Report

A randomized controlled study of 6% gabapentin topical

formulation for chronic kidney disease-associated pruritus
Terese Monette O. Aquino1, MD, Karla Angela C. Luchangco1, MD, Elizabeth V.
Sanchez1,2, MD and Vermen M. Verallo-Rowell1,3, MD

1
Skin and Cancer Foundation, Inc., Pasig
City, Philippines, 2V. Luna Medical Center,
Quezon City, Philippines, and 3VMV Skin
Research Centre + Clinics, Makati City,
Philippines
Correspondence
Terese Monette O. Aquino, MD
Unit 1611, Medical Plaza Ortigas
San Miguel Avenue
Pasig City 1605
Philippines
E-mail: teresemonetteaquino@gmail.com
Conflict of interest: None.
Funding source: None.
doi: 10.1111/ijd.14953
Abstract
Background Novel agents with good safety profiles are needed in the management of
chronic kidney disease–associated pruritus (CKD-AP). This study aims to assess the
efficacy and safety of topical gabapentin in the treatment of CKD-AP.
Methods The authors conducted a randomized, double-blind, vehicle-controlled study. The
key inclusion criteria were: (i) patients on hemodialysis for at least 8 weeks, and (ii) a
baseline visual analog scale (VAS) pruritus score ≥5. Patients were randomized into two
groups. Topical 6% gabapentin was used in the experimental group while plain permeation
cream was used for the control group. The primary endpoint was the mean change in
pruritus scores using the VAS (MCPS-VAS) from baseline after 1 and 2 weeks of once
daily application.
Results Thirty patients (15 per group) were included in the analysis. Treatment with 6%
topical gabapentin resulted in significantly decreased mean pruritus scores at 1 week
(mean score 2.7; range 0–5; P < 0.001) and 2 weeks (mean score 1.3, range 0–5;
P < 0.001) from baseline (mean score 5.9; range 5–8). The MCPS-VAS of the two groups
were not significantly different (P = 0.8) after 1 week. However, the MCPS-VAS of the
experimental group (mean change 4.6; range 0–7) was significantly greater (P = 0.01)
compared to control (mean change 2.6; range 1 to 5) after 2 weeks. There were no
drug-related adverse events reported.
Conclusion Our results suggest that short-term use of topical gabapentin may significantly
decrease CKD-AP severity after 2 weeks with no reported acute adverse events.

Peripheral sensitization is characterized by a decrease in the

Introduction
Chronic kidney disease-associated pruritus (CKD-AP), also
known as uremic pruritus, is a common complication affecting
patients with chronic kidney disease (CKD). Studies have
reported CKD-AP to occur in approximately 30–50% of patients
1,2
undergoing hemodialysis (HD). A multinational study by
Pisoni et al.3 also reported that 42% of HD patients complain of
moderate to extreme pruritus. In that study, CKD-AP was asso-
ciated with sleep disturbance, depression, impaired quality of
life, and increased risk of mortality.
Several mechanisms are linked with CKD-AP. This includes
xerosis, immune dysregulation, and opioidergic system dysfunc-
tion.4–6 Metabolic alteration in CKD may also cause hyper-
parathyroidism, which could trigger the release of pruritogenic
cytokines.6 HD patients were also observed to have an abnor-
mal pattern of cutaneous innervation, making them susceptible
to develop pruritus.7 Likewise, uremic toxins have been reported
to trigger neuropathy and sensitization to itch.8
Aramwit and Supasyndh9 have identified two mechanisms of
chronic itch: (i) peripheral, and (ii) central sensitization.
activation threshold and an increase in the basal activity of itch-
related receptors.9 On the other hand, central sensitization
results from neuroplasticity occurring in the brain and the spinal
cord. Itch and pain are believed to be correlated as both are
conveyed by C-fibers in the dorsal horns of the spinal cord.8
Gabapentin, a drug for neuropathic pain, emerged as a possible
treatment for severe or refractory CKD-AP because of this
pathogenic similarity.8,10
Gabapentin is an antiepileptic drug which reduces synaptic
transmission by acting on presynaptic voltage-gated channels.11
Although it is more commonly known for its use in the manage-
ment of neuropathic pain, oral gabapentin has also been
reported to decrease the intensity of CKD-AP.8,11 However,
increased toxicity with gabapentin use in CKD patients may be
possible because of its exclusive renal elimination.12,13 A poten-
tial alternative to circumvent the renal effects of this drug is to
use topical formulation. A study published in 2008 described the
efficacy of 6% topical gabapentin for the treatment of vulvodynia
without any reports of systemic adverse events.14 Physically,
gabapentin (molecular weight of 171.23678 g/mol) is a suitable 1

