Level I evidence
Gunal et al. studied 25 adult patients at a single center in Turkey on HD thrice weekly using a polysulfone dialyzer . Patients did not have concomitant dermatological, liver, or metabolic diseases. Patients had refractory pruritus unresolved for greater than 8 weeks and had failed trials of antihistamines, nicergoline, or moisturizers. All antipruritic medications were discontinued for 1 week prior to treatment. Patients were randomized to receive 4 weeks of gabapentin 300 mg thrice weekly post-HD or placebo for 4 weeks in a double-blinded, cross-over fashion with a 1-week washout between treatments. Severity of pruritus was recorded on a VAS (0–10) once daily and the median score at each treatment period was used as the outcome score. A reduction in score of greater than or equal to 50 % was considered clinically significant.
All 25 patients completed the study with no dropouts. The mean Kt/V was 1.37 ± 0.35, and baseline mineral bone disease blood work were all within treatment target ranges based on the KDIGO 2009 recommendations . From a baseline mean VAS of 8.4 ± 0.94, placebo decreased the mean score to 7.6 ± 2.6 (p = 0.098) with 4 patients achieving clinically significant improvement. Gabapentin decreased the mean score to 1.2 ± 1.8 (p = 0.001) with 1 patient failing to achieve a clinically significant response. The 1-week washout produced near-baseline VAS score of 7.9 ± 1.1. Although incidence was not reported, mild to moderate somnolence, dizziness, and fatigue that typically subsided within 7 days were commonly experienced with gabapentin.
Naini et al. randomized 34 patients from Iran on HD twice weekly with refractory pruritus to antihistamines and persistent symptoms for greater than 8 weeks . Patients received either gabapentin 400 mg or placebo twice weekly post-HD for 4 weeks. All had normal liver enzyme tests and were reviewed by a dermatologist to ensure no evidence of other skin diseases. Antipruritic medications were discontinued 1 week prior to the study. Efficacy was assessed with a VAS (0–10) measured at the commencement of study and after each HD session. The mean decrease in pruritus scores after the study period was compared between the two groups.
Patient-specific baseline characteristics were not provided. After a baseline VAS score of 7.2 ± 2.3, a mean decrease of 6.7 ± 2.6 and 1.5 ± 1.8 in the gabapentin and placebo groups was found, respectively (p < 0.001). Separation of VAS scores between gabapentin and placebo were notable by the second HD session. The full antipruritic effects of gabapentin were approximately achieved by the sixth HD session. The most commonly reported side effects were mild to moderate somnolence, dizziness, and nausea, usually subsiding within 5–10 days from the first gabapentin dose. Incidence of side effects was not reported and no dropouts due to adverse events occurred.
Tol et al. studied 14 patients in a randomized, blinded, placebo-controlled cross-over trial at a single center in Turkey on HD three times weekly using a polysulfone dialyzer . The type of blinding or how patients were randomized was not specified. The authors were contacted but we did not receive a reply by the time of publication. Patients were refractory to antihistamines, nicergoline, and moisturizers, with symptoms lasting for more than 8 weeks. Patients had no concomitant disease states associated with pruritus, and all antipruritic medications were discontinued 1 week before the study. The authors state that patients were assigned to receive 8 weeks of gabapentin 300 mg post-HD, followed by a placebo phase of unspecified duration, with a 1-week washout between the treatment phases. Patients recorded the severity of their pruritus on a VAS daily. Reduction in the VAS score by 50 % was considered clinically significant. Median pruritus VAS score at baseline and each treatment periods were measured. The study further evaluated sleep quality, depression, and quality of life using the modified post-sleep inventory, the Beck Depression Inventory, and the Medical Outcomes Study (SF-36), respectively.
All 14 patients completed the study and no adverse events were observed. Baseline calcium, phosphate, and PTH were within normal limits. Gabapentin decreased pruritus VAS score from a mean 7.6 ± 1.2 to 1.3 ± 1.4 (p = 0.01), post-sleep inventory decreased from 5.8 ± 3.3 to 1.8 ± 1.8 (p = 0.002), and Beck Depression Inventory decreased from 13.6 ± 5.2 to 7.1 ± 3.7 (p < 0.01). Both cognitive and somatic components of the Beck Depression Inventory were significantly reduced. Quality of life, as measured by both physical and mental components of the Medical Outcomes Study, improved from 45.1 ± 20.6 to 75.3 ± 11.4 and 56.9 ± 18.8 to 80.8 ± 10.3, respectively. Scores after the 1-week washout or placebo were not reported. No side effects were observed in this study.
Level II-1 evidence
Razeghi et al. conducted a multicenter, double-blind, placebo-controlled, single-arm cross-over trial at 3 HD sites in Tehran, Iran . Thirty-four patients undergoing HD thrice weekly, refractory to treatments with antihistamines and moisturizers, with ongoing pruritus for at least 2 weeks were treated. Gabapentin 100 mg post-HD was started for 4 weeks, then placebo for 4 weeks, with a 1-week washout in between the treatment periods. All patients were free from hepatic abnormalities with no skin lesions, metabolic diseases, drug allergies, or other disease states causing pruritus. Antipruritic drugs were stopped 1 week prior to the study. Patients were trained to use a VAS (0–100) daily to evaluate efficacy and the median score in each interval was used. A reduction in the score of 50 % or more was considered clinically significant.
