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Impact of treatment for fecal incontinence on constipation symptoms

Published:November 22, 2019DOI:https://doi.org/10.1016/j.ajog.2019.11.1256

      Objective

      Defecatory symptoms, such as a sense of incomplete emptying and straining with bowel movements, are paradoxically present in women with fecal incontinence. Treatments for fecal incontinence, such as loperamide and biofeedback, can worsen or improve defecatory symptoms, respectively. The primary aim of this study was to compare changes in constipation symptoms in women undergoing treatment for fecal incontinence with education only, loperamide, anal muscle exercises with biofeedback or both loperamide and biofeedback. Our secondary aim was to compare changes in constipation symptoms among responders and nonresponders to fecal incontinence treatment.

      Study Design

      This was a planned secondary analysis of a randomized controlled trial comparing 2 first-line therapies for fecal incontinence in a 2 × 2 factorial design. Women with at least monthly fecal incontinence and normal stool consistency were randomized to 4 groups: (1) oral placebo plus education only, (2) oral loperamide plus education only, (3) placebo plus anorectal manometry-assisted biofeedback, and (4) loperamide plus biofeedback. Defecatory symptoms were measured using the Patient Assessment of Constipation Symptoms questionnaire at baseline, 12 weeks, and 24 weeks. The Patient Assessment of Constipation Symptoms consists of 12 items that contribute to a global score and 3 subscales: stool characteristics/symptoms (hardness of stool, size of stool, straining, inability to pass stool), rectal symptoms (burning, pain, bleeding, incomplete bowel movement), and abdominal symptoms (discomfort, pain, bloating, cramps). Scores for each subscale as well as the global score range from 0 (no symptoms) to 4 (maximum score), with negative change scores representing improvement in defecatory symptoms. Responders to fecal incontinence treatment were defined as women with a minimally important clinical improvement of ≥5 points on the St Mark’s (Vaizey) scale between baseline and 24 weeks. Intent-to-treat analysis was performed using a longitudinal mixed model, controlling for baseline scores, to estimate changes in Patient Assessment of Constipation Symptoms scores from baseline through 24 weeks.

      Results

      At 24 weeks, there were small changes in Patient Assessment of Constipation Symptoms global scores in all 4 groups: oral placebo plus education (–0.3; 95% confidence interval, –0.5 to –0.1), loperamide plus education (–0.1, 95% confidence interval, –0.3 to0.0), oral placebo plus biofeedback (–0.3, 95% confidence interval, –0.4 to –0.2), and loperamide plus biofeedback (–0.3, 95% confidence interval, –0.4 to –0.2). No differences were observed in change in Patient Assessment of Constipation Symptoms scores between women randomized to placebo plus education and those randomized to loperamide plus education (P = .17) or placebo plus biofeedback (P = .82). Change in Patient Assessment of Constipation Symptoms scores in women randomized to combination loperamide plus biofeedback therapy was not different from that of women randomized to treatment with loperamide or biofeedback alone. Responders had greater improvement in Patient Assessment of Constipation Symptoms scores than nonresponders (–0.4; 95% confidence interval, –0.5 to –0.3 vs –0.2; 95% confidence interval, –0.3 to –0.0, P < .01, mean difference, 0.2, 95% confidence interval, 0.1–0.4).

      Conclusion

      Change in constipation symptoms following treatment of fecal incontinence in women are small and are not significantly different between groups. Loperamide treatment for fecal incontinence does not worsen constipation symptoms among women with normal consistency stool. Women with clinically significant improvement in fecal incontinence symptoms report greater improvement in constipation symptoms.

      Key words

      Defecatory symptoms, especially those associated with constipation, are paradoxically common in women with fecal incontinence. In a series of 262 subjects, 36% of patients presenting primarily with constipation reported fecal incontinence while 34% of subjects presenting primarily with fecal incontinence reported symptoms of constipation.
      • Mohammed S.D.
      Co-existence of constipation and fecal incontinence: a greatly underappreciated clinical problem.

      Why was this study conducted?

      • Loperamide, a medication widely used for the treatment of fecal incontinence, can worsen defecatory symptoms. The goal of this study was to compare changes in constipation symptoms in women undergoing treatment for fecal incontinence with education only; loperamide anal sphincter exercises with biofeedback; or both loperamide and biofeedback.

      Key findings

      • There were small improvements in constipation symptoms, which were not different between treatment groups.
      • Women with improved fecal incontinence symptoms had greater improvement in constipation symptoms than women who did not have improvement in fecal incontinence symptoms.

      What does this add to what is known?

