Gabapentin therapy for pruritus in haemodialysis patients: a randomized, placebo-controlled, double-blind trial

Ali Ihsan Gunal 2 3 Goksel Ozalp 2 3 Tahir Kurtulus Yoldas 1 2 Servin Yesil Gunal 0 2 Ercan Kirciman 2 3 Huseyin Celiker 2 3 0 Department of Biochemistry , F 1 Department of Neurology 2 U niversitesi Tp Fak u ltesi, Nefroloji Bilim Dal , 23200 Elaz g , Turkey 3 Department of Nephrology 4 rat University Medical School , Elazig , Turkey - Background. Uraemic pruritus is a common and distressing symptom in patients on haemodialysis for chronic renal failure. Gabapentin is an anticonvulsant that alleviates neuropathic pain. We conducted a double-blind, placebo-controlled, crossover study to assess its effectiveness against renal itch. Methods. We enrolled in the trial 25 adult patients on haemodialysis who were asked to daily record the severity of their pruritus on a visual analogue scale. The patients were randomly assigned to receive gabapentin for 4 weeks followed by placebo for 4 weeks or the reverse sequence. Gabapentin or placebo were administered thrice weekly, at the end of haemodialysis sessions. Results. The mean pruritus score of the cohort before the study was 8.40.94. After placebo intake, it decreased to 7.62.6 (P 0.098). The score of four patients decreased by >50% following placebo. After gabapentin administration, the mean score decreased significantly, to 1.21.8 (P 0.0001), although one patients symptoms did not improve significantly. No patient dropped out of the study due to adverse effects from gabapentin. Conclusions. Our study shows that gabapentin is safe and effective for treating uraemic pruritus in haemodialysis patients. Our results also support the neuropathic hypothesis of uraemic pruritus. Introduction Uraemic pruritus is commonly experienced by patients suffering from advanced chronic renal failure who already are on renal replacement treatment (haemodialysis or continuous ambulatory peritoneal dialysis). Because of the use of biocompatible haemodialysis membranes and the improvement in haemodialysis efficacy, the incidence of uraemic pruritus has declined over the years, from an estimated 85% in the 1970s and 5060% in the 1980s to a current estimated incidence of 22% [1]. The mechanism of uraemic pruritus is unknown and most treatments are ineffective. Several hypotheses have been proposed to explain the pathogenesis of uraemic pruritus. Its suggested causes include xerosis [2], involvement of the peripheral nervous system [3,4], opioid system involvement [5], mast cells and autacoids (histamine and serotonin), altered divalent ion metabolism, hyperparathyroidism [6] and derangements of the immune system [7]. Currently, there are two major concepts, however, for the pathophysiology of uraemic pruritus, the opioid and the cytokine hypotheses. Gabapentin is a potent anticonvulsant drug with an unknown mechanism of action. Initially approved only for use in controlling seizures, it soon showed promise in the treatment of chronic pain syndromes, especially neuropathic pain [8], and it has been clearly demonstrated to be effective for the treatment of neuropathic pain in diabetic neuropathy. Gabapentin is eliminated primarily through the kidney. Moreover, it is removed by haemodialysis. It has a significantly longer half-life in patients on haemodialysis than in those with normal renal function and, thus, these patients need lower doses at less frequent intervals than patients with normal renal function. The recommended dose for haemodialysis patients is 200300 mg after each haemodialysis session [8]. We use gabapentin for the relief of diabetic neuropathic pain in patients on haemodialysis in our centre. In addition to neuropathic pain, several of our patients have complained of pruritus and after gabapentin treatment, their pruritus has completely improved. Accordingly, we undertook a double-blind, placebo-controlled, crossover trial to assess the effectiveness of gabapentin against renal itch. Subjects and methods From the haemodialysis unit in F|rat University Hospital, we enrolled in the study 25 adult patients (14 men and 11 women; age: 18 years) all of whom were on haemodialysis and eight of whom were diabetic. Haemodialysis was performed for 45 h thrice weekly via a polysulphone dialyser [1.31.6 m2 surface area (Fresenius Medical Care, Bad Homburg, Germany)] using bicarbonate dialysis fluid containing 136 mmol/l Na, 1.5 mmol/l Ca, 0.5 mmol/l Mg, 110 mmol/l Cl, 2 mmol/l acetate and 33 mmol/l bicarbonate. Blood flow and dialysate flow were 250350 and 500 ml/min, respectively. Ultrafiltration was controlled volumetrically in all haemodialysis machines used in this study. All patients had histories of pruritus of >8 weeks duration. Their pruritus was not relieved by antihistamines, nicergoline or moisturizers. None of the patients had concomitant dermatological, liver or metabolic diseases associated with pruritus. Any medication with presumed antipruritic effects was discontinued 1 week before the study. The patients were asked to record the severity of their pruritus on a visual analogue scale once a day. The scale consisted of a 10 cm horizontal line marked from 0 (denoting no itch) to 10 (denoting worst possible imaginable itch). On a random and blinded basis, patients were assigned to receive 4 weeks of gabapentin therapy followed by 4 weeks of placebo or to the reverse sequence (4 weeks of placebo followed by gabapentin for 4 weeks). There was a 1 week washout period between the sequential treatment phases. The daily pruritus scores of patients were collected for each period of the study the 1 week preceding the trial, the active treatment phase, the placebo phase and the intervening washout period. The median of the scores for each period was accepted as the score of that period. Gabapentin 300 mg (Neurontin; Parke-Davis, Goedecke GmbH, Freiburg, Germany) or placebo was administered orally thrice weekly at the end of haemodialysis sessions. A reduction in scores of 50% was considered as the desired improvement in symptoms during treatment. Pre-dialysis blood samples were drawn for haematocrit, serum calcium, phosphate, albumin and parathyroid hormone levels. Dialysis efficacy was calculated using the urea kinetics model and expressed as Kt/Vurea. The differences in mean values were tested by a one-way analysis of variance. The significance of the differences between the groups was calculated by the paired-samples t-test. Statistical significance was assigned to P-values of <0.05. The Ethics Committee of F|rat University Hospital approved the study design. Informed consent was obtained from each patient. All 25 patients completed the study. Their demographic characteristics are listed in Table 1. The mean pruritus score before the study was 8.40.94 (range: 710). After placebo administration, that score decreased to 7.62.6 (range: 210; P 0.098). The scores of four patients decreased by >50% with placebo. These four patients with good response to placebo were not different from other patients with respect to their plas (...truncated)