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  1. 1. This article was downloaded by: [Khashayar, Patricia] On: 12 February 2009 Access details: Access Details: [subscription number 908662672] Publisher Informa Healthcare Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered office: Mortimer House, 37-41 Mortimer Street, London W1T 3JH, UK Renal Failure Publication details, including instructions for authors and subscription information: Gabapentin and Uremic Pruritus in Hemodialysis Patients Effat Razeghi a; Delaram Eskandari b; Mohammad Reza Ganji c; Ali Pasha Meysamie d; Mansooreh Togha e; Patricia Khashayar f a Internal Diseases Department (Nephrology), Sina Hospital, Urology Research Center, Tehran University of Medical Sciences, Tehran, Iran b Internal Diseases Department, Imam Hospital, Garmsar, Iran c Internal Diseases Department (Nephrology), Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran d Community Medicine, Tehran University of Medical Sciences, Tehran, Iran e Department of Neurology, Sina Hospital, Tehran University of Medical Sciences, Tehran, Iran f Research and Development Center, Sina Hospital, Tehran University of Medical Sciences, Tehran, Iran Online Publication Date: 01 February 2009 To cite this Article Razeghi, Effat, Eskandari, Delaram, Ganji, Mohammad Reza, Meysamie, Ali Pasha, Togha, Mansooreh and Khashayar, Patricia(2009)'Gabapentin and Uremic Pruritus in Hemodialysis Patients',Renal Failure,31:2,85 — 90 To link to this Article: DOI: 10.1080/08860220802595476 URL: PLEASE SCROLL DOWN FOR ARTICLE Full terms and conditions of use: This article may be used for research, teaching and private study purposes. Any substantial or systematic reproduction, re-distribution, re-selling, loan or sub-licensing, systematic supply or distribution in any form to anyone is expressly forbidden. The publisher does not give any warranty express or implied or make any representation that the contents will be complete or accurate or up to date. The accuracy of any instructions, formulae and drug doses should be independently verified with primary sources. The publisher shall not be liable for any loss, actions, claims, proceedings, demand or costs or damages whatsoever or howsoever caused arising directly or indirectly in connection with or arising out of the use of this material.
  2. 2. Renal Failure, 31:85–90, 2009 Copyright © Informa Healthcare USA, Inc. ISSN: 0886-022X print / 1525-6049 online DOI: 10.1080/08860220802595476 CLINICAL STUDY LRNF Gabapentin and Uremic Pruritus in Hemodialysis Patients Effat Razeghi Gabapentin and Uremic Pruritus in Hemodialysis Patients Internal Diseases Department (Nephrology), Sina Hospital, Urology Research Center, Tehran University of Medical Sciences, Tehran, Iran Delaram Eskandari Internal Diseases Department, Imam Hospital, Garmsar, Iran Mohammad Reza Ganji Internal Diseases Department (Nephrology), Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran Ali Pasha Meysamie Downloaded By: [Khashayar, Patricia] At: 08:39 12 February 2009 Community Medicine, Tehran University of Medical Sciences, Tehran, Iran Mansooreh Togha Department of Neurology, Sina Hospital, Tehran University of Medical Sciences, Tehran, Iran Patricia Khashayar Research and Development Center, Sina Hospital, Tehran University of Medical Sciences, Tehran, Iran periods, respectively. No significant correlation was found Background. Pruritus is a common and bothersome between age, sex, duration of dialysis, underlying diseases, and problem in 30–50% of hemodialysis patients. The aim of this systolic and diastolic blood pressures and the gabapentin study was to determine the effect of gabapentin, 100 mg/three effect. Conclusion. Gabapentin is an effective agent in treating times a week (after each hemodialysis session), on uremic uremic pruritus. pruritus. Study design. Patients older than 18 years who had undergone hemodialysis for more than three months were Keywords gabapentin, hemodialysis, pruritus enrolled in this double-blind clinical trial. They had experienced pruritus refractory to antihistamines for at least two weeks. The patients were assigned to receive gabapentin 100 mg following hemodialysis for a period of four weeks, and after a washout INTRODUCTION week, they received the placebo for another four weeks. They were asked to evaluate the severity of their pruritus using a visual Uremic pruritus is a troubling dermal disorder, sec- analogue scale (VAS). The reduction of pruritus ≥ 50% was ondary to chronic and progressive renal failure; it disturbs accepted as the response. Results. The mean pruritus score patients’ sleep and reduces their quality of life.