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Effects of a Gentle, Self-Administered Stimulation of Perineal Skin for Nocturia in Elderly Women: A Randomized, Placebo-Controlled, Double-Blind Crossover Trial

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Somatic afferent nerve stimuli are used for treating an overactive bladder (OAB), a major cause of nocturia in the elderly. Clinical evidence for this treatment is insufficient because of the lack of appropriate control stimuli. Recent studies on anesthetized animals show that gentle stimuli applied to perineal skin with a roller could inhibit micturition contractions depending on the roller's surface material. We examined the efficacy of gentle skin stimuli for treating nocturia.The study was a cross-over, placebo-controlled, double-blind randomized clinical study using two rollers with different effects on micturition contractions. Participants were elderly women (79-89 years) with nocturia. Active (soft elastomer roller) or placebo (hard polystyrene roller) stimuli were applied to perineal skin by participants for 1 min at bedtime. A 3-day baseline assessment period was followed by 3-day stimulation and 4-day resting periods, after which the participants were subjected to other stimuli for another 3 days. The primary outcome was change in the frequency of nighttime urination, for which charts were maintained during each 3-day period.Twenty-four participants were randomized, of which 22 completed all study protocols. One participant discontinued treatment because of an adverse event (abdominal discomfort). In participants with OAB (n = 9), change from baseline in the mean frequency of urination per night during the active stimuli period (mean ± standard deviation, -0.74 ± 0.7 times) was significantly greater than that during placebo stimuli periods (-0.15 ± 0.8 times [p < 0.05]). In contrast, this difference was not observed in participants without OAB (n = 13).These results suggest that gentle perineal stimulation with an elastomer roller is effective for treating OAB-associated nocturia in elderly women. Here the limitation was a study period too short to assess changes in the quality of sleep and life.UMIN Clinical Trial Registry (CTR) UMIN000015809.
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RESEARCH ARTICLE
Effects of a Gentle, Self-Administered
Stimulation of Perineal Skin for Nocturia in
Elderly Women: A Randomized, Placebo-
Controlled, Double-Blind Crossover Trial
Kaori Iimura
1,2
, Nobuhiro Watanabe
2
, Koichi Masunaga
3
, Shogo Miyazaki
1,2,4
,
Harumi Hotta
2
*, Hunkyung Kim
5
, Tatsuya Hisajima
1,4
, Hidenori Takahashi
1,4
,
Yutaka Kasuya
3
1Graduate School of Health Science, Teikyo Heisei University, Tokyo, Japan, 2Department of Autonomic
Neuroscience, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan, 3Department of Urology, Tokyo
Metropolitan Geriatric Hospital, Tokyo, Japan, 4Department of Acupuncture and Moxibustion, Faculty of
Health Care, Teikyo Heisei University, Tokyo, Japan,5Department of Promotion of Prevention of
Musculoskeletal Aging, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan
*hhotta@tmig.or.jp
Abstract
Background
Somatic afferent nerve stimuli are used for treating an overactive bladder (OAB), a major
cause of nocturia in the elderly. Clinical evidence for this treatment is insufficient because of
the lack of appropriate control stimuli. Recent studies on anesthetized animals show that
gentle stimuli applied to perineal skin with a roller could inhibit micturition contractions
depending on the rollers surface material. We examined the efficacy of gentle skin stimuli
for treating nocturia.
Methods
The study was a cross-over, placebo-controlled, double-blind randomized clinical study
using two rollers with different effects on micturition contractions. Participants were elderly
women (7989 years) with nocturia. Active (soft elastomer roller) or placebo (hard polysty-
rene roller) stimuli were applied to perineal skin by participants for 1 min at bedtime. A 3-day
baseline assessment period was followed by 3-day stimulation and 4-day resting periods,
after which the participants were subjected to other stimuli for another 3 days. The primary
outcome was change in the frequency of nighttime urination, for which charts were main-
tained during each 3-day period.
