Effects of Melatonin and Rilmazafone on Nocturia in the Elderly

Transcription

1 The Journal of International Medical Research 2007; 35: Effects of Melatonin and Rilmazafone on Nocturia in the Elderly K SUGAYA, S NISHIJIMA, M MIYAZATO, K KADEKAWA AND Y OGAWA Division of Urology, Department of Organ-oriented Medicine, Faculty of Medicine, University of the Ryukyus, Okinawa, Japan We compared the effects of melatonin, an antioxidant and sleep inducer in humans, and rilmazafone hydrochloride, a hypnotic, in elderly patients with nocturia. Patients received either melatonin (2 mg/day; n = 20) or rilmazafone (2 mg/day; n = 22) for 4 weeks. There were no significant differences in the mean age, the quality of life (QoL) score and the serum melatonin levels between the two groups at baseline. After 4 weeks treatment, the number of nocturnal urinations was significantly decreased and the QoL score was significantly improved in both groups. There was no significant difference between the patientreported effectiveness ratings between the two groups. The serum melatonin level was significantly increased in the melatonin-treated group, but it remained unchanged in the rilmazafone-treated group. Melatonin and rilmazafone were equally effective for nocturia in the elderly. We recommend that the problems of sleep disturbance should be considered when choosing a therapy for nocturia. KEY WORDS: RILMAZAFONE; HYPNOTIC; NOCTURIA; ELDERLY PATIENTS; MELATONIN; SLEEP DISTURBANCE; QUALITY OF LIFE Introduction Nocturnal urinary frequency is a common symptom in the elderly and one of the most bothersome urological symptoms. 1 Nocturia means that an individual has to wake once or more at night to void 2 and it may result in sleep disturbance leading to daytime fatigue as well as an impaired quality of life (QoL). 1,3 Patients are often uncertain, however, whether nocturia is the cause of their sleep disturbance or whether sleep disturbance leads to nocturia. 4 In patients with nocturia, the hypnotic agent, rilmazafone hydrochloride, may decrease nocturnal frequency. 4 Minor tranquilizers are especially effective for controlling nocturia in patients with low levels of human atrial natriuretic peptide (HANP). 5 In our previous study, the serum melatonin level was found to be very low in patients with nocturia compared with those patients without nocturia. 6 Moreover, the level was lower in patients with bothersome nocturia compared with patients without this condition. 7 It has also been reported that melatonin is effective for nocturia in patients with benign prostatic enlargement. 8 Melatonin is an antioxidant and sleep inducer in humans 9 and is available as a supplement in many countries. We therefore compared the effects of melatonin and the hypnotic, rilmazafone, on nocturia in elderly 685

2 patients. We also measured serum melatonin levels before and after treatment. Patients and methods STUDY POPULATION The subjects were selected from outpatients who consulted the Department of Urology at our University Hospital (University of the Ryukyus, Okinawa, Japan) or one of our affiliated hospitals between January 2005 and February Patients who met the following criteria were enrolled: (i) their lower urinary tract symptoms (except for nocturia) were already being controlled by medication (adrenergic α-1 receptor antagonists, antimuscarinic agents and/or herbal medicines) for a period of at least 2 months; (ii) they had nocturia that was bothersome and urinated at least twice during their sleeping period; (iii) they did not have a high fluid intake for health reasons and they were being careful to avoid excessive intake because it could cause nocturia; 10 (iv) they did not have neurological or psychological abnormalities, hepatic dysfunction, renal dysfunction, diabetes mellitus, or cardiovascular disease; (v) they were not taking tranquillizers, hypnotics or melatonin; and (vi) they were not performing regular physical exercise (walking has been shown to decrease nocturnal frequency). 11 Patients with bacterial cystitis, bacterial prostatitis or urinary tract cancer were excluded. STUDY METHODS The patients were randomly divided into two groups; one group received melatonin (2 mg/day) and the other group received rilmazafone hydrochloride (2 mg/day) for 4 weeks. Patients in both groups took their medication just before going to bed. This study was unblinded, hence patients knew which medicine they were using. We examined the mean number of daytime and nocturnal (during the sleeping period) urinations over 4 weeks, the QoL score using the International Prostatic Symptom Score (happy, 0; satisfied, 1; almost satisfied, 2; not satisfied/not dissatisfied, 3; slightly dissatisfied, 4; dissatisfied, 5; and unhappy, 6), 12 and the perception of nocturnal urination (not bothersome, slightly bothersome, bothersome, or very bothersome) before and after 4 weeks of treatment. Subjects who reported that nocturnal urination was not bothersome or only slightly bothersome were assigned to the non-bothersome category, while subjects who stated that it was bothersome or very bothersome were assigned to the bothersome category. We also examined the side effects of these agents and whether the subjects would like to continue treatment with melatonin or rilmazafone. Blood samples were taken from all subjects at 10:00 12:00 h at baseline and again after 4 weeks of melatonin or rilmazafone therapy for measurement. Serum melatonin, plasma HANP and brain natriuretic peptide (BNP) levels were measured by radioimmunoassay, and compared before and after treatment. This study was performed after obtaining approval from the Ethics Committee of the Faculty of Medicine, University of the Ryukyus, Japan, and all patients entered provided written informed consent to participate. STATISTICAL ANALYSIS Results are reported as the mean ± SD. Student s t-test for paired or unpaired data was used for the statistical analyses. A P-value < 0.05 was considered to be statistically significant. Differences between categorical variables were assessed with the χ 2 test. 686