      • Findings of this study should reassure clinicians that among women with normal stool consistency, treatment of fecal incontinence with loperamide does not worsen constipation symptoms.
      The quality of life of subjects with coexisting constipation and fecal incontinence is also significantly worse than either symptom alone.
      • Siproudhis L.
      • Pigot F.
      • Godeberge P.
      • Damon H.
      • Soudan D.
      • Bigard M.A.
      Defecation disorders: a French population survey.
      The presence of defecatory symptoms such as straining to defecate, feeling of incomplete bowel evacuation, digitation, sensation of blockage, and constipation indicate the presence of an underlying defecation dysfunction. Manometry studies have shown that potential markers of defecation dysfunction, such as poor rectal compliance, are common in women with fecal incontinence (FI).
      • Andrews C.
      • Bharucha A.E.
      • Seide B.
      • Zinsmeister A.R.
      Rectal sensorimotor dysfunction in women with fecal incontinence.
      Thus, it is important that providers treating FI understand potential implications of therapies on commonly coexisting defecatory symptoms.
      First-line treatments for FI include constipating medications, such as loperamide, and pelvic floor physical therapy, with or without anorectal biofeedback. Loperamide has been shown to reduce incontinence episodes and improve symptoms and quality of life but can exacerbate constipation symptoms.
      • Omar M.I.
      • Alexander C.E.
      Drug Treatment for fecal incontinence in adults.
      ,
      • Markland A.D.
      • Burgio K.L.
      • Whitehead W.E.
      • et al.
      Loperamide versus psyllium fiber for treatment of fecal incontinence: the Fecal Incontinence Prescription (Rx) Management (FIRM) randomized clinical trial.
      Pelvic floor physical therapy and anorectal biofeedback have been shown to improve defecatory symptoms such as such as straining and splinting for bowel movements.
      • Fernández-Fraga X.
      • Azpiroz F.
      • Aparici A.
      • Casaus M.
      • Malagelada J.R.
      Predictors of response to biofeedback treatment in anal incontinence.
      Despite the common coexistence of FI and defecatory symptoms and the potential impact of treatments of FI on defecatory symptoms, well-designed prospective studies exploring the relationship between defecatory symptoms and response to treatment for FI are lacking.
      We conducted a planned secondary analysis to the Controlling Anal incontinence by Performing Anal Exercises with Biofeedback or Loperamide (CAPABLe) trial
      • Jelovsek J.E.
      • Markland A.D.
      • Whitehead W.E.
      • et al.
      National Institute of Child Health and Human Development Pelvic Floor Disorders Network. Controlling faecal incontinence in women by performing anal exercises with biofeedback or loperamide: a randomised clinical trial.
      to determine the impact of first-line treatments for FI on constipation symptoms. Our primary aim was to compare the changes in constipation symptoms in women randomized to treatment for FI with education only, loperamide, anal muscle exercises with biofeedback or both loperamide and biofeedback. Our secondary aim was to compare changes in constipation symptoms among women who reported improved FI symptoms and those who did not report improvement in FI symptoms following treatment.

      Materials and Methods

      The CAPABLe trial is a randomized, controlled, factorial trial conducted between April 2014 and April 2016 at 8 sites participating in the Pelvic Floor Disorders Network, sponsored by the Eunice Kennedy Shriver National Institute of Child Health and Human Development. The study design has been previously published.
      • Jelovsek J.E.
      • Markland A.D.
      • Whitehead W.E.
      • et al.
      Pelvic Floor Disorders Network. Controlling anal incontinence in women by performing anal exercises with biofeedback or loperamide (CAPABLe) trial: design and methods.
      Women with bothersome FI occurring at least monthly over the preceding 3 months were invited to participate. Women who reported type 1 (hard) or type 7 (watery) stool consistency over the last 3 months using the Bristol Stool Form were excluded. All sites received institutional review board approval, and all participants gave written informed consent (Clinicaltrials.gov NCT02008565).
      Enrolled participants underwent a single randomization using a 0.5:1:1:1 allocation to 1 of 4 treatment combinations: (1) oral placebo plus education only, (2) oral loperamide plus education only, (3) oral placebo plus anal sphincter exercise training using manometry-assisted biofeedback, and (4) oral loperamide plus anal sphincter exercise training using manometry-assisted biofeedback.
      All participants were provided education consisting of the publicly available pamphlet from the National Institute of Diabetes and Digestive and Kidney Diseases with the deletion of a single reference to the drug loperamide. The pamphlet discusses symptoms, causes, diagnosis, and treatments including dietary treatment for bowel control problems.
      Participants not randomized to biofeedback had baseline and 12 and 24 week visits. Participants randomized to biofeedback had visits at baseline and 2, 4, 6, 9, 12, and 24 weeks. Participants randomized to the biofeedback group received an individualized program that included diagnostic anorectal manometry evaluation, biofeedback strength training, and sensory or urge resistance training (mcompass; Medspira, Minneapolis, MN). Biofeedback participants were prescribed a home exercise program based on their individual performance during the intervention visits. All study interventionists underwent standardized training.
      • Markland A.D.
      • Jelovsek J.E.
      • Whitehead W.E.
      • et al.
      Pelvic Floor Disorders Network. Improving biofeedback for the treatment of fecal incontinence in women: implementation of a standardized multi-site manometric biofeedback protocol.
      Participants initially received placebo or 2 mg of oral loperamide (1 capsule) per day with the option of dose escalation up to a maximum of 4 capsules daily and the option of dose reduction because of adverse effects to 1 capsule every other day. Dose escalation, maintenance or reduction was based on balancing efficacy and side effects of treatment using 2 Likert scales: the Patient Global Symptom Control rating scale (“My current treatment is giving me adequate control of my stool leakage”) and the Patient Global Tolerability rating Scale (“My current medication is giving me bothersome side effects”).
      Responses on both scales ranged from 1 (disagree strongly) to 5 (agree strongly). Those women reporting inadequate control of stool leakage and bothersome side effects were instructed to discontinue the study medication but were requested to remain in the study follow-up for the duration. Participants reporting deterioration in FI symptoms after discontinuing the study drug because of side effects were allowed to restart study drug after an assessment by the site investigator.
      The primary outcome for CAPABLe was the change from baseline to 24 weeks in the St Mark’s (Vaizey) FI severity scale. The primary outcome for this secondary study was change from baseline to 24 weeks in the Patient Assessment of Constipation Symptoms (PAC-SYM) global score.
      • Frank L.
      • Kleinman L.
      • Farup C.
      • Taylor L.
      • Miner Jr., P.
      Psychometric validation of a constipation symptom assessment questionnaire.
      The PAC-SYM consists of 12 items that contribute to a global score and 3 subscales: stool characteristics/symptoms (hardness of stool, size of stool, straining, inability to pass stool), rectal symptoms (burning, pain, bleeding, incomplete bowel movement), and abdominal symptoms (discomfort, pain, bloating, cramps). Subscales and global scores range from 0 (no symptoms) to 4 (maximum score), with decreasing scores representing improvement in defecatory symptoms.
      The minimal important difference (MID) for the PAC-SYM questionnaire is –0.6.
      • Yiannakou Y.
      • Tack J.
      • Piessevaux H.
      • et al.
      The PAC-SYM questionnaire for chronic constipation: defining the minimal important difference.
      Secondary outcomes included change from baseline to 24 weeks in the PAC-SYM subscale scores. Throughout the study, outcome evaluators were masked to the treatment assignment for the biofeedback intervention. Participants and all study staff other than the research pharmacist were masked to the medication assignment.
      A responder to treatment was defined as any subject who showed the minimally important clinical difference, at least a 5 point decrease, in the St Mark’s (Vaizey) score at 24 weeks.
      • Bols E.M.
      • Hendriks E.J.
      • Deutekom M.
      • et al.
      Inconclusive psychometric properties of the Vaizey score in fecally incontinent patients: a prospective cohort study.

