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Saudi Journal of Kidney Diseases and Transplantation
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Year : 2013  |  Volume : 24  |  Issue : 5  |  Page : 995-999
Therapeutic effect of oral nicotinamide on refractory uremic pruritus: A randomized, double-blind study


1 Department of Dermatology, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
2 Department of Nursing and Midwifery, Jundishapur University of Medical Sciences, Ahvaz, Iran
3 Department of Internal Medicine, Faculty of Medicine, Jundishapur University of Medical Sciences, Ahvaz, Iran
4 Department of Epidemiology and Biostatistics, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
5 Department of Dermatology and Mathematics, Islamic Azad University of Ardebil, Ardebil, Iran
6 Skin and Stem Cell Reasearch Center, Tehran University of Medical Sciences, Tehran, Iran

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Date of Web Publication12-Sep-2013
 

   Abstract 

To determine the efficacy of oral nicotinamide with placebo to ameliorate uremic pruritus (UP), we conducted a prospective, randomized, double-blind, 4-week study in 50 chronic kidney disease patients with refractory UP. The patients were randomly allocated to nicotinamide tablet 500 mg twice/day or placebo. All anti-pruritic agents were discontinued at least two weeks before the study. All the patients completed the period of the study and their severity of pruritus was evaluated before the start of the study and at the end of each week for four weeks by using a traditional Visual Analogue Scale and a modified questionnaire method (pruritus score). The average pruritus score before administration of oral nicotinamide in the study group and that in the placebo group was 2.96 ± 0.45 and 2.72 ± 0.37, respectively. In the nicotinamide group, the average score of pruritus gradually reduced to 1.29 ± 1.08 and in the placebo group it gradually decreased to 1.52 ± 1.61 at the end of the fourth week. There was no significant difference between the reductions of pruritus in both groups, but the interaction effect using a linear mixed model was significant between drug and time (P <0.026). We conclude that increasing the time of application of nicotinamide sodium to more than four weeks may be more effective than placebo in reducing itching in uremic patients.

How to cite this article:
Omidian M, Khazanee A, Yaghoobi R, Ghorbani AR, Pazyar N, Beladimousavi SS, Ghadimi M, Mohebbipour A, Feily A. Therapeutic effect of oral nicotinamide on refractory uremic pruritus: A randomized, double-blind study. Saudi J Kidney Dis Transpl 2013;24:995-9

How to cite this URL:
Omidian M, Khazanee A, Yaghoobi R, Ghorbani AR, Pazyar N, Beladimousavi SS, Ghadimi M, Mohebbipour A, Feily A. Therapeutic effect of oral nicotinamide on refractory uremic pruritus: A randomized, double-blind study. Saudi J Kidney Dis Transpl [serial online] 2013 [cited 2019 Nov 14];24:995-9. Available from: http://www.sjkdt.org/text.asp?2013/24/5/995/118070

   Introduction Top


During the last decades, a large number of substances were considered to be etiologic factors of uremic pruritus (UP), and a large number of therapeutic substances appeared with promising potentials and conflicting results in the course of their use, [1] mostly due to the lack of sound evidence on the pathogenic mechanisms that may potentiate UP. [1] Some of the probable mechanisms in uremic itching include xerosis, [2] hypervitaminosis A, an increase in the number of skin mast cells, [4] , [5] immunologic impairment, [6] hyperparathyroidism [5] , [7] and an increase of blood urea nitrogen [8] and substance P. [9]

Nicotinamide, also known as niacinamide and nicotinic acid amide, is the amide of nicotinic acid (vitamin B3/niacin), and it is a member of the vitamin B family. Nicotinamide has anti-inflammatory action but no side-effects of the nicotinic acid such as vasodilation or flushing, and it is considered generally safe as a food additive or as a component in cosmetics and medications. [10]

