Urinary incontinence (UI) is a common problem for women with approximately one third to one half of women reporting urinary frequency, urgency, nocturia, urgency urinary incontinence (UUI) or all of these.1,2 Urinary incontinence adversely affects quality of life and is associated with depression, limitations in daily functioning, falling, and fractures.3 One potential adverse consequence of UUI is sleep disruption. Many women who experience UUI episodes at night may have difficulty getting to sleep or staying asleep even after they fall asleep. Urinary incontinence at nighttime and frequent voiding at night during sleep increase with age and are common in older women. Approximately 20–45% of reproductive-aged women experience at least one void per night and 4–18% report two or more voids per night. Among women older than 70 years of age, approximately 75% report at least one and 28–62% report two or more voids per night.4 Women experiencing UUI report more disturbance of sleep compared with the general population who do not have UUI.5 Women are also more likely to experience a high quality-of-life effect if they have nighttime incontinence.6
Despite the association of UUI and sleep disturbances, there are very limited data on whether interventions that are specifically directed at improving UUI are effective in improving sleep outcomes or whether improvements in sleep experienced by women undergoing treatment for UUI are mediated by improvement in their incontinence symptoms. The goal of this analysis was to evaluate the association between pharmacologic therapy for UUI and sleep quality.
MATERIALS AND METHODS
We conducted a planned secondary analysis of data from a randomized trial of pharmacologic treatment for UUI to evaluate changes in quality of sleep, sleep duration, sleep efficiency, and daytime sleepiness. The parent study, Bringing Simple Urge Incontinence Diagnosis and Treatment to Providers, was a 12-week randomized, double-blind, placebo-controlled clinical trial of fesoterodine (antimuscarinic) therapy in ambulatory women aged 18 years or older who self-diagnosed as having UUI using the 3 Incontinence Questions, a validated three-item self-administered instrument to screen for and classify incontinence in women.7 Participants were enrolled in Bringing Simple Urge Incontinence Diagnosis and Treatment to Providers between February 2009 and January 2010. Eligibility criteria for Bringing Simple Urge Incontinence Diagnosis and Treatment to Providers have been described previously; 322 women were randomized to antimuscarinic medication and 323 to placebo.7 Briefly, these ambulatory women were recruited from the general community surrounding 13 clinical sites in the United States. Women who initially reported clinically frequent incontinence during preliminary telephone screening (ie, seven or more incontinence episodes/wk in the past 3 months) were asked to complete the 3 Incontinence Questions on paper during an in-person screening visit. Those who reported urgency-predominant UI on the 3 Incontinence Questions measure were eligible to continue.
Women were excluded if they had a urinary tract infection or hematuria on dipstick urinalysis, reported complex histories necessitating specialist referral, including anti-incontinence surgery in the past 5 years, other pelvic surgery in the past 6 months, more than three urinary tract infections in the past year, and other genitourinary disorders such as lower urinary tract or rectal fistula, interstitial cystitis, symptomatic pelvic organ prolapse, current or past urogenital cancer or radiation, congenital abnormality leading to incontinence, or major neurologic disorder such as stroke, Parkinson disease, spinal cord lesions, or multiple sclerosis. The study was approved by the institutional review board at each site and all participants provided written informed consent before enrollment.
Eligible women were randomly allocated in a one-to-one ratio to receive 12 weeks of pharmacologic treatment with 4–8 mg flexible-dose antimuscarinic (ie, fesoterodine group) or an identical placebo pill (placebo group) daily. Participants, clinical personnel, and statistical staff were masked to treatment assignment, and no unmasking occurred during the trial.
Participants were initially started either on 4 mg antimuscarinic or an identical placebo pill daily. At their 2-week telephone call and their 4-week follow-up visit, women were offered the option of increasing their dose to 8 mg antimuscarinic or an identical placebo daily. At their 8-week telephone call, they were invited to readjust their dose to a maximum of 8 mg or minimum of 4 mg daily.