      Statistical analysis

      Women who had constipation symptom outcome data at 12 or 24 weeks were included in analysis. The change from baseline in PAC-SYM global scores at 24 weeks was analyzed using a general linear mixed model. Independent variables included baseline PAC-SYM global score; treatment assignments; interactions between drug and exercise, week 12 or 24; interactions between week and treatment; and clinical site.
      The model accounted for the dependence between repeated measurements on the same subject by modeling the within-participant covariance structure. Combination treatment (oral loperamide plus anal sphincter exercise training using manometry-assisted biofeedback) was compared with oral loperamide plus education only or oral placebo plus biofeedback alone.
      Oral loperamide plus education only was compared with oral placebo plus education only, and oral placebo plus biofeedback was compared with oral placebo plus education only. Each comparison was evaluated at a type I error level of 0.05. Box plots were used to explore the relationship between baseline stool consistency (Bristol stool type) and change in PAC-SYM scores from baseline for each treatment group.
      The change from baseline in PAC-SYM global score at 24 weeks was also compared between responders to treatment and nonresponders. The baseline PAC-SYM global score was first compared between responders and nonresponders using a general linear model with responder status and clinical site as independent variables.
      The change from baseline in PAC-SYM global scores at 24 weeks was compared for responders and nonresponders using a general linear mixed model with responder status, treatment assignments, week 12 or 24, clinical site, and interactions between drug and exercise, week and treatment, and responder status and week as independent variables.
      The model accounted for the dependence between repeated measurements on the same subject by modeling the within-participant covariance structure. Responders were compared with nonresponders at a type I error level of 0.05. Subjects without 24 week data available for the St Mark’s (Vaizey) score were excluded from the analysis comparing responders and nonresponders.
      The other secondary outcomes, changes in PAC-SYM subscales, were evaluated similarly for both comparisons between treatments and between responders and nonresponders. Primary and secondary outcomes were analyzed using a modified intent-to-treat principle, with the limitation that only observed outcomes at 12 and 24 weeks were included in analysis. No adjustments were made for performing multiple statistical tests.