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2 Report Topical gabapentin for CKD-associated pruritus
topical agent as it respects the 500 Dalton rule.15 Thus, this
study was conducted with the aim to assess the early efficacy
and safety of topical gabapentin in the treatment of CKD-AP.
Materials and methods
This is a randomized, double-blind, vehicle-controlled study,
approved by the local Institutional Review Board (IRB). Patients
were recruited from two tertiary hospitals in the Philippines. The
inclusion criteria were: (i) adult (>18 years old) patients on HD
(at least twice a week sessions) for at least 8 weeks, and (ii) a
baseline 11-point visual analog scale (VAS) pruritus score ≥5,
unrelieved by antihistamines or emollients. Patients were
excluded if they were pregnant/nursing mothers, had a known
allergy to gabapentin/vehicle, had preexisting dermatitis
(infectious/noninfectious), had prior use of antipruritic
medications (oral or topical) within 1 week of recruitment, or
attained less than a high school degree.
Patients were allocated to either the experimental group (6%
topical gabapentin) or the control group (vehicle only) via block
randomization. The target sample size in this study was 30,
with 15 patients assigned to each group. This sample size was
based on prior trials which investigated similar outcomes in a
comparable study population, albeit using relatively different
agents.16,17
A licensed pharmacist compounded the topical preparations.
For the gabapentin topical formulation, contents of gabapentin
capsules were dissolved in water and compounded to a
permeation cream to yield a concentration of 6% (6 g
gabapentin: 100 g permeation cream). The major components
of the permeation cream were propylene glycol and
polyethylene glycol (PG + PEG). Other ingredients included
were as follows: purified water, petrolatum, sorbitol, cetearyl
alcohol, ceteareth-20, simethicone, glyceryl stearate, sorbic
acid, and butylated hydroxytoluene. The vehicle control was
composed of plain permeation cream only. Each topical
formulation was packed in a white jar (labeled A or B)
containing 2 grams of identical, odorless white cream. The
experimental cream contained approximately 113 mg of
gabapentin. The label designation was kept from the assessors
and the subjects until the end of the study.
Each patient was given a total of 14 jars. One jar
corresponded to one application per day. Patients were
instructed to apply the entire content of one jar at night to the
most pruritic area of the body. Daily application was done for 14
consecutive days. The primary site of application was
determined by the patient as the itchiest part. During the
treatment period, patients were: (i) asked to use only mild
soaps for bathing, (ii) advised proper skin care, and (iii)
instructed to refrain from applying anything besides the given
cream.
The primary outcome of interest was the mean change in
pruritus scores using the VAS (MCPS-VAS) from baseline to 1
International Journal of Dermatology 2020
Aquino et al.
and 2 weeks. Secondary outcome measures were rates of
acute adverse events and the mean change in pruritus scores
using the 5-D itch scale (MCPS-5D) from baseline to 2 weeks.
Upon enrollment, eligible patients were trained to use the 11-
point VAS for pruritus. The 11-point VAS is a horizontally-
oriented line labeled to indicate the intensity of the symptom.
The lower end of the scale refers to no pruritus (0 point) while
the opposite end represents the worst possible itch (10 points).
The patients were then instructed to mark the horizontal line at
the point that corresponded to the severity of their pruritus. On
the other hand, the 5-D itch scale is a multidimensional scale
composed of five components (degree, duration, direction,
disability, and distribution), with each component having its own
scoring criteria. Four physicians administered the 5-D itch scale.
Baseline scores were obtained for both the VAS and the 5-D
itch scale. VAS scores were taken after 1 and 2 weeks from
baseline, while the 5-D itch scale scores were obtained after
2 weeks from baseline. The treatment-related adverse events
were examined at weeks one and two by four independent
physicians.
Statistical analysis was done using the SPSS Statistics
Version 24. Intention-to-treat (ITT) analysis was used to
analyze the results. Missing data were handled using the last
observer carried forward (LOCF) method. Quantitative variables
were summarized and presented as mean, median, range, and
standard deviation (SD). Categorical variables were tested via
the Chi-squared statistic. The t-test for independent samples
was used to compare means between the two groups.
Comparison of the mean VAS pruritus scores at weeks one and
two vs. baseline were done using the paired t-test. The MCPS-
VAS of the two groups was compared using the Wilcoxon rank-
sum test. A P < 0.05 was regarded as statistically significant.
All statistical tests used were two-sided.
Figure 1 Consort diagram.
ª 2020 the International Society of Dermatology
Aquino et al. Topical gabapentin for CKD-associated pruritus Report 3