3 Results A total of 42 patients (25 men and 17 women, aged years) were enrolled in this study. All 25 male patients had benign prostatic enlargement with or without an overactive bladder, while 10 female patients had urethral syndrome and/or an overactive bladder. The remaining seven female patients only had nocturia. The residual urine volume of each patient was < 20 ml on abdominal ultrasonography. A total of 20 patients (13 men and seven women, aged 73 ± 7 years old) were randomly assigned to the melatonin group; and 22 patients (12 men and 10 women, aged 71 ± 8 years old) were randomly assigned to the rilmazafone group. All male patients were being treated with α-1 receptor antagonists (tamsulosin or naftopidil) and an anticholinergic agent (propiverine hydrochloride). All female patients were receiving an anticholinergic agent (propiverine hydrochloride). Five female patients from each group had taken herbal medicines for at least 8 weeks before the start of this study. These medications were continued during the present study. There were no significant differences in age, QoL score, serum melatonin level, and plasma HANP and BNP levels between the two groups at baseline (Table 1). At the start of the study, all patients considered their nocturnal urination to be bothersome. In both the melatonin- and rilmazafonetreated groups, the mean number of nocturnal urinations was significantly decreased (P < 0.001) after 4 weeks compared with baseline (Tables 1 and 2, Fig. 1). The mean number of daytime urinations, however, was unchanged. The mean QoL score was significantly improved in both groups (melatonin, P = 0.004; rilmazafone, P < 0.001) compared with baseline. The mean serum melatonin level in the melatonin-treated group was significantly increased (P < 0.001) after 4 weeks of melatonin administration, however, the mean level in the rilmazafone-treated group did not change after 4 weeks of rilmazafone administration (Tables 1 and 2). There was no change in the HANP and BNP levels following administration of either melatonin or rilmazafone. With regard to patients impression of the effectiveness of the study medication, seven TABLE 1: Baseline characteristics of patients with nocturia randomly assigned to receive either melatonin (2 mg/day) or rilmazafone (2 mg/day) for 4 weeks Melatonin Rilmazafone (n = 20) (n = 22) Male:female ratio 13:7 12:10 Age (years) 73 ± 7 71 ± 8 Number of daytime urinations 8.1 ± ± 1.3 Number of nocturnal urinations 3.4 ± ± 0.9 QoL score 4.7 ± ± 0.6 Serum melatonin level (pg/ml) 5.6 ± ± 3.0 Plasma HANP level (pg/ml) 22 ± ± 17 Plasma BNP level (pg/ml) 27 ± ± 15 Values are mean ± SD. QoL, quality of life (International Prostatic Symptom Score. 0, happy; 6, unhappy); 12 HANP, human atrial natriuretic peptide; BNP, brain natriuretic peptide. 687

4 TABLE 2: Patient characteristics after 4 weeks of treatment with either melatonin (2 mg/day) or rilmazafone (2 mg/day) Melatonin Rilmazafone (n = 20) (n = 22) No. of daytime urinations 7.9 ± ± 1.2 No. of nocturnal urinations 2.6 ± 0.9*** 2.5 ± 1.1*** QoL score 4.0 ± 0.8** 3.9 ± 0.7*** Serum melatonin level (pg/ml) 87.2 ± 71.7***,b 6.4 ± 4.9 b Plasma HANP level (pg/ml) 24 ± ± 18 Plasma BNP level (pg/ml) 29 ± ± 15 Non-bothersome nocturia 14 (70) 11 (50) Occurrence of side effects 1 (5) 2 (9) Patient s treatment effectiveness rating: Excellent 2 (10) 4 (18) Good 5 (25) 6 (27) Fair 9 (45) 4 (18) No change 4 (20) 8 (36) Willingness to continue with the same treatment 12 (60) a 6 (27) a Values are mean ± SD or number of patients (%). **P < 0.01 (P = 0.004), ***P < compared with baseline; a P < 0.05 (P = 0.032), b P < 0.01 between the two groups. QoL, quality of life (International Prostatic Symptom Score. 0, happy; 6, unhappy); 12 HANP, human atrial natriuretic peptide: BNP, brain natriuretic peptide. 5 *** *** Melatonin Rilmazafone Number of nocturnal urinations Before After administration of melatonin or rilmazafone FIGURE 1: Mean number (±SD) of nocturnal urinations before and after 4 weeks administration of melatonin (2 mg/day) or rilmazafone (2 mg/day) ***P <

