Fecal incontinence (FI), also known as anal incontinence and accidental bowel leakage (ABL), is common; it is reported by 2%–20% of community-dwelling women (1–3), 40% of whom report severe negative impact on quality of life. Effective, noninvasive therapies are limited (4,5). Neuromodulation has emerged as a promising third-tier therapy. Sacral neuromodulation, approved for both urgency urinary incontinence and FI, is safe and reversible but requires surgical intervention at substantial cost (6). Percutaneous tibial nerve stimulation (PTNS) is a minimally invasive, office-based, low-risk neuromodulation modality currently approved in the United States for urgency urinary incontinence. Promising response rates of 63%–82% in small, predominantly observational studies of FI (7) have supported device marketing approval for FI in the European Union. The National Institute for Health and Care Excellence (8) includes PTNS among treatment options for FI; however, it acknowledges the need for further research to inform efficacy and target populations. A multicenter, pragmatic, randomized trial of PTNS vs sham stimulation reported no group difference in a diary-based primary outcome of ≥50% reduction in weekly FI episodes (9), although PTNS did result in significantly greater reduction in total weekly FI and urgency-associated FI episodes. Post hoc analyses excluding subjects with obstructed defecation symptoms, a subset known to be refractory to FI therapy (10), found a significant clinical effect of PTNS (11). These findings support the need for additional controlled efficacy trials of PTNS in a well-characterized population.
The aim of this randomized clinical trial was to determine whether 12 weeks of treatment with PTNS is more effective than sham stimulation in reducing FI severity, as measured by change from baseline in St. Mark score, in women refractory to first-line therapies. Secondary aims included comparing changes from baseline in bowel diary measures, self-reported functional outcomes, and quality of life.
Study design and oversight
This multicenter, single-masked, randomized, superiority trial was conducted at 9 US clinical sites of the National Institutes of Health Pelvic Floor Disorders Network under approval of a Data and Safety Monitoring Board and the University of Pittsburgh institutional review board (NCT 03278613). All participants provided written informed consent. Study methods have been published (12), and the protocol and statistical analysis plan appear in supplementary materials. Enrollment for the trial began on February 9, 2018, and follow-up closed on March 9, 2020, on analysis of data from all subjects who completed initial treatment in the randomized trial (part 1) (see Study Flow Diagram, Supplementary Digital Content 1, https://links.lww.com/AJG/C371).
Women aged 18 years or older with moderate-to-severe ABL symptoms for ≥3 months, defined as a baseline St. Mark score ≥12 points, and inadequate symptom control from supervised pelvic muscle training and constipating medications, were eligible to enroll into a 4-week run-in period. Women were excluded for self-report of uncontrolled diarrhea or severe constipation as the predominant stool type in the preceding 3 months based on Bristol stool scale (13), anatomic compromise of the anus or rectum (unrepaired rectovaginal fistula or fourth-degree obstetrical laceration, rectal prolapse, congenital anorectal malformation, and colon resection), and known contraindications for PTNS (12).
The study included a 4-week run-in period before randomization to 12 weekly stimulation sessions (part 1). Treatment responders, defined as those reporting ≥4-point reduction in St. Mark score, underwent a second randomization to ‟as needed” or scheduled maintenance sessions (part 2) for an additional 9 months beyond treatment initiation. The protocol specified that if part 1 did not demonstrate superiority of PTNS over sham stimulation, part 2 would be discontinued.
During the run-in period, participants received standardized verbal and written information on causes and treatments for FI including dietary and lifestyle modifications (14). They also completed two 7-day bowel diaries in weeks 1 and 4. Women were eligible for randomization to part 1 if they provided 2 complete diaries (defined as having recorded events on ≥10 of 14 days with minimum of 3 consecutive days per week) and reported a St. Mark score of ≥12 points at the end of the run-in period.
Part 1 randomization assignment was 2:1 PTNS:sham stimulation, using randomly permuted blocks, stratified by site and type of run-in diary completed (eDiary or paper). Stimulation was delivered to a single lower extremity in 12 weekly 30-minute sessions. PTNS used the ES-130 pulse generator (ITO, Tokyo, Japan) programed to be consistent with the Stoller Afferent Nerve Stimulator (UroSurge, Coralville, Iowa), (US Patent No.: US 6,493,588) to deliver a threshold current to a needle electrode to induce toe twitch and/or sensation (15,16). The validated sham intervention used a Streitberger retractable placebo acupuncture needle and surface electrodes positioned on the top and bottom of the fifth metatarsal, each connected to a transcutaneous electrical nerve stimulator that created a sensory effect without delivering a therapeutic effect (17). Procedures are detailed in the protocol (Supplementary material) and methods article (12). Adherence to the study protocol was defined as completing 10 of 12 sessions within a 14-week window.