      Results

      In the CAPABLe trial, 296 eligible women were randomized to the following groups: oral placebo plus education (n = 42), loperamide plus education (n = 86), oral placebo plus biofeedback (n = 83), and the combined intervention of loperamide plus biofeedback (n = 85). Greater than 83% of participants had defecatory symptom outcome data at 12 or 24 weeks and were included in analysis: oral placebo plus education, 35 of 42 (83%); loperamide plus education, 71 of 86 (83%); oral placebo plus biofeedback, 69 of 83 (83%); and loperamide plus biofeedback, 72 of 85 (85%).
      Baseline demographic and clinical characteristics of participants included in this analysis are presented in Table 1. As expected in a randomized trial, women randomized to placebo plus education did not differ significantly from women randomized to loperamide plus education or oral placebo plus biofeedback. Similarly, baseline characteristics of women who received both active treatments (loperamide plus biofeedback) were not different from women who received 1 active treatment (loperamide plus education or placebo plus biofeedback) only. Baseline PAC-SYM scores were similar in all groups.
      Table 1Demographics: baseline clinical and demographic characteristics of participants in placebo, individual treatment, and combined treatment groups
      EndpointCategoryPlacebo, education only (n = 35)Loperamide, education only (n = 71)Placebo, exercise plus biofeedback (n = 69)Loperamide, exercise plus biofeedback (n = 72)
      Baseline characteristicBaseline characteristicBaseline characteristicBaseline characteristic
      Age, y, mean (SD) [minimum, maximum]62.5 (10.5) [40.2, 83.3]62.5 (10.7) [38.1, 83.3]65.5 (10.3) [39.7, 93.4]63.6 (12.4) [27.5, 87.6]
      Race, n (%)American Indian/Alaskan Native2 (5.7)0 (0.0)1 (1.4)0 (0.0)
      Black/African American6 (17.1)10 (14.1)10 (13.9)9 (13.0)
      More than 1 race0 (0.0)0 (0.0)4 (5.6)1 (1.4)
      Other2 (5.7)2 (2.8)1 (1.4)2 (2.9)
      White25 (71.4)59 (83.1)56 (77.8)57 (82.6)
      Ethnicity, No. (%)Hispanic/Latina2 (5.7)7 (9.9)7 (9.7)7 (10.1)
      Not Hispanic/not Latina32 (91.4)63 (88.7)64 (88.9)61 (88.4)
      Unknown/not reported1 (2.9)1 (1.4)1 (1.4)1 (1.4)
      Prior accidental bowel leakage surgery, n (%)0 (0.0)4 (5.6)3 (4.2)5 (7.2)
      Prior rectal or anal surgery, n (%)7 (20.6)6 (8.6)12 (17.1)8 (11.6)
      BMI, mean (SD) [minimum, maximum]30.5 (9.0) [20.2, 62.1]31.0 (6.7) [20.2, 48.5]29.9 (6.7) [19.5, 55.0]28.8 (6.6) [17.1, 43.2]
      Dietary fiber score, mean (SD) [minimum, maximum]15.1 (7.3) [2.0, 33.0]15.3 (6.3) [4.0, 31.0]16.5 (6.4) [4.0, 41.0]16.1 (5.8) [5.0, 29.0]
      Daily fiber intake, mean (SD) [minimum, maximum]14.6 (5.4) [4.9, 27.8]14.7 (4.7) [6.4, 26.3]15.6 (4.7) [6.4, 33.7]15.3 (4.3) [7.1, 24.9]
      Bristol Stool Index, n (%)Type 2, sausage shaped but lumpy6 (17.1)6 (8.5)16 (22.2)5 (7.2)
      Type 3, like a sausage or snake but with cracks on2 (5.7)14 (19.7)9 (12.5)10 (14.5)
      Type 4, like a sausage or snake, smooth and soft14 (40.0)24 (33.8)20 (27.8)25 (36.2)
      Type 5, soft blobs with clear cut edges5 (14.3)13 (18.3)12 (16.7)15 (21.7)
      Type 6, fluffy pieces with ragged edges, mushy stool8 (22.9)14 (19.7)15 (20.8)14 (20.3)
      Rome III IBS clinical status, n (%)5 (14.3)14 (19.7)14 (19.4)15 (21.7)
      PAC-SYM scores, mean (SD) [minimum, maximum]Stool score1.1 (0.8) [0.0, 2.6]1.2 (0.8) [0.0, 2.8]0.9 (0.9) [0.0, 3.8]1.1 (0.8) [0.0, 2.8]
      Rectal score0.8 (0.8) [0.0, 2.7]0.7 (0.7) [0.0, 2.7]0.9 (0.7) [0.0, 3.3]0.7 (0.7) [0.0, 2.3]
      Abdominal score1.0 (1.1) [0.0, 3.5]1.1 (0.9) [0.0, 3.3]1.1 (0.8) [0.0, 3.4]0.9 (0.8) [0.0, 3.0]
      Global score1.0 (0.7) [0.0, 2.7]1.1 (0.7) [0.0, 2.6]0.7 (0.8) [0.0, 3.0]0.9 (0.6) [0.0, 2.5]
      BMI, body mass index; IBS, irritable bowel syndrome; PAC-SYM, Patient Assessment of Constipation Symptoms.
      Andy et al. Defecatory symptoms and fecal incontinence. Am J Obstet Gynecol 2020.
      All groups demonstrated small improvements in global PAC-SYM scores at 24 weeks: oral placebo plus education (–0.3, 95% confidence interval [CI], –0.5 to –0.1), loperamide plus education (–0.1, 95% CI, –0.3 to 0.0), oral placebo plus biofeedback (–0.3, 95% CI, –0.4 to –0.2), and loperamide plus biofeedback (–0.3, 95% CI, –0.4 to –0.2). No differences in improvement in PAC-SYM global scores between women randomized to placebo plus education and women randomized to loperamide plus education or oral placebo plus biofeedback were observed (Table 2).
      Table 2Change in PAC-SYM at 24 weeks for placebo vs loperamide and placebo vs biofeedback