pruritic site. There were no significant differences in baseline

Results
characteristics between the two groups (Table 1).
A total of 30 eligible patients were randomly assigned to one of Table 2 and Figures 2 and 3 show a summary of the mean
the two treatment groups (Fig. 1). Two patients were lost to fol- VAS pruritus scores and the MCPS-VAS. In the experimental
low-up, one from each group. All 30 patients were included in group, the mean VAS pruritus scores were significantly lower at
the ITT analysis. The majority of the cohort were males (n = 26; 1 week (mean score 2.7; SD 2.1; range 0–5) and 2 weeks
86.6%). Mean age of the entire study group was 43.8 years old (mean score 1.3; SD 1.5; range 0–5) compared to baseline
(SD 12.4, range 27–70). Mean duration of dialysis was (mean score 5.9; SD 1.3; range 5–8) (P < 0.001 for both 1 and
19.5 months (SD 26.9, range 2–132), while mean duration of 2 weeks). Similar findings were seen in the control group, with
pruritus was 15.8 months (SD 24.8, range 1–120). Twenty-five decreased mean VAS pruritus scores at 1 week (mean score
(83.3%) reported the back as their primary pruritic site. The 3.3; SD 2.2; range 0–7) and at 2 weeks (mean score 3.6; SD
others reported the neck (n = 1), buttocks (n = 1), abdomen 2.0; range 1–7) from baseline (mean score 6.2; SD 1.4; range
(n = 1), upper arm (n = 1), or thighs (n = 1) as their primary 5–10) (P < 0.001 for both 1 and 2 weeks). Comparing the
MCPS-VAS between the two groups, there was no significant
Table 1 Patient characteristics difference (P = 0.08) between the experimental group (mean
change 3.2; SD 2.1; range 0–7) and the control group (mean
Experimental Control change 2.9; SD 2.0; range 1 to 6) after 1 week. On the
(n = 15) (n = 15) P-value other hand, the MCPS-VAS after 2 weeks was significantly
greater (P = 0.01) in the experimental group (mean change
Gender
Male 12 14 0.5977 a 4.6; SD 2.0; range 0–7) vs. the control group (mean change
Female 3 1 2.6; SD 1.9; range 1 to 5), with an effect size of 1.02.
Age For the secondary outcome measures, there were no
Mean 46.1 41.2 0.298203 reported treatment-related adverse events in the two groups
Standard 13.4 11.6
after 1 and 2 weeks. Table 3 and Figures 4 and 5 report a sum-
deviation
Range 29–70 27–62 mary of the mean 5D pruritus scores and the MCPS-5D. In the
Duration of dialysis experimental group, the mean 5D pruritus score was signifi-
Mean (months) 23.7 16.5 0.477493 cantly lower at 2 weeks (mean score 11.2; SD 13.6; range 7–
Median (months) 12 8 22) compared to baseline (mean score 16.1; SD 4.8; range 11–
Standard 34.1 18.4
27) (P = 0.003). Similar findings were seen in the control group,
deviation
Range 2–132 2–60 with a decreased mean 5D pruritus score at 2 weeks (mean
Duration of pruritus score 13.3; SD 5.7; range 7–25) vs. baseline (mean score 20.1;
Mean (months) 18.7 13.8 0.60029 SD 5.9; range 13–29) (P = 0.002). However, comparison of the
Median (months) 6 8 MCPS-5D at 2 weeks between the experimental group (mean
Standard 31.9 16.4
change 4.8; SD 5.2; range 12 to 17) and the control group
deviation
Range 1–120 2–60 (mean change 6.8; SD 7.2; range 0–21) did not show a signifi-
cant difference (P = 0.33). Except for degree, there was also no
a
Analyzed via chi-square statistic; comparison of means analyzed significant difference in the mean change in scores between the
via paired t-test for independent samples. two groups in all the individual 5D itch scale components

