Abstract
Introduction and Hypothesis
To evaluate change in fecal incontinence symptom severity after 8 weeks of darifenacin therapy in patients with double incontinence- urgency urinary incontinence (UUI) and fecal incontinence. Important secondary outcomes included fecal incontinence symptom distress and impact on quality of life, fecal incontinence episodes, global impression of improvement and overactive bladder symptom distress and impact.
Methods
Prospective open-label cohort study of women presenting primarily with UUI, diagnosed with double incontinence, and electing antimuscarinic therapy for UUI. Women ≥18 years with moderate or greater bothersome UUI and fecal incontinence of liquid/solid stool with St. Marks (Vaizey) score ≥12 were included. Subjects were treated with darifenacin 15mg daily for 8 weeks. The primary outcome was change in fecal incontinence symptom severity using St. Marks (Vaizey) score after 8 weeks. Sample size was based on minimally important difference of the St. Marks, −5, and standard deviation ±8.5; 30 subjects provided 80% power and type I error of 0.05, including 15% attrition rate.
Results
32 women were consented with mean baseline St. Marks (Vaizey) score of 18.0±3.0. Mean age was 66.5±10.3. Twenty-eight subjects (29/32, 87.5%) completed assessments. St. Marks (Vaizey) score significantly improved from 18.0 to 11.0 (mean difference −7.0, 95% confidence interval [CI]: −8.7, −5.3), and nineteen subjects (19/32,67.9%) met the minimally important difference. Statistically significant improvements were also noted in fecal incontinence frequency, quality of life, and overactive bladder symptom bother and quality of life (all p<0.01).
Conclusions
Darifenacin could be considered as a highly effective early intervention in women suffering with double incontinence.
Keywords: accidental bowel leakage, double incontinence, dual incontinence, fecal incontinence, overactive bladder, urge urinary incontinence
Brief Summary
Women with double incontinence achieved clinically significant improvement in fecal incontinence severity and quality of life when treated with darifenacin for 8 weeks.
Introduction
Urgency urinary incontinence (UUI) and fecal incontinence are two highly prevalent pelvic floor disorders, which negatively impact quality of life. Among women with UUI symptoms, up to 20% may also have fecal incontinence symptoms [1–4], termed double incontinence [5]. Initial management of both UUI and fecal incontinence consists of behavioral therapies with or without medication. First line management of fecal incontinence specifically includes diet, fluid and fiber intake adjustments, antidiarrheal medication, and exercises to strengthen and enhance sensation and coordination of anal sphincter function [6]. In addition to antidiarrheal treatments, medications with antimuscarinic effects such as hyoscyamine and tricyclic antidepressants are often used in the treatment of fecal incontinence and Irritable Bowel Syndrome with Diarrhea [7]. Antimuscarinic medications function in this setting by blockade of colonic muscarinic acetylcholine receptors causing smooth muscle relaxation, decreased gut motility and prolonged colon transit time [8–10].
In patients with UUI, antimuscarinic medications, a β3-adrenoreceptor agonist medication or combined therapy can be added to behavioral therapy as second line to optimize symptom control and quality of life [11]. In patients being treated for UUI, constipation is often viewed as an unwanted side effect of antimuscarinic medications, with varying constipation rates observed among the different medications. Non-selective antimuscarinic medications such as fesoterodine (Toviaz®) and tolterodine (Detrol ®) may be less likely to cause constipation, whereas newer M2 or M3-selective agents such as darifenacin (Enablex®), solifencin (Vesicare®) or trospium (Sanctura®) may be more constipating [12–13]. Darifenacin is notable for the highest reported constipation rates, up to 21% for the 15mg dose [14].
While currently there is little evidence to recommend antimuscarinic medication indicated primarily for overactive bladder (OAB) symptoms in patients suffering with double incontinence, providers may prescribe the more constipating antimuscarinic medications as treatment for UUI in this setting. More evidence is needed to determine if antimuscarinic medications are an effective early therapy in patients with double incontinence.
The primary aim of this study was to characterize change in fecal incontinence symptom severity using the St. Marks (Vaizey) score after 8 weeks of antimuscarinic therapy with darifenacin in patients with double incontinence. The hypothesis is that in patients with double incontinence, darifenacin would result in significant clinical improvement in fecal incontinence symptom severity after 8 weeks.
