Abstract
Background/Aim: Nocturia is defined as the symptom that an individual has to disrupt their sleep at night, for one or several times, in order to void. Nocturia is a bothersome event that markedly reduces a patient’s quality of life. The aim of the study was to elucidate which drugs, prescribed to reduce nocturia, show real-world efficacy in patients with bladder storage symptoms. Patients and Methods: One hundred consecutive patients who visited the Fukuoka University Medical Center were evaluated between May and July 2022. Anticholinergic drugs, β3 adrenoceptor agonists, α1 blockers, desmopressin, and other medicines were prescribed for relieving nocturia. Desmopressin was used as second-line treatment of nocturia only in males with nocturnal polyuria. The association between each drug and actual decrease in nocturia was investigated using multivariate analysis. Results: The number of nocturia episodes was reduced in patients using anticholinergic drugs, β3 adrenoceptor agonists, and desmopressin (−1.4±0.9, −1.3±0.9, −2.0 ±0.8 episodes/night, respectively). Multivariate analysis for the entire cohort showed that anticholinergic drugs and β3 adrenoceptor agonists were associated with significantly decreased nocturia episodes (p=0.01 and p=0.04, respectively). In males, only desmopressin was associated with a significant decrease in nocturia (p=0.03), and combination therapy significantly decreased the number of nocturia episodes compared to monotherapy (p=0.001). Conclusion: In a real-world clinical setting, anticholinergic drugs and β3 adrenoceptor agonists were similarly effective in reducing nocturia. Administration of desmopressin combined with anticholinergic drugs and/or β3 adrenoceptor agonists is the most effective method for reducing nocturia in male patients with both storage symptoms and nocturnal polyuria.
Nocturia is defined as the symptom that an individual has to disrupt its sleep at night, for one or several times, in order to void. Nocturia is a bothersome event that markedly reduces the patient’s quality of life (1). Nocturia has been observed in 48.6% of male patients and 54.5% of female patients with lower urinary tract symptoms (LUTS) (2). In addition, nocturia has been associated with an increased risk of bone fractures and increased mortality rate (3). Nocturia is, thus, considered an urgent matter to be resolved by physicians. Although behavioral therapy is reportedly effective against nocturia (4), nocturia associated with bladder storage symptoms due to benign prostatic hyperplasia (BPH) and/or overactive bladder (OAB) was initially treated by pharmacotherapy in daily medical practice. In fact, α1 blockers, antimuscarinic drugs, β3 adrenoceptor agonists, among other drugs have been reported as effective not only for bladder storage symptoms, but also for nocturia (5-7). However, little real-world evidence exists on drugs prescribed for improving bladder storage symptoms and relieving nocturia in patients with bladder storage symptoms.
Oral desmopressin has been used for nocturia related to nocturnal polyuria in adults. The efficacy of desmopressin has been demonstrated in several studies (8, 9). Combination therapy using desmopressin with tolterodine also demonstrated additional improvement of nocturia compared to desmopressin alone (10). In existing research evaluating the efficacy of drugs used against LUTS, the included participants were patients with no comorbidities other than LUTS (11). In addition, a washout period was generally provided for any other drugs that could potentially relieve LUTS (12). However, in daily clinical practice, drugs relieving LUTS are administered to patients with several comorbidities without a washout period.
The aim of the present study was to elucidate which drugs related to improvement of nocturia show real-world efficacy against nocturia in patients with bladder storage symptoms in daily clinical practice.
Patients and Methods
Patients. The clinical cohort of this observational study included 100 consecutive patients with bladder storage symptoms and nocturia who visited a doctor regularly at the Fukuoka University Academic Hospital, Fukuoka, Japan. In this study, nocturia was considered present when there was a complaint by the individual of having to wake one or more times per night in order to void (13). All these patients had been diagnosed with BPH and/or OAB. BPH was diagnosed according to the clinical guidelines of the Japanese Urological Association for BPH and clinical guidelines for male LUTS and BPH (14, 15). OAB was also diagnosed based on the International Continence Society definition (16, 17). All patients were receiving pharmacotherapy for both storage symptoms and nocturia. We suspended enrolment in this study at 100 patients because our Academic Hospital was introducing a new study of nocturia after the completion of this study.