      Change in PAC-SYM scorePlacebo- education (n = 35)Loperamide, education (n = 71)Placebo, biofeedback (n = 69)
      Mean change from baseline (95% CI)Mean change from baseline (95% CI)P value for comparisonMean change from baseline (95% CI)P value for comparison
      Change in PAC-SYM abdominal score–0.4 (–0.7 to –0.2)–0.2 (–0.3 to 0.0).052–0.3 (–0.5 to –0.2).537
      Change in PAC-SYM rectal score–0.3 (–0.5 to –0.1)–0.1 (–0.2 to 0.0).125–0.3 (–0.5 to –0.2).677
      Change in PAC-SYM stool score–0.2 (–0.4 to 0.0)–0.2 (–0.3 to 0.0).878–0.3 (–0.4 to –0.1).379
      Change in PAC-SYM global score–0.3 (–0.5 to –0.1)–0.1 (–0.3 to 0.0).169–0.3 (–0.4 to –0.2).819
      CI, confidence interval; PAC-SYM, Patient Assessment of Constipation Symptoms.
      Andy et al. Defecatory symptoms and fecal incontinence. Am J Obstet Gynecol 2020.
      Improvement in PAC-SYM global scores in women randomized to combination loperamide plus biofeedback therapy was also not significantly different from improvement in women randomized to loperamide or biofeedback alone (Table 3). Likewise, no differences between groups were noted in the subscales of the PAC-SYM with the exception of the rectal subscale when comparing loperamide plus biofeedback with loperamide plus education. No associations or patterns that might support an association between baseline stool consistency and improvement or worsening of PAC-SYM scores for any of the treatment groups were observed in visual box plots (data not shown).
      Table 3Change in PAC-SYM at 24 weeks for combined loperamide and biofeedback vs loperamide only and biofeedback only
      Change in PAC-SYM scoreLoperamide, biofeedback (n = 72)Loperamide, education (n = 71)Placebo, biofeedback (n = 69)
      Mean change from baseline (95% CI)Mean change from baseline (95% CI)P value for comparisonMean change from baseline (95% CI)P value for comparison
      Change in PAC-SYM abdominal score–0.3 (–0.5 to –0.1)–0.2 (–0.3 to 0.0).257–0.3 (–0.5 to –0.2).616
      Change in PAC-SYM rectal score–0.4 (–0.5 to –0.1)–0.1 (–0.2 to 0.0).010–0.3 (–0.5 to –0.2).862
      Change in PAC-SYM stool score–0.2 (–0.4 to 0.0)–0.2 (–0.3 to 0.0).549–0.3 (–0.4 to –0.1).499
      Change in PAC-SYM global score–0.3 (–0.4 to –0.2)–0.1 (–0.3 to 0.0).147–0.3 (–0.4 to –0.2).600
      CI, confidence interval; PAC-SYM, Patient Assessment of Constipation Symptoms.
      Andy et al. Defecatory symptoms and fecal incontinence. Am J Obstet Gynecol 2020.
      Of the women with FI symptom outcome data at 24 weeks, 137 had clinically significant improvement in Vaizey score (responders) and 129 did not (nonresponders). Of these women, 124 of 137 responders (91%) and 119 of 129 nonresponders (92%) had PAC-SYM defecatory symptom outcomes available at either 12 or 24 weeks. Responders had greater improvement in global PAC-SYM scores at 24 weeks than nonresponders (–0.4; 95% CI, –0.5 to –0.3 vs –0.2; 95% CI, –0.3 to –0.0, mean difference 0.2, 95% CI, 0.1–0.4) despite similar scores at baseline (Tables 4 and 5). Responders had greater improvement in all the subscales of the PAC-SYM (Table 5).
      Table 4Baseline PAC-SYM scores in responders and nonresponders to treatment for FI
      Baseline PAC-SYM scoreResponders (n = 124)Nonresponders (n = 119)P value for Comparison
      Mean (95% CI)Mean (95% CI)
      PAC-SYM abdominal score1.06 (0.89–1.23)0.88 (0.70–1.06).127
      PAC-SYM rectal score0.67 (0.52–0.81)0.67 (0.52–0.81).992
      PAC-SYM stool score1.10 (0.95–1.25)1.14 (0.99–1.30).675
      PAC-SYM global score0.98 (0.85–1.11)0.94 (0.80–1.07).641
      CI, confidence interval; PAC-SYM, Patient Assessment of Constipation Symptoms.
      Andy et al. Defecatory symptoms and fecal incontinence. Am J Obstet Gynecol 2020.
      Table 5Change in PAC-SYM scores at 24 weeks in responders and nonresponders to treatment for FI
      Change in PAC-SYM scoreResponders (n = 124)Nonresponders (n = 119)P value for Comparison
      Mean change from baseline (95% CI)Mean change from baseline (95% CI)
      Change in PAC-SYM abdominal score–0.48 (–0.63 to –0.32)–0.17 (–0.33 to –0.01).005
      Change in PAC-SYM rectal score–0.37 (–0.50 to –0.24)–0.16 (–0.29 to –0.03).020
      Change in PAC-SYM stool score–0.34 (–0.47 to –0.20)–0.13 (–0.26 to 0.01).022
      Change in PAC-SYM global score–0.39 (–0.50 to –0.28)–0.15 (–0.26 to –0.03).002
      CI, confidence interval; FI, fecal incontinence; PAC-SYM, Patient Assessment of Constipation Symptoms.
      Andy et al. Defecatory symptoms and fecal incontinence. Am J Obstet Gynecol 2020.

