Comparison of the Melatonin Receptor Agonist Ramelteon and the Non-Benzodiazepine Hypnotic Zolpidem for Nocturia

doi:10.4236/oju.2013.38055

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Open Journal of Urology, 2013, 3, 293-298

Published Online December 2013 (http://www.scirp.org/journal/oju)

http://dx.doi.org/10.4236/oju.2013.38055

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

Email: #[email protected]

Received November 4, 2013; revised November 25, 2013; accepted December 2, 2013

cense, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. In

ABSTRACT

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

anticholinergic agents.

Keywords: Ramelteon; Nocturia; Melatonin; Zolpid em

1. Introduction

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 [3]. 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.

#Corresponding autho

H. MUKOUYAMA ET AL.

294

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) [12], 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

of therapy.

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.

3. Results

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-

cines.

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

Basal disease

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.

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H. MUKOUYAMA ET AL. 295

(a)

(b)

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,

Blue: Zolpidem.

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

(a)

(b)

(c)

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.

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H. MUKOUYAMA ET AL.

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296

Excellent Good Fair No cha

nge

Good Fair No changeW

0 20406080

（％）

100

0 20406080

（％）

100

(a) Ｒamelteon

(b)．Ｚolpidem

4 wks

(n=25)

4 wks

(n=23)

Figure 3. The global self-assessment ratings assigned by the patients after four weeks. Ramelteon (a) and zolpidem groups (b).

W: worse.

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 [14]. 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 [8].

Many patients fear that they will be come dependent on

hypnotics if they take such drugs for too long [8], 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 [16].

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

medicines.

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 [17], 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-

latonin levels.

4. Discussion

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 [8] co mpared with that

Nocturia is defined as the need to wake once or more

times during the night to void [13]. Sleep disturbance is a

H. MUKOUYAMA ET AL. 297

in persons without nocturia [14]. Melatonin inhibits the

contraction of isolated rat bladder smooth muscle [18],

and increases bladder capacity in rats [19]. Therefore,

administering melatonin or ramelteon before sleeping

might also have a beneficial influence on lower urinary

tract function in the daytime.

5. Conclusion

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

anticholinergic agents.

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