Exclusion criteria. Patients with urinary tract infection, clean intermittent catheterization, or injection of onabotulinum toxin into the bladder for OAB were excluded from the study.
Evaluation frequency of nocturia. Nocturnal frequency was evaluated twice by the physician in the outpatient clinic, both before and after pharmacotherapy. Nocturnal frequency after medical treatment was assessed at the follow-up visit by the physicians between May and July 2022.
Treatment strategy for nocturia in patients with bladder storage symptom. Anticholinergic drugs, β3 adrenoceptor agonists, α1 blockers, desmopressin, and other medicines (e.g., herbal medicines) were selected for relieving nocturia. Desmopressin was used as a second-line treatment of nocturia only for males with nocturnal polyuria, defined as a nocturnal polyuria index >33% (8), as the Japanese insurance system does not cover the use of desmopressin for females. Medical treatment was started as monotherapy at clinically recommended doses. However, if the effect of therapy was insufficient, the drug was changed or a combination drug regimen was initiated according to the discretion of the physician. If adverse events were reported by the patient, switching to other drugs was applied. No wash-out period was set when drugs were changed.
When administration of medications was continued for more than 1 month, the drug was judged as possessing therapeutic effect against nocturnal frequency. When medications were continued for less than one month, the drug was not used for judgement. Informed consent was obtained from all participants before study enrolment, after providing an explanation of its objectives and methods employed. All study protocols were approved by the Ethics Committee at our Institution (IRB registration number: H21-09-003).
Primary and secondary outcomes. The primary outcome of the present study was to identify which drugs had real-world effectiveness in reducing nocturia in patients with bladder storage symptoms. We, therefore, investigated the association between each drug and decrease in number of nocturia episodes. The secondary outcome was the association between patient characteristics and change in number of nocturia episodes.
Statistical analysis. All values are presented as mean±standard deviation. A two-sided Mann-Whitney U-test was used to determine the significance of differences in numbers of nocturia episodes. Correlations between continuous variables were investigated by simple regression analysis using the square of Pearson’s correlation coefficient. Multivariate analyses were performed using multiple linear regression to identify the pharmacological agents associated with decreases in nocturnal frequency. Values of p<0.05 were considered significant. Analysis was performed using JMP version 11.0 software (SAS, Cary, NC, USA).
Results
Baseline characteristics and perioperative outcomes for the 100 patients (72 men, 28 women) are presented in Table I. Patient age was 74±10 years. Mean age was significantly higher in men (76±1.2 years) than women (71±1.9 years, p<0.04). BPH was present in 66 patients and 88 patients had OAB. In the male cohort, BPH was present in 91.7% (66 of 72 patients), OAB in 83.3% (60 of 72 patients), and both BPH and OAB in 73% (57 of 72 patients). On the other hand, all female patients showed OAB. The number of patients with hypertension, diabetes mellitus, and dyslipidemia was 49, 28, and 22, respectively.
Patient characteristics.
Anticholinergic drugs, β3 adrenoceptor agonists, α1 blockers, desmopressin, and other therapeutic drugs (e.g., herbal medicines) were used for 39, 41, 60, 4, and 9 patients, respectively. The types of anticholinergic drugs and β3 adrenoceptor agonists are shown in Figure 1. The mean number of nocturia episodes before and after medical therapy was 3.3±1.2 and 1.9±1, respectively (p<0.001). Timing of therapy evaluation was 3.0±2.3 months. However, no significant association between timing of therapy evaluation and number of therapeutic drugs was observed in the present cohort (p=0.41).
Types of anticholinergic drugs and β3 adrenoceptor agonists used in the cohort. (A) Types of anticholinergic drugs used in the cohort. (B) Types of β3 adrenoceptor agonists used in the cohort.
