Effects of β3 Agonists and Anticholinergic Drugs on Defecation in Patients With Overactive Bladder

Abstract

Background/Aim: In clinical practice, constipation is one of the most frequent adverse events caused by drugs for overactive bladder (OAB). The occurrence of constipation greatly deteriorates the patient’s quality of life. The aim of the study was to evaluate and compare the effects of three commonly used β3 agonists and anticholinergic drugs on the defecation status in patients with OAB.

Patients and Methods: We retrospectively reviewed the defecation status in patients who received mirabegron, solifenacin, or fesoterodine for OAB. We evaluated changes in the (a) urological parameters using the OAB symptom score (OABSS) and (b) defecation status using the Bristol Stool Form Scale (BSFS) and constipation scoring system (CSS) following 12 weeks of drug administration.

Results: We analyzed data from 165 patients (mirabegron=56, fesoterodine=52, and solifenacin=57). The solifenacin group showed a significant decrease in BSFS (from 3.2±1.0 at baseline to 2.3±1.2 post-treatment) and an increase in hardened stools (p<0.001). Elimination worsened as assessed by almost all items, and the total modified CSS scores worsened significantly from 4.8±2.6 points at baseline to 8.0±4.8 points after 12 weeks of solifenacin treatment (p<0.001). The mirabegron group showed no changes in any of the CSS items. In the fesoterodine group, the CSS scores for “completeness” and “assistance” increased significantly after treatment (p<0.001 and p=0.013, respectively).

Conclusion: All three drugs were effective for OAB. Mirabegron had almost no effect on constipation; fesoterodine, an anticholinergic drug, also had hardly any effect on defecation.

Overactive bladder (OAB) is a symptom syndrome characterized by urinary urgency, with or without urgency incontinence (1). The prevalence of OAB increases with age, and some epidemiological surveys suggest it to be 16-19% (2,3). β3-adrenergic receptor agonists and anticholinergic drugs are standard drug therapies for OAB worldwide. However, the persistence of drugs for OAB is lower than that of drugs for chronic diseases such as hypertension and diabetes (4). Furthermore, compared to β3-adrenergic receptor stimulants, anticholinergic drugs have a significantly lower continuation rate due to adverse events associated with them in the early phase of administration (5).

The adverse events associated with anticholinergic drugs include dry mouth, constipation, dementia, and dysuria. Among them, constipation has the greatest effect on patient satisfaction (6). While there are several meta-analyses on the risk of constipation associated with β3 adrenergic receptor agonists and anticholinergic drugs (7,8), there are no detailed studies on the changes in the defecation status before and after the administration of these drugs.

This study aimed to examine the differences in defecation status before and after administration of β3 agonists and anticholinergic drugs using an established questionnaire.

Patients and Methods

Ethics. The study protocol was approved by the Clinical Study Review Board of the Nagasaki University Hospital (#20122138). All procedures were performed in accordance with the principles of the Declaration of Helsinki. Written informed consent was obtained from all patients who participated in this study.

Patients. Newly diagnosed OAB patients were enrolled in this retrospective, single-center study. They were prescribed either a β3 adrenoreceptor agonist (mirabegron 50 mg once daily; Betanis^®, Astellas Pharma, Tokyo, Japan) or an anticholinergic [fesoterodine fumarate 4 mg once daily (Toviaz^®, Pfizer Japan Inc., Tokyo, Japan) or solifenacin 5 mg once daily (Vesicare^®, Astellas Pharma)]. We had prescribed branded formulations for all the patients with OAB. The defecation statuses before and 12 weeks after administration of each drug were recorded and compared using questionnaire surveys. Based on the OAB symptom score (OABSS), we defined participants with urinary urgency [Question (Q)3 score of ≥2 and those with a total score of ≥3] as having OAB (9). Those with constipation who had no apparent organic or functional abnormalities prior to the start of treatment for OAB were included in the analysis.

Evaluation of vital signs. We defined hypertension as a systolic blood pressure of ≥140 mmHg and/or a diastolic blood pressure of ≥90 mmHg or receiving therapy for hypertension. Renal dysfunction was defined as estimated glomerular filtration rate <60 ml/min/1.73 m².

