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Gabapentin and Uremic Pruritus in Hemodialysis PatientsEffat 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 ofMedical Sciences, Tehran, Iran b Internal Diseases Department, Imam Hospital, Garmsar, Iran c InternalDiseases 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, SinaHospital, Tehran University of Medical Sciences, Tehran, Iran f Research and Development Center, SinaHospital, 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 andKhashayar, Patricia(2009)'Gabapentin and Uremic Pruritus in Hemodialysis Patients',Renal Failure,31:2,85 — 90

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Renal Failure, 31:85–90, 2009 Copyright © Informa Healthcare USA, Inc.ISSN: 0886-022X print / 1525-6049 onlineDOI: 10.1080/08860220802595476

85

LRNFCLINICAL STUDY

Gabapentin and Uremic Pruritus in Hemodialysis Patients

Gabapentin and Uremic Pruritus in Hemodialysis PatientsEffat RazeghiInternal Diseases Department (Nephrology), Sina Hospital, Urology Research Center, Tehran University of Medical Sciences, Tehran, Iran

Delaram EskandariInternal Diseases Department, Imam Hospital, Garmsar, Iran

Mohammad Reza GanjiInternal Diseases Department (Nephrology), Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran

Ali Pasha MeysamieCommunity Medicine, Tehran University of Medical Sciences, Tehran, Iran

Mansooreh ToghaDepartment of Neurology, Sina Hospital, Tehran University of Medical Sciences, Tehran, Iran

Patricia KhashayarResearch and Development Center, Sina Hospital, Tehran University of Medical Sciences, Tehran, Iran

Background. Pruritus is a common and bothersomeproblem in 30–50% of hemodialysis patients. The aim of thisstudy was to determine the effect of gabapentin, 100 mg/threetimes a week (after each hemodialysis session), on uremicpruritus. Study design. Patients older than 18 years who hadundergone hemodialysis for more than three months wereenrolled in this double-blind clinical trial. They had experiencedpruritus refractory to antihistamines for at least two weeks. Thepatients were assigned to receive gabapentin 100 mg followinghemodialysis for a period of four weeks, and after a washoutweek, they received the placebo for another four weeks. Theywere asked to evaluate the severity of their pruritus using a visualanalogue scale (VAS). The reduction of pruritus ≥ 50% wasaccepted as the response. Results. The mean pruritus scorereached 6.44 ± 8.4 (p < 0.0001), 15 ± 11.2 (p < 0.001), and 81.11± 11.07 (p < 0.001) during gabapentin, washout, and placebo

periods, respectively. No significant correlation was foundbetween age, sex, duration of dialysis, underlying diseases, andsystolic and diastolic blood pressures and the gabapentineffect. Conclusion. Gabapentin is an effective agent in treatinguremic pruritus.

Keywords gabapentin, hemodialysis, pruritus

INTRODUCTION

Uremic pruritus is a troubling dermal disorder, sec-ondary to chronic and progressive renal failure; it disturbspatients’ sleep and reduces their quality of life.[1,2] Morethan half of dialysis patients (hemodialysis or peritonealdialysis) and about 30% of the patients with acute andchronic renal failure who do not undergo hemodialysiscomplain about pruritus to some degree.[3]

Pruritus may have peripheral (dermal or neuropathic),central (neuropathic, neurological, or psychogenic), ormixed origins. Uremic pruritus is classified as mixed, andvarious hypotheses have been formed for justifying itspathogens; accordingly, several treatments with different

Received 25 July 2008; revised 24 September 2008; accepted11 October 2008.

Address correspondence to Effat Razeghi, MD, Sina Hospital,Urology Research Center, P.O. Box: 11367-46911, Imam KhomeiniSt., Tehran, Iran; Tel.: +98-21-66716546; Fax: +98-21-66716546;E-mail: [email protected]

Downloaded By: [Khashayar, Patricia] At: 08:39 12 February 2009

86 E. Razeghi et al.

results were suggested based on the hypotheses. However,none of the treatments managed to cure the very disablingcomplication.[4,5]