Results
Twenty-four participants were randomized, of which 22 completed all study protocols. One
participant discontinued treatment because of an adverse event (abdominal discomfort). In
participants with OAB (n = 9), change from baseline in the mean frequency of urination per
night during the active stimuli period (mean ±standard deviation, 0.74 ±0.7 times) was
PLOS ONE | DOI:10.1371/journal.pone.0151726 March 22, 2016 1/14
OPEN ACCESS
Citation: Iimura K, Watanabe N, Masunaga K,
Miyazaki S, Hotta H, Kim H, et al. (2016) Effects of a
Gentle, Self-Administered Stimulation of Perineal
Skin for Nocturia in Elderly Women: A Randomized,
Placebo-Controlled, Double-Blind Crossover Trial.
PLoS ONE 11(3): e0151726. doi:10.1371/journal.
pone.0151726
Editor: Neal Shore, Carolina Urologic Research
Center, UNITED STATES
Received: June 16, 2015
Accepted: March 3, 2016
Published: March 22, 2016
Copyright: © 2016 Iimura et al. This is an open
access article distributed under the terms of the
Creative Commons Attribution License, which permits
unrestricted use, distribution, and reproduction in any
medium, provided the original author and source are
credited.
Data Availability Statement: All relevant data are
within the paper.
Funding: This study was supported by Translational
research fund in Tokyo Metropolitan Institute of
Gerontology (http://www.tmig.or.jp/index.html). The
funder had no role in study design, data collection
and analysis, decision to publish, or preparation of
the manuscript.
Competing Interests: The authors of this manuscript
have the following competing interests:a patent
significantly greater than that during placebo stimuli periods (0.15 ±0.8 times [p<0.05]).
In contrast, this difference was not observed in participants without OAB (n = 13).
Conclusions
These results suggest that gentle perineal stimulation with an elastomer roller is effective
for treating OAB-associated nocturia in elderly women. Here the limitation was a study
period too short to assess changes in the quality of sleep and life.
Trial Registration
UMIN Clinical Trial Registry (CTR) UMIN000015809
Introduction
Many elderly people have bladder problems such as frequent urination, incontinence, or noc-
turia [1]. Nocturia is a condition, in which the individual has to wake one or more times at
night to void [2]. The prevalence of nocturia increases with age in both men and women and
up to 60% of the elderly (70 years) void 2 times per night [3]. Nocturia should be appropri-
ately managed, since it has been reported that nocturia not only decreases the quality of life
(QOL) [4,5], but also increases fall-related fracture risks and mortality rates [6]. One of the
major causes of nocturia in the elderly is an overactive bladder (OAB). The most common
treatment for OAB-associated nocturia is pharmacological treatment such as anticholinergic
therapy. However, in a systematic review, its clinical efficacy was questioned, because the dif-
ference between active drugs and placebo was small and the rate of side-effects increased in
patients receiving active pharmacological treatment [7]. As non-pharmacological methods,
somatic afferent stimuli such as acupuncture [8] and transcutaneous electrical nerve stimula-
tion [9] have been used clinically for the treatment of OAB. However, the lack of appropriate
control stimuli makes it difficult to determine whether the effect of somatic afferent stimulation
is independent of the placebo effect [8]. It has been reported that not only electrical stimulation
but also a variety of noxious somatosensory stimuli, particularly applied to the perineal area,
consistently produced a decrease in the frequency of micturition contractions in anesthetized
animals [1013]. In the case of non-noxious mechanical stimuli, we have recently found that
the efficacy in suppressing micturition reflex depends on the materials in contact with the skin
in anesthetized rats [14,15]. When gentle stimuli were applied for 1 min by slowly rolling an
elastomer roller on top of the perineal skin, both micturition contractions and pelvic efferent
nerve discharges were suppressed during and after stimulation [14]. If similar effects can be
seen in humans, it may be useful as a self-administered therapy for nocturia. On the contrary,
when we used a hard plastic roller, the same gentle stimuli applied to the same skin area did
not produce significant inhibition [15]. The two stimuli applied with different rollers, being dif-
ficult to distinguish by our senses, would be useful in excluding the placebo effect in a clinical
study.