[1,2] More reached 6.44 ± 8.4 (p < 0.0001), 15 ± 11.2 (p < 0.001), and 81.11 than half of dialysis patients (hemodialysis or peritoneal ± 11.07 (p < 0.001) during gabapentin, washout, and placebo dialysis) and about 30% of the patients with acute and chronic renal failure who do not undergo hemodialysis Received 25 July 2008; revised 24 September 2008; accepted complain about pruritus to some degree.[3] 11 October 2008. Pruritus may have peripheral (dermal or neuropathic), Address correspondence to Effat Razeghi, MD, Sina Hospital, central (neuropathic, neurological, or psychogenic), or Urology Research Center, P.O. Box: 11367-46911, Imam Khomeini mixed origins. Uremic pruritus is classified as mixed, and St., Tehran, Iran; Tel.: +98-21-66716546; Fax: +98-21-66716546; various hypotheses have been formed for justifying its E-mail: pathogens; accordingly, several treatments with different 85
  3. 3. 86 E. Razeghi et al. results were suggested based on the hypotheses. However, where K is the dialyzer blood water urea clearance in L per none of the treatments managed to cure the very disabling hour, t is dialysis session length in hours, and V is the dis- complication.[4,5] tribution volume of urea in liters), and other laboratory Gabapentin is an anti-convulsion drug, similar to parameters including Ca, P, Alb, and ipTH were measured GABA transmitter in its structure. The effectiveness of at four intervals (i.e., one week prior to the treatment, the gabapentin in controlling convulsions is confirmed by drug administration phase, and the washed out, and pla- many studies; it has also been demonstrated to be effective cebo phases). All samples were taken from the patients in treating chronic neuropathic diseases. The suggested before undergoing hemodialysis. dose for stabilizing the serum level of hemodialysis A technician unaware of the phase the patients were patients is 200–300 mg following each session of hemodi- in asked them to define the severity of pruritus and the alysis; doses equal to 100 mg, however, are also proposed, effectiveness of the drug. The median score of pruritus in aiming at reducing the risk of developing neurotoxicity.[6–8] each interval was considered as the accepted score of pru- Recent studies have suggested that the effectiveness ritus in that period, and the reduction of pruritus for more of gabapentin on uremic pruritus by affecting the neural than 50% was accepted as the positive response. calcium channels.[9,10] There are not many studies assessing the effect of gaba- pentin 100 mg on uremic pruritus. As a result, the purpose RESULTS of the present study was to examine the effect of gabapentin 100 mg on uremic pruritus of hemodialysis patients. Thirty-four ESRD patients undergoing hemodialysis Downloaded By: [Khashayar, Patricia] At: 08:39 12 February 2009 were enrolled in this study. There were 8 male (23%) and 26 female (77%) patients. The mean age of the patients MATERIALS AND METHODS was 58.4± 12.5 years ranging between 28 and 73 years. The underlying diseases leading to ESRD in these patients This double blind clinical trial was conducted in three are outlined in Table 1. hemodialysis centers of Tehran in 2006. Patients with a Two of the patients discontinued the treatment and minimum age of 18 and minimum ESRD duration of three were excluded from the study due to representing the months, suffering from pruritus for at least two weeks, drug’s side effects (e.g., fatigue, dizziness, and drowsi- were enrolled in this study. They underwent hemodialysis ness). Another patient withdrew from the study, as he did three times a week for four hours. They had previous not show any improvement within 10 days after the start attempts of using antihistamines and moisturizers, neither of the study. Six other patients were also excluded because of which was reported to be useful. of not being cooperative (i.e., poor compliance to the The patients had normal hepatic function, and there drug). In other words, the complication and no-response were no specific underlying diseases intervening with the rate was calculated to be 8.8% (CI 95% = 0–18.4%). study. Those with skin lesions, metabolic diseases (pro- All patients underwent a complete neurological exam ducing pruritus), drug allergies, and noncompliant cases before initiating the treatment; 24 out of