Changes in urological parameters. Using the OABSS, we evaluated the subjective urological symptoms before and after 12 weeks of administration of each drug. Uroflowmetry and post-void residual (PVR) urine volume were used to assess the objective findings. The maximum flow rate was measured by free uroflowmetry using the AQUARIUS^® CTS (Laborie Medical Technologies, Corp, NH, USA), and PVR was assessed using transabdominal ultrasound sonography (HI VISION Avius^®, Hitachi-Aloka Medical, Ltd, Tokyo, Japan).

Changes in defecation status. Defecation status at baseline and 12 weeks after administration of the agents were assessed using the Bristol Stool Form Scale (BSFS) (10) and constipation scoring system (CSS) validated in Japanese (11,12). The scores were compared within and between groups. The BSFS is an ordinal scale for stool types, ranging from the hardest (Type 1) to the softest (Type 7). On the other hand, the overall CSS score ranges from 0 to 30, with a higher score indicating worse constipation. However, since the observation period of this retrospective study was relatively short, 12 weeks, a modified CSS (mCSS) score was created based on the previous study (12). That is, the “duration of constipation” was excluded from the item list as it was 12 weeks for all treatments. Therefore, the mCSS score ranged from 0 to 26.

Statistical analysis. All statistical values are represented as the mean±standard deviation. The Kruskal-Wallis test and Scheffe’s multiple comparison procedure were used to compare non-parametric continuous variables among groups. The paired t-test and Wilcoxon signed-rank test were performed to evaluate the changes in subjective symptoms based on OABSS, BSFS, and CSS, while objective findings were assessed based on uroflowmetry and PVR intragroup comparisons. All tests were two-sided, and a p-value of <0.05 was considered statistically significant. All statistical analyses were performed using the software JMP 15 (SAS Institute Inc., Cary, NC, USA).

Results

Patients’ diagrams of this retrospective study are showed in Figure 1. In addition, Table I summarizes the data of 165 patients analyzed in this study (mirabegron group: 56, fesoterodine group: 52, and solifenacin group: 57). The mean age of the participants was 65.5±13.9 years, and there were significant differences between the mirabegron and fesoterodine groups (p=0.047). Compared to the other two groups, the solifenacin group had a lower proportion of patients with diabetes mellitus (p<0.001) and chronic renal dysfunction (p=0.003). Except for “daytime frequency”, none of the OABSS items or the total OABSS score differed significantly among the three groups. No significant differences were seen in the voided volume, maximum flow rate, and PVR at baseline.

Figure 1. Patients study flow diagram. OAB, Overactive bladder; OABSS, overactive bladder symptom score; CSS; constipation scoring system; BSFS, Bristol Stool Form Scale.

Table I. Patient general and urological characteristics at baseline.

OABSS, Overactive bladder symptom score; PVR, post-void residual urine volume; SD, standard deviation; Q, question; *p<0.05 vs. Fesoterodine. Bold font indicates significant difference.

Table II compares the usage rate of laxatives and the defecation status before administration of the different drugs. The usage rate of medication for constipation before OAB treatment was significantly higher in the solifenacin group (p<0.001). Based on the BSFS, there were significant differences between the three groups (p=0.004). The solifenacin group had significantly harder stools than the fesoterodine group (p=0.002). Based on the CSS, the three groups showed significant differences in “difficulty”, “completeness”, “time”, “assistant”, “failure”, “history”, and the total mCSS scores. The fecal symptoms in the solifenacin group were slightly worse than the other groups.

Table II. Defecation status before treatment.

SD, Standard deviation; CSS, constipation scoring system; *p<0.05, **p<0.001 vs. Solifenacin. Bold font indicates significant difference.

Table III shows the efficacy of the different medications for OAB. All subjective symptoms evaluated using OABSS improved in each group, except for the “daytime frequency” in the solifenacin group. The objective findings showed a significant increase in the voided volume following drug treatment in all groups. However, a significant increase in the PVR was seen only in the fesoterodine and solifenacin groups but not in the mirabegron group.

