Open Journal of Urology, 2013, 3, 293-298
Published Online December 2013 (http://www.scirp.org/journal/oju)
Open Access OJU
Comparison of the Melatonin Receptor Agonist
Ramelteon and the Non-Benzodiazepine
Hypnotic Zolpidem for Nocturia*
Hideki Mukouyama1, Kimio Sugaya2,3#, Saori Nishijima2, Hidekatsu Naka4,
Misao Sakumoto5, Tomohiro Onaga6, Katsumi Kadekawa2,6, Katsuhiro Ashitomi2,7
1Department of Urology, Nanbu Tokushukai Hospital, Okinawa, Japan
2Southern Knights’ Laboratory LLP, Okinawa, Japan
3Kitakami Central Hospital, Okinawa, Japan
4Nishizaki Hospital, Okinawa, Japan
5Sakumoto Urology and Dermatology Clinic, Okinawa, Japan
6Department of Urology, Okinawa Kyodo Hospital, Okinawa, Japan
7Department of Urology, Okinawa Hokubu Hospital, Okinawa, Japan
Received November 4, 2013; revised November 25, 2013; accepted December 2, 2013
Copyright © 2013 Hideki Mukouyama et al. This is an open access article distributed under the Creative Commons Attribution Li-
cense, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. In
accordance of the Creative Commons Attribution License all Copyrights © 2013 are reserved for SCIRP and the owner of the intel-
lectual property Hideki Mukouyama et al. All Copyright © 2013 are guarded by law and by SCIRP as a guardian.
To examine the efficacy of the melatonin receptor agonist ramelteon for nocturia, it was compared with zolpidem, a
conventional non-benzodiazepine hypnotic. A total of 50 patients with nocturia (2 urinations/night) were enrolled.
Subjects assigned odd nu mbers or even numbers wer e respectively prescribed 8 mg of ramelteon (n = 27; mean age: 75
years) or 5 mg of zolpidem (n = 23; mean age: 73 years) once a day before sleeping for 4 weeks. The daytime and
nighttime frequencies of urination, as well as the results of global self-assessment by the patients, were compared be-
tween the two groups before and after 4 weeks of treatment. Both ramelteon and zolpidem caused a significant decrease
of nocturia to about once per n ight after 4 weeks. The g lobal self-assessment rating at 4 weeks was “good” or “fair” for
more patients in the zolpidem group than in the ramelteon group, while the rating was “excellent” or “no change” for
more patients in the ramelteon group. There were no serious adverse events in either group. Ramelteon was safe and
effective for nocturia, achieving similar results to zolpidem. However, responders and non-responders to ramelteon
were more clearly distinguished. Ramelteon might be effective for patients with sleep disturbance and nocturia because
of low melatonin levels. Therefore, as diagnostic therapy for identification of nocturia caused by sleep disturbance and
melatonin deficiency, ramelteon should be administered to patients who do not respond to alpha-1 antagonists and/or
Keywords: Ramelteon; Nocturia; Melatonin; Zolpid em
Nocturia is common in th e elderly, and is on e of the most
troublesome urologic symptoms [1,2]. Several prospec-
tive studies have shown that nocturia is associated with a
higher mortality rate, even after adjustment for con-
founding factors . Multiple factors may contribute to
the occurrence of nocturia, including various pathologi-
cal conditions such as cardiovascular disease, diabetes
mellitus, lower urinary tract obstruction, anxiety disor-
ders or primary sleep disorders, and various other be-
havioral and environmental factors [4-7]. Therefore,
various drugs and other methods have been tried for the
treatment of nocturia, including alpha-1 receptor antago-
nists, anticholinergic agents, nonsteroidal anti-inflam-
matory drugs, antidepressants (minor tranquilizers), diu-
retics, desmopressin, hypnotics, and melatonin [8,9].
Ramelteon was a novel hypnotic drug [10,11] that was
*Conflict of interest: None declared.
H. MUKOUYAMA ET AL.
released recently. It is an orally active chrono hypnotic
agent that acts selectively on melatonin MT1 and MT2
receptors, which are primarily located in the suprachias-
matic nucleus. In order to examine the efficacy of ra-
melteon (Rozerem®) for nocturia, we compared it with
zolpidem (Myslee®), a conventional non-benzodiazepine
hypnotic (GABAa receptor modulator) , in elderly
patients with nocturia.