the 25 patients were excluded from the study. who completed the study had a positive neurological After the institutional committee board’s approval, exam. All of these 24 cases had signs of distal symmetric informed consent was obtained from all patients. They polyneuropathy. Hyporeflexia to areflexia was reported in were asked to quit using anti-pruritus drugs one week prior 23 cases. Stocking-glove pattern of hypoesthesia was to the study. reported in all of the 24 studied cases, 20 of which had Subsequently, all of the patients underwent a com- abnormal response in position and vibration tests. Twelve plete neurological examination. The patients were trained to evaluate the severity of their pruritus using a 100 mm visual analogue scale (VAS). Results between 0–25 were Table 1 considered as low, 25–50 as moderate, 50–75 as high, and The frequency of the underlying diseases leading to 75–100 as severe. ESRD The patients were given gabapentin 100 mg following Underlying disease Number Percentage (%) each session of hemodialysis for four weeks at the begin- ning of the study. They then received the placebo for DM 9 36% another four weeks. One week was considered the wash- HTN 6 24% out period between the two treatment phases. Idiopathic 4 16% Blood pressure, Kt/V (i.e., the volume of plasma Others 3 12% cleared [Kt] divided by the urea distribution volume [V], DM+HTN 3 12%
  4. 4. Gabapentin and Uremic Pruritus in Hemodialysis Patients 87 cases had distal motor weakness. Proximal weakness was reported in neither of the cases. Moreover, carpal tunnel syndrome was also reported in one of the cases. All of the cases eligible for receiving the intervention had the pruritus score of 100 at the beginning of the study. Following the prescription of gabapentin, the score reached 6.44 ± 8.46 (p < 0.001). The mean pruritus score returned to 15 ± 11.27 (p < 0.001) following the one-week washout period. After administering the placebo, the pruri- tus score was calculated to be 81.88 ± 11.06 (p < 0.001). The pruritus score of the patients during the study period is presented in Figures 1–3 The mean score of pruritus at the end of gabapentin therapy, washout period, and placebo therapy were 6.44 ± 8.46 (p < 0.001), 15 ± 11.27 (p < 0.001), and 81.88 ± Figure 1. The daily mean pruritus score in gabapentin therapy 11.06 (p < 0.001), respectively. There was no meaningful phase. relationship between age, gender, the duration of dialysis, the underlying disease leading to ESRD, and KTV and the mean score of pruritus in the three phases of the study. Downloaded By: [Khashayar, Patricia] At: 08:39 12 February 2009 In the placebo phase, the mean score of pruritus was lower than the score prior to intervention. The mean score of pruritus in the three phases of gabapentin therapy, washout, and placebo was not corre- lated with the mean albumin serum (p = 0.84, Pearson cor- relation = 0.4). Moreover, the mean CRP in the three phases was not correlated with the mean score of pruritus (p = 0.42; Pearson correlation = 0.166). Some patients claimed that their pruritus was recov- ered following the treatment of hyperphosphatemia; how- ever, despite the high serum levels of phosphate at the beginning of the study (6.24 ± 2.31), there was no correla- tion between pruritus and the serum phosphate level. It should be noted that these patients were often treated in order to lower the phosphate level; this treatment did not Figure 2. The daily mean pruritus score in placebo phase. influence the results of our study. There was no significant relationship between the patients’ age, sex, duration of dialysis, underlying diseases, hemoglobin, Ca, P, Alb, P, ipTH, CRP, systolic and diastolic blood pressures, Kt/V, and the severity of pruritus in the three phases of gabapentin therapy, washout, and placebo therapy. The results are demonstrated in Tables 2 and 3. Complications secondary to drug use was reported in two of the total 34 patients enrolled in this study. The compli- cations were limited to dizziness, drowsiness, and unspecified fatigue; however, because the complications emerged by the administration of the drug and disappeared by discontinuing it, the two cases were ethically excluded from the study. DISCUSSION Figure 3. The daily mean pruritus score evaluated by the The etiology and pathogens of uremic pruritus is patients in the three phases of the study (i.e., gabapentin therapy, not clearly known. Neurological hypothesis,[11,12] the washed out, and placebo).