Gabapentin is an anti-convulsion drug, similar toGABA transmitter in its structure. The effectiveness ofgabapentin in controlling convulsions is confirmed bymany studies; it has also been demonstrated to be effectivein treating chronic neuropathic diseases. The suggesteddose for stabilizing the serum level of hemodialysispatients is 200–300 mg following each session of hemodi-alysis; doses equal to 100 mg, however, are also proposed,aiming at reducing the risk of developing neurotoxicity.[6–8]

Recent studies have suggested that the effectivenessof gabapentin on uremic pruritus by affecting the neuralcalcium channels.[9,10]

There are not many studies assessing the effect of gaba-pentin 100 mg on uremic pruritus. As a result, the purposeof the present study was to examine the effect of gabapentin100 mg on uremic pruritus of hemodialysis patients.

MATERIALS AND METHODS

This double blind clinical trial was conducted in threehemodialysis centers of Tehran in 2006. Patients with aminimum age of 18 and minimum ESRD duration of threemonths, suffering from pruritus for at least two weeks,were enrolled in this study. They underwent hemodialysisthree times a week for four hours. They had previousattempts of using antihistamines and moisturizers, neitherof which was reported to be useful.

The patients had normal hepatic function, and therewere no specific underlying diseases intervening with thestudy. Those with skin lesions, metabolic diseases (pro-ducing pruritus), drug allergies, and noncompliant caseswere excluded from the study.

After the institutional committee board’s approval,informed consent was obtained from all patients. Theywere asked to quit using anti-pruritus drugs one week priorto the study.

Subsequently, all of the patients underwent a com-plete neurological examination. The patients were trainedto evaluate the severity of their pruritus using a 100 mmvisual analogue scale (VAS). Results between 0–25 wereconsidered as low, 25–50 as moderate, 50–75 as high, and75–100 as severe.

The patients were given gabapentin 100 mg followingeach session of hemodialysis for four weeks at the begin-ning of the study. They then received the placebo foranother four weeks. One week was considered the wash-out period between the two treatment phases.

Blood pressure, Kt/V (i.e., the volume of plasmacleared [Kt] divided by the urea distribution volume [V],

where K is the dialyzer blood water urea clearance in L perhour, t is dialysis session length in hours, and V is the dis-tribution volume of urea in liters), and other laboratoryparameters including Ca, P, Alb, and ipTH were measuredat four intervals (i.e., one week prior to the treatment, thedrug administration phase, and the washed out, and pla-cebo phases). All samples were taken from the patientsbefore undergoing hemodialysis.

A technician unaware of the phase the patients werein asked them to define the severity of pruritus and theeffectiveness of the drug. The median score of pruritus ineach interval was considered as the accepted score of pru-ritus in that period, and the reduction of pruritus for morethan 50% was accepted as the positive response.

RESULTS

Thirty-four ESRD patients undergoing hemodialysiswere enrolled in this study. There were 8 male (23%) and26 female (77%) patients. The mean age of the patientswas 58.4± 12.5 years ranging between 28 and 73 years.The underlying diseases leading to ESRD in these patientsare outlined in Table 1.

Two of the patients discontinued the treatment andwere excluded from the study due to representing thedrug’s side effects (e.g., fatigue, dizziness, and drowsi-ness). Another patient withdrew from the study, as he didnot show any improvement within 10 days after the startof the study. Six other patients were also excluded becauseof not being cooperative (i.e., poor compliance to thedrug). In other words, the complication and no-responserate was calculated to be 8.8% (CI 95% = 0–18.4%).

All patients underwent a complete neurological exambefore initiating the treatment; 24 out of the 25 patientswho completed the study had a positive neurologicalexam. All of these 24 cases had signs of distal symmetricpolyneuropathy. Hyporeflexia to areflexia was reported in23 cases. Stocking-glove pattern of hypoesthesia wasreported in all of the 24 studied cases, 20 of which hadabnormal response in position and vibration tests. Twelve

Table 1 The frequency of the underlying diseases leading to

ESRD

Underlying disease Number Percentage (%)

DM 9 36%HTN 6 24%Idiopathic 4 16%Others 3 12%DM+HTN 3 12%


Gabapentin and Uremic Pruritus in Hemodialysis Patients 87

cases had distal motor weakness. Proximal weakness wasreported in neither of the cases. Moreover, carpal tunnelsyndrome was also reported in one of the cases.