All clinical efficacy outcomes were assessed at baseline and 12 weeks. For this analysis, the primary outcome was 12-week change in the quality of sleep assessed by the Pittsburgh Sleep Quality Index8 and daytime sleepiness assessed by Epworth Sleepiness Scale.9 The Pittsburgh Sleep Quality Index is a 19-item self-rated questionnaire for the evaluation of subjective sleep quality over the past 1 month, which has 19 questions that are combined into seven clinically derived component scores, each weighted equally from 0 to 3, and the seven component scores are added to obtain a global score ranging from 0 to 21 with higher scores indicating worse sleep quality.10 The clinical and psychometric properties of the Pittsburgh Sleep Quality Index have been formally evaluated by several research groups.11–13 The Pittsburgh Sleep Quality Index has a sensitivity of 89.6% and specificity of 86.5% for identifying sleep disorders using a cutoff score of 5 and the validity is further supported by similar differences between groups using Pittsburgh Sleep Quality Index or polysomnographic sleep measures.10 Sleep duration was defined as total hours of nocturnal sleep and sleep efficiency was calculated as a percentage of total hours slept/total time spent in bed×100%. The Epworth Sleepiness Scale consists of eight self-rated items, each scored from 0 to 3, that measure a participant's habitual “likelihood of dozing or falling asleep” in common situations of daily living, and this Epworth Sleepiness Scale score represents the sum of individual items and ranges from 0 to 24. Values greater than 10 are considered to indicate significant sleepiness.10
Voiding frequency and UI subtypes (urgency, stress, other) were assessed by a validated 3-day voiding diary.14 Participants recorded each time they voided in the toilet, leaked urine, and rated the severity of urgency associated with each void or incontinence episode as none, mild, moderate, or severe. Data from the voiding diaries were abstracted by trained analysts who completed centralized training in diary abstraction to calculate the average number of self-reported UUI, stress UI, total incontinence, daytime voiding, and nighttime voiding episodes per day.
Baseline characteristics of participants in each treatment group were compared using analysis of covariance models adjusted for clinical site. The association of changes in overall quality of sleep and voiding outcomes over 12 weeks was also examined using analysis of covariance adjusting for baseline values as well as site. No additional covariates were included in the models, because no demographic baseline differences were observed between intervention groups. Analyses were conducted without regard to adherence or final medication dosage. The following covariates were tested as potential mediators of change in sleep quality: age, ethnicity, smoking, alcohol use, nighttime UUI, nighttime stress UI, and nighttime voids. Mediators were tested by adding each individually to sleep quality change models and observing the percent change in the covariate for intervention in the revised model. All analyses were performed using SAS 9.4.
As previously reported, 322 women were randomized to antimuscarinic and 323 to placebo7 and were included in the analysis (Fig. 1). All but one woman randomized to antimuscarinic and two women randomized to placebo took at least one dose of medication. Adherence to medication (assessed through pill counts) was similar in both treatment groups with 86% of women in the antimuscarinic and 87% in the placebo group completing 80% of administrations (P=.82). Of those in the antimuscarinic group, final medication dosage was confirmed for 281 women who returned their unused pills. Ninety women (32.0%) remained at the 4-mg dose for the entire study, 152 (54.1%) increased to 8 mg and remained at this dose throughout the study, and 39 (13.9%) increased to 8 mg but returned to 4 mg before the end of the study.
At baseline (in this and the original study), the randomized groups were similar in demographic, clinical, incontinence, and sleep characteristics (P>.05; Table 1). The mean (SD) age of participants was 56 (±14) years, 68% were white women, the mean baseline frequency of any type UI episodes was 4.6 (±3.4), and UUI episodes was 3.9 (±3.0)/d. Mean (SD) Pittsburgh Sleep Quality Index scores for the placebo and antimuscarinic groups were similar at baseline (6.37 [3.26] and 6.63 [3.52], respectively; P>.05) (Table 2) as were Epworth Sleepiness Scale scores (6.71 [3.92] and 6.47 [3.99], respectively; P>.05; Table 2). More than half (57%) of participants reported poor sleep quality (Pittsburgh Sleep Quality Index score greater than 5) and 16% reported significant sleepiness (Epworth Sleepiness Scale score greater than 10). There was no difference in use of sleep medication between groups (P= 0.39).
Follow-up data at 12 weeks were obtained for 303 (94.4%) women in the antimuscarinic group and 301 (93.2%) in the placebo group. Women who were missing follow-up data tended to be younger (mean [SD] age of 50  vs 56  years), nonwhite (58.5% vs 32.1%), and unmarried (77.0% vs 56.1%; all P<.05), but did not differ from women contributing the follow-up data with respect to other characteristics, including baseline sleep variables, incontinence frequency, or bladder-specific questionnaire scores.
After 12 weeks, women randomized to the antimuscarinic group reported greater decrease in UUI frequency of 0.88 (95% CI 0.56–1.20; P<.001) episodes/d compared with women in the placebo group (P<.001) as well as reported greater decreases in total incontinence frequency (0.89 [95% CI 0.54–1.24] episodes/d; P<.001), daytime and nighttime incontinence (both P<.001), diurnal and nocturnal voiding frequency (both P<.05), and frequency of voids associated with moderate or severe urgency as compared with the placebo group (P<.01; Table 3).7
At 12 weeks, the antimuscarinic group reported a lower Pittsburgh Sleep Quality Index score (improved) when compared with the placebo group (P=.02; Table 2). Compared with the placebo group, women in the antimuscarinic group reported significantly greater improvement in sleep duration and sleep efficiency Pittsburgh Sleep Quality Index subscales (P<.05). There was no significant difference in Epworth Sleepiness Scale score between groups. Post hoc power analyses reveal that we had 80% power to detect a 0.68 change in Epworth Sleepiness Scale sleep quality scores.
