly reported side effects [120].

#### **6.5. Antihistaminic Agents**

**6. Systemic Treatments**

severe and persistent UP [2].

**6.2. Erythropoietin**

in hemoglobin levels [115].

**6.3. Serotonin Antagonists**

placebo group [117].

**6.4. Gabapentin**

Endogenous opioids have been implicated in the genesis of the pruritus associated with cholestasis [110,111]. One study demonstrated the effect of naltrexone 50 mg/day for a week in 15 dialyzed patients with severe UP in a randomized cross-over trial, and the results indicated that short-term amelioration of UP was found and attributed to the inhibition of basophil histamine release. Only mild upper gastrointestinal tract symptoms were found to be the side effects [112]. Opioid antagonists should therefore be considered for patients with

More recently, another perspective was elaborated on regarding the use of a κ-agonist, for κreceptor stimulation inhibits µ-receptor effects both peripherally and centrally and hence might inhibit itching induced by substance P [64]. A meta-analysis approach was used to assess the efficacy of nalfurafine, which is a κ-agonist, in two randomized placebo-controlled clinical studies. Nalfurafine was administered intravenously postdialysis over 2-4 weeks, and the results were encouraging, as improvements in the worst itching, itching intensity and sleep disturbances were noted in the nalfurafine group, with significant *p* values [113]. In addition,

De Marchi *et al*. studied the effect of erythropoietin in dialysis patients with elevated plasma histamine levels in a placebo-controlled, double-blind, crossover study. They found that erythropoietin improved UP and decreased plasma histamine concentrations. Further, they found that it can result in marked improvement of UP and that recurrence of pruritus occurred after discontinuation of erythropoietin [114]. However, this effect was not related to the change

Serotonin has been suggested as a possible mediator of cholestasis and UP. One study indicated that ondansetron, a selective inhibitor of serotonin type 3 receptors, at 4 mg twice a day for approximately 3 months can significantly reduce the severity of UP in peritoneal dialysis patients with moderate to severe pruritus [116]. This treatment was well tolerated and showed no significant side effects. However, the study by Ashmore *et al*. failed to show any significant change in the pruritus scores in patients treated with ondansetron in comparison with the

Gabapentin, a γ-aminobutyric acid analog, is a potent anticonvulsant drug that was has been clearly demonstrated as effective in the treatment of neuropathic pain, especially diabetic neuropathy. Considering that neuropathic pain and pruritus share common pathogenic

the evaluation of adverse events demonstrated that nalfurafine was well tolerated.

**6.1. Opioid Antagonists**

28 Updates in Hemodialysis

Despite the fact that histamine might be implicated in the pathogenesis of UP and the dem‐ onstration of elevated histamine levels in patients with ESRD with pruritus [91,121], classical antihistamines showed very limited efficacy in the treatment of UP [53,54,94,121]. The response to the administration of antihistaminic agents is marginal, at best [9]. Mast cell stabilizers including ketotifen, 2-4 mg per day for 8 weeks, [55] and cromolyn sodium [55], however, were demonstrated to be effective in case series.

#### **6.6. Long Chain Fatty Acids**

Abnormalities in the plasma composition of essential fatty acids may be related to the etiology of pruritus in patients undergoing hemodialysis. After administration of 6 grams of ethyl ester of either fish oil, olive oil or safflower oil in double-blind study of 25 hemodialysis patients, the results indicated that pruritus was significantly improved due to the altered plasma fatty acid profile and increased prostaglandin E2 (PGE2) plasma concentration [122]. Another study indicated that the improvement in pruritus was due to an increase in PGE1 plasma levels [123] after administration of γ-linoleic acid-rich evening primrose oil 2 grams per day for 6 weeks.

### **6.7. Lidocaine and Mexiletine**

Parenteral administration of lidocaine, a membrane-stabilizing antiarrhythmic agent, can relieve pruritus in double-blind study however, significant side effects such as hypotension and grand mal seizures were found [124]. An oral dosage form of mexiletine, a longer half-life and less toxicity than lidocaine, was found to be ineffective for the treatment of UP [125].

#### **6.8. Low Protein Diet**

Low protein diet has been proposed for the treatment of UP due to the rational of less accumulation of renally excreted pruritogen [126]. However, low protein diet may lead to malnutrition which can be dangerous in CKD patients and detoxification showed no benefit on pruritus [2].

### **6.9. Oral Activated Charcoal**

With the rationale of adsorbing an unidentified pruritogen, oral activated charcoal at the dose of 6 grams per day has been used for uremic pruritus. A double-blind crossover trial and a single-blind study have yielded impressive results [127,128]. This preparation is effective, inexpensive, and has a favorable side effect profile. However, this treatment has not yet been accepted and utilized in clinical practice [127,128].

#### **6.10. Cholestyramine**

The success of cholestyramine in treating PU is inconsistent. When administered at a dose of 5 grams twice a day, the gastrointestinal side effects are normally found. Moreover, the risk of acidosis must also be taken into consideration, particularly in patients who are not on dialysis [128,129].

#### **6.11. Heparin**

Patients on hemodialysis may develop pruritus when treated with porcine or bovine heparin. Pruritus is relieved promptly when another form of heparin is used, implying that these heparins act as allergens [9]. Paradoxically, administration of heparin at 75- 100 mg twice a day for 2-3 weeks can improve UP in some dialysis patients [130]. From the mechanism of action by inhibition of T-lymphocyte heparanase activity which is an important factor for Tcell migration to target tissues, low molecular weight heparin such as enoxaparin at low dose is effective in treating pruritus associated with lichen planus [2,131].

#### **6.12. Thalidomide**

Thalidomide is a relatively selective inhibitor of TNF-α production. The study indicated that thalidomide at 100 mg per day administered for 1 week can significantly reduce the intensity of pruritus by up to 80% in more than half of the subjects, suggesting a potential role for this agent in the treatment of persistent UP [132].

#### **6.13. Nicergoline**

Nicergoline is a dopamine receptor agonist and a partial α-adrenergic blocker related to ergot alkaloids. A double-blind, placebo-controlled study that investigated the effect of 30 mg per day by mouth and 5 mg per day intravenously during dialysis, indicated relief of pruritus in most patients, and the effect lasted for 24- 48 h with improvement persistent in long-term therapy (30 mg per day) in most patients who responded to the initial treatment [133].

#### **6.14. Nicotinamide**

Nicotinamide is the pyridine-3-carboxylic acid amide of niacin, a component of the vitamin B complex. Namazi *et al*. suggested 3 mechanisms through which nicotinamide can be effective in treating UP: the anti-inflammatory effect through the inhibition of the expression of major histocompatibility complex (MHC)-II and the production of IL- 12, TNF-α and IL-1; the inhibition of cyclic adenosine monophosphate (cAMP) phosphodiesterase and stabilization of mast cells and leukocytes and hence, blocking histamine release; and the increase of the biosynthesis of ceramides by keratinocytes with the resultant alleviation of xerosis [134]. For those reasons, nicotinamide could be an effective treatment for UP. However, clinical trials should be conducted to confirm its efficacy.