The aim of this study was to examine the efficacy of gentle perineal stimuli, applied by par-
ticipants at bedtime, to reduce the frequency of nighttime urination in community-dwelling
elderly women. For this purpose, we performed a cross-over, placebo-controlled, double-blind
randomized clinical study using two different rollers, which were shown to have a different
impact on micturition contractions in recent animal studies [14,15]. Because somatic afferent
stimuli have been used for the treatment of OAB [8,9], we hypothesized that perineal stimula-
tion would be effective for nocturia in elderly women, particularly those with OAB. However,
Gentle Skin Stimulation for Nocturia in the Elderly
PLOS ONE | DOI:10.1371/journal.pone.0151726 March 22, 2016 2/14
application on skin stimulation roller (Name: Urination
suppression device, Patent application number:
JP,2010-251392), the rollers that were kindly gifted by
Toyoresin Co. and research grant (Translation
research fund in Tokyo Metropolitan Institute of
Gerontology). The competing interests disclosed do
not alter the authors' adherence to PLOS ONE
policies on sharing data and materials.
when considering clinical relevance, we performed the minimum duration of intervention on
elderly women having nocturia, regardless of the presence or absence of OAB, and accordingly
carried out the analyses.
Methods
The protocol for this clinical trial and supporting CONSORT checklist are available as support-
ing information; see S1 and S2 Protocols and S1 CONSORT Checklist. The present study was
conducted at Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology between Janu-
ary and March 2014 in Tokyo. The study was conducted in accordance with the Declaration of
Helsinki and approved by the Human Research Ethics Committee of the Tokyo Metropolitan
Geriatric Hospital and Institute of Gerontology. We have changed the protocol from the ethics
approval document to exclude men, decrease the numbers of participants, and change the
method of analysis for the primary outcome. Written informed consent was obtained from all
participants. This trial was registered in the University Hospital Medical Information Network
Clinical Trial Registry (UMIN-CTR [UMIN000015809]) on December 1, 2014 (http://www.
umin.ac.jp/ctr/index-j.htmhttp://www.umin.ac.jp/ctr/index-j.htm). This study was rapidly
undertaken due to the fact that access to participant cohorts was permitted at the same time that
the time limit for expenditure of the research funds was approaching. Following permission, to
conduct the trial, ethical approval was obtained; however, registration to UMIN-CTR could not
be achieved by the time of recruitment and randomization of participants. We noticed after the
study had been completed that UMIN-CTR accepted trial registration even after participant ran-
domization [ctr_faq_e1http://www.umin.ac.jp/ctr/UMIN-CTR_e_FAQ.htm#ctr_faq_e1;under
2)-7; accessed on March 30, 2015]. Hence, we have agreed with the significance of UMIN-CTR
and registered this study. Such late registration does not affect study results and participants.
Participants
Participants were screened using surveys based on geriatric syndromes, including urinary
incontinence, conducted at the Tokyo Metropolitan Institute of Gerontology. One thousand
and sixteen elderly women were chosen randomly from the Basic Resident Register of Itabashi-
ku in Tokyo [16,17]. Out of 669 women who participated in the survey, we mailed a recruit-
ment survey to 70 potential participants who had described urinating 2 times at night and
asked them to participate in a face-to-face interview. A response was obtained from 46 women,
of whom 24 were eligible and then enrolled (Fig 1). The inclusion criteria included three main
points: 1) having nocturnal urination 2 times per night as assessed by a questionnaire; 2)
being able to visit our hospital during study periods; and 3) willing to participate after explana-
tion of our study protocols. The exclusion criteria included: underlying diseases and conditions
that should be excluded when diagnosing OAB such as bladder cancer, interstitial cysts, uro-
genital infections [18], or being unsuitable as a participant due to a cognitive disorder. For the
diagnosis of underlying diseases and conditions to be excluded, medical histories were
obtained, and bladder ultrasonographs and urine laboratory analyses were performed by a
urologist. There was no systematic bias in the eventually enrolled sample. The presence or
absence of OAB was evaluated using an OAB symptom score, which was based on four symp-
toms: 1) daytime urination frequency; 2) nighttime urination frequency; 3) urgency; and 4)
urgency incontinence during a 1-month recall period [1,18].
