Uremic pruritus is a common discomfort of hemodialysis patients. Gabapentin is an emerging treatment with increasing investigation of its efficacy and safety in these patients. Our qualitative analysis characterizes the current evidence available for gabapentin to manage uremic pruritus.

Gabapentin is likely effective for uremic pruritus but adverse events are common. Starting at a low dose of 100 mg orally after hemodialysis and titrating to effect may best provide effective and safe outcomes.

Uremic pruritus (UP) is a common discomfort of dialysis-dependent end-stage renal disease (ESRD). A global cross-sectional study of 18,801 hemodialysis (HD) patients found 42 % of patients experience moderate to extreme pruritus, with significant associations with decreased quality of life, poor sleep, depression, and increased mortality [1]. UP is characterized by daily itching bouts of symmetrical distribution with increasing intensity at night [2]. The pruritus may be generalized or localized, in particular, to the head, arms, back, and abdomen [2]. Despite its high incidence and significant impact on HD patients, the pathophysiology of UP is poorly understood.

Various pathophysiological mechanisms have been proposed, including skin xerosis, histamine binding to the H₄ receptor, xenobiotic agents, and the accumulation of uremic toxins [2, 3]. Neuropathic changes in ESRD is one of the newer mechanisms explored [4]. UP is thought to be of central origin, where uremic toxins may cause neuropathy and central sensitization to itch [2]. This proposed mechanism is further supported by the correlation between itch and pain, as both are conveyed by C-fibers in the dorsal horns and transmitted to the thalamus and somatosensory cortex via the lateral spinothalamic tract [2].

Gabapentin is an antiepileptic agent that has analgesic properties in neuropathic pain [3]. Its specific pharmacological mechanism is poorly understood but its involvement in inhibiting neuronal calcium influx may interrupt the series of neuropathic events that lead to pruritic sensation in uremia [5]. It is an emerging drug for UP with an increasing number of studies published investigating its efficacy and safety for this condition. No major renal societies have created guidelines for the management of UP in hemodialysis patients, but gabapentin is recognized as a second- or third-line agent for generalized UP refractory to topical emollients and/or oral antihistamines [6]. As gabapentin is renally eliminated, its significantly increased half-life in HD patients is concerning. As several studies have been published since the most recent systematic review by Vila et al. in 2008, we sought to conduct an updated qualitative systematic review investigating the efficacy and safety of gabapentin for UP in HD patients [7].

Studies were included in our systematic review if they were published randomized controlled trials (RCTs), quasi-RCTs, observational studies, open-label studies, or retrospective studies of any length of follow-up. Case series or case reports were excluded from our review. All studies evaluating gabapentin, with or without a comparator group for UP in adult HD patients, were included. Studies were obtained by searching in Ovid MEDLINE (1946–2015 June 19), EMBASE (1974–2015 June 19), Cochrane Central Register of Controlled Trials (June 2015), Clinicaltrials.gov (June 2015), and Google Scholar (June 2015) using the search strategy outlined in the Appendix. All publication types (e.g., conference abstracts or trial registries) and unpublished literature meeting our inclusion and exclusion criteria were considered. Reference lists of all identified articles were manually searched. We restricted our search to English-only studies.

Titles, abstracts, and full-text when needed were screened by TL and WL independently based on the above inclusion criteria. If disagreements occurred over the inclusion of studies, the two authors discussed their reasons for their decision until a consensus is reached. If a consensus could not be reached, SL independently assessed the study and made the final decision.

Studies were classified by their quality of evidence adapted from the 1996 United States Preventive Services Task Force classification system [8]. Level I studies are randomized controlled trials. Level II-1 studies are controlled trials (either as self-controls or with a comparator group) without randomization and level II-2 studies are cohort or case control studies. Level II-3 studies are multiple time series with or without intervention and level III evidences are descriptive studies, case reports, or expert opinion. TL and WL independently extracted and confirmed the data presented in this qualitative review. Any outcomes assessing efficacy or safety of gabapentin in the HD population were extracted and described. Authors of studies were contacted when data was missing or ambiguous. No funding was received for our systematic review.

Study quality was assessed using the Jadad scale for randomized controlled trials, with scores ranging from 0 to 5 [9]. For cohort studies, the Newcastle Ottawa scale was used to assess risk of bias on a scale ranging from 0 to 9 [10]. Level of agreement on study eligibility and quality assessment was tested using kappa statistic.