Materials and Methods
Approval from the Institutional Review Board at the University of Alabama at Birmingham was obtained for this single-arm prospective open-label cohort study. Subject eligibility included female patients 18 years or older presenting to the multidisciplinary urogynecology and continence clinics with concomitant UUI and fecal incontinence who elected treatment with antimuscarinic medication for UUI. UUI was defined as urinary leakage associated with a strong desire to urinate, with moderate or greater bother on question #2 of the urogenital distress inventory (UDI-6) questionnaire [15]: “Do you usually experience urine leakage associated with a feeling of urgency, that is a strong sensation of needing to go to the bathroom? If yes, how much does it bother you?” Fecal incontinence was defined as involuntary loss or passage of solid or liquid stool at least once monthly over the previous three months, with a St. Marks (Vaizey) score of ≥12.
Exclusion criteria included: severe constipation (> 50% of bowel movements categorized as Bristol stool form type 1 in the past month), history of fecal impaction, inflammatory bowel disease, colorectal cancer, neurologic conditions such as spinal cord injury, multiple sclerosis, prior stroke, infectious or chronic diarrhea (> 50% of bowel movements categorized as Bristol stool form type 6 or 7 in the past month), planning to undergo surgery or become pregnant during the study period, planning to initiate pelvic floor physical therapy during the study period, and contraindications to antimuscarinic medication. Concomitant use of opioids and/or fiber was allowed if on a stable dose prior to the initial study visit and the patient agreed not to change the dose during the course of the study. Concomitant use of loperamide was allowed if the total daily dose was 2mg or less, the patient was using loperamide prior to the initial study visit and agreed not to change the dose during the 8 weeks of the intervention. In patients taking more than 2mg of loperamide daily and in patients currently on a different antimuscarinic medication, a 2-week wash-out period was required prior to beginning the study.
After providing written informed consent, subjects completed the following baseline questionnaires: St. Marks (Vaizey) questionnaire [16], Fecal Incontinence Quality of Life score (FIQL) [17], and Overactive Bladder Questionnaire short form (OAB-q) [18]. Subjects completed a 7-day bowel diary prior to starting medication, which recorded incontinent and continent bowel movements, stool consistency (Bristol Stool Scale) and associated fecal urgency symptoms. Baseline demographic information was collected by patient interview along with pertinent medical, surgical, social and gynecologic history. Subjects were then provided with medication for treatment over a total of 8 weeks with darifenacin 15mg daily.
Adverse events and compliance were recorded by telephone interview at 4 weeks and by face-to-face interview at 8 weeks. To assess compliance, patients were asked “did you take the medication at least 5 of 7 days per week?” Additionally, remaining pills were counted at the end of the study. If subjects experienced intolerable side effects, the frequency of medication was initially adjusted to oral intake every other day for 1 week. If intolerable side effects persisted, frequency was further decreased to every third day for one week, and finally every fourth day for one week. After 8 weeks of treatment, subjects completed a second 7-day bowel diary and subsequently returned to clinic to complete post-treatment questionnaires: St. Marks (Vaizey), FIQL, OAB-q, and Patient Global Impression of Improvement (PGI-I) [19].
The primary outcome was change in fecal incontinence symptom severity using St. Marks (Vaizey) score after 8 weeks of treatment with darifenacin 15mg. Secondary aims were to characterize post-treatment change in fecal incontinence frequency by bowel diary, condition-specific quality of life, OAB symptom bother and quality of life, and to characterize adverse events during the study.
The St. Marks (Vaizey) questionnaire measures fecal incontinence symptom severity and is scored from 0–24 with lower scores meaning less symptom severity. The measure accounts for loss of solid and liquid stool as well as gas. Additional questions include effect on lifestyle, symptoms of fecal urgency, use of constipating medications and use of a pad or plug. The FIQL questionnaire consists of 4 subscales, which measure impact of fecal incontinence on lifestyle, coping, and embarrassment (scored 1–4), as well as depression/self-perception (scored 1–6), with higher scores meaning less impact on quality of life. The OAB-q consists of two subscales: the symptom bother subscale is scored from 0–100 with lower scores meaning less symptom bother, and the health-related quality of life (HRQL) subscale is scored from 0–100 with higher score meaning less impact on quality of life. Finally, the PGI-I measures the subject’s impression of improvement with treatment and consists of one question with scale ranging from 1 (very much better) to 7 (very much worse).