      Comment

      Principal findings

      We did not find differences in the change in constipation symptoms among women with at least monthly FI and normal stool consistency randomized to loperamide and/or biofeedback compared with placebo plus education. Women who reported improvement in FI symptoms had greater improvement in constipation symptoms as measured by the PAC-SYM compared with those with no improvement in FI symptoms.
      These findings are useful in understanding the relationship between defecatory symptoms and FI treatments and provide clinical reassurance that the use of loperamide in women with FI with normal stool consistency does not worsen constipation symptoms because all groups had small improvements in constipation symptoms.

      Results and clinical and research implications

      Defecatory symptoms commonly coexist in women with FI. Several retrospective or cross-sectional community-based studies and surveys in urogynecology clinics demonstrate a significant association between constipation that includes defecatory symptoms and FI.
      • Damon H.
      • Guye O.
      • Seigneurin A.
      • et al.
      Prevalence of anal incontinence in adults and impact on quality-of-life.
      • Bharucha A.E.
      • Seide B.M.
      • Zinsmeister A.R.
      • Melton 3rd, L.J.
      Relation of bowel habits to fecal incontinence in women.
      • Bharucha A.E.
      • Zinsmeister A.R.
      • Schleck C.D.
      • Melton 3rd, L.J.
      Bowel disturbances are the most important risk factors for late onset fecal incontinence: a population-based case-control study in women.
      • Boreham M.K.
      • Richter H.E.
      • Kenton K.S.
      • et al.
      Anal incontinence in women presenting for gynecologic care: prevalence, risk factors, and impact upon quality of life.
      Studies have also demonstrated that coexisting constipation can modify the response to treatment for fecal incontinence. In a retrospective study of 145 patients treated for FI using biofeedback, symptoms such as straining with bowel movements, use of splinting, and abnormal rectal compliance on anorectal manometry were significantly more common in women who had poor response to treatment.
      • Fernández-Fraga X.
      • Azpiroz F.
      • Aparici A.
      • Casaus M.
      • Malagelada J.R.
      Predictors of response to biofeedback treatment in anal incontinence.
      Despite lack of controlled studies, clinical guidelines recommend treating women with coexisting FI and underlying evacuation disorders with interventions such as biofeedback to train patients to relax their pelvic floor.
      • Wald A.
      • Bharucha A.E.
      • Cosman B.C.
      • Whitehead W.E.
      ACG clinical guideline: management of benign anorectal disorders.
      Unfortunately, these studies and recommendations have not been prospectively studied to assess treatment effect and did not use valid and reliable defecatory symptom-severity scales.
      In contrast, our study demonstrated that defecatory symptoms do not worsen with treatment with either loperamide or anal muscles exercises with biofeedback and suggest there may be marginal improvement. The biofeedback training protocol in this study included instruction on recto-anal coordination, which may have improved evacuation of the rectum. However, it is unclear why women randomized to loperamide did not report higher defecatory symptom severity after treatment compared with women not taking loperamide. One possibility is that loperamide improved stool consistency and this improved the efficiency of evacuation. However, we did not notice any association between baseline stool consistency and change in PAC-SYM score in women who received loperamide.
      Another possible explanation is that loperamide, which, in addition to established effects on improving stool consistency, has been shown to affect rectal perception and increase anal sphincter resting, and squeeze pressure impacts defecatory symptoms through these mechanisms.
      • Read M.
      • Read N.W.
      • Barber D.C.
      • Duthie H.L.
      Effects of loperamide on anal sphincter function in patients complaining of chronic diarrhea with fecal incontinence and urgency.
      ,
      • Fox M.
      • Stutz B.
      • Menne D.
      • Fried M.
      • Schwizer W.
      • Thumshirn M.
      The effects of loperamide on continence problems and anorectal function in obese subjects taking orlistat.
      When anal sphincter pressures are low, stool in the anorectum is sensed at lower volumes
      • Fox M.
      • Stutz B.
      • Menne D.
      • Fried M.
      • Schwizer W.
      • Thumshirn M.
      The effects of loperamide on continence problems and anorectal function in obese subjects taking orlistat.
      ; thus, our findings suggest that loperamide’s effect on increasing sphincter pressure may result in changes in visceral sensitivity, leading to improvement in symptoms such as a sense of incomplete emptying.
      Greater improvement in defecatory symptoms in responders compared with nonresponders may suggest shared underlying mechanisms between FI and defecatory dysfunction. Women with FI have been shown to have poor rectal compliance, indicating the presence of coexisting defecatory dysfunction.
      • Andrews C.
      • Bharucha A.E.
      • Seide B.
      • Zinsmeister A.R.
      Rectal sensorimotor dysfunction in women with fecal incontinence.
      Additionally, women with symptoms of defecatory dysfunction such as straining for bowel movements and sense of incomplete evacuation have weaker axial forces not only during expulsion but also during contraction of the pelvic floor muscles, suggesting an increased risk for FI.
      • Bharucha A.E.
      • Croak A.J.
      • Gebhart J.B.
      • et al.
      Comparison of rectoanal axial forces in health and functional defecatory disorders.
      In women in whom treatments affect these underlying mechanisms, both FI and defecatory symptoms may improve. Alternatively, our finding may reflect the significant impact of functional anorectal disorders on quality of life.
      In a prior study examining the risk factors for constipation and FI, poor self-rated health and depression were found to be common risk factors for both conditions.
      • Andy U.U.
      • Vaughan C.P.
      • Burgio K.L.
      • Alli F.M.
      • Goode P.S.
      • Markland A.D.
      Shared risk factors for constipation, fecal incontinence, and combined symptoms in older US adults.
      Thus, women who had improvement in FI severity may have perceived overall subjective improvement in quality of life including defecatory symptoms.

      Strengths and limitations

      The strengths of this study include the prospective study design of women randomly assigned to the 2 common conservative treatments for FI. Defecatory symptoms were evaluated using a valid, reliable, and responsive questionnaire that has been used in other clinical trials to assess patient-reported defecatory dysfunction. Despite the large sample size adequately powered for the primary study,
      • Jelovsek J.E.
      • Markland A.D.
      • Whitehead W.E.
      • et al.
      National Institute of Child Health and Human Development Pelvic Floor Disorders Network. Controlling faecal incontinence in women by performing anal exercises with biofeedback or loperamide: a randomised clinical trial.
      there was limited power to detect marginal differences between the combined vs individual treatments and single treatment versus control groups.
      The study findings are generalizable to women with normal stool consistency who are seeking treatment for FI rather than constipation symptoms, and the study did not collect additional objective measures of defecatory dysfunction such as transit studies or balloon testing. Additionally, we excluded women with large rectoceles and we did not assess for high tone dysfunction, 2 conditions that could have an impact on constipations symptoms, and as such, our data may not be generalizable to women with those conditions. Furthermore, although all intervention groups as well as the responder group had defecatory symptom improvements compared with baseline, the change in scores did not meet the minimal important difference (–0.6) for the PAC-SYM questionnaire.
      • Yiannakou Y.
      • Tack J.
      • Piessevaux H.
      • et al.
      The PAC-SYM questionnaire for chronic constipation: defining the minimal important difference.
      The concept of MID, the smallest difference in score associated with a clinically meaningful improvement, is frequently used in clinical trials to determine whether the difference observed is not only statistically significant but also clinically relevant. The proposed MID of 0.6 for the PAC-SYM was derived from trials evaluating the treatment efficacy of a medication for chronic constipation. Therefore, the improvement in defecatory symptoms observed in the current study may not have the same magnitude of change in symptoms compared with the clinical trials evaluating the treatment of constipation.