Nicotinamide has been used in dermatology for more than 40 years for a diverse range of conditions, including acne, rosacea, autoimmune bullous dermatoses, photo-aging and photo-immunosuppression. Nicotinamide plays a significant role in DNA repair, maintenance of genomic stability and cellular response to injury, including inflammation and apoptosis. This explains the use of nicotinamide for inflammatory dermatoses and photoprotection. [11]

Nicotinamide has been shown to be capable of inhibition of the expression of MHC-II and the production of IL-12, TNF-α and IL-1. [12] It has been shown to be a potent stabilizer of mast cells and leukocytes hence exerting considerable histamine-release blocking activity and increasing the biosynthesis of ceramide by keratinocytes. [12]

The aim of our study was to evaluate the efficacy and of the nicotinamide efficacy of ameliorating the UP in a placebo-controlled and randomized clinical trial in uremic patients on hemodialysis (HD).


   Patients and Methods Top


We studied 50 patients with end-stage renal disease on HD with complaint of pruritus resistant to conventional therapy. These patients were recruited from the Department of Kidney Disease, Jundishapur University of Medical Sciences, Ahvaz, Iran from June 2011 to July 2011. The inclusion criteria were: (1) known cases of end-stage renal disease patients treated with HD, (2) ages between 18 and 60 years, (3) at least six weeks history of pruritus and (4) no systemic or topical treatment for the pruritus.

The exclusion criteria were: (1) a known hypersensitivity to nicotinamide, (2) suffering from other known skin diseases, liver disorders, metabolic disorders any other condition except for chronic kidney disease (CKD) causing pruritus, (3) any serious systemic diseases, (4) usage of antihistamines or other anti-pruritus drugs in the last three months and (5) pregnant females and breast-feeding mothers. The study was approved by the Ethics Committee of the Faculty of Medicine before starting the trial, and all patients signed written informed consents for the study.

All the patients were on three-times per week HD and none of them had any change in the HD prescription during the study period.

We designed a randomized, comparative, doubled-blind study of nicotinamide versus placebo. Randomization was performed by using a simple random table and the study patients were randomly allocated to one of the two arms of the study: Study group (oral nicotinamide 500 mg two times a day) for four weeks or control group (placebo) for four weeks. The placebo was formulated by a pharmacist to have similar base with the drug but not containing the active ingredient.

The used medications were not revealed to the treating physicians. The patients were instructed to take the medication two times a day for four weeks and were prohibited from using any other treatments for pruritus during the study, but they were allowed to use their other routine medications, e.g. antihypertensive agents. Each patient was encountered five times in total, one time at the beginning of the treatment and weekly for one month. At each visit, the patients were oriented as to how to interpret their pruritus based on Visual Analogue Scale (VAS) numbers from 0 to 5 (0: No pruritus and 5: The worst pruritus). The patients were then asked to indicate their pruritus level based on the VAS and to report any side-effects. Dialysis adequacy was equal in both groups and the KT/V ratio was 1.2- 1.4.


   Statistical Analysis Top


Results of this study were analyzed using SPSS software version 17. The reduction of the score of patients' pruritus based on the VAS in the oral nicotinamide group was compared with that of the placebo group. Descriptive statistics and graphics were used in data analysis and the independent T-test was used to determine differences in both treatment groups.

The linear mixed model was used to evaluate the correlation between the measured times for each individual, and it was used for both groups of patients. A P-value of <0.05 was considered statistically significant.