2. Materials and Methods
A total of 50 patients with nocturia were enrolled from
January 2011 to April 2012. The inclusion criterion for
this study was urination 2 times/night. Patients with a
history of diseases or conditions that could affect lower
urinary tract function were excluded from this study, in-
cluding urinary tract surgery within 6 months, an in-
dwelling bladder catheter, intermittent catheterization,
electrical stimulation therapy, bladder training, prostatic
cancer, bladder cancer, bladder stones, active urinary
tract infection, and interstitial cystitis. If the patients were
taking drugs for nocturia, including alpha-1 receptor an-
tagonists and/or anticholinergic agents, administration
was continued during the study. However, patients using
sedatives or hypnotics and those with a high water intake
were excluded from the study. The Okinawa Kyodo
Hospital Ethics Committee approved the conduct of this
study on behalf of all participating facilities, and in-
formed consent was obtained from all participants b efore
they entered the trial.
Subjects who were assigned odd numbers or even
number sat each hospital were respectively administered
8 mg of ramelteon (Rozerem® Tablet 8 mg) or 5 mg of
zolpidem (Myslee® Tablet 5 mg) once a day before
sleeping for 4 weeks. This study was not blinded. The
prostate volume (in men) and the post-voiding residual
urine (PVR) volume (in men and women) were measured
by transabdominal u ltrasonograph y before the start of th e
study. The systolic and diastolic blood pressure, heart
rate, International Prostate Symptom Score (IPSS), Qual-
ity of Life (QOL) score, Overactive Bladder Symptom
Score (OABSS), daytime and nighttime frequency, and
PVR were evaluated before starting study and after 4
weeks of treatment. Global self-assessment ratings as-
signed by the patients themselves (excellent, good, fair,
no change, or worse) and adverse events were also ex-
amined after 4 weeks of treatment. The overall clinical
status was also compared between the ramelteon and
zolpidem groups before starting study and after 4 weeks
Results are reported as the mean ± standard deviation
(SD). Student’s t-test and the Wilcoxon signed-ranks test
were used for statistical analysis of paired or unpaired
data, while differences of categorical variables were as-
sessed with the chi-square test. In all analyses, p < 0.05
was considered to indicate statistical significance.
In the ramelteon group, 27 patients were prescribed ra-
melteon at 8 mg nightly, including 20 men and 7 women
with a mean age of 75 ± 8 years (range: 58 - 94 years).
Twenty-five of these 27 patients were assessed after 4
weeks of medication, while 2 patients stopped treatment
because of adverse events. In the zolpidem group, 23
patients were prescribed zolpidem at 5 mg nightly, in-
cluding 14 men and 9 wo men with a mean age of 73 ± 12
years (range: 49 - 94 years). All 23 patients were assess ed
after 4 weeks of medication. Before starting treatment,
there were no significant differences of age, systolic
blood pressure, diastolic blood pressure, heart rate, com-
plications, prostate volu me, duration of nocturia, daytime
and nighttime frequency, OABSS and IPSS items, total
OABSS, total IPSS, and QOL score between the 2
groups (Table 1). The PVR volume was small in both
groups, but was larger in the ramelteon group (10 ± 13
ml) than in the zolpidem group (2 ± 5 ml). Nineteen pa-
tients from the ramelteon group (70%) and 18 patients
from the zolpidem group (78%) had already received
treatment for lower urinary tract symptoms with alpha-1
antagonists, anticholinergic agents, and/or herbal medi-
In the ramelteon group, the daytime frequency of uri-
nation decreased significantly from 8.1 ± 3.0 times be-
fore treatment to 7.9 ± 3.1 times (n = 25, p = 0.045) after
4 weeks (Figure 1). The nighttime frequency of urination
also decreased significantly from 3.8 ± 1.4 times before
Table 1. Demographic profile of the patients with nocturia.
Group Ramelteon Zolpidem
Case number (male:female) 27 (20:7) 23 (14:9)
Age (years) 75 ± 8 73 ± 12
Benign prostatic hyperplasia 14 11
Chronic prostatitis 1 0
Post-prostatectomy 1 1
Overactive bladder 8 10
Stress incontinence (post-op.)1 1
Hypertension 8 8
Diabetics 4 1
Cerebrospinal disorders 7 5
Systolic blood pressure (mmHg)134 ± 12 131 ± 20
Diastolic blood press ure (mmHg)74 ± 10 76 ± 10
Heart rate (/min) 75 ± 9 75 ± 9
Prostate volume (ml) 30 ± 18 24 ± 8
Post-voiding residual volume (ml) 10 ± 13 2 ± 51
Duration of nocturia (months) 41 ± 51 53 ± 54
Mean ± SD, 1p = 0.041.