  5. 5. 88 E. Razeghi et al. Table 2 Variations of the laboratory variables in different intervention phases Time of measurement Before starting the End of Gabapentin End of washed-out End of placebo Variable treatment (phase 0) therapy (phase 1) phase phase Hb 10.6 ± 1.8 11.1 ± 1.7 10.1 ± 2.6 10.6 ± 1.7 Ca 9.5 ± 2.5 9.2 ± 0.9 9.38 ± 1.1 8.9 ± 2.8 P 6.24 ± 2.31 6.46 ± 2.24 6.78 ± 2.8 6.4 ± 2.4 Alb 4.25 ± 0.6 4.01 ± 0.3 5.45 ± 7.2 4.14 ± 0.5 iPTH 111.12 ± 103 115.57 ± 115.3 120.9 ± 115.5 147.68 ± 179 CRP 11023.3 ± 16630 15354 ± 20077 11249.1 ± 12040 14120.4 ± 16576 Kt/V 1.31 ± 0.2 1.32 ± 0.2 1.35 ± 0.17 1.35 ± 0.17 Table 3 increased sensitivity to itching stimuli. An abnormal ener- The correlation between the variables and their responsiveness to vation is pointed out in hemodialysis patients. the treatment (reduction in pruritus) In the present study, all patients were neurologically Downloaded By: [Khashayar, Patricia] At: 08:39 12 February 2009 examined to compare the treatment results regarding neur- Mean (at the opathy findings; but as 24 of the 25 studied patients were beginning Pearson Variable of the study) correlation p value* reported to have nearly similar evidences of neurological problems, further comparison was not performed. The Age 58.44 ± 12.5 −0.37 0.64 aforementioned evaluation was not conducted in previous Median dialysis 50 months 0.15 0.4 studies. duration (25–75) (19.5–36.5) Similar to the previous studies,[21,22] there was no sig- Kt/V 1.31 ± 0.21 0.1 0.61 nificant correlation between pruritus and the demographic SBP 113.3 ± 14.1 −0.21 0.3 factors, Kt/V, the duration of dialysis, and the type of renal DBP 66 ± −7.7 −0.21 0.29 dysfunction in the present study. Hb 10.6 ± 1.8 0.28 0.16 Ca 9.5 ± 2.5 −0.22 0.91 The results of the present study support the findings P 6.24 ± 2.31 −0.14 0.48 of a similar study conducted by Maneti et al. in 2005.[10] In Alb 4.25 ± 0.6 0.4 0.84 another study carried out on 25 hemodialysis patients, iPTH 111.12 ± 103 0.13 0.52 Gunal et al.[9] showed that the mean score of pruritus in CRP 11023.3 ± 16630 0.166 0.42 the gabapentin phase was significantly different from that of the placebo phase. *Fisher’s z transformation. We evaluated the relationship of pruritus with inflam- matory parameters, albumin as a negative phase protein and CRP as a positive phase protein. Unlike Virga’s study,[23] no relation was found between the mean score of intervention of the opioid system,[13,14] the transformed pruritus in the three phases of gabapentin therapy, wash- metabolism of bi-valence ions,[15–17] hyperparathyroid- out, and placebo and the mean serum albumin level in the ism,[18,19] and the increase of mast cells and etacoids[18,20] current study. It can be concluded that albumin is influ- are the most important mechanisms raised. enced by non-inflammatory factors, including nutritional Neuropathy is prevalent among uremic patients. More status as well as the inflammatory factors.[24] In other than 65% of the patients with renal failure represent a words, according to that very fact and albumins’ relatively peripheral nervous disorder,[9] confirming a possible link long half-life, albumin cannot be considered as a proper between the neurologic origins of uremic pruritus. criterion for evaluating inflammation. Conduction disorder in sensory-motor pathways is It is noteworthy that the mean CRP in the three phases one of the most prevalent representations in the initial was not correlated with the mean score of pruritus. This stages of uremia; it is characterized by paresthesia, prick- was similar to the findings of Virga et al.[23] ing of the feet, and uneasy foot syndrome.[9] Several previous studies had considered the resistant Pruritus may also be secondary to a reduction in the and disabling pruritus as a representing sign of hyperthy- perception threshold. Nerve root damage may lead to an roidism[20,21]; however, many others—including the