Table 2 Mean change in pruritus scores using the VAS

Experimental (n = 15) Control (n = 15) P-value (experimental vs. control)

Mean pruritus score at baseline 5.9  1.3/5 (5–8) 6.2  1.4/6 (5–10) 0.58b
Mean pruritus score at week 1 2.7  2.1/2 (0–5) 3.3  2.2/4 (0–7)
Mean pruritus score at week 2 1.3  1.5/1 (0–5) 3.6  2.0/4 (1–7)
Mean change in pruritus scores from baseline to week 1 3.2  2.1/3 (0–7) 2.9  2.0/3 ( 1 to 6) 0.80b
P valuea (baseline vs. week 1) <0.001 <0.001
Mean change in pruritus scores from baseline to week 2 4.6  2.0/5 (0–7) 2.6  1.9/3 ( 1 to 5) 0.01b
P valuea (baseline vs. week 2) <0.001 <0.001

Data are mean  SD/median (range). P < 0.05 considered as statistically significant.
a
Difference in pruritus scores between baseline and week 1/week 2 analyzed via paired t-test.
b
Difference in pruritus scores between control and experimental groups analyzed via Wilcoxon rank sum test.

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4 Report Topical gabapentin for CKD-associated pruritus Aquino et al.

component of pain. Likewise, our results suggest that gabapentin

Figure 2 Mean VAS pruritus scores of both experimental and
control groups.
Figure 3 Comparison of the mean change in VAS pruritus scores
between groups.
(Table 4). For the degree component, the experimental group
had a significantly greater mean change in pruritus score from
baseline vs. the control group ( 1.13 vs. 0.4, P = 0.012), with
an effect size of 1.16.
Discussion
To the authors’ knowledge, this is the only study investigating
the use of topical gabapentin in the management of CKD-AP.
The only prior study reporting the use of topical gabapentin was
the study by Boardman et al.,14 which investigated its efficacy
in the management of vulvodynia.
The results of the study of Boardman et al.14 imply a signifi-
cant clinical effect of topical gabapentin on the peripheral
in topical formulation may also significantly decrease pruritus
severity after 2 weeks of use compared to control (Table 2,
Fig. 3). These findings may provide clinical support to the
assumption that pain and pruritus share a similar afferent path-
way. Our results are also in line with prior studies reporting
decreased VAS pruritus scores after treatment with oral gaba-
pentin.8,18,19
The control group in our study also had decreased pruritus
severity scores at 1 and 2 weeks compared to baseline. This
may have been because of the potential effect of moisturizers
in alleviating itch.4 A significant ‘placebo effect’ with the use of
plain cream may have also occurred in the control group. This
finding is similar to the results of the study by Laarhoven
et al.,20 which reported decreased itch with placebo use com-
pared to baseline. However, our results which showed a signifi-
cant difference in MCPS-VAS between the groups at 2 weeks
may indicate a possible decline in the ‘placebo effect’ through
time.
Previously known adverse events associated with oral gaba-
pentin use were fatigue, somnolence, dizziness, nausea,
unsteadiness, and blurring of vision.17,21–24 These treatment-re-
lated adverse events were not reported in our cohort. It is possi-
ble that the topical formulation used in our study minimized any
systemic effect that may cause these toxicities. In addition, one
may consider the cutaneous dose used in this study to be con-
servative as it is comparable to the usual starting dose of oral
gabapentin for uremic patients (100 mg/day).8 In fact, the sys-
tematic review by Lau et al.8 reported that some CKD patients
may require and even tolerate up to 900 mg of oral gabapentin
per day. Nevertheless, systemic absorption is still a possibility
in patients with CKD-AP because of the likelihood of an already
impaired skin barrier. For future studies, objective assessment
of the percutaneous absorption of gabapentin will give valuable
information regarding the possibility of systemic toxicity. It may
also help elucidate whether the efficacy of topical gabapentin is
primarily because of its peripheral effect on the skin or its cen-
tral suppression of pruritus.
Our treatment duration of 2 weeks may have been too short
to identify any systemic toxicity with the use of topical gabapen-
tin. However, the study by Boardman et al.14 which used a