      Conclusion

      In summary, women seeking treatment for FI had modest improvements in defecatory symptoms, regardless of treatment group. These improvements were more marked in women who reported improvement in FI. In contrast to other studies, the addition of loperamide did not have a negative impact on defecatory symptoms.

      Acknowledgments

      The ClinicalTrials.gov identifier was NCT02008565. We thank the Pelvic Floor Disorders Network Contributors who made this study possible: Cleveland Clinic, Cleveland OH, Mathew D. Barber, coinvestigator, Marie Fidela R. Paraiso, coinvestigator, Mark D. Walters, coinvestigator, Beri Ridgeway, coinvestigator, Brooke Gurland, coinvestigator, Massarat Zutshi, coinvestigator, Geetha Krishnan, research nurse, Ly Pung, research nurse, Annette Graham, research nurse; Alpert Medical School of Brown University–Women and Infant’s Hospital of Rhode Island, Providence, RI, Vivian W. Sung, principal investigator; Deborah L. Myers, coinvestigator; Charles R. Rardin, coinvestigator; Cassandra Carberry, coinvestigator; B. Star Hampton, coinvestigator; Kyle Wohlrab, coinvestigator; Ann S. Meers, RN, research nurse; Duke University, Durham, NC, Anthony Visco, principal investigator, Cindy Amundsen, coinvestigator, Alison Weidner, coinvestigator, Nazema Siddiqui, coinvestigator, Amie Kawasaski, coinvestigator, Shantae McLean, clinical site coordinator, Nicole Longoria, clinical research coordinator, Jessica Carrington, clinical research coordinator, Niti Mehta, clinical research specialist, Ingrid Harm-Ernandes, interventionist, Jennifer Maddocks, interventionist, Amy Pannullo, interventionist; University of Alabama at Birmingham, Alayne Markland, primary investigator, Holly E. Richter, coinvestigator, R. Edward Varner, coinvestigator, Robert Holley, coinvestigator, L. Keith Lloyd, coinvestigator, Tracy S. Wilson, coinvestigator, Alicia Ballard, coinvestigator, Jeannine McCormick, interventionist, Velria Willis, research nurse, Nancy Saxon, research nurse, Kathy Carter, research nurse, Julie Burge, research coordinator; Northwest Physician Group, Amarillo, TX, Susan Meikle, coinvestigator; University of California, San Diego, Charles Nager, principal investigator, Michael Albo, coinvestigator, Emily Lukacz, coinvestigator, Cindy Furey, interventionist, Patricia Riley, interventionist, JoAnn Columbo, research coordinator, Sherella Johnson, research coordinator; Kaiser Permanente–San Diego, Shawn Menefee, coinvestigator, Karl Luber, coinvestigator, Gouri Diwadkar, coinvestigator, Jasmine Tan-Kim, coinvestigator; University of New Mexico, Albuquerque, NM, Yuko Komesu, coinvestigator, Gena Dunivan, coinvestigator, Peter Jeppson, coinvestigator, Sara Cichowski, coinvestigator, Christy Miller, interventionist, Erin Yane, interventionist, Julia Middendorf, research nurse, Risela Nava, research coordinator; RTI International, Research Triangle Park, NC, Dennis Wallace, alternate principal investigator, Amanda Shaffer, research operations manager, Poonam Pande, chemistry, manufacturing, and controls project leader, Kelly Roney, regulatory project leader, Ryan E. Whitworth, statistician, Lauren Klein Warren, statistician, Kevin A. Wilson, clinical research informatics project leader, Brenda Hair, clinical research informatics manager, Kendra Glass, data manager, Daryl Matthews, data manager, James W. Pickett II, programmer, Yan Tang, programmer, Tamara L. Terry, research services manager, Lynda Tatum, research services supervisor, Barbara Bibb, programmer, Jutta Thornberry, program manager, Kristin Zaterka-Baxter, clinical study specialist, Lindsay Morris, research coordinator; University of Pennsylvania, Philadelphia, PA, Lily Arya, principal investigator, Ariana Smith, coinvestigator, Heidi Harve, coinvestigator, Pamela Levin, coinvestigator, Diane K. Newman, coinvestigator, Mary Wang, interventionist, Donna Thompson, interventionist, Teresa Carney, interventionist, Michelle Kinglee, research coordinator, Lorraine Flick, research nurse; University of Pittsburgh, Pittsburgh, PA, Halina M. Zyczynski, MD, principal investigator, Pam Moalli, PhD, MD, coinvestigator, Gary Sutkin, MD, coinvestigator, Jonathan Shepherd, MD, coinvestigator, Michael Bonidie, MD, coinvestigator, Steven Abo, MD, coinvestigator, Janet Harrison, MD, coinvestigator, Christopher Chermansky, MD, coinvestigator, Lori Geraci, research coordinator, Judy Gruss, research coordinator, Karen Mislanovich, research coordinator, Ellen Eline, interventionist, Beth Klump, interventionist, Susan E. George, DPT, interventionist; University of North Carolina at Chapel Hill, William E. Whitehead, PhD, coinvestigator.