   Results Top


All the patients but one completed the study course of four weeks. The patients' mean age was 49.6 ± 12.7 years (ranged from 18-60 years). The average dialysis time before treatment was 44 months. At the beginning of the study, the treatment groups were not significantly different with respect to age, weight, duration of disease before treatment, male- female ratio and number of dialysis sessions in weeks, besides blood levels of urea, creatinine and hemoglobin. Twenty-four patients in the nicotinamide group and 25 patients in the placebo group were evaluated for efficacy. The average pruritus score before administration of the drug in the nicotinamide and placebo groups was 2.96 ± 0.42 and 2.72 ± 0.41, respectively. In the nicotinamide group, the average score of pruritus gradually reduced to 1.29 ± 0.22 at the end of week 4 of the study. Notably, the reduction of pruritus in these consecutive weeks was statistically significant in all weeks (P <0.03). In the placebo group, the average score of pruritus was 2.72 ± 0.41 before the administration of the placebo, and gradually decreased to 1.52 ± 0.23 at the end of week 4 of the study. Interestingly, the decline was also statistically significant just in the second week of the study (P <0.01).

The method of repeated measurement analysis indicated that there was no significant difference between the reduction of pruritus in the nicotinamide and the placebo groups in the study [Table 1]. However, the interaction effect using the linear mixed model was significant between drug and time (P = 0.026) [Table 2]. Overall, patients' compliance of both tablets was good. There were no side-effects reported by the patients in any of the groups.
Table 1: Comparison of the efficacy of oral nicotinamide (based on VAS) with placebo in this 4-week study.

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Table 2: Results of the linear mixed model for itching.

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   Discussion Top


UP is one of the most disabling symptoms in CKD that affects up to 50% of the patients on dialysis. [13],[14] UP can cause discomfort, skin damage, sleeping disorders and diminished quality of life.

Pathophysiology of pruritus in CKD is not clearly understood. Autoimmune reactions, ure-mic skin, mast cell proliferation, atrophy of adipose cells, secondary hyperparathyroidism, skin pH changes, electrolyte imbalances, anemia, peripheral neuropathy, hypervitaminosis A and high concentration of bile acids [15] have been suggested as causes of pruritus in these patients. Considering the wide variety of the probable causes of pruritus in HD patients, [16] several treatments such as erythropoietin, [17] gabapentin, [16] skin moisturizing creams [11] and ultraviolet light [18] have been suggested, but none of these treatments is known as the treatment of choice for this condition. It has been shown that the skin of CKD patients with pruritus has a greater number of mast cells [4],[11] and also increased plasma histamine levels compared with those without pruritus. [19] It is noteworthy that in patients with UP, Th1 predominance recruits and activates inflammatory leucocytes. In contrast, T helper 2 (Th2) cells secrete anti-inflammatory cytokines and, in this subset, the cytokine pattern is associated with antibody and allergic responses. [20] Namazi et al [2] proposed, according to the anti-inflammatory and Th1 to Th2 switching effects of nicotinamide, and the anti-xerosis and mast-cell stabilizing effects of this agent, that it could be an effective treatment against UP, [2] but until now no study has been performed to prove this hypothesis.

In our study, there was no significant difference between reduction of pruritus in the nicotinamide and placebo groups, but the interaction effect using a linear mixed model was significant between the drug and the time (P = 0.026). Our study was limited for four weeks and, probably, a longer study duration would show a difference in the effect for nicotinamide than the effect of placebo in reducing UP. Accordingly, we believe that given the safety and eventual effectiveness of oral nicotinamide, it can still be regarded as a potential therapeutic option in the treatment of UP, and we suggest a study of a longer duration and in a larger population to assess this hypothesis.

 
   References Top

1.Chen YC, Chiu WT, Wu MS. Therapeutic effect of topical gamma-linolenic acid on refractory uremic pruritus. Am J Kidney Dis 2006;48:69-76.  Back to cited text no. 1
[PUBMED]    
2.Namazi MR, Fallahzadeh MK, Roozbeh J. Nicotinamide as a potential novel addition to the Anti-uremic pruritus weaponry. Saudi J Kidney Dis Transpl 2009;20:291-2.  Back to cited text no. 2
[PUBMED]  Medknow Journal  
3.Kosmadakis GC, Zerefos N. Uremic pruritus. Int J Artif Organs 2006;29:938-43.  Back to cited text no. 3
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4.Szepietowski JC, Balaskas E, Taube KM, Taberly A, Dupuy P. Quality of life in patients with uraemicxerosis and pruritus. Acta Derm Venereol 2011;91:313-7.  Back to cited text no. 4
    