The primary outcome was change from baseline in St. Mark score measured after 12 weekly treatments. The St. Mark score is a 7-item, validated patient-reported outcome (18–20). Higher scores (range 0–24 points) indicate greater symptom severity, and the minimal important difference is 3–5 points (20). The St. Mark score was assessed at baseline and after the 4th, 8th, and 12th weekly sessions.
The secondary outcomes included bowel movement and stool leakage episodes per week qualified by urgency and stool consistency recorded for 14 days on the PFDN Bowel eDiary phone application (21) at baseline and with start dates at the 6th and 12th stimulation sessions. In the absence of a single superior measure for ABL, a robust panel of patient-reported outcome measures was collected assessing FI symptom severity, quality of life (22,23), coexistent bowel and bladder symptoms (24), constipation symptoms (25), global impression of improvement, behavior adaptations for pelvic floor disorders (26), and sexual function (27). The Patient Global Symptom Control rating (20) and adverse events were ascertained at each treatment visit.
Assuming a 2-sided alpha of 0.05 and SD of 7 (28), using a 2:1 treatment allocation, 147 women provided 90% power to detect a between-group difference of 4 points in the mean change from baseline in St. Mark scores after 12 weeks of stimulation. After adjusting for 10% dropout, 165 (PTNS group = 110, Sham stimulation group = 55) was the target sample size for part 1.
Baseline characteristics were compared between groups using the Student t tests for continuous variables and the χ2 tests for categorical variables. The primary analysis used an intention-to-treat approach, and models included all eligible randomized participants with outcome data at 1 or more time points. A general linear mixed model estimated the change from baseline in St. Mark score across all time points through 12 weeks of treatment. Treatment group, time as a linear and quadratic effect, the stratification factor of site, and interactions between treatment group and time were included as fixed effects. The correlation between repeated measures on the same participant was modeled using an autoregressive covariance structure. The model-estimated change from baseline in St. Mark score after 12 treatments was compared between groups using a 2-sided test at an alpha level of 0.05. In a sensitivity analysis, multiple imputation was used to estimate missing values.
A per-protocol analysis included participants who attended at least 10 of 12 stimulation sessions. Other secondary outcomes were analyzed using similar methods to the primary analysis for continuous variables or analogous generalized linear mixed models for categorical outcomes. No alpha adjustments were made for evaluation of multiple outcomes. Analyses were performed using SAS statistical software, version 9.4 (SAS Institute, Cary, NC).
Between February 9, 2018, and September 24, 2019, a total of 199 women entered the run-in period; 166 of 170 eligible participants were randomized (111 PTNS vs 55 sham stimulation) (Figure 1). Table 1 summarizes baseline sociodemographic and clinical characteristics. Overall, participants were 63.6 (±11.6) years old, predominantly White (80.7%), and overweight or obese (76.2%) individuals. The run-in period resulted in modest improvement in symptom severity with mean change in St. Mark scores −0.54 (±2.75). Before randomization, participants reported 13.3 (±7.3) bowel movements and 6.6 (±5.5) leaks per week, of which half were associated with urgency.
The unadjusted mean St. Mark score for the PTNS group at baseline was 17.5 (±2.5) and after 12 weeks was 12.2 (±5.0) for an adjusted mean change of −5.3 points (95% confidence interval [CI], −6.2 to −4.3) vs sham group unadjusted mean scores of 17.3 (±3.0) at baseline and 13.3 (±4.7) points after 12 weeks for an adjusted mean change of −3.9 points (95% CI, −5.2 to −2.7) (Table 2). There was no significant difference between groups in improvement of St. Mark scores (adjusted difference −1.3, 95% CI, −2.8 to 0.2). Responders to treatment were 64 of the 104 (61.5%) assigned to PTNS and 26 of the 54 (48.1%) assigned to sham stimulation (unadjusted odds ratio 1.71, 95% CI, 0.86–3.39; P = 0.12). Sensitivity and protocol analyses were consistent with the primary analysis. The observed divergence in total St. Mark scores after 8 weeks (Figure 2) was largely due to a significantly lower proportion of PTNS subjects reporting daily or weekly solid stool leakage and less use of protection with pads or plugs compared with sham subjects (Table 3).
