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Efficacy and Safety of Gabapentin for Uremic Pruritus and Restless Legs Syndrome in Conservatively Managed Patients With Chronic Kidney Disease
Accepted Manuscript Efficacy and Safety of Gabapentin for Uremic Pruritus and Restless Legs Syndrome in Conservatively Managed Patients With Chronic Kidney Disease Hicham I. Cheikh Hassan, MD Frank Brennan, MBBS Gemma Collett, BHSc Elizabeth A. Josland, RN, DipNursing(NZ), MPH Mark A. Brown, MBBS, MD PII:
S0885-3924(14)00445-X
DOI:
10.1016/j.jpainsymman.2014.08.010
Reference:
JPS 8747
To appear in:
Journal of Pain and Symptom Management
Received Date: 23 March 2014 Revised Date:
28 July 2014
Accepted Date: 14 August 2014
Please cite this article as: Cheikh Hassan HI, Brennan F, Collett G, Josland EA, Brown MA, Efficacy and Safety of Gabapentin for Uremic Pruritus and Restless Legs Syndrome in Conservatively Managed Patients With Chronic Kidney Disease, Journal of Pain and Symptom Management (2014), doi: 10.1016/ j.jpainsymman.2014.08.010. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Brief Report
14-00163R2
Efficacy and Safety of Gabapentin for Uremic Pruritus and Restless Legs Syndrome in
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Conservatively Managed Patients With Chronic Kidney Disease
Hicham I. Cheikh Hassan, MD, Frank Brennan, MBBS, Gemma Collett, BHSc, Elizabeth A
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Josland, RN, DipNursing(NZ), MPH, and Mark A. Brown, MBBS, MD
Department of Renal Medicine (H.I.C.H., F.B., G.C., E.A.J., M.A.B.), St. George Hospital,
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Sydney, and University of New South Wales (H.I.C.H., F.B.), Sydney, New South Wales, Australia
Address correspondence to:
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Frank Brennan, MBBS Department of Renal Medicine St. George Hospital
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50 Montgomery Street
Kogarah, NSW 2217, Australia
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E-mail: [email protected] AU: PLS CHECK ALL AUTHOR DEGREES AND CORRECT IF NECESSARY
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Abstract Context. Pruritus and restless legs syndrome (RLS) frequently affect patients with chronic kidney disease (CKD) and end-stage kidney disease (ESKD), impacting quality of life.
patients on the conservative pathway.
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Gabapentin alleviates these symptoms in hemodialysis (HD) patients but data are lacking for
Objectives. To determine the safety and effectiveness of gabapentin for pruritus or RLS
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in conservatively managed patients (n=34) with CKD and ESKD.
Methods. This was a single center, retrospective cohort study. We compared dosing and
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side effects in the 34 CKD/ESKD patients to similar patients receiving HD (n=15). Results. Forty-four percent of conservatively managed patients complained of RLS and/or pruritus; 18% were excluded for a non-uremic cause of symptoms. Thirty-four patients were included in the final analysis. The most common starting daily dose of gabapentin was the
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equivalent of 50mg (44.1%) or 100mg (38.2%) daily, with the median daily dose 100mg (range 39-455mg). Side effects occurred in 47% of patients, with 17% discontinuing gabapentin. Gabapentin reduced symptoms of pruritus (P<0.001) and RLS (P<0.05). There was no statistical
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difference when comparing HD and conservatively managed patients for daily starting dose (P=0.88), median dose (P=0.84) and final dose (P=0.18). Patients conservatively managed were
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more likely to manifest side effects compared with HD patients (47.1% vs. 14.3%, P=0.023). Dose was not found to be a factor associated with side effects in univariate analysis. Conclusion. Gabapentin is a viable treatment for conservatively managed CKD and ESKD patients with pruritus and/or RLS but side effects are common. Gabapentin should be used with caution although higher doses do not appear to be a factor associated with side effects.
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Key Words: Gabapentin, pruritus, restless legs syndrome, dialysis, end-stage kidney disease, conservative management Running title: Gabapentin for Pruritis and RLS in ESKD
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Accepted for publication: August 14, 2014.
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Introduction Patients with end-stage kidney disease (ESKD) are heavily burdened with symptoms. Two of the most common are uremic pruritus and restless legs syndrome (RLS). RLS is a
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neurological disorder characterised by sensorimotor symptoms such as paraesthesia and
restlessness mainly affecting the lower limbs, occurring during rest in the evening or overnight, and at least partially relieved by movement (1). The prevalence of RLS in patients with ESKD
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on hemodialysis (HD) ranges from 5% to 62% (2-5), whereas pruritus affects 22-42% (6-9). Singularly or in combination, pruritus (9) and RLS (4, 5) have a profound effect on sleep, quality
patients who suffer from these symptoms.
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of life and mortality. Their aggravating nature and unpredictability can make life a misery to
Gabapentin (1-aminomethyl cyclohexane acetic acid) is a structural analogue of gammaaminobutyric acid (GABA) developed for the treatment of epilepsy. It is effective in managing
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both uremic pruritus (10-12) and RLS (3, 13, 14) in ESKD patients receiving renal replacement therapy (RRT). However, to date there have been no studies examining the use of gabapentin for the treatment of RLS symptoms in patients with ESKD who are managed conservatively. Only
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one study examined its use in uremic pruritus for patients with chronic kidney disease (CKD) managed conservatively (15). This is especially important because this subgroup of patients is
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elderly, frail and often has multiple comorbidities. As renal function deteriorates, their ability to renally clear gabapentin decreases, with an increased risk of developing side effects. Therefore, we set out 1) to determine the effectiveness of gabapentin in the treatment of pruritus and RLS in patients conservatively managed for CKD, including patients with ESKD, and 2) to establish its safely in this group. Methods
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We conducted a retrospective, single center, cohort study. All patients for conservative management of ESKD and CKD referred to the Renal Supportive Care Clinic (RSC-C) in a tertiary care facility (St. George Hospital, Sydney) between April 2010 and June 2013 were
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identified. We defined conservative management in ESKD as any patient who a) did not wish to commence dialysis or undergo kidney transplantation or b) did not pursue dialysis treatment based on medical advice and/or ethical grounds as a shared decision. Inclusion criteria were
years of age and attended the outpatient RSC-C at least twice.
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patients with CKD stage II-V on a non-dialysis conservative pathway who were older than 18
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A palliative care physician reviewed all patients for the duration of the study. We excluded patients with an identifiable non-CKD cause of RLS or pruritus, incomplete/missing data and incomplete questionnaires, or who started gabapentin before attending the clinic. We simultaneously identified dialysis patients referred to the RSC-C for symptom management for
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comparison of differences in dosing and side effects. This study was approved by the Human Research Ethics Committee, South Eastern Sydney Local Health District (reference number HREC/10/STG/121).
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Sociodemographic, clinical and laboratory data were obtained at the initial review, including age, gender, body mass index (BMI), smoking status, and history of diabetes and
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cerebrovascular disease (CVD). Laboratory parameters included serum urea (mmol/L), creatinine (umol/L), eGFR, albumin (g/L), calcium (mmol/L), phosphate (mmol/L), HbA1c (%) for diabetic patients, hemoglobin (g/L), C-reactive protein (CRP) (mg/L) and parathyroid hormone (PTH) (pmol/L).