Figure 1 depicts a PRISMA flow diagram of our study selection process. Of the 198 studies identified from the database search, 9 full-text articles were screened for eligibility. Upon further review, we excluded 1 case report [11], and 1 trial studying patients with neuropathy or neuropathic pain that did not meet our inclusion criteria (kappa = 1, perfect) [12]. One study published in Persian had an English abstract; but based on the abstract alone, we could not determine if the population studied were HD patients and was not included in our review [13]. We contacted the authors but did not receive a response up until the time of publication. The characteristics of the final 7 studies with a total of 179 patients included in the systematic review are depicted in Table 1. Where studies compared gabapentin to alternative agents [14, 15], or compared HD patients to non-HD patients [16], only data from the relevant arm were extracted and discussed below.

Authors (year)	Design	Patient characteristics	Previous medication trialed	Exclusion	Gabapentin regimen	Efficacy outcomes	Quality assessment	Safety outcomes (n)
Level I evidence
Gunal et al. (2004) [17]	R DB PC cross-over	N = 25 HD 3×/week, 4–5-h sessions Kt/V 1.37 ± 0.35 (0.5–1.93) Males 56.0 % Mean age 55 ± 11 (32–77) Baseline: Ca 2.15 ± 0.23 mmol/L PO4 1.45 ± 0.39 mmol/L iPTH 20.5 ± 14.3 pmol/L	Refractory to antihistamines, nicergoline, moisturizers	NR	Gabapentin 300 mg 3× weekly post-HD × 4 weeks, then 1-week washout, then placebo × 4 weeks vs. the reverse	In chronological order: Baseline VAS (0–10) 8.5 ± 0.94 After 4 weeks placebo 7.6 ± 2.6 (p = 0.098) After 1-week washout 7.9 ± 1.1 After 4 weeks gabapentin 1.2 ± 1.8 (p = 0.0001) Follow-up: 9 weeks	3a	Mild to moderate somnolence, dizziness, fatigue
Naini et al. (2007) [19]	RCT DB PC	N = 34 HD 2×/week Males 47.1 % Mean age 62 ± 10 (43–81)	Refractory to antihistamines	Hgb < 70 g/L, PTH > 33 pmol/L, PO4 > 2.26 mmol/L, Other skin disease	Gabapentin 400 mg 2× weekly post-HD vs. placebo × 4 weeks	Baseline VAS (0–10) 7.2 ± 2.3 After 4 weeks 6.7 ± 2.6 vs. 1.5 ± 1.8 (p < 0.001) Follow-up: 4 weeks	4a	Mild to moderate somnolence, dizziness, nausea
Tol et al. (2010) [20]	R blinded cross-over	N = 14 HD 3×/week, 4–5-h sessions Kt/V 1.33 ± 0.17 (1.0–1.7) Males 50 % Mean age 59.7 ± 17.2 (41–88) Baseline: Ca 2.23 ± 0.18 mmol/L PO4 1.62 ± 0.29 mmol/L iPTH 31.68 ± 12.87 pmol/L	Refractory to antihistamines, nicergoline, moisturizers	<18 years old, pregnant/lactating	Gabapentin 300 mg 3× weekly post-HD × 8 weeks, then 1-week washout, then placebo (unknown duration)	Pruritus VAS score (0–10): Before gabapentin 7.6 ± 1.2 After gabapentin 1.3 ± 1.4 (p < 0.01) Follow-up: NR	2a	No side effects observed
Level II-1 evidence
Razeghi et al. (2009) [18]	DB PC single-arm cross-over	N = 34 HD 3×/week, 4-h sessions Kt/V 1.31 ± 0.2 Males 23 % Mean age 58.4 ± 12.5 (28–73) Baseline: Ca 2.38 ± 0.63 mmol/L PO4 2.02 ± 0.75 mmol/L iPTH 12.2 ± 11.33 pmol/L	Refractory to antihistamines and moisturizers	Skin lesions, metabolic diseases, drug allergies, non-compliance	Gabapentin 100 mg 3× weekly post-HD × 4 weeks, then 1-week washout, then placebo × 4 weeks	In chronological order: Baseline VAS (0–100) 100 After 4 weeks gabapentin 6.4 ± 8.5 (p < 0.001) After 1-week washout 15 ± 11.3 (p < 0.001) After 4 weeks placebo 81.9 ± 11.1 (p < 0.001) Follow-up: 9 weeks	2a	Dizziness, drowsiness, and fatigue (2)
Marquez et al. (2012) [14]	Quasi-randomize, OL cross-over	N = 19 HD 3×/week, 4-h sessions Kt/V 1.23 ± 0.3 Males: NR Mean age 54 ± 18 Baseline: Ca 2.35 ± 0.3 mmol/L PO4 1.65 ± 0.53 mmol/L iPTH 5.79 ± 5.0 pmol/L	NR	Chronic skin or liver diseases, malignancy, chronic opiates or corticosteroids	Gabapentin 300 mg 3× weekly post-HD × 3 weeks, then 1-week washout, then desloratadine 5 mg 3× weekly × 3 weeks, vs. the reverse	Baseline VAS (0–10) 5.95 After 3 weeks gabapentin 4.6 (p = 0.07) After 3 weeks desloratadine 3.44 (p = 0.004) Follow-up: 7 weeks	1a	Fatigue and somnolence (9) Medication discontinuation (4)
Level II-2 evidence
Rayner et al. (2012)[15]	Step-wise OL	N = 40 HD (71 including PD and CKDND) Kt/V: NR Males 77.5 % Median age 64 (35–88) Baseline: Ca 2.45 mmol/L PO4 1.54 mmol/L iPTH 25.3 pmol/L	Refractory to emollients or antihistamines 58 % of HD patients tried antihistamines	NR	Gabapentin 100 mg daily post-HD, adjusted to efficacy and tolerability; final median 700 mg/week Min: 100 mg post-HD Max: 900 mg daily	Significant reduction of itch 31 (77.5 %) Median follow-up: 2.5 months	5b	Unknown adverse event (8)
Chiekh Hassan et al. (2015)[16]	R, cohort	N = 13 HD with pruritus (15 total) Kt/V: NR Males 73.3 % Mean age 70.1 ± 10.6 Baseline: Ca 2.26 ± 0.2 mmol/L PO4 1.6 ± 0.5 mmol/L iPTH 16.8 pmol/L (IQR 11.3–23.9)	NR	Identifiable non-CKD cause of RLS or pruritus, incomplete/missing data, on gabapentin prior to attending institution	Gabapentin 100 mg q2d, adjusted by 25 mg for efficacy and tolerability Final average 90 mg/day	POS-S Renal score (pruritus): Baseline 17.9 Subsequent visits: NR, p < 0.05 Follow-up: 27 weeks	6b	Unsteadiness (2) Blurred vision (1)