Prespecified secondary and exploratory outcomes are summarized in Tables 2 and 3. Weekly frequency of diary-documented bowel events and FI episode-free days did not differ between groups. Approximately half of participants reported ≥50% reduction in weekly FI episodes, and a third had a ≥75% reduction, without meaningful differences between groups. Furthermore, both groups reported high levels of symptom control: 79% (PTNS group) vs 74% (sham stimulation group) with no group difference in perceived improvement (Table 3). Significant group differences were noted in adaptive behaviors, with the PTNS group reporting greater decreases from baseline in the hygiene and avoidance-related activities domains of the adaptive behavior index (Table 2). Group differences in condition-specific quality of life measures varied. Compared with sham stimulation group, the PTNS group reported significantly greater improvement in 3 of 4 subscales of the Fecal Incontinence Quality of Life Scale for the Lifestyle, Depression/Self-perception, and Embarrassment scores (see Table 1, Supplementary Digital Content 2, https://links.lww.com/AJG/C372). Most other quality of life measures did not indicate group differences.
Both groups demonstrated high adherence to the treatment schedule (99/111 [89.2%] PTNS group, 51/55 [92.7%] sham stimulation group). Validity of the sham was assessed at the close of part 1: 61 of the 103 (59.2%) of PTNS group and 32 of the 54 (59.3%) of the sham stimulation group reported not knowing their group assignment. Of those who guessed, 29 of the 42 (69%) assigned to PTNS group and 10 of the 22 (45.5%) in the sham stimulation group were correct. Interventionists recorded sensory, motor, or both responses to PTNS in 97.5%, 31.8%, and 29.7% of sessions, respectively. New nonpharmacological treatment for ABL was initiated by 5 PTNS and 3 sham subjects with an additional 9 PTNS and 2 sham subjects starting new medication for ABL. The proportion of subjects taking constipating medications was similar between groups at the end of part 1.
Adverse events were summarized by classification (see Table 2, Supplementary Digital Content 3, https://links.lww.com/AJG/C373) and by system organ class (see Table 3, Supplementary Digital Content 4, https://links.lww.com/AJG/C374). Paresthesia was reported in 11 (10%) of the PTNS group and 2 (4%) of the sham stimulation group. Bleeding (8%) and pain (2%) at the needle insertion site were exclusively reported in the PTNS group. Six participants experienced serious adverse events, 4 (4%) in the PTNS group and 2 (4%) in the sham stimulation group; none were treatment related.
In this randomized controlled trial of women with refractory FI, PTNS and sham stimulation did not differ in their impact on symptom severity, incontinence events, or most quality-of-life measures after 12 weekly sessions. Both groups experienced significant, clinically important reductions in patient-reported symptoms, weekly frequency of FI episodes compared with baseline, and compelling symptom control of 74%–78%, highlighting the importance of a sham arm when investigating therapeutic interventions for functional bowel disorders, in which placebo effects approximate 40% (29,30) There were, however, secondary outcomes including the FI Quality of Life and Adaptive Behaviors Index, which favored PTNS over sham. Nonetheless, group differences were modest, and overall, the findings of this study do not support the broad use of this PTNS protocol as standard FI therapy.
This study was conducted to address conflicting evidence on the efficacy of PTNS for treatment of ABL and the need for confirmatory level I evidence before clinical adoption of this therapy in the United States. Near the end of protocol development, Knowles and colleagues published the largest, most rigorous evaluation of PTNS for the treatment of FI in 227 women and men recruited from colorectal surgery clinics in the United Kingdom. Similar to NOTABLe, the CONFIDeNT trial found no significant treatment response in active PTNS treatment compared with sham stimulation for the primary outcome of ≥50% reduction in weekly FI episodes, conditional and related pelvic symptom quality-of-life measures, and patient global impression of improvement (9). The NOTABLe trial addresses some of the limitations of CONFIDeNT trial and distinguishes itself for its objective eligibility criteria of a study population with moderate-to-severe symptom burden in the absence of extremes of stool consistency; collection of bowel events with an electronic bowel diary to manage concerns of veracity of diary data; a run-in phase to address the potential therapeutic effect of journaling; selection of a comprehensive primary outcome, which accounts for elements of frequency, severity, volume, bother, and desire for treatment; and the use of a validated sham stimulation.