5 patients (35%) in the melatonin-treated group rated the treatment as either excellent or good and nine (45%) rated it as fair (Table 2). In the rilmazafone-treated group, an excellent or good rating was reported by 10 (45%) patients and a fair rating by four (18%). There was no significant difference between the effectiveness ratings between the two groups. Before administration of melatonin or rilmazafone, all patients considered their nocturia to be bothersome. After 4 weeks of treatment, 14 (70%) patients from the melatonin-treated group and 11 (50%) patients from the rilmazafone-treated group considered their nocturia to be no longer bothersome. In one (5%) patient from the melatonintreated group and two (9%) from the rilmazafone-treated group an unsteady feeling was sometimes noted when they woke at night to urinate, however these side effects were slight and the patients continued with the study treatment for 4 weeks. After administration for 4 weeks, 12 (60%) patients in the melatonin-treated group wanted to continue therapy. This number was significantly larger than the six patients (27%) who wanted to continue rilmazafone therapy (P = 0.032). The reason for not wanting to continue therapy with either melatonin or rilmazafone was little or no effectiveness in eight (40%) patients from the melatonin-treated group and 10 (45%) patients from the rilmazafone-treated group. In eight (36%) patients from the rilmazafone-treated group, the fear of becoming unable to sleep without hypnotics was a reason for not wishing to continue with the medication. The three patients who had noted unsteadiness when they woke at night to urinate reported this as a reason for not wishing to continue with the medication. Discussion In the present study, we compared the effectiveness of melatonin and rilmazafone hydrochloride in nocturia. In elderly patients who did not have an excessive intake of water and whose plasma natriuretic peptide levels were not very high, the efficacy of melatonin was almost equal to that of rilmazafone. The percentage of patients who assigned an excellent or good rating was, however, larger in the rilmazafone-treated group and the percentage that assigned a rating of fair or better was larger in the melatonin-treated group, although there was no significant difference between the two groups. The percentage of patients who came to consider nocturia as nonbothersome was larger (not statistically significant) in the melatonin-treated group and a significantly higher percentage of patients given melatonin hoped to continue with it compared with those given rilmazafone. Although the patients were randomly divided into the two groups, the study was unblinded and the patients knew which medicine they were using. Few patients were concerned about using melatonin, probably because it is available as a supplement, but several patients were concerned about using rilmazafone because they were worried about the potential risk of becoming dependent on hypnotics. Hypnotics have been reported to be useful for treating nocturia. 4,5,13,14 Fujikawa et al. 5 reported that minor tranquillizers are especially effective for controlling nocturia in patients with low HANP levels. It has also been reported that patients taking nitrazepam (a medium-acting hypnotic) have less difficulty returning to sleep compared with those who take triazolam (an ultra-short acting hypnotic), and that nitrazepam may be more appropriate for 689