Ca calcium, CKD chronic kidney disease, CKDND chronic kidney disease non-dialysis, DB double-blind, HD hemodialysis, Hgb hemoglobin, h hour(s), iPTH intact parathyroid hormone, IQR interquartile range, Kt/V number used to quantify hemodialysis treatment adequacy, NR not reported, OL open-label, PC placebo-controlled, PD peritoneal dialysis, PO ₄ phosphate, R randomized, RCT randomized controlled trial, SB single-blinded, VAS visual analog scale

^aJadad score (0–5)

^bNewcastle Ottawa score (0–9)

Four studies reported no conflicts of interest [15–18] and the remaining three studies did not provide a statement of conflicts of interest [14, 19, 20]. Marquez et al. declared that gabapentin was supplied without charge from a local pharmaceutical company [14].

In general, the studies were small in size, ranging from 13 to 40 HD patients, and study designs were variable. Mean age ranged from 54 to 70 years and the percentage of males was variable. Where reported, HD was conducted three times weekly in all studies with the exception of the study by Naini et al. where patients are dialyzed twice weekly [19]. The mean Kt/V was only reported in four studies ranging from 1.23 to 1.37. Follow-up ranged from 4 to 27 weeks and was unreported in the study by Tol et al. [20]. Quality assessment of each study is reported in Table 1; overall, the initial agreement amongst the two assessors determined by kappa statistic was poor amongst the clinical studies (kappa = 0.167; poor agreement) and the kappa statistic for the cohort studies was perfect (kappa = 1.00; perfect agreement). After discussions, we determined the final reported quality scores as reported in Table 1.

Gabapentin dosing ranged from 100 mg post-HD (300 mg weekly) to 900 mg daily (6300 mg weekly). Five studies evaluated efficacy based on a visual analog scale (VAS) ranging from 0 to 10 with the exception of Razeghi et al. where a scale ranging from 0 to 100 was used [18]. The presence or absence of adverse events were reported in all studies and, when reported, were typically consistent with symptoms of central nervous system depression.

Current evidence supports a trial of gabapentin for the relief of UP in HD patients refractory to antihistamines and/or moisturizers. Since the first systematic review by Vila et al., there have been five new studies published but none were randomized controlled trials. Six of seven studies in our systematic review reported favorable outcomes on pruritus from baseline after administering gabapentin orally at various oral doses ranging from 100 to 400 mg post-HD or 900 mg daily. One study found statistically significant benefits on sleep, depression, and quality of life [20] and another commented on improvements with pain [15]. Razeghi et al. had 24 of 25 patients experiencing neuropathy but did not comment on whether the improvement in pruritus was accompanied by improvement in neuropathy [18]. Only one study found no difference between gabapentin and baseline [14]. Overall, we support recommendations that gabapentin is a suitable alternative for generalized UP after failing antihistamines and/or topical emollients [6].