NOTABLe findings generally align with those of the CONFIDeNT trial; however, there are important differences in the population studied and design of the trial, which lend confidence and generalizability to the combined conclusions. The populations had similar baseline frequency of incontinence episodes (6–7/wk) with half associated with urgency and similar baseline FI quality-of-life scores. However, the NOTABLe trial exclusively enrolled women, recruited from the community through advertising and from urogynecology clinics, compared with colorectal specialty clinics. They were slightly older (by 6 years), more symptomatic based on St. Mark score (17 vs 15 points), and less likely to report previous ano/rectal surgery for FI than those enrolled in the CONFIDeNT trial. The difference in population, diary modality, or inclusion of run-in phase in this study may account for the differences in results between these studies. The UK study found significantly greater improvement in diary-documented FI episodes/wk compared with sham stimulation, but not in any of the FI quality-of-life domains. By contrast, the women in this study had no group difference in reduction of incontinence episodes but did report greater improvements with PTNS compared with sham stimulation in lifestyle, depression, and embarrassment domains of the Rockwood Fecal Incontinence Quality of Life Scale questionnaire. In addition, at the end of part 1, the PTNS group reported less use of adaptive behaviors to manage their ABL symptoms, which may reflect improved confidence in their ability to be continent despite unchanged symptom severity.
Despite deliberate, prerandomization interventions intended to isolate the effects of education, lifestyle modifications, and journaling in diaries, the sham stimulation group reported statistically significant reductions in St. Mark score of 3.9 points within the minimal important difference range of 3–5 points, leading to a nonsignificant difference between groups. The placebo effect noted in this trial is similar to that noted by this same research network in a 2 × 2 factorial designed trial comparing first-line FI interventions: oral placebo to loperamide and anal sphincter exercise training with biofeedback to an educational pamphlet (28). Participants assigned to oral placebo and educational materials reported reductions in St. Mark scores of 3.4 at 12 weeks and 4.5 at 24 weeks. A systematic review of sham PTNS stimulation techniques in FI and constipation studies found variations in needle insertion and activation of nerve stimulators (31). In the absence of a gold standard, this study used a validated sham stimulation technique for PTNS studies of overactive bladder syndrome (32). Despite the run-in and proven sham technique, the symptom reduction reported by the sham group was significant and consistent with the literature (28–31). Although the underlying mechanism for sham effects is unknown, proposed theories include natural variation in symptoms, regression to the mean, and psychological and neurobiological effects (31,33–36). Future analyses are planned to identify predictors of the sham response and potential genetic contributions to this phenomenon in this cohort of women.
The protocol choice of a generic electrical stimulation device in lieu of more costly proprietary devices for PTNS lends generalizability to study findings and accessibility of this therapy globally. The technique elicited the desired sensory and/or motor response in more than 97% of sessions with outcomes comparable with other trials using marketed devices that are US FDA–approved for urgency urinary incontinence (Cogentix/Uroplasty, Medtronic). While possible, it is unlikely that results of this trial would be different with the use of an alternate pulse generator because US FDA approvals of PTNS stimulators have been predicated on equivalence to the Stoller Afferent Nerve Stimulator unit. Consistent with other PTNS trials, adverse events were infrequent, mostly mild, and similar across treatment groups with no treatment-related serious adverse events.
Trial strengths include its rigorous study design with run-in and eligibility criteria that aided in enrollment of participants with moderate-to-severe symptoms less likely to spontaneously resolve with time or diary-prompted dietary and behavioral modifications. The validated sham effectively maintained masking, likely contributing to the high adherence to treatment schedules in both groups.
Our findings were limited to women, many seeking care for pelvic floor disorders at urogynecology clinics, and to the protocol-specified frequency and duration of PTNS sessions. Results should not be extrapolated to men who are equally affected by FI (1). The absence of a ‟no-treatment” control arm prevented us from quantifying the effect of the sham. Despite exclusion of women who regularly experienced watery diarrhea (Bristol stool 7), a substantial number of subjects reported symptoms of irritable bowel syndrome, with 75 of the 166 (45.2%) reporting loose/mushy/watery stools, often/most of the time/always in the last 3 months. Although participants were not characterized with anorectal imaging or functional testing, a secondary analysis is planned to identify predictors of clinically meaningful response, including stool frequency, consistency, and symptoms attributed to obstructive defecation. Finally, the primary end point after 12 weekly, 30-minute treatment sessions was empirically adopted from OAB studies of PTNS. Continuation of assigned stimulation sessions in the maintenance phase (part 2) will enable exploratory analyses of longer treatment exposure in both groups.