Patients were asked to complete the Palliative care Outcome Scale-Symptoms (POS-S)Renal (16), a validated symptom inventory instrument, on the first visit prior to commencing
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gabapentin and on each subsequent visit. The POS-S Renal was used to assess progress and management of symptoms. We apportioned a numerical figure to the level of reported severity (0 to 4 according to whether the reported severity was not at all, slight, moderate, severe, or
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overwhelming).The scores for pruritus, RLS and total symptom (TS) were recorded at the initial visit before gabapentin was started as a baseline. All subsequent visits were compared to this. The usual starting dose of gabapentin in patients with ESKD was 100mg on alternate
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nights, and in CKD stage III-IV, 100- 200mg nightly. The dose was increased if no symptomatic relief was achieved while documenting, monitoring and informing patients of potential side
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effects. We requested a compounding pharmacist to arrange 25mg tablets to facilitate small incremental increases in dosing for patients who manifested side effects at higher doses. We documented the initial dose of gabapentin, the daily dose between the first clinic visit and the final clinic visit, and the final dose of gabapentin at the last clinic visit within the study period.
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When gabapentin was administered on alternate days or once every three days, we calculated the average daily dose. We documented duration of therapy, changes in the POS-S Renal, side effects and cessation of gabapentin.
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Our primary outcomes were: a) changes in POS-S Renal score for pruritus, RLS and TS, b) side effects and need for cessation of gabapentin, and c) doses of gabapentin used. We
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compared outcomes in patients on the conservative pathway with those on HD receiving gabapentin for symptom control. Statistical Analysis
Categorical data are expressed as frequency (%) and compared using the Chi-squared test. Continuous data are expressed as medians with interquartile ranges [IQR; 25th -75th percentile] or mean with standard deviation (SD) and compared by the Student’s t-test or Mann-
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Whitney U test as appropriate. For comparison between POS-S Renal at baseline and on subsequent visits, we used the Wilcoxon signed rank test. We did not censor patients who subsequently ceased gabapentin. Univariate logistic regression analysis was performed to
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calculate the odds ratio (OR) and 95% confidence intervals (CI) of factors associated with the emergence of side effects. All statistical analyses were performed using SPSS v. 19.0 (SPSS Inc., Chicago, IL). A P-value of <0.05 was considered significant.
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Results
Between April 2010 and June 2013, there were 184 new referrals to the RSC-C, including
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125 patients for conservative management of CKD and ESKD (Fig. 1). In this group, 44% (55 patients) complained of RLS and/or pruritus and met the inclusion criteria. We excluded 10 patients for non-uremic causes of pruritus and RLS (18%) and nine who started gabapentin prior to the clinic assessment. Two patients commenced HD after referral and were included until
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commencing HD, then censored. The final study group comprised 34 patients, 30 with uremic pruritus and 18 with RLS (some patients had both symptoms). During the same time period, 59 patients on HD were referred for symptom control;15 met the inclusion criteria and received
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gabapentin (13 with pruritus and six with RLS). Table 1 highlights the demographics of the conservatively managed group. Most were
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elderly, average age 80 years, with a mean creatinine on presentation of 317 umol/L. Patients with CKD stage V accounted for 47% (16 patients), CKD stage IV 41% (14 patients) and CKD stage III 12% (four patients). During the study period, 41.2% (14 patients) died within 8.0 months [range 4.4- 9.0].
Gabapentin Dose and Toxicity in the Conservatively Managed Group
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Thirty-four patients on the conservative non-dialysis pathway received gabapentin for symptom control. Gabapentin was commenced for pruritus in 30 patients, RLS in 18 patients (16 patients with both RLS and pruritus). The mean (SD) TS score for the study group, using the
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POS-S Renal, was 22.1 (8.8). In the pruritus group, the TS score was 22.6 (8.9) and in the RLS group, 23.4 (7.9).
The most common daily starting dose was the equivalent of 50mg (44.1%) and 100mg
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daily (38.2%), followed by <50 mg (8.8%) and 200mg (8.8%). The dose was titrated at
subsequent visits to achieve symptom control while balancing side effects. The median daily
clinic visit of 100mg (range 50mg- 600mg).
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dose was 100mg (range 39- 455mg), which was similar to the median daily dose on the final
At least one side effect occurred in 47% (16 patients), with 29% (10 patients) stopping gabapentin after a median of 2.6 [1.2, 4.8] months. In total, 17% (six patients) permanently
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discontinued gabapentin. The most common side effect was drowsiness, followed by dizziness and fatigue (Table 2).
Effectiveness of Gabapentin in the Conservatively Managed Group
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Gabapentin was effective in reducing symptoms of pruritus in patients with CKD and ESKD managed conservatively (Fig. 2). By visit 4 (median 12.6 weeks of treatment) and on the
0.001).
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final visit (median 27.0 weeks), more than 80% had a POS-S Renal pruritus score ≤ 1 (P<
Gabapentin was similarly effective for the patients with RLS (Fig. 3). There was a statistically significant improvement in symptom control of RLS when comparing the first visit with subsequent visits (P<0.05). Conservatively Managed Group vs. Dialysis Group
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Fifteen HD patients were included for comparison. Table 1 shows the baseline characteristics of this group and Table 2, the side effect profile from gabapentin. Similar to patients managed conservatively, gabapentin was found to be effective in relieving symptoms of
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pruritus in patients on HD (P<0.05 between the first visit and on subsequent visits). For patients with RLS, this only reached statistical difference when comparing the first pre-gabapentin visit to the final visit at the end of the study (P=0.038).
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We compared baseline characteristics (Table 1) and outcomes between the two groups of patients receiving gabapentin (Table 3). There was no statistically significant difference when
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comparing the starting daily dose of gabapentin (P=0.88), average daily dose (P=0.84), final daily dose (P=0.18) or number of patients who discontinued gabapentin (P=0.20). However, patients on the conservative management pathway were more likely to manifest a side effect (47% vs. 14%, P= 0.023).
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To establish which variables were associated with side effects, we performed a univariate analysis in the conservatively managed group. No single variable emerged that was significantly associated with side effects including the starting dose of gabapentin (P=0.86), average
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equivalent daily dose (P=0.99) and final dose (P=0.93). When we combined the study population into one group (HD and conservatively managed patients, n=49), univariate analysis confirmed
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that being a conservatively managed patient was the only variable predicting a higher likelihood of developing side effects (OR 5.8; 95% CI 1.1, 29.6, P=0.035). Discussion
Previous studies confirmed the symptomatic improvement in uremic pruritus and RLS for ESKD patients receiving RRT treated with gabapentin (3, 10-14), with one study examining its use in patients with CKD suffering from uremic pruritus (15). Our retrospective study of
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consecutive, symptomatic, conservatively managed ESKD patients further adds to this knowledge by confirming the use of gabapentin for this group and examining its safety profile. Patients with ESKD are heavily burdened with symptoms, with two of the most common
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being RLS and pruritus. In our cohort of CKD patients, 44% were affected (20% with RLS and 37% with pruritus). This is consistent with previous studies documenting that 4.7%-68% of HD patients are affected with RLS (2, 3, 13, 17, 18). The prevalence of pruritus in ESKD is similarly
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high and affects 22%- 90% of patients (6, 19, 20). It is noteworthy that 18% of our patients had a potentially non-ESKD reversible cause, highlighting the importance of a thorough history and
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physical examination as part of the assessment process.
Treatment aims to reduce the burden caused by these symptoms and improve quality of life. Pruritus is disabling and distressing, significantly impacting patients’ mental and physical capacity by contributing to daytime fatigue, agitation, depression, poor sleep and decreased
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quality of life (6, 19, 20). Similarly, RLS negatively impacts patients with ESKD undergoing HD, affecting sleep (5, 18) and quality of life (5). There is a modest but growing body of literature showing the efficacy of gabapentin in
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the management of both uremic RLS and pruritus. There are two principal concerns when prescribing gabapentin to this cohort of patients: dose strength and frequency. Gabapentin is not
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metabolized, does not bind to plasma protein and is completely dependent on renal elimination (21). It exhibits a prolonged half-life in anuric subjects on non-HD days (132 hours) compared with anuric patients on HD days (52 hours) and healthy subjects (5-7 hours) (21). There is a significant rise in side effects and plasma gabapentin levels when comparing patients with normal renal function, those with impaired function, and those on RRT (22). In our group of HD patients receiving gabapentin for symptomatic management, a side effect occurred in 13% of
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cases. This is comparable to the 6%-20% (3, 11, 15) exhibited in other studies. In populations with normal renal function treated with gabapentin for RLS, a side effect occurred in 25% of patients (23, 24). Our conservatively managed group exhibited a much higher rate, with 47% of
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patients reporting a side effect and 17% having to permanently discontinue the drug. This is similar to a study examining gabapentin use for uremic pruritus in CKD patients not on RRT reporting a side effect profile of 40%, with 48% discontinuing the drug (15)
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In view of a reduced clearance and an increase in side effects, it is important to determine the correct dosing of gabapentin. In the studies on the efficacy of gabapentin for HD patients, the
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dosing regimen varied considerably, from 100mg to 400mg postdialysis (100mg post HD [11, 15, 25], 100-300mg post HD [20], 200mg post HD [3], 200-300mg post HD [13], 300mg post HD [10] 400mg post HD [12]). This is similar to the dose we used in our group to achieve symptom control. However, on univariate analysis, we did not find dosing to be a factor
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influencing the likelihood of side effects. In the entire study group (HD and conservatively managed), the only statistically significant factor was being on the conservative pathway. Another retrospective study also showed dosing did not influence the emergence of side effects,
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which was more affected by age and comorbidities (22). A limitation of our study is the large number of exclusions, especially those who
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commenced gabapentin before a questionnaire was completed. We did not have a control group to compare the common side effects present in this group of patients, such as fatigue or drowsiness, which may have causes other than gabapentin. We also had a small number of patients with RLS on HD, possibly contributing to the lack of statistical significance. No distinction was made between the frequency of dosing (more than once a day, daily, on alternate days or more), instead calculating the daily dosing. Given the reduction in renal clearance, the
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frequency of dosing may contribute equally to the emergence of side effects. This requires further investigation. Finally the retrospective nature of our analysis yields only suggestive
between the two groups, including reporting and observer bias.
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conclusions as a result of the likelihood of bias related to factors that systematically differ
Although a blinded randomized trial would yield the most accurate results, we did not pursue such an approach. Several well-conducted studies have shown gabapentin has efficacy for
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the symptomatic relief of RLS and uremic pruritus in those with HD. Given the high burden of symptoms in our group of conservatively managed patients with a high mortality rate (41%
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within eight months), the primary objective was to determine effective dosing for reduction of symptoms and increased comfort without causing undue side effects. In summary gabapentin is a viable treatment option for CKD patients with pruritus and RLS who are conservatively managed without dialysis. Although side effects are more common
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and the risks are higher, it still results in symptom improvement and was continued in 83% of patients. The next step will be to determine the optimum dosing, frequency and amount in these patients to balance symptom control with risks.
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Disclosures and Acknowledgments
No funding was received for this study and the authors declare no conflicts of interest.
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4. Perl J, Unruh ML, Chan CT. Sleep disorders in end-stage renal disease: 'markers of inadequate dialysis'? Kidney Int 2006;70:1687-1693.
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11. Razeghi E, Eskandari D, Ganji MR, et al. Gabapentin and uremic pruritus in hemodialysis patients. Ren Fail 2009;31:85-90.
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12. Naini AE, Harandi AA, Khanbabapour S, et al. Gabapentin: a promising drug for the treatment of uremic pruritus. Saudi J Kidney Dis Transpl 2007;18:378-381. 13. Thorp ML, Morris CD, Bagby SP. A crossover study of gabapentin in treatment of restless
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15. Rayner H, Baharani J, Smith S, Suresh V, Dasgupta I. Uraemic pruritus: relief of itching by gabapentin and pregabalin. Nephron Clin Pract 2012;122:75-79.
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16. POS Development Team. Palliative care Outcome Scale Symptoms Renal. Available from http://pos-pal.org/maix/.
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18. Merlino G, Piani A, Dolso P, et al. Sleep disorders in patients with end-stage renal disease undergoing dialysis therapy. Nephrol Dial Transplant 2006;21:184-190. 19. Pisoni RL, Wikstrom B, Elder SJ, et al. Pruritus in haemodialysis patients: international
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23. Garcia-Borreguero D, Larrosa O, de la Llave Y, et al. Treatment of restless legs syndrome with gabapentin: a double-blind, cross-over study. Neurology 2002;59:1573-1579.
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24. Mellick GA, Mellick LB. Management of restless legs syndrome with gabapentin
25. Bassilios N, Launay-Vacher V, Khoury N, et al. Gabapentin neurotoxicity in a chronic
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haemodialysis patient. Nephrol Dial Transplant 2001;16:2112-2113.
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Table 1. Baseline Characteristics of Patients on Conservative Pathway or HD With Pruritus and RLS.