      References

        • Mohammed S.D.
        Co-existence of constipation and fecal incontinence: a greatly underappreciated clinical problem.
        Neurogastroenterol Motil. 2010; 22: 37
        • Siproudhis L.
        • Pigot F.
        • Godeberge P.
        • Damon H.
        • Soudan D.
        • Bigard M.A.
        Defecation disorders: a French population survey.
        Dis Colon Rectum. 2006; 49: 219-227
        • Andrews C.
        • Bharucha A.E.
        • Seide B.
        • Zinsmeister A.R.
        Rectal sensorimotor dysfunction in women with fecal incontinence.
        Am J Physiol Gastrointest Liver Physiol. 2007; 292: G282-G289
        • Omar M.I.
        • Alexander C.E.
        Drug Treatment for fecal incontinence in adults.
        Cochrane Database Syst Rev. 2013; : CD 002116
        • Markland A.D.
        • Burgio K.L.
        • Whitehead W.E.
        • et al.
        Loperamide versus psyllium fiber for treatment of fecal incontinence: the Fecal Incontinence Prescription (Rx) Management (FIRM) randomized clinical trial.
        Dis Colon Rectum. 2015; 58: 983-993
        • Fernández-Fraga X.
        • Azpiroz F.
        • Aparici A.
        • Casaus M.
        • Malagelada J.R.
        Predictors of response to biofeedback treatment in anal incontinence.
        Dis Colon Rectum. 2003; 46: 1218-1225
        • Jelovsek J.E.
        • Markland A.D.
        • Whitehead W.E.
        • et al.
        National Institute of Child Health and Human Development Pelvic Floor Disorders Network. Controlling faecal incontinence in women by performing anal exercises with biofeedback or loperamide: a randomised clinical trial.
        Lancet Gastroenterol Hepatol. 2019; 4: 698-710
        • Jelovsek J.E.
        • Markland A.D.
        • Whitehead W.E.
        • et al.
        Pelvic Floor Disorders Network. Controlling anal incontinence in women by performing anal exercises with biofeedback or loperamide (CAPABLe) trial: design and methods.
        Contemp Clin Trials. 2015; 44: 164-174
        • Markland A.D.
        • Jelovsek J.E.
        • Whitehead W.E.
        • et al.
        Pelvic Floor Disorders Network. Improving biofeedback for the treatment of fecal incontinence in women: implementation of a standardized multi-site manometric biofeedback protocol.
        Neurogastroenterol Motil. 2017; 29
        • Frank L.
        • Kleinman L.
        • Farup C.
        • Taylor L.
        • Miner Jr., P.
        Psychometric validation of a constipation symptom assessment questionnaire.
        Scand J Gastroenterol. 1999; 34: 870-877
        • Yiannakou Y.
        • Tack J.
        • Piessevaux H.
        • et al.
        The PAC-SYM questionnaire for chronic constipation: defining the minimal important difference.
        Aliment Pharmacol Ther. 2017; 46: 1103-1111
        • Bols E.M.
        • Hendriks E.J.
        • Deutekom M.
        • et al.
        Inconclusive psychometric properties of the Vaizey score in fecally incontinent patients: a prospective cohort study.
        Neurourol Urodyn. 2010; 29: 370-377
        • Damon H.
        • Guye O.
        • Seigneurin A.
        • et al.
        Prevalence of anal incontinence in adults and impact on quality-of-life.
        Gastroenterol Clin Biol. 2006; 30: 37-43
        • Bharucha A.E.
        • Seide B.M.
        • Zinsmeister A.R.
        • Melton 3rd, L.J.
        Relation of bowel habits to fecal incontinence in women.
        Am J Gastroenterol. 2008; 103: 1470-1475
        • Bharucha A.E.
        • Zinsmeister A.R.
        • Schleck C.D.
        • Melton 3rd, L.J.
        Bowel disturbances are the most important risk factors for late onset fecal incontinence: a population-based case-control study in women.
        Gastroenterology. 2010; 139: 1559-1566
        • Boreham M.K.
        • Richter H.E.
        • Kenton K.S.
        • et al.
        Anal incontinence in women presenting for gynecologic care: prevalence, risk factors, and impact upon quality of life.
        Am J Obstet Gynecol. 2005; 192: 1637-1642
        • Wald A.
        • Bharucha A.E.
        • Cosman B.C.
        • Whitehead W.E.
        ACG clinical guideline: management of benign anorectal disorders.
        Am J Gastroenterol. 2014; 109 (quiz, 1158): 1141-1157
        • Read M.
        • Read N.W.
        • Barber D.C.
        • Duthie H.L.
        Effects of loperamide on anal sphincter function in patients complaining of chronic diarrhea with fecal incontinence and urgency.
        Dig Dis Sci. 1982; 27: 807-814
        • Fox M.
        • Stutz B.
        • Menne D.
        • Fried M.
        • Schwizer W.
        • Thumshirn M.
        The effects of loperamide on continence problems and anorectal function in obese subjects taking orlistat.
        Dig Dis Sci. 2005; 50: 1576-1583
        • Bharucha A.E.
        • Croak A.J.
        • Gebhart J.B.
        • et al.
        Comparison of rectoanal axial forces in health and functional defecatory disorders.
        Am J Physiol Gastrointest Liver Physiol. 2006; 290: G1164-G1169
        • Andy U.U.
        • Vaughan C.P.
        • Burgio K.L.
        • Alli F.M.
        • Goode P.S.
        • Markland A.D.
        Shared risk factors for constipation, fecal incontinence, and combined symptoms in older US adults.
        J Am Geriatr Soc. 2016; 64: e183-e188