Open Access OJU
H. MUKOUYAMA ET AL. 295
Figure 1. Frequency of urination before and after four
weeks of treatment in the ramelteon and zolpidem groups.
Daytime (a) and nighttime frequency (b). Red: Ramelteon,
treatment to 2.5 ± 1.4 times (n = 25, p < 0.001) after 4
weeks. With the decrease of both daytime and nighttime
urination, the total OABSS an d total IPSS also decreased
significantly at 4 weeks (Figure 2). Furthermore, the
QOL score decreased significantly from 4.7 ± 1.0 before
treatment to 3.5 ± 1.4 (p < 0.001) after 4 weeks. The
systolic blood pressure, diastolic blood pressure, heart
rate, and PVR did not change. The global self-assessment
rating at 4 weeks was “excellent” in 6 patients (24%),
“good” in 4 (16%), “fair” in 5 (20%), and “no change” in
10 (40%) (Figure 3). None of the patients rated them-
selves as “worse”. Adverse events were observed in 5 out
of 27 patients (19%). The symptoms noted up to 4 weeks
were lassitude (n = 3, one dropped out at 2 weeks), un-
steadiness (n = 1), and palpitations plus edema of lower
extremities (n = 1, this patient dropped out at 2 weeks).
These events were not serious and resolved promptly
after discontinuation of ramelteon.
In the zolp idem g roup, the nighttime frequency of uri-
nation (but not daytime frequency) decreased signifi-
cantly from 3.5 ± 1.5times before treatment to 2.5 ± 1.6
Figure 2. Total OABSS, total IPSS, and QOL score of the
ramelteon and zolpidem groups. Total OABSS (a), Total IPS S
(b), and QOL score (c). Red: Ramelteon, Blue : Zolpidem.
Open Access OJU
H. MUKOUYAMA ET AL.
Open Access OJU
Excellent Good Fair No cha
Good Fair No changeW
Figure 3. The global self-assessment ratings assigned by the patients after four weeks. Ramelteon (a) and zolpidem groups (b).
times (n = 23, p < 0.001) after 4 weeks (Figure 1). With
the decrease of frequency, total OABSS and total IPSS
also decreased significantly at 4 weeks (Figure 2). Fur-
thermore, the QOL score decreased significantly from
4.7 ± 0.9 before treatment to 3.7 ± 1.1 (p < 0.001) after 4
weeks. The systolic blood pressure, diastolic blood pres-
sure, heart rate, and PVR did not change. The global self-
assessment rating at 4 weeks was “good” in 6 patients
(26%), “fair” in 10 (43%), “no change” in 6 (26%), and
“worse” in 1 (4%) (Figure 3). No patient gave a rating of
“excellent”. Adverse events were observed in 2 of the 23
patients (9%), both of whom had lassitude at 4 weeks.
These events were not serious and resolved promptly
after discontinuation of zolpidem.
typical cause of nocturia, and the plasma melatonin level
of patients with nocturia is significantly lower than that
of those without nocturia . Hypnotics including zol-
pidem reduce the frequency of nocturia to about once
nightly [8,12,15], and the effect of melatonin on nocturia
has been reported to be similar to that of hypnotics .
Many patients fear that they will be come dependent on
hypnotics if they take such drugs for too long , so the
drugs were administered for 4 weeks in this study. Ra-
melteon is a melatonin MT1 and MT2 receptor agonist
that is recently reported to be effective for nocturia .
In the present study, both ramelteon and zolpidem proved
nocturia in patients who had shown a poor response to
alpha-1 antagonists, anticholinergic agents, and/or herbal
There were no significant differences of the daytime
and nighttime frequency, total OABSS, total IPSS, QOL
score, blood pressure, heart rate, PVR, and adverse
events between the two groups at 4 weeks. There were
also no significant between-group differences in the
number of patients with “excellent” or “good” self-as-
sessment ratings. However, there was a significantly
greater difference between the number of patients with
“excellent” or “no change” ratings and those with “good ”
or “fair” ratings in the ramelteon group compared with
the zolpidem group (chi-square test, p = 0.020).