In order to characterize a clinically and statistically significant difference before and after treatment, the sample size calculation was based on prior data with the minimally important difference for the St. Marks (Vaizey) of −5, and standard deviation (SD) ±8.5 [20–21]. The required sample size was estimated to be 30 subjects to provide 80% power and type I error probability of 0.05, accounting for a 15% attrition rate.
Results are presented as mean with standard deviation (SD) or median with interquartile range (IQR) for continuous variables, and proportion for categorical variables. Variables were analyzed using paired t-test, Wilcoxon-signed rank test, or McNemar’s test as appropriate. A p value of 0.05 or less was considered statistically significant. Statistical analysis was performed using SAS 9.4 (SAS Institute Inc., Cary, NC). Allergan, Inc. (Irvine, CA) had no role in the design, implementation or interpretation of this study only providing the medication.
Results
Participants were recruited and underwent treatment from May 2018 to February 2019. A total of 32 women consented to participation in the study. Patient accrual flow diagram is shown in Figure a. Relevant demographic and clinical characteristics are provided in Table 1. Mean age was 66.5 ± 10.3 and mean body mass index (BMI) was 30.2 ± 6.4kg/m2. The majority of subjects were white, parous, and postmenopausal. Eleven of 32 (34.4%) subjects reported irritable bowel syndrome, 7/32 (21.9%) subjects were using fiber supplementation and 5/32 (15.6%) of subjects had undergone prior surgical treatment for fecal incontinence including anal sphincteroplasty and sacral neuromodulation. As shown in Table 2, baseline mean St. Marks (Vaizey) score was 18± 3.0 and median baseline fecal incontinence episodes per week was 7 (IQR 12) with a median Bristol stool classification of 6 (IQR 1.5). 27/32 (84.4%) subjects reported baseline fecal urgency.
Figure 1a.
Patient Accrual
UUI, urgency urinary incontinence
Table 1.
Baseline Demographic and Clinical Characteristics
| Baseline Characteristics | Value |
|---|---|
| Age* | 66.5±10.3 |
| Race | |
| White | 27 (84.4%) |
| Black | 5 (15.6%) |
| BMI* | 30.2±6.4 |
| Vaginal parity | |
| 0, | 2 (6.3%) |
| 1–2, | 19 (59.4%) |
| >3, | 11 (34.4%) |
| Post-menopausal | |
| Yes | 27 (84.4%) |
| No | 3 (9.4%) |
| Unsure | 2 (6.3%) |
| Medical Comorbidities | |
| Hypertension | 23 (71.9%) |
| Type 2 diabetes mellitus | 9 (28.1%) |
| COPD or Asthma | 6 (18.8%) |
| Irritable bowel syndrome | 11 (34.4%) |
| Oral estrogen use | 3 (9.4%) |
| Vaginal estrogen use | 14 (43.8%) |
| Vaginal or oral estrogen use | 15 (46.9%) |
| Caffeine use | 29 (90.6%) |
| Smoker | 0 (0.0%) |
| Current OAB medication | 2 (6.3%) |
| Current fiber supplementation | 7 (21.9%) |
| Current narcotic use | 2 (6.3%) |
| Prior 3rd or 4th degree laceration | 7 (21.9%) |
| Prior forceps delivery | 13 (40.6%) |
| Surgical history | |
| Hysterectomy | 22 (68.8%) |
| Cholecystectomy | 12 (37.5%) |
| Surgery for fecal incontinence | 5 (15.6%) |
| Surgery for urinary incontinence | 16 (50.0%) |
| Surgery for pelvic organ prolapse | 14 (43.8%) |
| Rectal surgery | 3 (9.4%) |
BMI, body mass index; COPD, chronic obstructive pulmonary disease; OAB, overactive bladder.
Data are n(%) unless otherwise noted.
Data are mean±standard deviation.
Table 2.