Study design and schedule
The present study was designed as a randomized, placebo-controlled, double-blind cross-over
trial using two different rollers having a different impact on micturition contractions as was
Gentle Skin Stimulation for Nocturia in the Elderly
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shown in recent animal studies [14,15]. We set a minimum duration for the study period,
including a 3-day stimulation period and a 4-day recovery period, based on results from a pre-
liminary study in four OAB patients (unpublished material). The volume and frequency of
nighttime urination was assessed by frequency volume charts maintained for 3 days as the
baseline assessment period. After that period, participants received either an active or placebo
stimuli roller. The stimulation period lasted for 3 days. After a 4-day resting period, partici-
pants performed the other stimuli for an additional 3 days. On the day after the each 3-night
stimulation period had ended, researchers visited the participants home to collect completed
frequency charts and the used roller and to provide a new frequency chart and roller (first visit
only). For safety assessments, the presence or absence of adverse events were determined by
the researcher at this visit and recorded on the charts. The study period lasted 15 days for each
participant.
Skin stimulation
We used two different rollers, each having the same size of 17 mm in diameter and 15 mm in
length and weighing 4 g (Fig 2A). These rollers have a similar appearance (same shape and sim-
ilar color). The only difference between the rollers was surface material that would come into
contact with the skin. A roller (SOMAPLANE, Toyoresin Co., Shizuoka, Japan) having a
smooth and soft elastic surface (made of elastomer) as described [14] was used for the active
Fig 1. CONSORT flow chart. The flow chart illustrates the basic layout of the clinical trial including steps
involved in recruitment of study participants and the actual steps in the clinical trial.
doi:10.1371/journal.pone.0151726.g001
Gentle Skin Stimulation for Nocturia in the Elderly
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stimulation. A roller having a hard non-elastic surface (made of polystyrene, custom-made for
our research use by Toyoresin Co.) was used as the placebo, since stimuli with a hard surface
did not influence micturition contractions in anesthetized rats [15]. We have confirmed in
healthy volunteers [19] that it was possible to camouflage the two types of rollers, by asking
whether the roller was active or placebo and by comparing answers between two types of rol-
lers. However, in the present study, we did not confirm this.
Each participant applied stimuli with the roller to their perineum (Fig 2B). We instructed
each participant on how to apply the stimuli once-a-day before bedtime for 3 consecutive days.
This was done by gently and slowly rolling the roller over top of skin for a period of 1 min,
using a force equivalent to the rollers weight of 4 g. The doseof stimulation was determined
by the preliminary study performed on OAB patients (unpublished), using the active roller.
The participants were not told about the firmness of application of the stimulus. We confirmed
that participants properly performed skin stimulation by two parameters: (1) participants com-
pleted time of skin stimulation on the frequency chart and (2) researchers visited participants
home the morning after the 3-night stimulation period had ended and asked them about their
skin stimulation performance and any difficulties associated with the study.
After each session ended, the participants were asked their perception on the simplicity of
roller use by a written questionnaire with a five-point scale: 1) very difficult; 2) difficult; 3) no
opinion; 4) simple; and 5) very simple.
Outcome measure
The primary outcome was the mean change in nighttime frequency of micturition as deter-
mined by a 3-day frequency chart, maintained only at night. We defined nighttime as the
period between bedtime (participants intended to sleep) and arising (participants initiated
daily activities). Participants completed the times of each micturition during the nighttime
period. Mean nocturnal micturition frequency for 3 nights (times/night) was calculated for
each baseline, and active and placebo stimulation periods. In two cases participants missed
entering data into the frequency chart on one night; mean micturition frequency was obtained
from the data of two nights. There were no missing data on frequency charts from the other
participants. To focus on frequency during the stimuli periods and to reduce the participants'
workload, urine volume measurements were performed only at baseline.
Sample size
The sample size was based on the preliminary estimates from the study results indicating that
nocturnal micturitions 2 voids per night may be associated with impaired QOL [36]. To
detect a clinically meaningful difference in the frequency of urination of one void per night in
Fig 2. A method for a perineal skin stimulation. (A) is a specification of roller, (B) is stimulation site.
doi:10.1371/journal.pone.0151726.g002
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mean change from baseline between active and placebo treatments (standard deviation was
assumed to be 0.9 [20]) with 90% power and a two-sided significance level of 5%, the required
group size was 11 participants with OAB. Forty-nine percent of nocturia occurring in elderly
patients (6080 years old) was related to OAB [21]. Hence, the total sample size required was
23 participants.