HD Group
(n= 34)
(n=15)
Age (yrs)
80.0 (7.1)
70.1 (10.6)
Male
19 (55.9)
11 (73.3)
BMI
29.6 (5.9)
29.1 (7.4)
Height (cm)
163.1 (10.5)
166.2 (12.4)
Weight (Kg)
79.2 (18.6)
81.9 (29.4)
0.67
21 (61.8)
7 (46.7)
0.59
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Smoking: None
P-value
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Conservative Group
< 0.001 0.25
0.78
0.48
Former
9 (26.5)
6 (40.0)
0.32
Current
4 (11.8)
2 (11.3)
0.85
9 (26.5)
1 (6.7)
0.11
20 (58.5)
12 (80.0)
0.15
25.1 (11.4)
18.2 (4.5)
0.03
316.8 (132.0)
572.9 (110.2)
< 0.001
18.4 (10.8)
-
-
36.0 (6.2)
31.3 (3.6)
0.009
2.32 (0.2)
2.26 (0.2)
0.47
1.3 [1.2- 1.7]
1.6 (0.5)
0.34
7.8 (1.3)
6.8 (1.7)
0.27
112.0 [103.7- 118.0]
116.5 (11.5)
0.24
CRP n=25
5.0 [2.0- 16.5]
9.0 [2.0- 16.5]
0.27
PTH n=21
23.0 [10.4- 40.0]
16.8 [11.3- 23.9]
0.28
14 (41.2)
7 (46.7)
0.72
0.67 [0.37- 0.96]
0.91 [0.22- 1.99]
0.44
Comorbidity: CVD Diabetes
Creatinine (umol/L) eGFR Albumin (g/L)
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Calcium (mmol/L) n=33 Phosphate (mmol/L)
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HbA1c (%) n=10
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Pathology: Urea (mmol/L) n=27
Hb (g/L)
Mortality Time to Mortality (Years)
Data expressed as number of patients (%). Continuous data expressed as mean (standard deviation) or median
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[interquartile range] as appropriate. HD = hemodialysis; RLS = restless legs syndrome; BMI = body mass index; CVD = cerebrovascular disease; eGFR = estimated glomerular filtration rate; Hb = haemoglobin; CRP =C-reactive protein; PTH= parathyroid
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hormone.
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Table 2. Gabapentin Side Effects Hemodialysis Group
(n= 34)
n=15
16 (47.0)
2 (13.3)
Drowsiness
8 (50)
-
Dizziness
3 (19)
-
Fatigue
3 (19)
-
Blurred vision
2 (12.5)
1 (6.66)
Unsteadiness
2 (12.5)
2 (13.3)
Confusion
1 (6.25)
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≥ 1 side effect
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Conservative Group
-
Data expressed as number of patients (%). Patients may have had more than
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one side effect.
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Table 3. Comparison Between Conservatively Managed and HD Patients Receiving Gabapentin Haemodialysis Group
(n= 34)
(n=15)
14 (41.2)
7 (46.7)
0.48
0.67 [0.37-0.75]
1.1 (0.85)
0.18
22.1 (8.8)
17.9 (6.1)
0.10
Gabapentin daily starting (mg)
50.0 (25.0-200.0)
42.8 (42.8-171.4)
0.88
Gabapentin daily average (mg)
100.0 (38.6-454.5)
90.0 (42.8-206.8)
0.84
Gabapentin daily final (mg)
100.0 (50.0-600.0)
128.6 (42.8-257.1)
0.18
Time to Mortality (yrs)
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POS-S (Renal) TS
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Mortality
P-value
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Conservative Group
Side effects
16 (47.1)
2 (13.3)
0.023
Ceased
10 (29.4)
2 (13.3)
0.20
Data expressed as number of patients (%), mean (standard deviation) or median [interquartile range] as
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appropriated. Gabapentin doses are expressed as daily doses. P< 0.05 considered significant and in bold.
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6 patients Started Gabapentin prior to clinic
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4 patients None uremic cause of pruritus 1 Scabies 1 Fungal/Infective 1 Histamine/ food related 1 Severe leg burns
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2 Patients Inaccurate assessment from severe pain, psychiatric history/noncompliance.
15 Patients - 13 Pruritus - 6 RLS
Figure 1: Flowchart showing patient selection.
Meets inclusion criteria
55 patients
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27 patients
125 Patients Conservative
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59 Patients Dialysis
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184 patients Referred to Renal supportive care clinic between April 2010 and July 2013
34 Patients - 30 pruritus - 18 RLS
9 patients Started Gabapentin prior to clinic 2 patients Incomplete data 10 patients None uremic cause of pruritus - 1 Inflammatory - 1 Scabies - 5 Fungal/Infective - 1 Histamine/ food related - 1 Herpatic neuralgia None uremic cause of RLS - 1 Familial RLS
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p< 0.001 p< 0.001 p< 0.001 p< 0.001 100%
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POS Scale 4 90% 80%
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70% 60%
POS Scale 2 POS Scale 1 POS Scale 0
POS-S Pruritus Score Scale 4 Scale 3 Scale 2 Scale 1 Scale 0
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50%
POS Scale 3
40% 30% 20%
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10% 0%
Visit 1
Visit 3
Visit 4
Visit Final
29 27 24 30 3.0 [1.0,4.5] 7.0 [4.0,9.0] 12.6 [7.9,14.8] 27.0 [14.2,73.0] 16.1 (6.8) p<0.001 14.1 (6.1) p<0.001 17.2 (7.8) p=0.021 16.9 (8.7) p=0.003
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Number of patients 30 Time, weeks [IQR] Total Symptom POS-S 22.6 (8.9)
Visit 2
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Figure 2: POS-S pruritus symptom score change following gabapentin administration after visit 1 for patients with pruritus. Time is the interval between the initial consultation (visit 1) and subsequent visits in weeks [Intrequartile Range]. Total symptom POS-S expressed as mean (SD) for the whole group. Pruritus score between visit 1 and subsequent visits compared using Wilcoxon signed rank test. We did not censor patients who discontinued gabapentin.
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p= 0.023 p= 0.003 p= 0.002 p= 0.001
100%
POS Scale 3 90%
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POS Scale 2
80% 70%
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60% 50%
30% 20% 10%
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0%
Visit 1 Number of patients 18 Time, weeks [IQR] Total POS score 23.4 (8.1)
Visit 2
Visit 3
Visit 4
Visit Final
18 16 13 18 3.0 [1.1,5.2] 7.0 [4.0,10.6] 13.0 [8.5,22.0] 29.5 [14.2,62.5] 17.3 (6.8) p=0.004 16.1 (6.4) p=0.001 17.6 (8.5) p=0.074 18.4 (8.8) p=0.009
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Figure 3: POS-S RLS symptom score change, following gabapentin administration after visit 1, for patients with RLS. Time is the interval between the initial consultation (visit 1) and subsequent visits in weeks [Intrequartile Range]. Total POS score expressed as mean (SD) for the whole group. RLS scores between visit 1 and subsequent visits compared using Wilcoxon signed rank test. We did not censor patients who discontinued gabapentin.