  6. 6. Gabapentin and Uremic Pruritus in Hemodialysis Patients 89 present study—were unable to find any correlation REFERENCES between pruritus and iPTH, Ca, and P.[17,18] It seems that severe hyperparathyroidism, as the cause of pruritus, 1. Lugon JR. Uremic pruritus: A review. Hemodialysis Interna- emerges in only few patients. tional. 2005;9:180–188. In the present study, there was no relationship 2. Schwartz IF, Iaina A. Uremic pruritus. Nephrol Dial Trans- between the hemoglobin level of the patients and their pru- plant. 1999;14:834–839. 3. Urbonas A, et al. Uremic pruritus—an update. Am J Nephrol. ritus; however, pruritus is reported as the relatively rare 2001;21:343–350. complication of iron deficiency anemia. 4. Mettang T, Pauli-Magnus C, Alscher DM. Uremic pruri- Despite the fact that Gunal et al.[9] had prescribed tus—new perspectives and insights from recent trials. Neph- higher doses of gabapentin, they did not report any com- rol Dial Transplant. 2002;17:1558–1563. plications; in our study, however, complications were 5. Kimmel M, et al. The role of micro-inflammation in the found in two cases. It is possible that the larger sample pathogenesis of uremic pruritus in hemodialysis patients. size or the emotional stress of the patients enrolled in our Nephrol Dial Transplant. 2006;21:749–755. study had contributed to the higher number of complica- 6. Rose MA, Kam CA. Gabapentin: Pharmacology and its use tions. It is noteworthy that these complications were all in pain management. Anaesthesia. 2002;57:451–462. unspecific and did not cause any problems for the 7. Taylor CP, et al. A summary of mechanistic hypotheses of gaba- patients. pentin pharmacology. Epilepsy Research. 1998;29:233–249. 8. Bassilios N, Launay-Vacher V, Khoury N, Rondeau E, Deray G, Sraer JD. Gabapentin neurotoxicity in a chronic Downloaded By: [Khashayar, Patricia] At: 08:39 12 February 2009 hemodialysis patient. Nephrol Dial Transplant. CONCLUSION 2001;16:2112–2113. 9. Gunal AI, et al. Gabapentin therapy for pruritus in Gabapentin is revealed to be an effective drug in treat- hemodialysis patients: A randomized, placebo-con- ing uremic pruritus. It is possible that the neurological trolled, double-blind trial. Nephrol Dial Transplant. 2004; hypothesis has a significant role in managing uremic pruri- 19:3137–3139. tus. Also, considering the similar effects of administering 10. Maneti L, et al. Gabapentin in the treatment of uremic itch: gabapentin 100 mg and 300 mg, it is recommended that An index case and a pilot evaluation. J Nephrol. 2005; 18:86–91. smaller doses are more cost-beneficial and are probably 11. Jedras M, Zakrzewska-Pniewska B, Wardyn K, Switalski M. accompanied by fewer complications in treating these Uremic neuropathy. II. Is pruritus in dialyzed patients related patients; however, further studies are required to approve to neuropathy? Pol Arch Med Wewn. 1998; 99:462–469. this hypothesis. 12. Breneman DL, Cardone JS, Blumsack RF, Lather RM, Seaile EA, Pollack VE. Topical capsaicin for the treatment of hemodialysis-related pruritus. J Am Acad Dermatol. ACKNOWLEDGMENT 1992;26:91–94. 13. Kumagai H, Utsumi J, Suzuki T, Hayasi M, Saruta T. The present study is the report of the research Endogenous opioid system in uremic pruritus. Abstracts project supported by Tehran University of Medical Sci- of the Joint Meeting of Seventh World Conference on Clinical Pharmacology and Therapeutics IUPHAR & 4th ences and Health Services (Contract No. 2988). We are Congress of the European Association for Clinical Phar- also indebted to the Urology Research Center, and macology and Therapeutics. Br J Clin Pharmacol. Research and Development Center of Sina Hospital for 2000;282. their support. We would also like to thank the personnel 14. Okano K, Tagashi Y, Umeuchi H, Ando N, Tanaka T, of the Urology Research Center of Sina Hospital, par- Kawamura K, Endo T, Kamei J, Nagase H. Anti-pruritic ticularly Ms. Shekarpour and Ms. Heidari. In addition, effect of opioid kappa receptor agonist TRK-820. we appreciate the cooperation of the personnel of the Abstracts of the Joint Meeting of Seventh World Confer- hemodialysis centers of Sina, Imam Khomeini, and ence on Clinical Pharmacology and Therapeutics Milad hospitals. IUPHAR & 4th Congress of the European Association for Clinical Pharmacology and Therapeutics. Br J Clin Pharmacol. 2000;283. 15. Morton CA, Lafferty M, Hau C, Henderson I, Jones M, DECLARATION OF INTEREST Lowe JG. Pruritus and skin hydration during dialysis. Neph- rol Dial Transplant. 1996;11:2031–2036. The authors report no conflicts of interest. The 16. Cho YL, Liu HN, Huang TP, Tarng DC. Uremic pruritus: authors alone are responsible for the content and writing of Roles of parathyroid hormone and substance P. J Am Acad the paper. Dermatol. 1997;36:538–541.
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