In conclusion, the study findings do not support the general use of PTNS in women with FI refractory to exercise and medication therapy. Although the improvement in St. Mark score after 12 weekly sessions of PTNS met the threshold of clinical importance, compared with sham stimulation, PTNS did not result in significantly greater improvement in symptom severity, incontinence events, or symptom-specific quality of life.
CONFLICTS OF INTEREST
Guarantor of the article: Marie Gantz, PhD.
Specific author contributions: H.M.Z., H.E.R., V.W.S., E.S.L., L.A.A., D.D.R., A.G.V., D.M., and M.G.G.: made substantial contributions to trial design, acquisition, and interpretation of the data and authorship of the manuscript. They have each reviewed and approved the final version submit to AJG. B.C.: contributed to analysis and interpretation of data and authorship of the manuscript and reviewed and approved the final version of the manuscript submitted to AJG. B.C. and M.G.G.: had full access to all the data in the study and took responsibility for the integrity of the data and the accuracy of the data analysis.
Financial support: Eunice Kennedy Shriver National Institute of Child Health and Human Development and NIH Office of Research on Women's Health 2 UG1 HD069006, 2 UG1 HD041261, 2 UG1 HD069013, 2 UG1 HD069010, UG1 HD054214, 2 UG1 HD041267, and 2 U24 HD069031.
Potential competing interests: H.E.R.: research funding: Renovia, Allergan, NIA/UTSW, NICHD, and NIDDK; royalties: Up to Date; travel reimbursement related to editor duties: Obstet Gynecol & IUJ; Board: Worldwide Fistula Fund; DSMB: Bluewind; and CME speaker: Symposia Medicus. E.S.L.: consultant: Axonics & Urovant outside submitted work; royalties: UpToDate; and research support: Boston Scientific & Cogentix/Uroplasty; D.D.R.: research support: Pfizer. A.G.V.: outside submitted work. D.M.: Grant: Boston Scientific. H.M.Z.: Board: American College Obstetrics and Gynecology (no salary compensation); Benjamin Carper, M.G.G., V.W.S., and L.A.A.: report no conflicts of interest.
Previous presentation: PFD Week 2020, Virtual Meeting; October 6–10, 2020.
Trial Registration Number: Clinical Trials.gov NCT 03278613.
WHAT IS KNOWN
- ✓ Fecal incontinence is common and debilitating with few noninvasive treatment options.
- ✓ Percutaneous tibial nerve stimulation (PTNS) is a potential low-cost, minimally invasive neuromodulation therapy with conflicting evidence for efficacy.
WHAT IS NEW HERE
- ✓ Although improvement in St. Mark score after PTNS exceeded the minimally important difference, PTNS did not differ from sham stimulation in reducing fecal incontinence severity, incontinence events, or quality of life.
University of Alabama at Birmingham: Danielle Aaron, CRNP, Kathy Carter, RN, David Ellington, MD, Ryanne Johnson, CRNP, Alayne Markland, DO, MSc, Jeannine McCormick, CRNP, Isuzu Meyer, MD, MSPH, R. Edward Varner, MD, and Robin Willingham, RN. Brown University Women & Infants Hospital of Rhode Island: Cassandra Carberry, MD, B. Star Hampton, MD, Nicole Korbly, MD, Ann Schantz Meers, BS, RN, Deborah L. Myers, MD, Charles R. Rardin, MD, Kyle Wohlrab, MD, Sarashwathy K. Veera, BS, and Elizabeth-Ann R. Viscione, BA. University of California at San Diego: Michael Albo, MD, Marianna Alperin, MD, Stephanie Armstrong, RN, Laura Aughinbaugh, RNP, CNM, Linda Brubaker, MD, Tatiana Catanzarite, MD, Kyle Herrala, Stephanie Micucci, Charles Nager, MD, Dulce Rodriguez-Ponciano, Sandra Romano, LVN, Erika Ruppert, and Yahir Santiago-Lastra, MD. Kaiser Permanente San Diego: Keisha Dyer MD, Shawn Menefee MD, Jasmine Tan-Kim MD, Kimberly Ferrante MD, Gouri Diwadkar MD, Christina Doan, Rebekah Dozier, Alyssa David-Tucker, Josephine Salunga, Lynn Hall, Gisselle Zazueta, and Linda Mackinnon. Duke University Medical Center: Cindy L. Amundsen, MD, Matthew D. Barber, MD, MHS, Yasmeen Bruton, MA, Nortorious Coleman-Taylor, MA, Cassandra Hanson, WHNP-BC, John E. Jelovsek, MD, MMEd, