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Abstract
Itching along with other problems can be one of the factors exacerbating the sufferings and disturbing the comfort of patients with chronic renal failure. The present research aimed to study the effects of omega-3 on the treatment of uremic pruritus in hemodialysis (HD) patients. In this crossover randomized clinical trial study, 52 HD patients with pruritus were evaluated. After the random assignment of the participants to Group 1 (treatment mode A) (omega-3 plus cetirizine) and Group 2 (treatment mode B) (cetirizine), they received the treatments for six weeks and then after one week washout period, treatments were changed between the two groups. The pruritus severity was measured using the Yosipovitch pruritus questionnaire before the intervention and at the end of each treatment period. The obtained data were analyzed using descriptive statistics, analysis of variance with repeated measures, and Pearson correlation coefficient. The results of this study showed that pruritus severity reduced in both groups, but it was more significant in Group 1 (omega-3 plus cetirizine). The study findings indicated that omega-3 is effective in the reduction of uremic pruritus. Therefore, this supplement can be used as a convenient method for reducing pruritus in HD patients.
Introduction 
Chronic renal failure (CRF) is one of the major health problems in the world,[1] which is associated with high rates of pathogenicity and mortality.[2] Uremic pruritus is a common condition in patients with kidney failure undergoing hemodialysis (HD). The mean prevalence of this condition has been reported to be 55% (10%−70%) in various studies.[3],[4] Although no specific etiology has been identified for uremic pruritus, some factors such as skin dryness and eczema, attachment of the histamine to H4 receptor, inadequate dialysis, anemia, iron deficiency, and increased susceptibility to the products used in the HD procedure have been shown to involved in causing pruritus in patients with kidney failure undergoing HD.[5] Pruritus in these patients has a significant relationship with decreased quality of life, sleep disorders, depression, and increased mortality.[6] The European guideline on chronic pruritus defines uremic pruritus as a symptom and not a condition and has specified the symptomatic treatment according to the identified etiologies for uremic pruritus. Antihistamines are the first line of systemic drug treatment for chronic itching.[7]
One of the mechanisms of itching in endstage renal disease (ESRD) patients include increased inflammatory factors, free radicals, B4 leukotriene, and immune system weakness. Considering the effects of omega-3 (fish oil) on the reduction of inflammation, free radicals, and B4 leukotriene and support of the immune system, it has been hypothesized that omega-3 can be effective in treating uremic pruritus.[8] According to the study of Liu et al, with an increase in serum cholesterol and low-density lipoprotein, the risk of uremic pruritus increases[9].
As previously mentioned, the mechanism of itching in HD patients is very complex and many factors are involved in its control and intensification. The important point here is that itching, along with other problems, can be one of the factors exacerbating the suffering and disturbing the comfort of patients with CRF. Hence, the present research aimed to study the effects of omega-3 on the treatment of uremic pruritus in HD patients.
Subjects and Methods Study population
The present research aimed to study the effects of omega-3 on the treatment of uremic pruritus in HD patients. This clinical trial study (IRCT2017040433206N1) was conducted on 52 patients with uremic pruritus referred to the Dialysis Center of Imam Hossein Hospital of Shahroud in 2017. According to the results of Dakhale et al and with the effect of size = 0.4, power = 8%, and alpha = 5%, the sample size was estimated at 47 patients in each group. Considering the loss of samples, the final sample size was 52 in each group.[10]
The inclusion criteria were an age of over 18, no drinking alcohol, being conscious of time, location, and people at the time of data collection, elapse of at least four weeks from the diagnosis of CRF, being under HD for at least two sessions per week, and complaining of chronic itching for at least four weeks. In addition, the exclusion criteria included taking other antipruritic, death of patient during the study, history of skin diseases which may cause itching and is not related to uremic pruritus (based on the diagnosis of a dermatologist), contraindication of antihistamines (visual impairment, glaucoma, enlarged prostate, forgetfulness, neuromuscular diseases), taking any drug that has an anti-itching effect except cetirizine. Receiving medications or treatments, such as topical lubricants and UV rays, which can induce itching, sensitivity to omega-3, and indigestion or any type of digestive problems (e.g. chronic diarrhea for more than 2 weeks).
First, patients with uremic pruritus undergoing HD in dialysis centers affiliated with Shahroud University of Medical Sciences were identified and 52 of them, who met the inclusion criteria, were selected as the sample. After obtaining a written consent form, the participants were randomly assigned to the control and intervention groups.