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POS Scale 0
POS-S RLS Score Scale 4 Scale 3 Scale 2 Scale 1 Scale 0
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40%
POS Scale 1
S0885-3924(14)00445-X
DOI:
10.1016/j.jpainsymman.2014.08.010
Reference:
JPS 8747
To appear in:
Journal of Pain and Symptom Management
Received Date: 23 March 2014 Revised Date:
28 July 2014
Accepted Date: 14 August 2014
Please cite this article as: Cheikh Hassan HI, Brennan F, Collett G, Josland EA, Brown MA, Efficacy and Safety of Gabapentin for Uremic Pruritus and Restless Legs Syndrome in Conservatively Managed Patients With Chronic Kidney Disease, Journal of Pain and Symptom Management (2014), doi: 10.1016/ j.jpainsymman.2014.08.010. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Brief Report
14-00163R2
Efficacy and Safety of Gabapentin for Uremic Pruritus and Restless Legs Syndrome in
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Conservatively Managed Patients With Chronic Kidney Disease
Hicham I. Cheikh Hassan, MD, Frank Brennan, MBBS, Gemma Collett, BHSc, Elizabeth A
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Josland, RN, DipNursing(NZ), MPH, and Mark A. Brown, MBBS, MD
Department of Renal Medicine (H.I.C.H., F.B., G.C., E.A.J., M.A.B.), St. George Hospital,
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Sydney, and University of New South Wales (H.I.C.H., F.B.), Sydney, New South Wales, Australia
Address correspondence to:
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Frank Brennan, MBBS Department of Renal Medicine St. George Hospital
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50 Montgomery Street
Kogarah, NSW 2217, Australia
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E-mail: [email protected] AU: PLS CHECK ALL AUTHOR DEGREES AND CORRECT IF NECESSARY
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Abstract Context. Pruritus and restless legs syndrome (RLS) frequently affect patients with chronic kidney disease (CKD) and end-stage kidney disease (ESKD), impacting quality of life.
patients on the conservative pathway.
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Gabapentin alleviates these symptoms in hemodialysis (HD) patients but data are lacking for
Objectives. To determine the safety and effectiveness of gabapentin for pruritus or RLS
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in conservatively managed patients (n=34) with CKD and ESKD.
Methods. This was a single center, retrospective cohort study. We compared dosing and
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side effects in the 34 CKD/ESKD patients to similar patients receiving HD (n=15). Results. Forty-four percent of conservatively managed patients complained of RLS and/or pruritus; 18% were excluded for a non-uremic cause of symptoms. Thirty-four patients were included in the final analysis. The most common starting daily dose of gabapentin was the
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equivalent of 50mg (44.1%) or 100mg (38.2%) daily, with the median daily dose 100mg (range 39-455mg). Side effects occurred in 47% of patients, with 17% discontinuing gabapentin. Gabapentin reduced symptoms of pruritus (P<0.001) and RLS (P<0.05). There was no statistical
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difference when comparing HD and conservatively managed patients for daily starting dose (P=0.88), median dose (P=0.84) and final dose (P=0.18). Patients conservatively managed were
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more likely to manifest side effects compared with HD patients (47.1% vs. 14.3%, P=0.023). Dose was not found to be a factor associated with side effects in univariate analysis. Conclusion. Gabapentin is a viable treatment for conservatively managed CKD and ESKD patients with pruritus and/or RLS but side effects are common. Gabapentin should be used with caution although higher doses do not appear to be a factor associated with side effects.
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Key Words: Gabapentin, pruritus, restless legs syndrome, dialysis, end-stage kidney disease, conservative management Running title: Gabapentin for Pruritis and RLS in ESKD
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Accepted for publication: August 14, 2014.
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Introduction Patients with end-stage kidney disease (ESKD) are heavily burdened with symptoms. Two of the most common are uremic pruritus and restless legs syndrome (RLS). RLS is a
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neurological disorder characterised by sensorimotor symptoms such as paraesthesia and
restlessness mainly affecting the lower limbs, occurring during rest in the evening or overnight, and at least partially relieved by movement (1). The prevalence of RLS in patients with ESKD
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on hemodialysis (HD) ranges from 5% to 62% (2-5), whereas pruritus affects 22-42% (6-9). Singularly or in combination, pruritus (9) and RLS (4, 5) have a profound effect on sleep, quality
patients who suffer from these symptoms.
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of life and mortality. Their aggravating nature and unpredictability can make life a misery to
Gabapentin (1-aminomethyl cyclohexane acetic acid) is a structural analogue of gammaaminobutyric acid (GABA) developed for the treatment of epilepsy. It is effective in managing
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both uremic pruritus (10-12) and RLS (3, 13, 14) in ESKD patients receiving renal replacement therapy (RRT). However, to date there have been no studies examining the use of gabapentin for the treatment of RLS symptoms in patients with ESKD who are managed conservatively. Only
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one study examined its use in uremic pruritus for patients with chronic kidney disease (CKD) managed conservatively (15). This is especially important because this subgroup of patients is
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elderly, frail and often has multiple comorbidities. As renal function deteriorates, their ability to renally clear gabapentin decreases, with an increased risk of developing side effects. Therefore, we set out 1) to determine the effectiveness of gabapentin in the treatment of pruritus and RLS in patients conservatively managed for CKD, including patients with ESKD, and 2) to establish its safely in this group. Methods
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We conducted a retrospective, single center, cohort study. All patients for conservative management of ESKD and CKD referred to the Renal Supportive Care Clinic (RSC-C) in a tertiary care facility (St. George Hospital, Sydney) between April 2010 and June 2013 were
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identified. We defined conservative management in ESKD as any patient who a) did not wish to commence dialysis or undergo kidney transplantation or b) did not pursue dialysis treatment based on medical advice and/or ethical grounds as a shared decision. Inclusion criteria were
years of age and attended the outpatient RSC-C at least twice.
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patients with CKD stage II-V on a non-dialysis conservative pathway who were older than 18
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A palliative care physician reviewed all patients for the duration of the study. We excluded patients with an identifiable non-CKD cause of RLS or pruritus, incomplete/missing data and incomplete questionnaires, or who started gabapentin before attending the clinic. We simultaneously identified dialysis patients referred to the RSC-C for symptom management for
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comparison of differences in dosing and side effects. This study was approved by the Human Research Ethics Committee, South Eastern Sydney Local Health District (reference number HREC/10/STG/121).
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Sociodemographic, clinical and laboratory data were obtained at the initial review, including age, gender, body mass index (BMI), smoking status, and history of diabetes and
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cerebrovascular disease (CVD). Laboratory parameters included serum urea (mmol/L), creatinine (umol/L), eGFR, albumin (g/L), calcium (mmol/L), phosphate (mmol/L), HbA1c (%) for diabetic patients, hemoglobin (g/L), C-reactive protein (CRP) (mg/L) and parathyroid hormone (PTH) (pmol/L).
Patients were asked to complete the Palliative care Outcome Scale-Symptoms (POS-S)Renal (16), a validated symptom inventory instrument, on the first visit prior to commencing
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gabapentin and on each subsequent visit. The POS-S Renal was used to assess progress and management of symptoms. We apportioned a numerical figure to the level of reported severity (0 to 4 according to whether the reported severity was not at all, slight, moderate, severe, or
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overwhelming).The scores for pruritus, RLS and total symptom (TS) were recorded at the initial visit before gabapentin was started as a baseline. All subsequent visits were compared to this. The usual starting dose of gabapentin in patients with ESKD was 100mg on alternate
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nights, and in CKD stage III-IV, 100- 200mg nightly. The dose was increased if no symptomatic relief was achieved while documenting, monitoring and informing patients of potential side
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effects. We requested a compounding pharmacist to arrange 25mg tablets to facilitate small incremental increases in dosing for patients who manifested side effects at higher doses. We documented the initial dose of gabapentin, the daily dose between the first clinic visit and the final clinic visit, and the final dose of gabapentin at the last clinic visit within the study period.