Randomization
The 24 participants were divided into two groups with an allocation ratio of 1:1, according to
computer-generated random numbers at the Teikyo Heisei University by S.M. Allocation of
which group would apply the active roller for the first three days was also randomly generated.
Blinded study
The rollers were placed in similar cartridges before use. Allocation and packaging were blinded
except to one of the researchers who did not have any contact with the participants. The other
researchers were not allowed to open the cartridge, to view, or to touch the surface of the roller.
Participants were not informed as to which type of roller was expected to be effective.
Statistical analysis
The change in micturition frequency during the stimulation periods from that seen in the base-
line period was calculated. Additionally, a difference in micturition frequency between the
active and placebo stimuli periods was computed. These values were compared using a paired
or unpaired t-test (two-tailed), after confirming normal distribution of the data using the Sha-
piroWilk normality test (Prism 6 software, GraphPad Software, La Jolla, CA, USA). The effect
size (d) was estimated [22]. A correlation between a difference in micturition frequency
(active-placebo) and each variable was evaluated as bivariate analysis with the Spearmans rank
correlation coefficient (two-tailed). In addition, multiple regression analysis was used as multi-
variate analysis to explore how explanatory variables affect the difference in micturition fre-
quency (IBM SPSS Statistics version 19.0.0, Tokyo, Japan). Two variables, i.e., baseline
frequency or OAB symptom score, entered for the regression analysis. Participants perception
on simplicity of roller use was statistically analyzed by Chi-square test. The statistical signifi-
cance level was set at 5%. Data were expressed as mean ± standard deviation.
Results
The flow chart for the layout and steps in the study is presented in Fig 1. Of the 24 participants
enrolled, 22 completed all study sessions and were included in all analyses. Two participants
discontinued the treatment before completion of the study. One was due to an adverse event
consisting of a feeling of abdominal distension on the second and first day of placebo and active
stimulation period, respectively. The other declined to participate after placebo stimuli period
due to personal reasons not related to the study. No adverse events were reported during either
active or placebo stimuli periods by the other 22 participants.
Participant characteristics
The age of the 22 participants ranged between 79 and 89 years old. The presence of OAB, eval-
uated by the OAB symptom score, was nine out of the 22 (40.9%). Baseline characteristics of
the nine OAB and 13 non-OAB participants were shown in Table 1. There were non-OAB par-
ticipants with residual volumes >100 ml, who were receiving anticholinergic drugs and who
suffered from Parkinsons disease and diabetes. These symptoms are well known to affect
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bladder functions but were not observed in OAB participants. Other geriatric symptoms such
as hypertension, hyperlipidemia, and osteoporosis were observed in both OAB and non-OAB
participants. Of the nine participants with OAB, five performed the active stimuli session first
and four did the placebo stimuli session first.
Frequency of nocturnal urination
The frequency of urination in all 22 participants during the baseline period was 3.2 ± 1.2 times/
night. Changes in nighttime urination frequency during active stimulation from that during
baseline period was greater than that during placebo stimuli period, but the difference was not
statistically significant (0.39 ± 0.7 vs. 0.17 ± 0.6, 95% CI for stimulation difference -0.067 to
0.51, p = 0.13, d = 0.46; Fig 3A).
Table 1. Baseline characteristics.
OAB (n = 9) non-OAB (n = 13)
Age (years old) 82.33 ±1.66 83.08 ±3.12
Urination frequency (times/night) 3.52 ±1.43 2.97 ±0.99
Volume per void (mL) 234.8 ±87.9 233.4 ±64.3
Residual volume >100 ml 0 4
Anticholinergic drugs 0 2
Parkinsons disease 0 1
Diabetes 0 3
Hypertension 4 6
Hyperlipidemia 1 2
Osteoporosis 2 6
Data are expressed as mean ±standard deviation.
doi:10.1371/journal.pone.0151726.t001
Fig 3. Changes in nighttime urination frequency during placebo and active stimulation periods from that during the baseline assessment period.