The required data were collected using a demographics form, laboratory indices, and Yosipovitch pruritus questionnaire. The latter was developed by Yosipovitch et al based on the McGill questionnaire and its reliability and validity are at an acceptable level. This questionnaire measures items such as the history of pruritus, history of taking antipruritic, effects of pruritus on sleep, daily activities, quality of life, and emotional dimensions of pruritus. In addition, this questionnaire investigates pruritus site and severity based on visual analog scale (VAS) in three modes (interview time, worst case, and best case).[11]
The participants were randomly assigned to Groups 1 and 2. After evaluating the pruritus score of patients (Time 0), Group 1 received the treatment mode of A (1 g of omega-3 three times a day and 5 mg of cetirizine three times a week) for six weeks and Group 2 received the treatment mode of B (5 mg of cetirizine three times a week) for six weeks. The pruritus status was again measured after these six weeks (Time 1). Then, after a washout period of one week, groups changed the treatments as follows: Group 1 received the treatment mode of B (5 mg of cetirizine three times a week) and Group 2 received the treatment mode of A (1 g of omega-3 three times a day and 5 mg of cetirizine three times a week) for six weeks. After this period, the pruritus score was measured once again (Time 2). The most common complication after taking fish oil is gastrointestinal disturbances, including nausea which occurs in 4% of the patients in doses of 3 g per day or above.[12] The use of Fish oil in doses of over 3−4 g per day reduces the serum triglyceride concentration to 25%−30%.[13],[14] The used fish oil contained 30% long-chain n- 3 polyunsaturated fatty acids as 1 g capsule that contained 180 mg of eicosapentaenoic acid and 120 mg of docosahexaenoic acid.[15] It is noteworthy that the serum level of calcium, phosphorus, parathyroid hormone (PTH), and hemoglobin was measured during the trial (before the intervention, at the end of the 6th week, and at the end of intervention) in order to ensure that these factors do not interfere with the results. Out of the patients undergoing HD in the Dialysis Center of Imam Hossein Hospital of Shahroud, 52 patients were selected as the sample using the consecutive sampling method. The participants were briefed on the research objectives and procedures and a written consent form was obtained from them. Then, they were assigned to two groups based on a predetermined random pattern of quadruple blocks. Accordingly, 52 series of A and B cards were put in separate pockets and provided to the desired physician. After examining patients and confirming the presence of uremic pruritus, the physician assigned them to one of the A or B groups based on the order of pockets (blind concealment). One patient died and the data of 51 patients were analyzed [Figure 1]. The present research was a crossover randomized clinical trial. The data collector and analyzer were not aware of the interventions of groups A and B until the end of the trial.
Before the beginning of the study, participants were briefed on research objectives and procedure and then a written informed consent form was obtained from them. This study was approved by the Ethics Council of Shahroud University of Medical Sciences (No: IR.SHMU.REC.1395.187). The study was conducted in accordance with the ethical principles regulated by the Declaration of Helsinki and the guidelines of the Iranian Ministry of Health and Medical Education. The obtained data were analyzed using descriptive statistics, analysis of variance with repeated measures, and Pearson correlation coefficient.
Results According to the results, the mean age of patients was 61.34 ± 15.7 and most of them (57.7%) were males. The mean years of education in patients were 7.01. In addition, most of the participants were married (63.5%) and retired (48.1%) [Table 1].
The study results showed that hypertension alone and in combination with diabetes is the cause of CRF in most participants (67.3%). The mean duration of HD in this study was 42.33 ± 24.08. Half of the patients twice a week and the other half three times a week were under HD. In addition, 73.1% and 26.9% of patients experienced itching during the day and at night, respectively.
The results indicated that 75.2% and 24.8% of participants were complaining of general and local pruritus. Half of the participants (50%) experienced a moderate level of pruritus and the other half underwent severe pruritus. The mean severity of pruritus based on VAS was equal to 6.37 ± 0.74. In this study, pruritus severity presented no significant relationship with age, gender, and treatment duration. In the present study, pruritus was more severe at night in most participants (73.1%).
The results of repeated measures ANOVA showed that the mean pruritus score significantly reduced in both groups following the administration of cetirizine and omega-3 plus cetirizine (mean square = 124.78, F = 363.42, P >0.001).There was a significant difference between the two groups in terms of the mean pruritus at Time 1 and Time 2 (P <0.001), as the mean pruritus reduced more significantly in patients treated with omega-3 plus cetirizine [Figure 2].
The results of the Pearson correlation coefficient demonstrated that pruritus in the two groups was significantly correlated with only the serum level of PTH. In addition, the mean PTH level significantly reduced over time in both groups. However, the results showed that the level of PTH had no impact on the mean pruritus of patients [Figures 2 and 3].
Discussion In the present study, half of the participants experienced a moderate level of pruritus and the other half underwent severe pruritus. In the study conducted by Lin et al 51.6% and 34.4% of HD patients experienced moderate and severe levels of pruritus, respectively.[16] Karimi et al also reported patients undergoing HD were complained of severe (51.9%) and moderate levels (19.7%) of pruritus.[17] This is consistent with the findings of the present study.
In this study, the mean score of pruritus based on the VAS scale was 6.37, while it was 3.01 ± 4.86 and 6 at Kavurmaci[4] and Liu et al studies,[9] respectively.