Association between therapeutic drugs and decrease in nocturia episodes. The number of nocturia episodes was significantly reduced in patients receiving anticholinergic drugs (−1.4±0.9 episodes per night) compared to those not receiving (−1.0±0.8 episodes per night) (p=0.02) (Figure 2). The number of nocturia episodes was also significantly reduced in patients receiving β3 adrenoceptor agonists (−1.3±0.9 episodes per night) compared to those not receiving (−1.0±0.9 episodes per night) (p=0.04) (Figure 2). The number of nocturia episodes was not significantly reduced in patients receiving α1 blockers (−1.1±0.9 episodes per night) compared to those not receiving (−1.2±0.9 episodes per night) (p=0.62) (Figure 2). The number of nocturia episodes was significantly reduced in patients receiving desmopressin (−2.0±0.8 episodes per night) compared to those not receiving (−0.9±0.8 episodes per night) (p=0.03) (Figure 2).
Association between therapeutic drugs and change in number of nocturia episodes. (A) Anticholinergic drugs. (B) β3 adrenoceptor agonists. (C) α1 blockers. (D) Desmopressin. *p<0.05.
To confirm the therapeutic drugs affecting nocturia episodes, multivariate regression analysis was performed to determine which therapeutic drugs were most strongly associated with a decrease in the number of nocturia episodes (Table II and Table III). In analyses of the entire cohort, anticholinergic drugs, β3 adrenoceptor agonists, α1 blockers, and other therapeutic drugs were selected as independent variables (Table II). Multivariate regression analysis showed that anticholinergic drugs and β3 adrenoceptor agonists correlated significantly with a decrease in the number of nocturia episodes (p=0.01 and p=0.04, respectively). In analyses limited to the male cohort, anticholinergic drugs, β3 adrenoceptor agonists, α1 blockers, and desmopressin were selected as independent variables (Table III). Multivariate regression analyses showed that only desmopressin correlated significantly with a decrease in nocturia episodes (p=0.03).
Multivariate analyses of various therapeutic drugs affecting improvement in nocturia.
Multivariate analyses of various therapeutic drugs producing improvement in nocturia.
Association of patient characteristics and changes in nocturia episodes. No significant difference in the number of nocturia episodes before therapy was evident between males (3.1±1.1 episodes per night) and females (3.6±1.4 episodes per night) (p=0.24). After introducing therapeutic drugs, the decrease in the number of nocturia episodes was significantly greater in females (−1.7±1.0 episodes per night) than in males (−1.1±1.0 episodes per night, p=0.02). In the present study, an increased number of comorbidities (i.e., hypertension, diabetes mellitus, and dyslipidemia) was not significantly associated with an increase in the number of nocturia episodes.
In this study, 56 patients received one therapeutic drug and 44 patients received ≥2 drugs. Taking ≥2 drugs was associated with a significantly decreased number of nocturia events (−1.5±0.8 episodes per night) compared to one drug (−0.9±0.9 episodes per night) (p=0.001). No significant association was seen between timing of therapy evaluation and decrease in nocturia events in the present cohort (r=0.05) (p=0.51).
Discussion
In the present study, we evaluated which drugs showed real-world effectiveness for decreasing nocturia in patients with bladder storage symptoms. In the entire cohort, antimuscarinic drugs and β3 adrenoceptor agonists were seen to be significantly more effective than other drugs. The average decrease in nocturia was around 1.5 events per night for both agents. Few studies have investigated the efficacy of antimuscarinic drugs and β3 adrenoceptor agonists in reducing nocturia for patients with bladder storage symptoms. Weiss et al.. demonstrated that the anticholinergic drug fesoterodine significantly reduced nocturia by approximately 1.1 episodes per night compared to controls in a randomized controlled trial (RCT) (18). In addition, Yoshida et al.., in another RCT demonstrated that the β3 adrenoceptor agonist vibegron reduced nocturia by about 0.6 episodes per night compared to controls. Although the reduction in frequency of nocturia was better for anticholinergic drugs in those studies, the relative merits with regard to decreasing nocturia of antimuscarinic drugs and β3 adrenoceptor agonists remained unclear in the present study.