All of the cases eligible for receiving the interventionhad the pruritus score of 100 at the beginning of the study.Following the prescription of gabapentin, the scorereached 6.44 ± 8.46 (p < 0.001). The mean pruritus scorereturned to 15 ± 11.27 (p < 0.001) following the one-weekwashout 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 periodis presented in Figures 1–3

The mean score of pruritus at the end of gabapentintherapy, washout period, and placebo therapy were 6.44 ±8.46 (p < 0.001), 15 ± 11.27 (p < 0.001), and 81.88 ±11.06 (p < 0.001), respectively. There was no meaningfulrelationship between age, gender, the duration of dialysis,the underlying disease leading to ESRD, and KTV and themean score of pruritus in the three phases of the study.

In the placebo phase, the mean score of pruritus waslower than the score prior to intervention.

The mean score of pruritus in the three phases ofgabapentin 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 threephases 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 thebeginning of the study (6.24 ± 2.31), there was no correla-tion between pruritus and the serum phosphate level. Itshould be noted that these patients were often treated inorder to lower the phosphate level; this treatment did notinfluence the results of our study.

There was no significant relationship between thepatients’ age, sex, duration of dialysis, underlying diseases,hemoglobin, Ca, P, Alb, P, ipTH, CRP, systolic and diastolicblood pressures, Kt/V, and the severity of pruritus in the threephases of gabapentin therapy, washout, and placebo therapy.The results are demonstrated in Tables 2 and 3.

Complications secondary to drug use was reported intwo of the total 34 patients enrolled in this study. The compli-cations were limited to dizziness, drowsiness, and unspecifiedfatigue; however, because the complications emerged by theadministration of the drug and disappeared by discontinuingit, the two cases were ethically excluded from the study.

DISCUSSION

The etiology and pathogens of uremic pruritus isnot clearly known. Neurological hypothesis,[11,12] the

Figure 1. The daily mean pruritus score in gabapentin therapyphase.

Figure 2. The daily mean pruritus score in placebo phase.

Figure 3. The daily mean pruritus score evaluated by thepatients in the three phases of the study (i.e., gabapentin therapy,washed out, and placebo).



intervention of the opioid system,[13,14] the transformedmetabolism of bi-valence ions,[15–17] hyperparathyroid-ism,[18,19] and the increase of mast cells and etacoids[18,20]

are the most important mechanisms raised.Neuropathy is prevalent among uremic patients. More

than 65% of the patients with renal failure represent aperipheral nervous disorder,[9] confirming a possible linkbetween the neurologic origins of uremic pruritus.

Conduction disorder in sensory-motor pathways isone of the most prevalent representations in the initialstages of uremia; it is characterized by paresthesia, prick-ing of the feet, and uneasy foot syndrome.[9]

Pruritus may also be secondary to a reduction in theperception threshold. Nerve root damage may lead to an

increased sensitivity to itching stimuli. An abnormal ener-vation is pointed out in hemodialysis patients.

In the present study, all patients were neurologicallyexamined to compare the treatment results regarding neur-opathy findings; but as 24 of the 25 studied patients werereported to have nearly similar evidences of neurologicalproblems, further comparison was not performed. Theaforementioned evaluation was not conducted in previousstudies.

Similar to the previous studies,[21,22] there was no sig-nificant correlation between pruritus and the demographicfactors, Kt/V, the duration of dialysis, and the type of renaldysfunction in the present study.

The results of the present study support the findingsof a similar study conducted by Maneti et al. in 2005.[10] Inanother study carried out on 25 hemodialysis patients,Gunal et al.[9] showed that the mean score of pruritus inthe gabapentin phase was significantly different from thatof the placebo phase.

We evaluated the relationship of pruritus with inflam-matory parameters, albumin as a negative phase proteinand CRP as a positive phase protein. Unlike Virga’sstudy,[23] no relation was found between the mean score ofpruritus in the three phases of gabapentin therapy, wash-out, and placebo and the mean serum albumin level in thecurrent study. It can be concluded that albumin is influ-enced by non-inflammatory factors, including nutritionalstatus as well as the inflammatory factors.[24] In otherwords, according to that very fact and albumins’ relativelylong half-life, albumin cannot be considered as a propercriterion for evaluating inflammation.