Data are expressed as mean ±standard deviation. *p<0.05; tested by paired t-test between active and placebo stimulation periods.
doi:10.1371/journal.pone.0151726.g003
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Subsequently, further analyses were performed by dividing participants into groups with or
without OAB. In the nine participants with OAB, a change in nighttime urination frequency
during the active stimulation period from that seen during the baseline period was significantly
greater than that during the placebo stimuli period (0.74 ± 0.7 vs. 0.15 ± 0.8, 95% CI 1.1 to
0.07, p = 0.031, d = 1.12; Fig 3B left). In contrast, in participants without OAB, changes in
micturition frequency during the active and placebo stimuli periods were not significantly dif-
ferent (0.14 ± 0.6 vs. 0.18 ± 0.5, 95% CI 0.33 to 0.26, p = 0.78, d = 0.09; Fig 3B right).
Fig 4 shows a summary of the degree of differences in frequency of nighttime urination
between the active and placebo stimuli periods for each participant. To exclude the placebo
effect, values of nighttime urination frequency during the placebo stimuli period were sub-
tracted from those during the active stimuli period. The unpaired t-test revealed that the fre-
quency difference was significantly greater in participants with OAB, compared to those
without OAB (0.59 ± 0.7 vs. 0.04 ± 0.5, 95% CI for group difference 1.2 to 0.11, p= 0.02,
d = 0.92).
To clarify factors that are associated with a change in nighttime urination frequency during
the active stimuli period, bivariate analysis was performed. The differences in urination fre-
quency between active and placebo stimuli showed no significant correlation with urination
frequency during the baseline period (Table 2). On the other hand, the frequency difference
Fig 4. Differences in frequency of nighttime urination between active and placebo stimuli. Data are
expressed as mean ±standard deviation. Each dot represents individual data. *p<0.05; tested by unpaired
t-test.
doi:10.1371/journal.pone.0151726.g004
Table 2. Association between difference in urination frequency and explanatory variables (n = 22).
Bivariate Analysis Multivariate Analysis
Explanatory variables Correlation Coefcient P-value Standardized Partial Regression Coefcient
P-value
Urination frequency -0.13 0.56 -0.04 0.84
OAB symptom score
-0.57 <0.01 -0.69 <0.01
adjusted R
2
0.45
Overactive bladder (OAB) symptom score; Total score can therefore range from 0 to 15, with higher scores indicating increasing symptom severity.
Variance ination factors <10.
doi:10.1371/journal.pone.0151726.t002
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was negatively correlated with the OAB symptom score (r = 0.57, p = 0.0059). Similar results
were also obtained by multivariate analysis (Table 2).
Perception on simplicity of skin stimulation method
The majority of participants answered that they felt it was simple to use the rollers (Table 3).
The Chi-square test revealed that there was no significant difference in perception scores
between active and placebo rollers (p= 0.45).
Discussion
The present study examined the effects of gentle perineal stimuli on the frequency of nighttime
urination in elderly women with nocturia. Experiments were performed in a randomized, pla-
cebo-controlled, double-blind crossover manner by using two different rollers with different
surface materials (soft vs. hard). Participants applied the perineal stimuli for 3 consecutive days
for a period of 1 min at bedtime. The results showed that stimulation with a soft elastomer
roller (used as the active roller), but not with a hard polystyrene roller (used as the placebo),
decreased frequency of nighttime urination, especially in participants with OAB. The inhibi-
tory effect on the frequency of urination by the active stimulation was consistent with the
inhibitory effect on the frequency of rhythmic micturition contractions of the expanded blad-
der by the same stimuli in our previous animal studies under anesthesia [14,15]. The difference
in the inhibitory efficacy between stimulation with the two different rollers was also in accor-
dance with our animal study [15]. The present results suggest that an inhibitory effect on blad-
der contraction caused by OAB can be achieved by perineal stimulation.