Adverse events including dizziness, fatigue, and somnolence were frequently reported across the studies, including one study where 9 (47 %) patients reported fatigue and somnolence, and 4 (21 %) discontinued gabapentin due to adverse events [14]. Renal clearance of gabapentin may vary in different dialysis patients depending on residual renal function and a lower starting dose is recommended for patients who are anuric. From the adverse events that were reported, they often subsided over 5–10 days [17, 19]. Although no serious neurotoxicities were found, their occurrences in this population have been reported in the literature, emphasizing the importance of renal dosing adjustments to mitigate this preventable risk [22, 23].

Although 6 positive gabapentin trials for UP suggest the drug is efficacious, it is important to discuss the various limitations, confounders, and biases in the included trials. Improving dialysis efficacy, frequency, and duration has not been firmly linked with improved UP outcomes, but the possibility must be considered [2]. Patients in the Marquez et al. study underwent dialysis using reused low-flux dialyzers, a practice that contrasts to the high-flux dialyzers used in North America [14]. HD was only scheduled twice weekly in the trial by Naini et al., and the Kt/V, which is recommended to be greater than 1.2, was reported to be an average of 1.23 ± 0.3 in the study by Marquez et al., raising the possibility of underdialysis in a proportion of the study population [14, 19]. Multiple studies did not report information about dialysis duration, frequency, and other parameters important in assessing adequacy [15, 16, 19].

Further, the included level II-1 and II-2 studies were generally of lower quality, making the interpretation of the subjective outcome of pruritus difficult. Four studies had a cross-over design with 1-week washout for each and thus the possibility of residual gabapentin effects encroaching the placebo phases cannot be excluded [14, 17, 18, 20]. Tol et al. state that patients were randomized to receive gabapentin, but no obvious concurrent comparator group or arm was stated [20]. Our inability to interpret the study design precludes our ability to fully evaluate the outcomes presented in the study. In Table 1, we have elected to describe study design as reported by the authors. The quasi-randomization in the study by Marquez et al. and the lower Kt/V of 1.23 ± 0.3 compared to other studies may have accounted for the lack of statistically significant improvement [14]. The patients in Marquez et al. also had a lower baseline pruritic VAS score of 5.95 compared to the other studies, and exposures were measured only once at the end of each treatment period and not multiple times within that period [14]. There may thus be a smaller role for gabapentin for patients with mild pruritus, but direct comparisons cannot be inferred. Various studies used mean VAS scores instead of medians, which may have skewed the data given the small study sizes. None of the studies explicitly stated whether the data was analyzed by intention-to-treat or per-protocol. Given the presence of dropouts in the studies by Rayner et al. and Marquez et al., analyzing the data by intention-to-treat would be the conservative approach [14, 15]. When assessing for bias, it was noted that carryover effects were seen in Razeghi et al. where post gabapentin washout, the pruritus score was significantly lower than prior to intervention. All cross-over studies used a 1-week washout between phases and though the medication is noted to have a half-life of 5 to 7 h in healthy individuals, there was a study (n = 11) that found an apparent elimination half-life of 132 h in anuric hemodialysis patients (24). This leads one to question whether 1 week is sufficient to ensure that there is no active medication in the serum. Finally, the method of administration of the various scales and tools were not explicitly stated across the studies. As severity of pruritus is subjective, variations in administration and the presence of investigators may significantly bias results.

Our systematic review of seven studies supports the consideration of gabapentin for UP in HD patients refractory to first-line antihistamines and/or topical emollients, but the results should be interpreted cautiously due to the inclusion of generally lower quality studies. Alongside improvements in pruritus, gabapentin may additionally have a role in sleep, pain, quality of life, and depression in HD patients [15, 20]. If antihistamines and/or topical emollients are ineffective, we recommend considering starting gabapentin at the lowest possible dose of 100 mg orally post-HD and titrating slowly to minimize adverse events. Residual kidney function may contribute to variations in effective and tolerable dosages; Rayner et al. demonstrated that some patients may require dosages up to 900 mg daily [15]. Symptom improvement should be seen by 3 weeks and likely sooner [19]. The expected benefit is in the range of an absolute decrease of 5.7 to 9.4 points from baseline on a 10-point VAS scale by 3 to 8 weeks of medication use. Studies with titrations demonstrated that some patients may need higher dosages and would recommend titrations weekly depending on efficacy, tolerability, and availability of dosage forms. Side effects are often mild to moderate with this dosage and commonly occur within the first dose of medication and subsiding after 7 days.

Larger, well-designed, double-blinded, and controlled studies are required to minimize performance bias and placebo effect. Future studies may add to the literature by studying the additive efficacy of emollients and moisturizers to minimize the dosage of gabapentin or by comparing gabapentin with other agents like topical corticosteroids or more common antihistamines like diphenhydramine.