6 elderly patients who awaken because of nocturia. 13 Some patients, however, refuse to use hypnotics due to their fear of becoming dependent, even though they have insomnia. Sleep disorders can cause nocturia, while nocturia is one of the most bothersome urological symptoms and also results in sleep disturbance. 1,3,15 It is, therefore, common for patients to be uncertain whether nocturia is the cause of their sleep disturbance or if it is the sleep disturbance that leads to nocturia and for these patients, rilmazafone, a mediumacting hypnotic, has been shown to be effective. 4 Melatonin is produced by the pineal gland and is one of the strongest natural antioxidants; it is also closely involved in the timing of sleep in humans. 9,16 18 In our previous study, the night-time serum melatonin level was significantly lower in elderly persons than younger persons, and the serum melatonin level of elderly persons with nocturia was lower than that of elderly persons without nocturia. 6 Moreover, we found a significant correlation between daytime and night-time serum melatonin levels. 19 Administration of melatonin was reported safely to improve nocturia in patients with bladder outlet obstruction, 8 while treatment with melatonin (3 mg/day) for up to 6 months improved sleep quality and decreased sleep onset latency in patients with insomnia. 20 In the present study, the serum melatonin level was increased by administration of melatonin (2 mg/day), but not by rilmazafone (2 mg/day), suggesting that the decrease of nocturnal urination after treatment with rilmazafone did not depend on the serum melatonin level. This suggests that monitoring the levels of melatonin is probably not important in patients with nocturia. Melatonin and rilmazafone appear to have different mechanisms of action, however they were both found to be effective for treating nocturia in the elderly. We suggest, therefore, that when choosing a therapy for nocturia, physicians not only consider lower urinary tract function but also sleep disturbance. Acknowledgements This study was supported by a research grant (H16-Choju-008) for Comprehensive Research on Aging and Health from the Japanese Ministry of Health, Labour and Welfare, and a 2005 grant from the Mitsui Sumitomo Insurance Welfare Foundation of Japan. Conflicts of interest No conflicts of interest were declared in relation to this paper. Received for publication 10 May 2007 Accepted subject to revision 16 May 2007 Revised accepted 1 August 2007 Copyright 2007 Field House Publishing LLP References 1 Blanker MH, Bohnen AM, Groeneveld FP, et al: Normal voiding patterns and determinants of increased diurnal and nocturnal voiding frequency in elderly men. J Urol 2000; 164: Abrams P, Cardozo L, Fall M, et al: The standardisation of terminology in lower urinary tract function: report from the standardisation sub-committee of the International Continence Society. Urology 2003; 61: Asplund R: Mortality in the elderly in relation to nocturnal micturition. BJU Int 1999; 84: Sugaya K: Pharmacological evaluation of rilmazafone hydrochloride in urological clinics: Effect of rilmazafone hydrochloride on nocturia. Pharma Medica 1991; 9: Fujikawa K, Kasahara M, Matsui Y, et al: 690

7 Human atrial natriuretic peptide is a useful criterion in treatment of nocturia. Scand J Urol Nephrol : Sugaya K, Nishijima S, Oda M, et al: Biochemical analysis of nocturia in the elderly. Neurourol Urodyn : Nishijima S, Sugaya K, Owan T, et al: Study of factors related to non-bothersome nocturnal urination. Nippon Hinyokika Gakkai Zasshi 2007; 98: Drake MJ, Mills IW, Noble JG: Melatonin pharmacotherapy for nocturia in men with benign prostatic enlargement. J Urol 2004; 171: Brzezinski A: Mechanisms of disease: melatonin in humans. N Engl J Med 1997; 336: Sugaya K, Nishijima S, Oda M, et al: Change of blood viscosity and urinary frequency by high water intake. Int J Urol 2007; 14: Sugaya K, Nishijima S, Owan T, et al: Effects of walking exercise on nocturia in the elderly. Biomed Res 2007; 28: Cockett ATK, Khoury S, Aso Y, et al: In: Proceedings of the 2nd International Consultation on Benign Prostatic Hyperplasia (Cockett ATK, Khoury S, Aso Y, et al, eds). Channel Islands: Scientific Communication International, 1994; pp Takami N, Okada A: Triazolam and nitrazepam use in elderly outpatients. Ann Pharmacother 1993; 27: Marschall-Kehrel D: Update on nocturia: the best of rest is sleep. Urology 2004; 64: Weiss JP, Blaivas JG: Nocturia. J Urol 2000; 163: Dijk DJ, Cajochen C: Melatonin and the circadian regulation of sleep initiation, consolidation, structure, and the sleep EEG. J Biol Rhythms 1997; 12: Zhdanova IV, Tucci V: Melatonin, circadian rhythms, and sleep. Curr Treat Options Neurol 2003; 5: Zhdanova IV: Melatonin as a hypnotic: pro. Sleep Med Rev 2005; 9: Sugaya K, Nishijima S, Oda M, et al: Biochemical and body composition analysis of nocturia in the elderly. Neurourol Urodyn in press. 20 Siegrist C, Benedetti C, Orlando A, et al: Lack of changes in serum prolactin, FSH, TSH, and estradiol after melatonin treatment in doses that improve sleep and reduce benzodiazepine consumption in sleep-disturbed, middle-aged, and elderly patients. J Pineal Res 2001; 30: Author s address for correspondence Dr Kimio Sugaya Division of Urology, Department of Organ-oriented Medicine, Faculty of Medicine, University of the Ryukyus, 207 Uehara, Nishihara, Okinawa , Japan. sugaya@med.u-ryukyu.ac.jp 691