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When gabapentin was administered on alternate days or once every three days, we calculated the average daily dose. We documented duration of therapy, changes in the POS-S Renal, side effects and cessation of gabapentin.
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Our primary outcomes were: a) changes in POS-S Renal score for pruritus, RLS and TS, b) side effects and need for cessation of gabapentin, and c) doses of gabapentin used. We
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compared outcomes in patients on the conservative pathway with those on HD receiving gabapentin for symptom control. Statistical Analysis
Categorical data are expressed as frequency (%) and compared using the Chi-squared test. Continuous data are expressed as medians with interquartile ranges [IQR; 25th -75th percentile] or mean with standard deviation (SD) and compared by the Student’s t-test or Mann-
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Whitney U test as appropriate. For comparison between POS-S Renal at baseline and on subsequent visits, we used the Wilcoxon signed rank test. We did not censor patients who subsequently ceased gabapentin. Univariate logistic regression analysis was performed to
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calculate the odds ratio (OR) and 95% confidence intervals (CI) of factors associated with the emergence of side effects. All statistical analyses were performed using SPSS v. 19.0 (SPSS Inc., Chicago, IL). A P-value of <0.05 was considered significant.
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Results
Between April 2010 and June 2013, there were 184 new referrals to the RSC-C, including
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125 patients for conservative management of CKD and ESKD (Fig. 1). In this group, 44% (55 patients) complained of RLS and/or pruritus and met the inclusion criteria. We excluded 10 patients for non-uremic causes of pruritus and RLS (18%) and nine who started gabapentin prior to the clinic assessment. Two patients commenced HD after referral and were included until
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commencing HD, then censored. The final study group comprised 34 patients, 30 with uremic pruritus and 18 with RLS (some patients had both symptoms). During the same time period, 59 patients on HD were referred for symptom control;15 met the inclusion criteria and received
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gabapentin (13 with pruritus and six with RLS). Table 1 highlights the demographics of the conservatively managed group. Most were
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elderly, average age 80 years, with a mean creatinine on presentation of 317 umol/L. Patients with CKD stage V accounted for 47% (16 patients), CKD stage IV 41% (14 patients) and CKD stage III 12% (four patients). During the study period, 41.2% (14 patients) died within 8.0 months [range 4.4- 9.0].
Gabapentin Dose and Toxicity in the Conservatively Managed Group
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Thirty-four patients on the conservative non-dialysis pathway received gabapentin for symptom control. Gabapentin was commenced for pruritus in 30 patients, RLS in 18 patients (16 patients with both RLS and pruritus). The mean (SD) TS score for the study group, using the
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POS-S Renal, was 22.1 (8.8). In the pruritus group, the TS score was 22.6 (8.9) and in the RLS group, 23.4 (7.9).
The most common daily starting dose was the equivalent of 50mg (44.1%) and 100mg
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daily (38.2%), followed by <50 mg (8.8%) and 200mg (8.8%). The dose was titrated at
subsequent visits to achieve symptom control while balancing side effects. The median daily
clinic visit of 100mg (range 50mg- 600mg).
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dose was 100mg (range 39- 455mg), which was similar to the median daily dose on the final
At least one side effect occurred in 47% (16 patients), with 29% (10 patients) stopping gabapentin after a median of 2.6 [1.2, 4.8] months. In total, 17% (six patients) permanently
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discontinued gabapentin. The most common side effect was drowsiness, followed by dizziness and fatigue (Table 2).
Effectiveness of Gabapentin in the Conservatively Managed Group
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Gabapentin was effective in reducing symptoms of pruritus in patients with CKD and ESKD managed conservatively (Fig. 2). By visit 4 (median 12.6 weeks of treatment) and on the
0.001).
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final visit (median 27.0 weeks), more than 80% had a POS-S Renal pruritus score ≤ 1 (P<
Gabapentin was similarly effective for the patients with RLS (Fig. 3). There was a statistically significant improvement in symptom control of RLS when comparing the first visit with subsequent visits (P<0.05). Conservatively Managed Group vs. Dialysis Group
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Fifteen HD patients were included for comparison. Table 1 shows the baseline characteristics of this group and Table 2, the side effect profile from gabapentin. Similar to patients managed conservatively, gabapentin was found to be effective in relieving symptoms of
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pruritus in patients on HD (P<0.05 between the first visit and on subsequent visits). For patients with RLS, this only reached statistical difference when comparing the first pre-gabapentin visit to the final visit at the end of the study (P=0.038).
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We compared baseline characteristics (Table 1) and outcomes between the two groups of patients receiving gabapentin (Table 3). There was no statistically significant difference when
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comparing the starting daily dose of gabapentin (P=0.88), average daily dose (P=0.84), final daily dose (P=0.18) or number of patients who discontinued gabapentin (P=0.20). However, patients on the conservative management pathway were more likely to manifest a side effect (47% vs. 14%, P= 0.023).
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To establish which variables were associated with side effects, we performed a univariate analysis in the conservatively managed group. No single variable emerged that was significantly associated with side effects including the starting dose of gabapentin (P=0.86), average
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equivalent daily dose (P=0.99) and final dose (P=0.93). When we combined the study population into one group (HD and conservatively managed patients, n=49), univariate analysis confirmed
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that being a conservatively managed patient was the only variable predicting a higher likelihood of developing side effects (OR 5.8; 95% CI 1.1, 29.6, P=0.035). Discussion
Previous studies confirmed the symptomatic improvement in uremic pruritus and RLS for ESKD patients receiving RRT treated with gabapentin (3, 10-14), with one study examining its use in patients with CKD suffering from uremic pruritus (15). Our retrospective study of
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consecutive, symptomatic, conservatively managed ESKD patients further adds to this knowledge by confirming the use of gabapentin for this group and examining its safety profile. Patients with ESKD are heavily burdened with symptoms, with two of the most common
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being RLS and pruritus. In our cohort of CKD patients, 44% were affected (20% with RLS and 37% with pruritus). This is consistent with previous studies documenting that 4.7%-68% of HD patients are affected with RLS (2, 3, 13, 17, 18). The prevalence of pruritus in ESKD is similarly
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high and affects 22%- 90% of patients (6, 19, 20). It is noteworthy that 18% of our patients had a potentially non-ESKD reversible cause, highlighting the importance of a thorough history and
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physical examination as part of the assessment process.