In the ramelteon group, fewer patients gave a global
self-assessment rating of “good” or “fair” compared with
ratings of “excellent” or “no change”. Although there
was no significant difference, the frequency of adverse
events and drop-out was higher in the ramelteon group
than in the zolpidem group. Therefore, there was a clear
difference between patients who responded or failed to
respond to ramelteon. When various morning parameters
were compared between subjects who were troubled by
nocturnal urination (nocturia) and those who were not,
the plasma melatonin level was significantly lower in the
former group , suggesting that persons with nocturia
are likely to have sleep disturbance. The present results
may indicate that ramelteon is effective for patients with
sleep disturbance and nocturia due to low melatonin lev-
els. However, routine measurement of the plasma mela-
tonin level in patients with nocturia is not feasible.
Therefore, ramelteon could be administered to patients in
whom nocturia is not improved by alpha-1 antagonists
and/or anticholinergic agents as diagnostic therapy for
nocturia associated with sleep disturbance and low me-
In the present study, both ramelteon and zolpidem de-
creased nocturia to about on ce per night after 4 weeks of
treatment. In the ramelteon group, but not the zolpidem
group, the dayti me frequen cy of urination also decreased
significantly. Adverse events and drop-out were slightly
more common in the ramelteon group than in the zolpi-
dem group, but the difference was not significant and
there were no serious even ts in either group. The number
of patients with a “good” or “fair” global self-assessment
rating was larger in the zolpidem group, while more pa-
tients gave a rating of “excellent” or “no change” in the
ramelteon group. This difference was thought to be due
to the characteristic effect of ramelteon on nocturia.
In the ramelteon group, but not the zolpidem group,
the daytime frequency of urination decreased signifi-
cantly. When 2 mg of melatonin was administered to
patients with nocturia before sleeping, the morning plas-
ma melatonin level was very high  co mpared with that
Nocturia is defined as the need to wake once or more
times during the night to void . Sleep disturbance is a
H. MUKOUYAMA ET AL. 297
in persons without nocturia . Melatonin inhibits the
contraction of isolated rat bladder smooth muscle ,
and increases bladder capacity in rats . Therefore,
administering melatonin or ramelteon before sleeping
might also have a beneficial influence on lower urinary
tract function in the daytime.
Ramelteon was safe and effective for nocturia, achieving
similar results to zolpidem, although responders and
non-responders to ramelteon were more clearly distin-
guished. Ramelteon may be effective for patients who
have sleep disturbance and nocturia associated with low
melatonin levels. Accordingly, ramelteon could be used
as diagnostic therapy for nocturia caused by sleep dis-
turbance and low melatonin levels in patients whose
nocturia is not improved by alpha-1 antagonists and/or
 M. H. Blanker, A. M. Bohnen, F. P. Groeneveld, R. M.
Bernsen, A. Prins and J. L. Ruud Bosch, “Normal Void-
ing Patterns and Determinants of Increased Diurnal and
Nocturnal Voiding Frequency in Elderly Men,” Journal
of Urology, Vol. 164, No. 4, 2000, pp. 1201-1205.
 M. H. Blanker, R. M. Bernsen, J. L. Bosch, S. Thomas, F.
P. Groeneveld, A. D. Prins and A. M. Bohnen, “Relation
between Noc turnal Voiding Freque ncy and Nocturnal U ri ne
Production in Older Men,” Urology, Vol. 60, No. 4, 2002,
 K. Yoshimura, “Correlates for Nocturia: A Review of
Epidemiological Studies,” Journal of Urology, Vol. 19,
No. 4, 2012, pp. 317-329.
 J. P. Weiss, J. G. Blaivas, D. S. Stember and M. M. Brooks,
“Nocturia in Adults. Etiology and Classification,” Neuro-
urology and Urodynamics, Vol. 17, No. 5, 1998, pp. 467-
 J. P. Weiss, J. G. Blaivas, D. S. Stember and D. C. Chai-
kin, “Evaluation of the Etiology of Nocturia in Men: The
Nocturia and Nocturnal Bladder Capacity Indices,” Neu-
rourology and Urodynamics, Vol. 18, No. 6, 1999, pp.
 K. Yoshimura, N. Terada, Y. Matsui, A. Terai, N. Kinu-
kawa and Y. Arai, “Prevalence of and Risk Factors for
Nocturia: Analysis of a Health Screening Program,”
International Journal of Urology, Vol. 11, No. 5, 2004,
 L. W. Gourova, C. van de Beek, M. G. Spigt, F. H.
Nieman and P. E. van Kerrebroeck, “Predictive Factors
for Nocturia in Elderly Men: A Cross-Sectional Study in
21 General Practices,” BJU International, Vol. 97, No. 3,
2006, pp. 528-532.