OAB vs. non-OAB
In contrast to the significant decrease in the frequency of nighttime urination by active stimula-
tion in participants with OAB, there was no significant effect on the frequency of urination in
participants without OAB. That was predicted and then confirmed by our present results. In
particular, a greater reduction in the frequency of nighttime urination was seen in participants
with higher OAB symptom scores, suggesting that the active roller is effective for inhibiting
bladder contractions associated with OAB. However, since the pathogenesis of OAB has not
been thoroughly clarified, we cannot explain the cause(s) of the different efficacy of the active
stimuli on OAB vs. non-OAB. A variety of factors known to affect bladder functions (such as
residual volume, use of anticholinergic drugs, Parkinsons disease, and diabetes) appeared to be
involved as causes of nocturia in the present non-OAB participants. Although we did not
examine polyuria or nocturnal polyuria in the present study, these two factors could be the
main cause of nocturia in non-OAB participants. In future studies examining long-term stimu-
lation, we should just focus on nocturia with OAB.
Table 3. Participants perception on simplicity of roller use.
Active roller Placebo roller
Very difcult 1 2
Difcult 1 3
No opinion 7 4
Simple 10 7
Very simple 3 6
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Efficacy
The effect of the active stimuli was significant in nocturia participants with OAB and the
decrease of frequency of nighttime urination during active stimuli was about 0.59 times/night
compared with that during placebo stimuli. This effect was significantly greater than that seen
with drugs that are highly recommended for OAB, such as tolterodine or solifenacin, which are
administered for 412 weeks. Although current treatments for OAB are recommended in vari-
ous guidelines, based on the statistically significant differences compared to placebo, the clini-
cal relevance of this effect [2325] is very small. Such drug treatment for OAB is not often
directed at nocturia, but the recent trial concerning the effect of fesoterodine on nocturnal
urgency as the primary outcome also showed only a small decrease (by 0.21 times/night) when
compared to placebo [26]. Therefore, the present results suggest that gentle perineal stimula-
tion with the active roller can be useful as an alternative for pharmacological nocturia treat-
ments. In the case of non-pharmacological therapy such as acupuncture [27], moxibustion
[28], transcutaneous electrical nerve stimulation [29], and magnetic stimulation [30], 112
weeks of treatment decreased the frequency of nighttime urination by 0.32.4 times/night
when compared with baseline levels. Such somatosensory stimuli were not always possible to
administer in a randomized clinical trial [8]. However, the present results may partially explain
the efficacy of these alternate treatments.
Safety
During the course of the study, adverse events were not reported except for one participant
who discontinued because of the feeling of abdominal distension. That adverse event occurred
during both the active and placebo stimuli periods. Adverse events selectively produced by
active stimulation were not observed in this study. Safety of the active stimulation was pre-
dicted because of very gentle skin stimulation and then confirmed by the present results. The
dropout rate after randomization was only 8% even though the ages of the participants were
quite high (7989 years old), supporting the safety of self-administered cutaneous stimulation.
However, safety should be carefully analyzed in trials carried out over a longer period.
Placebo stimulation vs. active stimulation
In contrast to the decrease in nocturnal frequency of urination seen with the active roller, pla-
cebo stimulation did not produce any consistent effect on urination frequency. Therefore, the
placebo effect was negligible in this study. We used two different rollers for stimulation. The
difference between the two sets of stimuli was produced solely by the difference in the roller
surface materials in contact with skin. Both stimuli were gentle and the participants perception
of the simplicity of roller use was not significantly different (Table 2). Although it is hard to
perceptually distinguish between these rollers, the properties of the materials used for the roller
surfaces were different; the active roller was soft and sticky, whereas the placebo roller was
hard and slippery. Therefore, such differences may produce different excitation frequencies
and patterns of various types of mechanoreceptive afferent fibers that innervate the perineal
skin. We previously showed that the active stimulation applied to rats' perineal areas excited
low-threshold cutaneous mechanoreceptive Aβ,Aδ, and C fibers at mean frequencies of 2, 3,
and 8 Hz, respectively [14]. Studies on the effects of electrical stimulation of cutaneous afferent
nerves have suggested that inhibitory effects on bladder contractions are dependent on the
types of afferent nerve fibers and frequency of evoked discharges [31,32]. Therefore, it will be
important to compare responses of each cutaneous afferent nerve fiber after active and placebo
stimuli in the future to clarify the afferent mechanism for inhibition of frequency of nighttime
urination.