Bowel and Bladder Symptom Distress and Impact: Baseline and Post-treatment
| Measure | Pre-treatment n=28 | Post-treatment n=28 | Post–Pre Δ | Δ score 95% CI (if applicable) | P-value |
|---|---|---|---|---|---|
| St. Marks (Vaizey) score | 18.0±3.0 | 11.0±5.1 | −7.0 | (−8.7, −5.3) | <0.01 |
| FIQL lifestyle subscale | 2.2±0.7 | 2.7±1.0 | 0.52 | (0.22, 0.82) | <0.01 |
| FIQL coping/behavior subscale | 1.6±0.5 | 2.2±1.0 | 0.65 | (0.34, 0.95) | <0.01 |
| FIQL depression subscale | 2.4±0.8 | 2.8±0.9 | 0.34 | (0.11, 0.57) | <0.01 |
| FIQL embarrassment subscale | 1.6±0.6 | 2.4±1.0 | 0.73 | (0.37, 1.09) | <0.01 |
| FIQL total score | 7.9±2.1 | 10.1±3.7 | 2.2 | (1.1, 3.2) | <0.01 |
| OAB-q, symptom severity subscale* | 75.0 (43.3) | 40.0 (36.7) | −27.6 | (−37.7, −17.6) | <0.01 |
| OAB-q, Health Related Quality of Life subscale* | 43.1 (35.4) | 78.5 (50.6) | 24.4 | (16.0, 32.8) | <0.01 |
| Fecal Urgency† | 24 (85.7) | 13 (46.4) | <0.01 | ||
| Fecal incontinence with solid stool† | 24 (85.7) | 18 (64.4) | 0.06 | ||
| Fecal incontinence with liquid stool† | 27 (96.4) | 20 (71.4) | <0.01 | ||
| Number of continent bowel movements per week* | 11 (9) | 10 (6) | −0.67 | (−2.9, 1.6) | 0.55 |
| Continent stool Bristol classification* | 5 (1) | 4 (1) | −0.32 | (−0.79, 0.15) | 0.17 |
| Number of Fecal incontinence episodes per week* | 7.5 (11.5) | 1 (9) | −6.0 | (−8.8, −3.3) | <0.01 |
| Fecal incontinence Bristol classification* | 6 (1.5) | 5 (2) | −0.58 | (−1.1, −0.06) | 0.03 |
| % continent bowel movements per week | 58.3±24.3 | 77.5±25.1 | 19.4 | (8.2, 30.6) | <0.01 |
| Number of continent days per week* | 2 (4.5) | 6 (4) | 2.3 | (1.4, 3.2) | <0.01 |
Δ, change; FIQL, Fecal Incontinence Quality of Life Score; OAB-q, Overactive Bladder Questionnaire Short Form.
Data are mean ± standard deviation, unless otherwise noted.
Data are median interquartile range, IQR
Data are n (%)
The study was completed by 28 of the 32 subjects (87.5%). Four subjects left the study for the following reasons: intolerable adverse effects of the medication (n=2), liver impairment that was not disclosed prior to informed consent (n=1), lost to follow up/unable to contact after initial visit (n=1). One subject completed treatment and post-treatment questionnaires but did not complete a final bowel diary. After 8 weeks of darifenacin therapy, mean St. Marks (Vaizey) score significantly improved from 18.0 ± 3.0 to 11.0± 5.1 (mean difference −7.0, 95% confidence interval (CI): −8.7, −5.3 (Table 2)), with 19/28 (67.9%) subjects meeting the minimal important difference for this measure (Table 3). FIQL scores significantly improved in all subscales as well as the total score (Table 2, all p<0.01). While number of weekly continent bowel movements and consistency of continent bowel movements did not change significantly (Table 2, p=0.55 and p=0.17, respectively), subjects experienced a significant improvement in number of fecal incontinence episodes per week, 7.5 (IQR 11.5) at baseline, to 1 (IQR 9) post treatment, median difference −6.0, 95%CI: −8.8, −3.3 (Table 2). Subjects also experienced a significant improvement in proportion of continent bowel movements per week from 58.3% (±24.3) baseline to 77.5% (±25.1) post treatment, mean difference 19.4%, 95% CI: 8.2, 30.6, as well as in number of continent days per week, from 2 days (IQR 4.5) at baseline to 6 days (IQR 4) post treatment, median difference 2.3, 95% CI: 1.4, 3.2 (Table 2). The proportion of subjects with fecal urgency also significantly improved, from 85.7% at baseline to 46.4% after treatment (p<0.01, Table 2). 16/27 (59%) subjects reported at least 50% improvement in fecal incontinence episodes per week, and 17/28 (60.7%) subjects reported fecal incontinence symptoms that were at least “much better,” with median PGI-I response of 2 (IQR 2), or “much better” (Table 3).