 K. Sugaya S. Nishijima, M. Miyazato, K. Kadekawa and
Y. Ogawa, “Effects of Melatonin and Rilmazafone on
Nocturia in the Elderly,” Journal of International Medical
Research, Vol. 35, No. 5, 2007, pp. 685-691.
 O. Nishizawa, I. Araki, O. Ishizuka, N. Uchimura, H.
Oh-oka, S. Ozono, H. Kakizaki, M. Kasahara, M. Gotoh,
R. Sakakibara, H. Shinbo, K. Sugaya, Y. Suzuki, A. Sone,
M. Takei, M. Takeda, A. Hirayama, Y. Homma, O. Ya-
maguchi, T. Yamanishi, O. Yokoyama and M. Yoshida,
“Clinical Guidelines for Nocturia,” International Journal
of Urology, Vol. 17, No. 5, 2010, pp. 379-409.
 G. Zammit, S. Wang-Weigand, M. Rosenthal and X. P en g,
“Effect of Ramelteon on Middle-of-the-Night Balance in
Older Adults with Chronic Insomnia,” Journal of Clinical
Sleep Medicine, Vol. 15, No. 1, 2009, pp. 34-40.
 S. R. Pandi-Perumal, V. Srinivasan, D. W. Spence, A.
Moscovitch, R. Hardeland, G. M. Brown and D. P. Car-
dinali, “Ramelteon: A Review of Its Therapeutic Potential
in Sleep Disorders,” Advances in Therapy, Vol. 26, No. 6,
2009, pp. 613-626.
 Y. S. Song and J. H. Ku, “Zolpidem Pharmacotherapy
Combined with Alpha-Blocker Therapy for Nocturia Un-
responsive to Alpha-Blocker Monotherapy in Men with
Lower Urinary Tract Symptoms: A Preliminary Study,”
International Urology and Nephrology, Vol. 39, No. 4,
2007, pp. 1147-1152.
 P. Abrams, L. Cardozo, M. Fall, D. Griffiths, P. Rosier, U.
Ulmsten, P. Van Kerrebroeck, A. Victor and A. Wein,
“Standardisation Sub-Committee of the International Con-
tinence Society: The Standardisation of Terminology in
Lower Urinary Tract Function: Report from the Stan-
dardisation Sub-Committee of the International Conti-
nence Society,” Urology, Vol. 61, No. 1, 2003, pp. 37-49.
 K. Sugaya, S. Nishijima, M. Oda, T. Owan, M. Miyazato
and Y. Ogawa, “Biochemical and Body Composition
Analysis of Nocturia in the Elderly,” Neurourology and
Urodynamics, Vol. 27, No. 3, 2008, pp. 205-211.
 K. Fujikawa, M. Kasahara, Y. Matsui and H. Takeuchi,
“Human Atrial Natriuretic Peptide Is a Useful Criterion in
Treatment of Nocturia,” Scandinavian Journal of Urology
and Nephrology, Vol. 35, No. 4, 2001, pp. 310-313.
 N. Shimizu, M. Nozawa, Y. Itami, Y. Yamamoto and Y.
Hayashi, “A Study on Efficacy of Ramelteon in Patients
with Insomnia and Nocturia,” Japanese Journal of Uro-
logical Surgery, Vol. 24, 2011, pp. 1473-1479.
 K. Sugaya, S. Nishijima, M. Miyazato, T. Owan, Y. Oshi-
ro, A. Uchida, S. Hokama and Y. Ogawa, “Investigation
of Biochemical Factors Related to Non-Bothersome Noc-
turnal Urination,” BioMed Research, Vol. 28, No. 4, 2007,
pp. 458-460. http://dx.doi.org/10.2220/biomedres.28.213
 J. H. Han, I. H. Chang, S. C. Myung, M. Y. Lee, W. Y.
Open Access OJU
H. MUKOUYAMA ET AL.
Open Access OJU
Kim, S. Y. Lee, S. W. Lee and K. D. Kim, “A Novel
Pathway Underlying the Inhibitory Effects of Melatonin
on Isolated Rat Urinary Bladder Contraction,” The Ko-
rean Journal of Physiology & Pharmacology, Vol. 16, No.
1, 2012, pp. 37-42.
 Y. Matsuta, A. Yusup, K. Tanase, H. Ishida, H. Akino
and O. Yokoyama, “Melatonin Increases Bladder Capac-
ity via GABAergic System and Decreases Urine Volume
in Rats,” Journal of Urology, Vol. 184, No. 1, 2010, pp.