Table III. Changes in urological parameters after medication.

PVR, Post-void residual urine volume; SD, standard deviation; Q, question. Bold font indicates significant difference.

Compared to pre-treatment BSFS, no significant changes were seen in the BSFS following treatment with mirabegron (3.5±1.0 to 3.4±1.1, p=0.182) and fesoterodine (3.8±1.0 to 3.6±1.3, p=0.668). On the other hand, in the solifenacin group, the BSFS dropped from 3.2±1.0 (baseline) to 2.3±1.2 at 12 weeks post-administration, and the stools became harder (p<0.001) (Table IV).

Table IV. Changes of defecation status after medication.

CSS, Constipation scoring system; SD, standard deviation; W: weeks. Bold font indicates significant difference.

Using the CSS, the mirabegron group showed a significant decrease in the scores for “frequency of bowel movements” and “history” (p<0.001), while no change was seen in the mCSS total score (p=0.427). In the fesoterodine group, while the scores for “difficulty” showed a significant decrease (p=0.026), those for “completeness” and “assistance” showed a significant increase (p<0.001 and p=0.013, respectively), and the mCSS total score showed no significant change (p=0.766). On the other hand, in the solifenacin group, a significant increase was observed in all the CSS items except “failure” and “history”. The defecation condition worsened after the oral administration of solifenacin. Furthermore, in the solifenacin group alone, the proportion of patients taking laxatives after OAB treatment was statistically significantly higher than before the therapy for OAB (p<0.001) (Table IV).

Discussion

Our findings demonstrate the effectiveness of both β3-adrenergic receptor agonists and anticholinergic drugs for treating urinary symptoms associated with OAB. While there was no obvious deterioration in the defecation status after administration of mirabegron, deterioration was seen in the BSFS and some CSS items in patients who received anticholinergic drugs. In particular, the solifenacin group showed a remarkable deterioration in the defecation status compared to the fesoterodine group.

Improvement was seen in almost all subjective OAB findings following treatment with the three medications. The solifenacin group showed no improvement in the daytime frequency after medication, possibly due to the group’s lower baseline frequency. On the other hand, the urodynamics studies showed an increase in the voided volume in all three groups, which is not a major problem in clinical practice. PVR increased in the fesoterodine and solifenacin groups. None of the three groups showed urinary retention. The mirabegron group was the oldest of the three groups and had a relatively large amount of residual urine before treatment compared to that of other groups. However, no significant increase in PVR was observed in the mirabegron group. Hence, as reported previously, mirabegron might be relatively safer than anticholinergic medications for patients with lower urinary tract function (13-16).

Constipation is considered one of the risk factors for OAB, although there are no detailed prospective studies (17). It is also well known that the prevalence of OAB increases with age (3,18) and that elderly patients with deteriorated physiological functions are more likely to develop constipation than young individuals (19). Thus, constipation is closely related to OAB, and medications for OAB should be avoided to exacerbate constipation.

Previous meta-analyses have reported that anticholinergic drugs are more likely to cause constipation than placebo (20). In addition, several systematic reviews have reported that the β3 agonist mirabegron is generally safer for defecation than anticholinergic drugs (21,22). However, some other studies have reported that fesoterodine has a lower risk of constipation than mirabegron (7,8). Furthermore, fesoterodine (4 mg) has been shown to have a lower risk of constipation than solifenacin (5 mg) (23). Hence, although several reports indicate constipation as an adverse effect of medications for OAB, the definition of constipation is ambiguous in many of these studies. There are no detailed studies using questionnaires on constipation. Since constipation caused by anticholinergic drugs has a greater impact on patient satisfaction than dry mouth, (6) another typical adverse event, it is necessary to examine the difference in the onset of constipation with the different drugs.

Manjunatha et al. conducted the only head-to-head study of the effects of anticholinergic drugs on defecation (24). In a clinical study on patients with OAB, they examined the changes in defecation status before and after treatment with darifenacin and trospium (24), commonly used anticholinergic drugs for OAB. Interestingly, based on the constipation assessment scale, both drugs caused significant deterioration in the patients’ condition two weeks after the start of oral administration (24). However, currently in Japan, neither of these drugs is indicated for OAB. Therefore, in this study, we compared the effects of mirabegron, fesoterodine, and solifenacin, which are generally available in Japan, on the defecation status, although this was a retrospective study.