Table 3.
Notable results
| Measure | Value |
|---|---|
| Subjects who met St. Marks (Vaizey) minimal important difference (−5) | 19 (67.9%) |
| Subjects with 50% improvement in fecal incontinence frequency* | 16 (59.0%) |
| Patients who reported fecal incontinence was “much better”, or “very much better” | 17 (60.7%) |
| Fecal incontinence PGI-I† | 2 (2) |
| Patients who reported OAB was “much better”, or “very much better” | 12 (42.9%) |
| OAB PGI-I† | 3 (2) |
| Subsequent treatment after study period* | |
| Continued on darifenacin | 14 (51.9%) |
| Started other antimuscarinic | 0 (0.0%) |
| Started β3 agonist | 1 (3.7%) |
| Behavioral therapy | 4 (14.8%) |
| Other | 8 (29.6%) |
FIQL, Fecal Incontinence Quality of Life Score; PGI-I, Patient Global Impression of Improvement questionnaire; OAB, overactive bladder.
Data are n (%) unless otherwise noted
n=27 (bowel diary data and follow up visit missing for one subject), all other n=28
Data are median (IQR)
OAB symptom severity and quality of life also significantly improved, both p<0.01. (Table 2); 12/28 (42.9%) subjects reported OAB symptoms that were at least “much better” than before treatment, and median PGI-I score for OAB symptoms was 3 (IQR 2, Table 3). Side effects are noted in Table 4, with the most frequent being dry mouth (21/29, 72.4%) and constipation (12/29, 41.4%). There were no serious side effects in this study. 8/29 (27.6%) subjects required a dose frequency reduction due to intolerable side effects. Subsequent patient choices for continued treatment at the conclusion of the study are shown in Table 3. Over half (14/27, 51.9%) of the subjects elected to continue darifenacin.
Table 4.
Side effects
| Side effect | Value |
|---|---|
| Dry mouth | 21 (72.4%) |
| Constipation | 12 (41.4%) |
| Dry eyes | 11 (37.9%) |
| Fatigue | 10 (34.5%) |
| Blurred vision | 9 (31.0%) |
| Dizziness | 3 (10.3%) |
| Confusion | 3 (10.3%) |
| Other | 13 (44.8%) |
| Required decreased dosage | 8 (27.6%) |
n=29 (side effect data recorded at weeks 4 & 8. Sample size includes data from one patient who did not complete the study but reported side effects at week 4)
Data presented as n (%)
Discussion
The current study demonstrated that a single medication can effectively treat both UUI and fecal incontinence concomitantly. Subjects with double incontinence treated with darifenacin achieved clinically and statistically significant improvement in fecal incontinence symptom severity, frequency and quality of life. Nearly 68% of subjects achieved an improvement in symptoms meeting the minimal important difference for the St. Marks (Vaizey) measure, 61% of subjects reported fecal incontinence symptoms that were at least “much better” than before, and more than half of subjects elected to continue on darifenacin at the conclusion of the study. Additionally, the mean difference in total FIQL score met the minimal important difference, using a conservative estimate of ½ the standard deviation [22]. Women had fewer days of the week with fecal incontinence, and a significant number of women achieved resolution of fecal urgency. As expected, OAB symptom severity and quality of life significantly improved. These results are consistent with the hypothesis that in patients with double incontinence, darifenacin would result in significant clinical improvement in fecal incontinence symptom severity.