Treatment aims to reduce the burden caused by these symptoms and improve quality of life. Pruritus is disabling and distressing, significantly impacting patients’ mental and physical capacity by contributing to daytime fatigue, agitation, depression, poor sleep and decreased
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quality of life (6, 19, 20). Similarly, RLS negatively impacts patients with ESKD undergoing HD, affecting sleep (5, 18) and quality of life (5). There is a modest but growing body of literature showing the efficacy of gabapentin in
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the management of both uremic RLS and pruritus. There are two principal concerns when prescribing gabapentin to this cohort of patients: dose strength and frequency. Gabapentin is not
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metabolized, does not bind to plasma protein and is completely dependent on renal elimination (21). It exhibits a prolonged half-life in anuric subjects on non-HD days (132 hours) compared with anuric patients on HD days (52 hours) and healthy subjects (5-7 hours) (21). There is a significant rise in side effects and plasma gabapentin levels when comparing patients with normal renal function, those with impaired function, and those on RRT (22). In our group of HD patients receiving gabapentin for symptomatic management, a side effect occurred in 13% of
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cases. This is comparable to the 6%-20% (3, 11, 15) exhibited in other studies. In populations with normal renal function treated with gabapentin for RLS, a side effect occurred in 25% of patients (23, 24). Our conservatively managed group exhibited a much higher rate, with 47% of
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patients reporting a side effect and 17% having to permanently discontinue the drug. This is similar to a study examining gabapentin use for uremic pruritus in CKD patients not on RRT reporting a side effect profile of 40%, with 48% discontinuing the drug (15)
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In view of a reduced clearance and an increase in side effects, it is important to determine the correct dosing of gabapentin. In the studies on the efficacy of gabapentin for HD patients, the
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dosing regimen varied considerably, from 100mg to 400mg postdialysis (100mg post HD [11, 15, 25], 100-300mg post HD [20], 200mg post HD [3], 200-300mg post HD [13], 300mg post HD [10] 400mg post HD [12]). This is similar to the dose we used in our group to achieve symptom control. However, on univariate analysis, we did not find dosing to be a factor
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influencing the likelihood of side effects. In the entire study group (HD and conservatively managed), the only statistically significant factor was being on the conservative pathway. Another retrospective study also showed dosing did not influence the emergence of side effects,
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which was more affected by age and comorbidities (22). A limitation of our study is the large number of exclusions, especially those who
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commenced gabapentin before a questionnaire was completed. We did not have a control group to compare the common side effects present in this group of patients, such as fatigue or drowsiness, which may have causes other than gabapentin. We also had a small number of patients with RLS on HD, possibly contributing to the lack of statistical significance. No distinction was made between the frequency of dosing (more than once a day, daily, on alternate days or more), instead calculating the daily dosing. Given the reduction in renal clearance, the
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frequency of dosing may contribute equally to the emergence of side effects. This requires further investigation. Finally the retrospective nature of our analysis yields only suggestive
between the two groups, including reporting and observer bias.
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conclusions as a result of the likelihood of bias related to factors that systematically differ
Although a blinded randomized trial would yield the most accurate results, we did not pursue such an approach. Several well-conducted studies have shown gabapentin has efficacy for
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the symptomatic relief of RLS and uremic pruritus in those with HD. Given the high burden of symptoms in our group of conservatively managed patients with a high mortality rate (41%
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within eight months), the primary objective was to determine effective dosing for reduction of symptoms and increased comfort without causing undue side effects. In summary gabapentin is a viable treatment option for CKD patients with pruritus and RLS who are conservatively managed without dialysis. Although side effects are more common
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and the risks are higher, it still results in symptom improvement and was continued in 83% of patients. The next step will be to determine the optimum dosing, frequency and amount in these patients to balance symptom control with risks.
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Disclosures and Acknowledgments
No funding was received for this study and the authors declare no conflicts of interest.
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2. La Manna G, Pizza F, Persici E, et al. Restless legs syndrome enhances cardiovascular risk and mortality in patients with end-stage kidney disease undergoing long-term haemodialysis treatment. Nephrol Dial Transplant 2011;26:1976-1983.
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3. Micozkadioglu H, Ozdemir FN, Kut A, et al. Gabapentin versus levodopa for the treatment of Restless Legs Syndrome in hemodialysis patients: an open-label study. Ren Fail 2004;26:393397.
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4. Perl J, Unruh ML, Chan CT. Sleep disorders in end-stage renal disease: 'markers of inadequate dialysis'? Kidney Int 2006;70:1687-1693.
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5. Mucsi I, Molnar MZ, Ambrus C, et al. Restless legs syndrome, insomnia and quality of life in patients on maintenance dialysis. Nephrol Dial Transplant 2005;20:571-577. 6. Patel TS, Freedman BI, Yosipovitch G. An update on pruritus associated with CKD. Am J Kidney Dis 2007;50:11-20.
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7. Mettang T, Pauli-Magnus C, Alscher DM. Uraemic pruritus--new perspectives and insights from recent trials. Nephrol Dial Transplant 2002;17:1558-1563. 8. Urbonas A, Schwartz RA, Szepietowski JC. Uremic pruritus--an update. Am J Nephrol
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11. Razeghi E, Eskandari D, Ganji MR, et al. Gabapentin and uremic pruritus in hemodialysis patients. Ren Fail 2009;31:85-90.
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12. Naini AE, Harandi AA, Khanbabapour S, et al. Gabapentin: a promising drug for the treatment of uremic pruritus. Saudi J Kidney Dis Transpl 2007;18:378-381. 13. Thorp ML, Morris CD, Bagby SP. A crossover study of gabapentin in treatment of restless
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15. Rayner H, Baharani J, Smith S, Suresh V, Dasgupta I. Uraemic pruritus: relief of itching by gabapentin and pregabalin. Nephron Clin Pract 2012;122:75-79.
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16. POS Development Team. Palliative care Outcome Scale Symptoms Renal. Available from http://pos-pal.org/maix/.
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18. Merlino G, Piani A, Dolso P, et al. Sleep disorders in patients with end-stage renal disease undergoing dialysis therapy. Nephrol Dial Transplant 2006;21:184-190. 19. Pisoni RL, Wikstrom B, Elder SJ, et al. Pruritus in haemodialysis patients: international
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23. Garcia-Borreguero D, Larrosa O, de la Llave Y, et al. Treatment of restless legs syndrome with gabapentin: a double-blind, cross-over study. Neurology 2002;59:1573-1579.
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24. Mellick GA, Mellick LB. Management of restless legs syndrome with gabapentin
25. Bassilios N, Launay-Vacher V, Khoury N, et al. Gabapentin neurotoxicity in a chronic
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haemodialysis patient. Nephrol Dial Transplant 2001;16:2112-2113.
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Table 1. Baseline Characteristics of Patients on Conservative Pathway or HD With Pruritus and RLS.