In our male cohort, desmopressin significantly reduced nocturia compared to other drugs (i.e., antimuscarinic drugs, β3 adrenoceptor agonists, α1 blockers, etc.). The decrease in nocturia episodes roughly doubled with the addition of desmopressin. These data were consistent with findings from other RCTs (9). Thus, in real-world settings, desmopressin might be the most effective option for reducing nocturia in male patients with both bladder storage symptoms and nocturnal polyuria.
In the present study, combination therapy was seen to contribute significantly to a reduction in nocturia. Several studies have demonstrated that combination therapy comprising an anticholinergic drug with a β3 adrenoceptor agonist was effective against OAB symptoms (7, 19, 20). Thus, given our results and findings from other Institutions, combination therapy appears to be more effective than switching to another monotherapy when first-line efficacy is insufficient.
Regarding sex differences, nocturnal frequency was found to be significantly reduced in female patients than in male patients. This finding is consistent with other reports (21). The reason why greater efficacy was seen for female patients in reduction of nocturnal frequency has been suggested to involve a greater magnitude of a placebo effect in female patients than in male patients (8).
Kopelke et al.. demonstrated that pre-radiotherapy sleep disturbances occurred in prostate cancer patients receiving definitive or adjuvant radiotherapy (22). The risk factors for pre-radiotherapy sleep disturbances were significantly associated with a depressive tendency, as evaluated by a patient questionnaire (22). However, the authors did not show that the depressive tendency was induced by an increase in nocturnal void frequency. If depressive tendency was indeed associated with nocturia, the drugs used to improve the nocturnal frequency might also relieve the pre-radiotherapy sleep disturbances.
Several limitations must be considered when interpreting the results presented herein. First, because the present study was performed in a real-world clinical setting, the sequential order of drugs, types of drugs, administration of mono- or combination therapy, etc., depended on decisions made by the individual physician. Treatment strategies were, thus, inconsistent in the present study. These matters might affect the degree of decrease in nocturia episodes. Second, because patients in the present study were regularly visiting a doctor at a University Hospital, some degree of selection bias for patients was likely present. The patients might have had a greater number of comorbidities or severe lower urinary symptoms; therefore, the efficacy of drugs for nocturnal frequency might have had different effects on them. Third, the timing of drug efficacy evaluation was different for each patient. It is possible that longer assessment intervals could have induced an increase in the number of drugs taken orally. However, no significant association was found between longer intervals between evaluations and increase of the number of drugs, or between longer interval and decreased nocturnal frequency. Inconsistencies in the timing of evaluations might, thus, have had a minimal effect on the present results. Finally, in the present study, nocturnal frequency was not evaluated through frequency volume charts, but based on inquiries made during follow-up at the outpatient clinic. Some recall bias may therefore have occurred.
Conclusion
In a real-world clinical setting, anticholinergic drugs and β3 adrenoceptor agonists showed similar efficacy in reducing nocturia for patients with bladder storage symptoms. Desmopressin was the only treatment significantly associated with a reduction in nocturia for the male-only cohort. In addition, combination therapy was more effective than monotherapy in reducing nocturia. The addition of desmopressin after administration of an anticholinergic drug and/or β3 adrenoceptor agonist might, thus, represent the most effective option for reducing nocturia in male patients with both bladder storage symptoms and nocturnal polyuria.
Footnotes
Authors’ Contributions
Kazuna Tsubouchi contributed to the conception and design of the study. Naotaka Gunge contributed to drafting the manuscript. Wataru Matsuoka contributed to drafting the manuscript. Taiki Emoto, Takeshi Miyazaki, Kosuke Tominaga, Yu Okabe, Hiroshi Matsuzaki, Shintaro Aso, and Masahiro Tachibana contributed to data acquisition. Chizuru Nakagawa contributed to analysis and interpretation of data. Aiko Fujikawa and Nobuyuki Nakamura contributed to analysis and interpretation of data. Hirofumi Matsuoka and Nobuhiro Haga supervised the study.
Conflicts of Interest
The Authors declare no conflicts of Interest.
- Received September 27, 2022.
- Revision received October 13, 2022.
- Accepted October 20, 2022.
- Copyright © 2023 The Author(s). Published by the International Institute of Anticancer Research.
This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).