It is noteworthy that the mean CRP in the three phaseswas not correlated with the mean score of pruritus. Thiswas similar to the findings of Virga et al.[23]

Several previous studies had considered the resistantand disabling pruritus as a representing sign of hyperthy-roidism[20,21]; however, many others—including the

Table 2 Variations of the laboratory variables in different intervention phases

Variable

Time of measurement

Before starting the treatment (phase 0)

End of Gabapentin therapy (phase 1)

End of washed-out phase

End of placebo phase

Hb 10.6 ± 1.8 11.1 ± 1.7 10.1 ± 2.6 10.6 ± 1.7Ca 9.5 ± 2.5 9.2 ± 0.9 9.38 ± 1.1 8.9 ± 2.8P 6.24 ± 2.31 6.46 ± 2.24 6.78 ± 2.8 6.4 ± 2.4Alb 4.25 ± 0.6 4.01 ± 0.3 5.45 ± 7.2 4.14 ± 0.5iPTH 111.12 ± 103 115.57 ± 115.3 120.9 ± 115.5 147.68 ± 179CRP 11023.3 ± 16630 15354 ± 20077 11249.1 ± 12040 14120.4 ± 16576Kt/V 1.31 ± 0.2 1.32 ± 0.2 1.35 ± 0.17 1.35 ± 0.17

Table 3 The correlation between the variables and their responsiveness to

the treatment (reduction in pruritus)

Variable

Mean (at the beginning

of the study)Pearson

correlation p value*

Age 58.44 ± 12.5 −0.37 0.64Median dialysis

duration (25–75)50 months (19.5–36.5)

0.15 0.4

Kt/V 1.31 ± 0.21 0.1 0.61SBP 113.3 ± 14.1 −0.21 0.3DBP 66 ± −7.7 −0.21 0.29Hb 10.6 ± 1.8 0.28 0.16Ca 9.5 ± 2.5 −0.22 0.91P 6.24 ± 2.31 −0.14 0.48Alb 4.25 ± 0.6 0.4 0.84iPTH 111.12 ± 103 0.13 0.52CRP 11023.3 ± 16630 0.166 0.42

*Fisher’s z transformation.


Gabapentin and Uremic Pruritus in Hemodialysis Patients 89

present study—were unable to find any correlationbetween pruritus and iPTH, Ca, and P.[17,18] It seems thatsevere hyperparathyroidism, as the cause of pruritus,emerges in only few patients.

In the present study, there was no relationshipbetween the hemoglobin level of the patients and their pru-ritus; however, pruritus is reported as the relatively rarecomplication of iron deficiency anemia.

Despite the fact that Gunal et al.[9] had prescribedhigher doses of gabapentin, they did not report any com-plications; in our study, however, complications werefound in two cases. It is possible that the larger samplesize or the emotional stress of the patients enrolled in ourstudy had contributed to the higher number of complica-tions. It is noteworthy that these complications were allunspecific and did not cause any problems for thepatients.

CONCLUSION

Gabapentin is revealed to be an effective drug in treat-ing uremic pruritus. It is possible that the neurologicalhypothesis has a significant role in managing uremic pruri-tus. Also, considering the similar effects of administeringgabapentin 100 mg and 300 mg, it is recommended thatsmaller doses are more cost-beneficial and are probablyaccompanied by fewer complications in treating thesepatients; however, further studies are required to approvethis hypothesis.

ACKNOWLEDGMENT

The present study is the report of the researchproject supported by Tehran University of Medical Sci-ences and Health Services (Contract No. 2988). We arealso indebted to the Urology Research Center, andResearch and Development Center of Sina Hospital fortheir support. We would also like to thank the personnelof the Urology Research Center of Sina Hospital, par-ticularly Ms. Shekarpour and Ms. Heidari. In addition,we appreciate the cooperation of the personnel of thehemodialysis centers of Sina, Imam Khomeini, andMilad hospitals.

DECLARATION OF INTEREST

The authors report no conflicts of interest. Theauthors alone are responsible for the content and writing ofthe paper.

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