Table 3 Mean change in pruritus scores using the 5-D itch scale

Experimental (n = 15) Control (n = 15) P-value (experimental vs. control)

Mean pruritus score at baseline 16.8  5.0/17 (11–30) 20.1  5.9/18 (13–29) 0.07b
Mean pruritus score at week 2 11.2  3.6/10 (7–22) 13.3  5.7/11 (7–25)
Mean change in pruritus scores from baseline to week 2 4.86  5.24/4 (0–20) 6.8  7.2/6 (0–21) 0.47b
P valuea (baseline vs. week 2) 0.003 0.002

Data are mean  SD/median (range). Mean scores are the sum of all five components of the 5-D scale. P < 0.05 considered as statistically
significant.
a
Difference in pruritus scores between baseline and week 2 analyzed via paired t-test.
b
Difference in pruritus scores between control and experimental groups analyzed via Wilcoxon rank sum test.

International Journal of Dermatology 2020 ª 2020 the International Society of Dermatology

Aquino et al. Topical gabapentin for CKD-associated pruritus Report 5

events in our cohort may be because of the relatively short

Figure 4 5-D itch scale scores of both experimental and control
groups.
Figure 5 Comparison of the change in 5-D itch scale scores
between groups.
similar agent (100 g/day of gabapentin in topical formulation) for
at least 8 weeks also did not report any systemic adverse
events. On the other hand, that study reported discontinuation
in 14% of their population because of local side effects (irritation
and urinary complaints). The absence of any local adverse
treatment duration and follow-up period.
There are several rating scales available to quantify pruritus.
Among these, the VAS is probably the most used in prior publi-
cations.25–27 This includes similar studies which also investi-
gated the efficacy of agents for CKD-AP.8,18,19 Likewise, the
authors elected to use the change in VAS pruritus scores as
the primary outcome measure in this trial. Since pruritus cannot
be truly measured objectively, some authors have suggested
using more than one rating scale to assess pruritus intensity.25
To supplement our VAS results, we utilized the 5-D itch scale in
our cohort. The 5-D itch scale was validated in 2010 by Elman
et al.,28 reporting good correlation with VAS pruritus scores. In
our study, there was a significant decrease in the mean 5D pru-
ritus scores at 2 weeks compared to baseline in both groups
(Table 3, Fig. 4). These findings were similar to our results
using the VAS. However, unlike our MCPS-VAS findings, com-
parison of the MCPS-5D between groups showed no significant
difference at 2 weeks (Table 3, Fig. 5). It is possible that the
effect of the intervention was attenuated after summation of the
different component scores into a single sum score. This is in
contrast with the VAS pruritus scale, which only attempts to
quantify pruritus severity. Interestingly, analysis of the individual
5-D scale components showed a significant difference only in
the degree component, favoring the experimental group
(Table 4). Therefore, the significantly greater change in mean
scores in the experimental group for both the VAS and the
degree component of the 5-D itch scale suggests that the pri-
mary early effect of topical gabapentin is reduction in severity of
pruritus. Longer treatment may be needed in order to better
observe whether the use of 6% topical gabapentin may posi-
tively impact the other aspects of pruritus (duration, direction,
disability, distribution).
The authors opted for an alternative permeation base in
PG + PEG. The use of the PG + PEG combination has been