5.Coriæ-Martinoviæ V, Basiæ-Jukiæ N. Uremic pruritus. Acta Med Croatica 2008;62 Suppl 1:32-6.  Back to cited text no. 5
    
6.Greaves MW. Pathogenesis and treatment of pruritus. Curr Allergy Asthma Rep 2010;10: 236-42.  Back to cited text no. 6
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7.Lugon JR. Uremic pruritus: A review. Hemodial Int 2005;9:180-8.  Back to cited text no. 7
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8.Pauli-Magnus C, Klumpp S, Alscher DM, Kuhlmann U, Mettang T. Short-term efficacy of tacrolimus ointment in severe uremic pruritus. Perit Dial Int 2000;20:802-3.  Back to cited text no. 8
    
9.Narita I, Iguchi S, Omori K, Gejyo F. Uremic pruritus in chronic hemodialysis patients. J Nephrol 2008;21:161-5.  Back to cited text no. 9
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10.Narita I, Alchi B, Omori K, et al. Etiology and prognostic significance of severe uremic pruritus in chronic hemodialysis patients. Kidney Int 2006;69:1626-32.  Back to cited text no. 10
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11.Cho YL, Liu HN, Huang TP, Tarng DC. Uremic pruritus: Roles of parathyroid hormone and substance P. J Am Acad Dermatol 1997; 36:538-43.  Back to cited text no. 11
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12.Namazi MR. Nicotinamide: a potential addition to the anti-psoriatic weaponry. FASEB J 2003; 17(11):1377-9.  Back to cited text no. 12
    
13.Rosner MH. Cromolyn sodium: A potential therapy for uremic pruritus? Hemodial Int 2006;10:189-92.  Back to cited text no. 13
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14.Stockenhuber F, Sunder-Plassmann G, Balcke P. Increased plasma histamine levels in chronic renal failure. N Engl J Med 1987;317:386.  Back to cited text no. 14
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15.Mettang T, Fritz P, Weber J, Machleidt C, Hübel E, Kuhlmann U. Uremic pruritus in patients on hemodialysis or continuous ambulatory peritoneal dialysis (CAPD). The role of plasma histamine and skin mast cells. Clin Nephrol 1990;34:136-41.  Back to cited text no. 15
    
16.ghorbani AR, Feily A, Khalili A, Dormanesh B. Lack of efficacy of topical calcineurin inhibitor pimecrolimus 1% on pruritus of severely uremic patients: A randomized double-blind study in 60 patients. Dermatitis 2011;22:167-8.  Back to cited text no. 16
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17.Leslie RB, John D. Cutaneous manifestations of-end-stage renal disease. Dermatology 2000;43:975-90.  Back to cited text no. 17
    
18.Razeghi E, Eskandari D, Ganji MR, Meysamie AP, Togha M, Khashayar P. Gabapentin and uremic pruritus in hemodialysis patients. Renal Fail 2009;31:85-90.  Back to cited text no. 18
    
19.Vessal G, Sagheb MM, Shilian S, Jafari P, Samani SM. Effect of oral cromolyn sodium on CKD-associated pruritus and serum tryptase level: A double-blind placebo-controlled study. Nephrol Dial Transplant 2010;25:1541-7.  Back to cited text no. 19
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20.Abbas AK, Murphy KM, Sher A. Functional diversity of helper T lymphocytes. Nature 1996;383:787-93.  Back to cited text no. 20
[PUBMED]    

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Correspondence Address:
Amir Feily
Skin and Stem Cell Research Center, Tehran University of Medical Sciences, Tehran
Iran
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DOI: 10.4103/1319-2442.118070

PMID: 24029269

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