In this study, the mean pruritus did not present a significant relationship with age, gender, and treatment duration. In this regard, the results of Mesic et al suggested no significant relationship between gender and prevalence of pruritus.[18] In a study conducted by Szepietowski and Salomon, no significant relationship was found between age, gender, and the period on HD and uremic pruritus.[19] Akhyani et al also reported that uremic pruritus has no significant relationship with age, gender, HD duration.[20] In addition, Zucker et al observed no significant relationship between the occurrence of pruritus and demographics and medical parameters (underlying diseases and duration of treatment).[21] These results are consistent with the findings of the present study.
In the present study, pruritus was more severe at night in most participants (73.1%). Nakhai et al conducted a study in order to determine and compare the effectiveness of vinegar and oat in the treatment of uremic pruritus and showed that pruritus severity was higher in patients at night.[22] In addition, the results of Lin et al, Yosipovitch et al and Combs et al indicate that patients experience the greatest severity of pruritus at night.[11],[16],[23]
The results of this study demonstrated that pruritus severity has no significant relationship with the serum level of calcium, phosphorus and hemoglobin. In this regard, the findings of Subach and Marx showed that there is no difference between patients with pruritus and without pruritus in terms of laboratory parameters.[24] In Pakfetrat et al’s study, there was a significant correlation between serum calcium and phosphorus levels with severity of itching in HD patients.[25] This difference may be attributed to the difference in the mean duration of treatment with HD in these two studies.
Due to the unknown pathophysiology of uremic pruritus, several therapies have been used to treat this symptom.[26] The present research studied the relieving effects of omega-3 on pruritus. The participants also received the standard treatment (antihistamines). A second-generation antihistamine named cetirizine was in this study. Antihistamines are recommended to be used at night because of their sedative properties. The results of this study showed that the administration of cetirizine is effective in relieving pruritus. Noiri et al studied the therapeutic dose of cetirizine for patients with ESRD and reported that the administration of 5 mg of this drug three times a week is the most effective and safest procedure for these patients.[27]
Antipruritic effects of antihistamines have been confirmed in several studies. For example, Amirkhanlou et al compared the efficiency of gabapentin and ketotifen in the treatment of uremic pruritus in HD patients and reported that gabapentin and ketotifen significantly improved pruritus in HD patients.[28] In a study conducted by Dakhal et al. about the effects of cetirizine and ranitidine and measured variables such as pruritus severity, number of hives, size of hives, and impact of pruritus on sleep quality. After three weeks of drug administration, their results showed that pruritus relief and other parameters improved more in patients treated with cetirizine. However, at the end of the trial (the 6th week), the effects of ranitidine on pruritus relief and other parameters were greater than cetirizine. They concluded that the therapeutic effects of ranitidine on pruritus relief may appear later, but, in general, its effect is greater than cetirizine.[10]
The results of this study showed that the severity of pruritus reduced in both groups, but this reduction was more significant in patients treated with omega-3 plus cetirizine. Ghanei et al reported that omega-3 causes a more significant reduction in symptoms of pruritus than the placebo.[29] In this regard, Panahi et al in a literature review of four small studies reported the potential benefits of omega-3 fatty acids on symptoms of uremic pruritus.[30] In a randomized clinical trial conducted by Begum et al, the effects of fish oil (omega-3) and safflower oil (omega-6) on uremic pruritus were studied and the results showed the reduction of leukotriene B4 in both groups, but the reduction of pruritus severity in patients with omega-3 was more significant than those received omega-6.[8] Fallahzadeh et al reported that the serum level of interleukin 2 in patients with uremic pruritus is significantly higher than patients without pruritus. Reducing pruritus in patients after taking omega-3 can be due to decreased production of leukotriene B413 or reduced effects of interleukin 2.[31]
Conclusion The study findings showed that the severity of pruritus reduced in both groups, but this reduction was more significant in patients treated with omega-3 plus cetirizine. Considering the positive effects of omega-3 on the relief of pruritus in HD patients and because of the side effects of chemical drugs, this supplement can be used as a convenient method for reducing pruritus in HD patients.
In this study, the level of omega-3 fatty acids before and after the intervention was not checked. This is a limitation of this study because fish oil is nutritious in many seafood and can affect the amount of omega-3 consumed by patients. Crossover design can help obtain more accurate results and reduce this limitation.
Acknowledgments The present paper was extracted from a master thesis in nursing which was conducted at Shahroud University of Medical Sciences. This research was approved by this university under the code 9612 and registered in the Iranian clinical trial system with code IRCT2017040433206N1. The authors would like to thank the Deputy of Research and Technology of this university and all staff and patients of the Dialysis Center of Imam Hospital of Shahroud, who helped us in this research. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. The authors declare that they have no conflict of interest. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Conflict of interest: None declared.
References 
Correspondence Address:
Hossein Ebrahimi
Center for Health Related Social and Behavioral Sciences Research, Shahroud University of Medical Sciences, Shahroud, Iran.
Iran
Source of Support: None, Conflict of Interest: None
CheckDOI: 10.4103/1319-2442.352416
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