Gentle Skin Stimulation for Nocturia in the Elderly
PLOS ONE | DOI:10.1371/journal.pone.0151726 March 22, 2016 10 / 14
Possible mechanisms
The present results, in conjunction with previous animal studies [14,15], suggest that there are
common mechanisms in rats and humans that indicate some form of somatosensory stimuli
that inhibit transmissions of micturition reflex pathways. Similarities between the effects of
gentle skin stimulation on nociceptive stimulation-induced cardiovascular reflexes in con-
scious humans and anesthetized rats have also been reported recently [3335]. In our experi-
ments with anesthetized rats, we recorded discharges from the vesical pelvic efferent nerve
fibers or skin afferent nerve fibers and bladder contractions before and after administration of
an opioid receptor antagonist. Using these techniques, we showed that excitation of low thresh-
old cutaneous mechanoreceptive myelinated and unmyelinated fibers inhibited the vesico-pel-
vic parasympathetic reflex; this occurred via activation of the opioid system in the spinal cord
and by reducing both the ascending (afferent) and descending (efferent) transmissions between
bladder and pontine micturition center [36,37]. Such inhibitory mechanisms could modify
urgency in OAB with or without detrusor overactivity. The mechanism, as revealed by animal
experiments, may explain the present clinical outcome of gentle perineal stimulation to reduce
the frequency of nighttime urination due to OAB.
Limitations and future study needed
The major limitation of this study was the restricted treatment period. Nocturia can lead to
sleep impairment and lower QOL [38]. Therefore, the reduction in frequency of nighttime uri-
nation observed in the present study could lead to improvements in sleep quality and QOL.
However, the present stimulation period of 3 days was too short to convincingly assess QOL.
Results from neural mechanisms derived from animal studies support the idea that stimulation
possibly increases functional bladder capacity; consequently, repeated stimulation for longer
periods may gradually induce greater clinical outcome. Further study is needed to examine the
effects of repeated stimulation for longer periods, in which the effects on sleep quality and
QOL (such as using a Nocturnal QOL Questionnaire [39,40]) should be examined
concurrently.
Conclusion
The present results provide the first clinical evidence that stimulation of the perineal skin with
a soft roller may be effective for OAB-associated nocturia in elderly patients. The significant
decrease in the frequency of nighttime urination was obtained by self-stimulation for only 1
min at bedtime once-a-day. Gentle perineal stimulation is expected to be a novel self-adminis-
tered therapy for nocturia.
Supporting Information
S1 CONSORT Checklist.
(DOC)
S1 Protocol. Trial Protocol. Approved ethics application form for the present study. This doc-
ument includes inclusion and exclusion criteria and trial protocol.
(DOCX)
S2 Protocol. Trial Protocol written in Japanese. Approved ethics application form written in
Japanese (original document) for the present study.
(DOC)
Gentle Skin Stimulation for Nocturia in the Elderly
PLOS ONE | DOI:10.1371/journal.pone.0151726 March 22, 2016 11 / 14
Acknowledgments
The authors thank Ms. Tsuruko Maekawa for her technical support.
Author Contributions
Conceived and designed the experiments: SM HH HK KM. Performed the experiments: KI
NW HH KM. Analyzed the data: KI NW HH SM HK TH HT YK. Wrote the paper: KI NW
KM HH SM HK TH HT YK.
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... In recent years, studies have demonstrated the effects of pleasant touch on single afferent ber activities in cutaneous nerves [22][23][24][25] . Pleasant touch activates mechanoreceptors in the skin 23 , which changes autonomic function, and suppresses stress [23][24][25] . ...
... In recent years, studies have demonstrated the effects of pleasant touch on single afferent ber activities in cutaneous nerves [22][23][24][25] . Pleasant touch activates mechanoreceptors in the skin 23 , which changes autonomic function, and suppresses stress [23][24][25] . The afferent bers involved in regulating muscle tone consist of not only Ib and II bers of the homonymous muscle, but also bers in the cutaneous nerves 21 . ...
... Based on their ndings, we had expected the contact acupuncture to be superior to the sham acupuncture ; however, this was not the case herein. Another study found that cutaneous stimulation with a roller made of the same material as the sham acupuncture device used in the present study was effective for treating overactive bladder-related nocturia in elderly women 25 . Further investigations of stimulation modalities are needed, including the degree of skin compression and the stimulation materials. ...
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