Table 4 Mean change in scores of the individual components of the 5-D itch scale

Experimental Control

Mean change in Mean change in P-value (experimental

Component scores at 2 weeks P-valuea scores at 2 weeks P-valuea vs. control)b

1. Duration 0.087 (SD 3.6) 0.008 1.5 (SD 1.7) 0.005 0.093
2. Degree 1.13 (SD 0.74) <0.001 0.4 (SD 0.5) 0.008 0.012
3. Direction 1.1 (SD 1.4) 0.01 0.5 (SD 1.0) 0.09 0.23
4. Disability
Sleep 0.86 (SD 1.18) 0.01 1.6 (SD 1.6) 0.002 0.21
Leisure/social 0.46 (SD 1.5) 0.23 1.0 (SD 1.1) 0.004 0.26
Housework/errands 0.6 (SD 1.3) 0.09 0.8 (SD 1.16) 0.07 0.57
Work/school 0.33 (SD 1.4) 0.11 0.53 (SD 1.7) 0.25 0.74
5. Distribution 0.73 (0.96) 0.01 0.6 (1.12) 0.057 0.69

SD, standard deviation. P < 0.05 considered as statistically significant.

a
Difference in pruritus scores between baseline and week 2 analyzed via paired t-test.
b
Difference in pruritus scores between control and experimental groups analyzed via Wilcoxon rank sum test.

ª 2020 the International Society of Dermatology International Journal of Dermatology 2020

6 Report Topical gabapentin for CKD-associated pruritus
reported as a possible permeation enhancer, although different
drugs (cetirizine, tramadol) were used in those studies.29,30 In
addition, the combination’s reported pH of 5.8–7.229 was similar
to the pH range of 6.0–7.0 that was described by Martin et al.31
to be ideal for the gabapentin molecule to maintain stability and
ionization state. The gabapentin molecule is also known to be a
polar molecule, making it more challenging to traverse the stra-
tum corneum when applied transdermally. Similar to Lipoderm
and Carbopol, the combination of PG + PEG has also been
reported to be an effective transdermal permeator of a polar
molecule (Tramadol).30
The authors used a sample size of 30 which was deemed
large enough to yield data that will approximate the normal dis-
tribution upon invoking the central limit theorem. This sample
size was also comparable to similar studies which utilized the
VAS in assessing pruritus for CKD patients. The study by
Young et al.16 (n = 28) reported superior efficacy of a pramox-
ine-based topical agent vs. control, while the study by Gunal
et al.17 (n = 25) demonstrated the effectiveness of oral gaba-
pentin therapy for CKD-AP.
Our study was limited by the relatively small sample size,
short treatment duration and follow-up period, and the lack of
objective measures to assess percutaneous absorption. These
restricted the evaluation of the long-term efficacy of topical
gabapentin and its possible systemic and late treatment-related
adverse events.
Conclusion
Short-term use of topical 6% gabapentin was able to decrease
VAS pruritus scores at 1 and 2 weeks vs. baseline. Decrease in
VAS pruritus scores after 2 weeks of topical gabapentin applica-
tion was significantly greater compared to vehicle placebo.
There were no reports of acute local or systemic adverse
events. Longer follow-up in a larger cohort of patients may be
needed to adequately assess the long-term efficacy and possi-
ble late toxicities of topical gabapentin use for CKD-AP.
Acknowledgment
We thank our colleagues from Ospital ng Makati, Quirino
Memorial Medical Center, V. Luna Medical Center, and the fol-
lowing: Ruth Bausas, Dr. Claudine Ramos, Dr. Raphaela
Pineda, Dr. Jasmin Jamora, Josephine Frilles, and Ana Ernacio
who provided support and assisted the research. We also show
our gratitude to Dr. Kristine Nograles for sharing her wisdom
with us during the course of this research and Dr. Ryan
Anthony Agas for thoroughly checking our manuscript.
Declarations
We confirm that this work is original and has not been published
anywhere else nor is it currently under consideration for
International Journal of Dermatology 2020
Aquino et al.
publication elsewhere. We disclose that there are no conflicts of
interest or external source of funding for the manuscript. All
authors have been personally and actively involved in substan-
tive work leading to the manuscript and will hold themselves
jointly and individually responsible for its content. This study
was conducted in adherence to the World Medical Association
Declaration of Helsinki. The study was presented at the resi-
dents and fellows’ symposium of the American Academy of Der-
matology annual meeting, Washington, DC, USA, March 3,
2019; the residents’ annual research forum of the Philippine
Dermatological Society, Philippines, November 7, 2018; and the
annual research contest of Quirino Memorial Medical Center,
Philippines, November 22, 2018.
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