In mediation analysis, improvement in nighttime voiding frequency had the largest association with sleep quality and explained 13% of the treatment association on sleep quality.
A 12-weeks, pharmacologic intervention for UUI was associated with improvement in overactive bladder symptoms (observed in the original study) and as well as improvements in overall sleep quality, sleep duration, and sleep efficiency among ambulatory women with UUI as compared with a control group. Those in the treatment group had improvements in their frequency of nocturnal voids and urge incontinence. Both fewer voids at night and decreased urge incontinence reduce the number of awakenings during the night, which may be reflected in higher sleep efficiency and longer sleep duration. It is also possible that participants in the treatment arm had increased ability to fall asleep more quickly at night (ie, shorter sleep latency). These three components make up the overall Pittsburgh Sleep Quality Index score; thus, it is not surprising there were significant improvements in overall Pittsburgh Sleep Quality Index scores. Interestingly, some Pittsburgh Sleep Quality Index domains were not significantly improved. The use of sleep medications did not differ between groups; their use is often a complex decision, can be used out of habit, and may not be directly affected by improved sleep. Day time sleepiness is not directly related to inability to sleep at night. We were unable to take napping behavior into account.
In mediation analysis, improvement in nighttime voiding frequency had the largest association with sleep quality, yet explained only 13% of the treatment association on sleep quality. No other strong mediators were identified, leaving the mechanism for most of the treatment association unexplained. Yet there are several reasons that treatment with antimuscarinic resulted in improved sleep quality. Antimuscarinic medications are known to improve incontinence and nocturia. This has been shown in other randomized clinical trials.15,16 It is also possible that fesoterodine, like other antimuscarinic medications, may have a sedating effect resulting in overall improved quality of sleep.17 This study looked specifically at fesoterodine, but the results may be generalizable to other anticholinergic and antimuscarinic medications.7 Although Bringing Simple Urge Incontinence Diagnosis and Treatment to Providers examined the effect of the antimuscarinic therapy fesoterodine on women with UUI, antimuscarinic medication has been shown to reduce nighttime voiding as well as improves sleep quality in patients with nocturia.18
A clinically meaningful change in the Pittsburgh Sleep Quality Index is 3 or more points, which is greater than the effect we observed.19 In a community-based sample of participants aged 45–75 years old, 50.5% had Pittsburgh Sleep Quality Index scores greater than 5, indicating poor sleep quality, and 25.7% had Epworth Sleepiness Scale scores greater than 10, indicating daytime sleepiness. Our sample, therefore, had a somewhat higher proportion of participants who met criteria for poor sleep quality (57%) and lower proportion of daytime sleepiness (16%) than other studies.10
In Bringing Simple Urge Incontinence Diagnosis and Treatment to Providers, serious adverse events were uncommon and unrelated to treatment, and no woman was found to have a concerning elevation in posttreatment postvoid residual volume of greater than 250 mL, suggesting that empiric therapy for UUI is a safe treatment for both UUI and its associated sleep disturbance.7
Several limitations of this study should be noted. This study included generally well-functioning women who would be most appropriate for evaluation in a primary care or general gynecology setting, and results should not be extrapolated to women with more complicated histories or to men with UUI. Women were excluded in this study if they reported major comorbidities because the 3 Incontinence Questions were developed for use in nonspecialist settings. Second, our study did not include women with urinary urgency in the absence of incontinence. Therefore, results cannot be extrapolated to patients with “dry” overactive bladder symptoms. Although we did measure and control for some medical comorbidities associated with poor sleep (eg, obesity, alcohol use) in the analyses, we did not measure or control for others (eg, specific sleep disorders such as obstructive sleep apnea and restless leg syndrome or levels of physical activity and hypnotic use, which may also affect sleep quality). Measured variables were similarly distributed between groups but we do not know the association of unmeasured variables on the results.
Our results suggest that the improvement in sleep quality may be another benefit to treatment of UUI for women. Because both incontinence and sleep disturbance are prevalent and bothersome conditions in middle-aged and older women, a treatment that may improve both conditions may provide clinical value. This analysis provides new data that indicate initiating pharmacologic treatment for UUI in ambulatory women is associated with improvement in important domains of sleep. Among community-dwelling women with UUI, flexible-dose antimuscarinic therapy not only resulted in improvement in incontinence measures, but was also associated with significant improvements in overall quality of sleep, sleep duration, and sleep efficiency.
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