After enrolment, 9 patients were excluded from the study: 2 for discontinuation due to adverse events (fatigue, dizziness, and drowsiness), 1 for inefficacy within 10 days, and 6 for poor compliance. Of the remaining 25 patients, 24 patients were found to exhibit distal symmetric polyneuropathy. Overall, none of the baseline parameters exhibited statistically significant change throughout the treatment phases of the study and were not significantly correlated with responsiveness of treatment including serum albumin, C- reactive protein (CRP), Kt/V, and phosphate levels. All patients had a baseline VAS of 100, decreasing to a mean score of 6.44 ± 8.46 (p < 0.001) with gabapentin and rising to 81.88 ± 11.06 during the placebo period (p < 0.001). Withdrawal of gabapentin during the 1-week washout period produced a mean VAS of 15 ± 11.27 (p < 0.001). Initial antipruritic effects were reported by approximately days 2–3, with maximal effects achieved by approximately days 24–25.
Marquez et al. investigated the efficacy and safety of gabapentin versus desloratadine at a single center in 19 adult patients undergoing HD thrice weekly using low-flux Polysulfone membranes in Argentina . Potential patients were screened with a pruritus assessment tool on two occasions, 60 days apart. Those with persistent pruritus, defined as pruritus of any intensity occurring three times a week, were eligible for the study. All antipruritic agents were discontinued 1 week before the study. In a quasi-randomized open-label cross-over design, patients were assigned to either desloratadine 5 mg or gabapentin 300 mg three times weekly based on the dialysis schedule of each patient. Concomitant emollients or antipruritic agents were not permitted. Patients crossed over to the other treatment arm after 3 weeks with a 1-week washout in between treatment periods. The pruritus assessment tool, which included the pruritus VAS (0–10), was done at baseline and at the end of each treatment and washout periods. The questionnaire administrator was blinded to the drug assignment.
Ninety-two patients were screened: 22 were assigned to treatment groups and 19 completed the study. Baseline Kt/V, calcium, phosphate, and intact parathyroid hormone (iPTH) were within normal limits. From a baseline VAS for pruritus of 5.95 (range 4–8), gabapentin reduced the VAS to 4.6 (p = 0.07) compared to 3.44 (p = 0.004) with desloratadine. Although desloratadine had a greater reduction than gabapentin, the differences between the two agents when comparing the final VAS for each group were not statistically significant (p = 0.16). Desloratadine was more successful in producing clinically significant reductions (VAS reduction of at least 50 %) in 11 (58 %) patients compared with 5 (16 %) patients in the gabapentin group (p = 0.049). Nine (47 %) patients experienced fatigue and somnolence from gabapentin, leading to 4 discontinuations after the first dose. One subject on desloratadine withdrew because of nervousness.
Level II-2 evidence
Rayner et al. studied 71 CKD non-dialysis (CKDND), peritoneal dialysis (PD), or HD patients in a single center in East Birmingham, England . It was an open-label, uncontrolled trial to evaluate gabapentin and pregabalin for UP. No dialysis parameters were provided. Patients were enrolled in the study if the pruritus was troublesome, persistent, and refractory to emollients or antihistamines during routine consultations. Gabapentin was started at 100 mg post-HD and the dose was titrated according to symptoms by the patients in collaboration with their physician (ranging from 100 mg post-HD to 900 mg daily). Patients experiencing persistent pruritus or adverse events with gabapentin were offered pregabalin starting at 25 mg after HD.
A total of 40 consecutive HD patients were enrolled in the study with a median itching duration of 6 months; 88 % had sleep disturbances and 65 % had bleeding secondary to scratching. Baseline calcium, phosphate, and PTH were within normal limits. Baseline median severity of itch was 9 out of 10 measured with an unspecified tool. A median weekly dose of gabapentin 700 mg was reached at the end of the study with 31 (77.5 %) patients reporting a significant reduction in itch. Thirteen (32.5 %) patients’ final dose was 100 mg after dialysis, and 11 (27.5 %) received 100 mg daily. The remaining 16 (40 %) patients had final doses ranging from 300 mg post-HD to 900 mg daily. The authors reported use of a scale from 0 to 10 for measuring efficacy but did not provide the exact scale nor the specific median decrease in score in the HD group. The onset of action for gabapentin was reportedly after the first 1–2 doses or after up-titrations in dose. Eight patients discontinued gabapentin due to adverse events, and 1 patient discontinued due to inefficacy. Side effects specific to HD group were not reported, but the most common symptoms were over-sedation and dizziness. Four patients in the entire study who discontinued either gabapentin or pregabalin remained free of itch. Notably, 6 patients in the entire study achieved relief in concomitant pain conditions.
Cheikh Hassan et al. investigated the efficacy of gabapentin for UP and restless leg syndrome (RLS) in CKDND patients and sought to compare the results with HD patients at a single center in Sydney . Efficacy of gabapentin was evaluated based on the validated Palliative care Outcome Scale-Symptoms (POS-S) Renal, which contains a pruritus score rated from 0 to 4. Dialysis parameters were unavailable. Gabapentin was started at 100 mg every 2 days in ESRD patients (CKD stages II–V). The authors did not define their classification of CKD stages II–V; we contacted the corresponding author for clarification but received no answer up until the time of publication. A pharmacist compounded 25-mg tablets for incremental titration.
Fifty-nine HD patients were referred to the center during the study period and 15 were enrolled (13 had symptoms of pruritus). Baseline calcium, phosphate, and PTH were within normal limits. The mean initial, daily average, and final gabapentin daily doses were 42.8, 90.0, and 128.6 mg respectively in HD patients. Although specific pruritus scores were not provided, the authors state that gabapentin was effective in reliving pruritus in HD patients between the first and subsequent visits to the clinic (p < 0.05). Two HD patients experienced adverse events (blurred vision and unsteadiness) compared with 16 patients in the CKDND group experiencing at least one adverse event. Univariate analyses were done in the CKDND group and none emerged to be associated with side effects including starting dose, average daily dose, and final dose.