Consistent with previous reports (8,22), we found no exacerbation of defecation symptoms in the mirabegron group based on the BSFS and CSS, largely due to mirabegron’s mechanism of action. Mirabegron is a selective β3 receptor stimulant that does not affect intestinal peristalsis and is unlikely to cause or exacerbate constipation. In contrast, we found that anticholinergic drugs worsened the defecation status. In particular, solifenacin treatment decreased the BSFS and caused stool hardening. It also increased the scores for several CSS items and the mCSS total score.

On the other hand, fesoterodine treatment did not significantly change the BSFS values. However, it increased the scores for “feeling of residual stool” and “frequency of laxative use” in the CSS but did not change the total mCSS score. Fesoterodine and mirabegron treatments had comparable effects on defecation.

Previous studies, including a meta-analysis that compared fesoterodine (4 mg) with mirabegron (50 mg), reported similar effects on constipation as an adverse event (20). However, fesoterodine 8 mg has been shown to cause more constipation than mirabegron 50 mg (7,8). In addition, a recent study using a multicriteria decision analysis showed that mirabegron 50 mg and fesoterodine 4 mg had the same risk of constipation as placebo (25). On the other hand, solifenacin 5 mg, like many other anticholinergic drugs, was associated with a high incidence of constipation (25).

The discrepancy in the findings on constipation as an adverse event following treatment with anticholinergic drugs is largely related to their selectivity for muscarinic receptors. Solifenacin, which is highly selective for M3 receptors, has a greater effect on the colon’s transit time than fesoterodine, which is non-selective for M3 receptors (26). Yamada et al. reported that fesoterodine administered both orally and intravesically showed little and transient binding to muscarinic receptors in the colon (27). The higher affinity for muscarinic receptors is believed to be one of the reasons why anticholinergic drugs with high M3 selectivity harden stools. Furthermore, they also suppress chloride and water secretion into the intestinal lumen, leading to constipation (28).

Our study has certain limitations. First, it was a retrospective study and included patients who continued to take each drug for three months. We did not include patients who discontinued medication due to adverse events, such as constipation. Second, the number of patients was relatively small. Third, the patient backgrounds varied for each group. The defecation status before drug administration was worse in the solifenacin group than in the other two groups. It is unclear how this fact affected changes in defecation status after drug administration. Therefore, a large-scale prospective study is needed in the future to address these limitations. Despite these limitations, this is the first detailed evaluation of the changes in defecation status using various questionnaires before and after the administration of commonly used medications for OAB. In addition, the strengths of this study, using real-world clinical data, were that we clarified that mirabegron was the safest OAB agent for defecation compared to the three medications and that fesoterodine was of relatively low risk for deterioration of defecation status in anticholinergic drugs.

Finally, from the results of this study, it can be stated that the use of β3-adrenergic receptor stimulants as an OAB therapeutic agent is most appropriate, especially in elderly patients with OAB who are concerned about deterioration of defecation status. In addition, we consider that fesoterodine should be recommended for OAB patients who are not suitable for administration of β3 receptor stimulants because of the general comorbidities such as severe hypertension.

Conclusion

β3-adrenergic receptor stimulants, such as mirabegron were considered to be the safest in OAB patients with constipation and in patients who are concerned about the appearance of adverse events of constipation due to oral therapy. Furthermore, in this study, we found that fesoterodine, an anticholinergic drug, also had little effect on the defecation status of patients. Therefore, fesoterodine may be considered as a first-line drug when using anticholinergic drugs for OAB.

Conflicts of Interest

The Authors declare no conflicts of interest.

Authors’ Contributions

HI, TM, HK, MM, KM, KO and YM planned the case study, collected, and analyzed the clinical data. HI, TM and YM wrote the manuscript. Supervision, project administration, YM. All Authors have read and agreed to the published version of the manuscript.

Acknowledgements

The Authors thank all the patients who contributed to this study.