A previous study examined the effect of antimuscarinic medication for OAB on bowel-related quality of life. In this observational study, 90 patients who were treated with antimuscarinic medication for OAB were followed to measure change in bowel symptom bother and quality of life using the electronic Personal Assessment Questionnaire (ePAQ) score. Investigators reported significant improvement in bowel-related quality of life 3–6 months after treatment, although authors did not specify pre-treatment diagnoses including whether double incontinence was present and symptoms or details of the antimuscarinic regimen [23]. The current study builds on these findings by using well defined inclusion and exclusion criteria, specifically investigating subjects with clinically significant double incontinence and using a predefined dosing protocol. The current study also characterizes fecal incontinence symptoms using validated and commonly used questionnaires with an established minimal important difference, as well as bowel diaries.
Regarding conservative treatment of fecal incontinence, but not specifically double incontinence, one study investigated the effectiveness of loperamide compared with psyllium fiber for fecal incontinence using a double-blind placebo-controlled crossover design. After 4 weeks of treatment, subjects in the loperamide-first group experienced a decrease in mean fecal incontinence episodes per week from 7.9 to 4.1 at the end of the first treatment (p<0.01) and reported a 46.7% improvement in symptoms. Subjects in the psyllium-first group experienced a decrease in mean fecal incontinence episodes per week from 7.3 to 4.8 (p=0.008) and reported a 38.3% improvement in symptoms [24]. In the current study, frequency of fecal incontinence episodes decreased from 7 to 1 episode per week after treatment (p<0.01). The efficacy in the current study is comparable, if not improved compared to the study noted above, with antimuscarinic medication providing the added benefit of one single effective medication for both fecal and urgency urinary incontinence in those patients with double incontinence.
Limitations of the current study include the observational design without a placebo comparison and possible Hawthorne effect. Additionally, the shorter 8-week follow up period prevents conclusions regarding long-term use of darifenacin for double incontinence. Ideally, a randomized controlled trial would be performed in which subjects are randomized to darifenacin versus placebo, with a longer 12-week treatment period. Finally, as the 15mg dose of darifenacin was utilized, the efficacy of 7.5mg is unclear, though dose escalation would be feasible if started on a lower dose.
This study explores the use of a commonly prescribed OAB medication in women with concomitant fecal incontinence. These findings may guide providers to a practical conservative treatment option for patients with double incontinence, prior to considering more invasive and costly options. Additional strengths of this study include the prospective design and use of validated measures and bowel diaries to assess symptom severity and condition-specific quality of life of both fecal incontinence and UUI. Subjects included in this study reported moderate to severe [22] fecal incontinence with a mean St. Marks (Vaizey) score of 18.0 ± 3.0. This significant degree of fecal incontinence makes the results generalizable to most patients with double incontinence, though the results may not be reproducible in patients with milder forms of fecal incontinence.
The cohort of women suffering from double incontinence is a highly impacted population who commonly visit multiple providers seeking separate treatment for both urinary urgency and fecal incontinence [25]. The current findings suggest that antimuscarinic medication, specifically darifenacin, could be considered early in the treatment algorithm for women with double incontinence. As primary care providers commonly prescribe OAB medications, this study introduces the idea that treatment for double incontinence could be initiated in the primary care setting, thus expediting the treatment of women with this debilitating condition. The benefit of a single effective medication for two separate but commonly co-existing pelvic floor disorders may increase compliance by decreasing polypharmacy.
In conclusion, darifenacin is a safe and clinically effective treatment option for double incontinence and could be considered early in the management algorithm. This prospective study provides important evidence to guide providers treating patients with these common and impactful pelvic floor disorders.
Acknowledgements
The authors thank Sunita Patel of the University of Alabama at Birmingham for her logistical support of this project, The Center for Clinical and Translational Science at the University of Alabama at Birmingham for statistical support, and Allergan, Inc for providing the medication for this study.
Financial Disclaimer/Conflict of Interest: Allergan Inc, provided medication for this study. Partially funded by 5K12HD001258–20 to IM and HER.
Footnotes
Clinical Trial Registration: Bladder Antimuscarinic Medication and Accidental Bowel Leakage (BAMA), https://clinicaltrials.gov/ct2/show/NCT03543566, NCT03543566
Presented orally at the International Continence Society annual meeting, September 3–6, 2019, Gothenburg, Sweden, and as a poster at the AUGS/IUGA joint scientific meeting, September 24–28, 2019, Nashville, Tennessee.
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