HD Group
(n= 34)
(n=15)
Age (yrs)
80.0 (7.1)
70.1 (10.6)
Male
19 (55.9)
11 (73.3)
BMI
29.6 (5.9)
29.1 (7.4)
Height (cm)
163.1 (10.5)
166.2 (12.4)
Weight (Kg)
79.2 (18.6)
81.9 (29.4)
0.67
21 (61.8)
7 (46.7)
0.59
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Smoking: None
P-value
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Conservative Group
< 0.001 0.25
0.78
0.48
Former
9 (26.5)
6 (40.0)
0.32
Current
4 (11.8)
2 (11.3)
0.85
9 (26.5)
1 (6.7)
0.11
20 (58.5)
12 (80.0)
0.15
25.1 (11.4)
18.2 (4.5)
0.03
316.8 (132.0)
572.9 (110.2)
< 0.001
18.4 (10.8)
-
-
36.0 (6.2)
31.3 (3.6)
0.009
2.32 (0.2)
2.26 (0.2)
0.47
1.3 [1.2- 1.7]
1.6 (0.5)
0.34
7.8 (1.3)
6.8 (1.7)
0.27
112.0 [103.7- 118.0]
116.5 (11.5)
0.24
CRP n=25
5.0 [2.0- 16.5]
9.0 [2.0- 16.5]
0.27
PTH n=21
23.0 [10.4- 40.0]
16.8 [11.3- 23.9]
0.28
14 (41.2)
7 (46.7)
0.72
0.67 [0.37- 0.96]
0.91 [0.22- 1.99]
0.44
Comorbidity: CVD Diabetes
Creatinine (umol/L) eGFR Albumin (g/L)
EP
Calcium (mmol/L) n=33 Phosphate (mmol/L)
AC C
HbA1c (%) n=10
TE D
Pathology: Urea (mmol/L) n=27
Hb (g/L)
Mortality Time to Mortality (Years)
Data expressed as number of patients (%). Continuous data expressed as mean (standard deviation) or median
16
ACCEPTED MANUSCRIPT
[interquartile range] as appropriate. HD = hemodialysis; RLS = restless legs syndrome; BMI = body mass index; CVD = cerebrovascular disease; eGFR = estimated glomerular filtration rate; Hb = haemoglobin; CRP =C-reactive protein; PTH= parathyroid
AC C
EP
TE D
M AN U
SC
RI PT
hormone.
17
ACCEPTED MANUSCRIPT
Table 2. Gabapentin Side Effects Hemodialysis Group
(n= 34)
n=15
16 (47.0)
2 (13.3)
Drowsiness
8 (50)
-
Dizziness
3 (19)
-
Fatigue
3 (19)
-
Blurred vision
2 (12.5)
1 (6.66)
Unsteadiness
2 (12.5)
2 (13.3)
Confusion
1 (6.25)
SC
M AN U
≥ 1 side effect
RI PT
Conservative Group
-
Data expressed as number of patients (%). Patients may have had more than
AC C
EP
TE D
one side effect.
18
ACCEPTED MANUSCRIPT
Table 3. Comparison Between Conservatively Managed and HD Patients Receiving Gabapentin Haemodialysis Group
(n= 34)
(n=15)
14 (41.2)
7 (46.7)
0.48
0.67 [0.37-0.75]
1.1 (0.85)
0.18
22.1 (8.8)
17.9 (6.1)
0.10
Gabapentin daily starting (mg)
50.0 (25.0-200.0)
42.8 (42.8-171.4)
0.88
Gabapentin daily average (mg)
100.0 (38.6-454.5)
90.0 (42.8-206.8)
0.84
Gabapentin daily final (mg)
100.0 (50.0-600.0)
128.6 (42.8-257.1)
0.18
Time to Mortality (yrs)
M AN U
POS-S (Renal) TS
SC
Mortality
P-value
RI PT
Conservative Group
Side effects
16 (47.1)
2 (13.3)
0.023
Ceased
10 (29.4)
2 (13.3)
0.20
Data expressed as number of patients (%), mean (standard deviation) or median [interquartile range] as
AC C
EP
TE D
appropriated. Gabapentin doses are expressed as daily doses. P< 0.05 considered significant and in bold.
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ACCEPTED MANUSCRIPT
6 patients Started Gabapentin prior to clinic
AC C
EP
-
4 patients None uremic cause of pruritus 1 Scabies 1 Fungal/Infective 1 Histamine/ food related 1 Severe leg burns
TE D
2 Patients Inaccurate assessment from severe pain, psychiatric history/noncompliance.
15 Patients - 13 Pruritus - 6 RLS
Figure 1: Flowchart showing patient selection.
Meets inclusion criteria
55 patients
M AN U
27 patients
125 Patients Conservative
SC
59 Patients Dialysis
RI PT
184 patients Referred to Renal supportive care clinic between April 2010 and July 2013
34 Patients - 30 pruritus - 18 RLS
9 patients Started Gabapentin prior to clinic 2 patients Incomplete data 10 patients None uremic cause of pruritus - 1 Inflammatory - 1 Scabies - 5 Fungal/Infective - 1 Histamine/ food related - 1 Herpatic neuralgia None uremic cause of RLS - 1 Familial RLS
ACCEPTED MANUSCRIPT
p< 0.001 p< 0.001 p< 0.001 p< 0.001 100%
RI PT
POS Scale 4 90% 80%
SC
70% 60%
POS Scale 2 POS Scale 1 POS Scale 0
POS-S Pruritus Score Scale 4 Scale 3 Scale 2 Scale 1 Scale 0
M AN U
50%
POS Scale 3
40% 30% 20%
TE D
10% 0%
Visit 1
Visit 3
Visit 4
Visit Final
29 27 24 30 3.0 [1.0,4.5] 7.0 [4.0,9.0] 12.6 [7.9,14.8] 27.0 [14.2,73.0] 16.1 (6.8) p<0.001 14.1 (6.1) p<0.001 17.2 (7.8) p=0.021 16.9 (8.7) p=0.003
EP
Number of patients 30 Time, weeks [IQR] Total Symptom POS-S 22.6 (8.9)
Visit 2
AC C
Figure 2: POS-S pruritus symptom score change following gabapentin administration after visit 1 for patients with pruritus. Time is the interval between the initial consultation (visit 1) and subsequent visits in weeks [Intrequartile Range]. Total symptom POS-S expressed as mean (SD) for the whole group. Pruritus score between visit 1 and subsequent visits compared using Wilcoxon signed rank test. We did not censor patients who discontinued gabapentin.
ACCEPTED MANUSCRIPT
p= 0.023 p= 0.003 p= 0.002 p= 0.001
100%
POS Scale 3 90%
RI PT
POS Scale 2
80% 70%
SC
60% 50%
30% 20% 10%
TE D
0%
Visit 1 Number of patients 18 Time, weeks [IQR] Total POS score 23.4 (8.1)
Visit 2
Visit 3
Visit 4
Visit Final
18 16 13 18 3.0 [1.1,5.2] 7.0 [4.0,10.6] 13.0 [8.5,22.0] 29.5 [14.2,62.5] 17.3 (6.8) p=0.004 16.1 (6.4) p=0.001 17.6 (8.5) p=0.074 18.4 (8.8) p=0.009
EP
Figure 3: POS-S RLS symptom score change, following gabapentin administration after visit 1, for patients with RLS. Time is the interval between the initial consultation (visit 1) and subsequent visits in weeks [Intrequartile Range]. Total POS score expressed as mean (SD) for the whole group. RLS scores between visit 1 and subsequent visits compared using Wilcoxon signed rank test. We did not censor patients who discontinued gabapentin.
AC C
POS Scale 0
POS-S RLS Score Scale 4 Scale 3 Scale 2 Scale 1 Scale 0
M AN U
40%
POS Scale 1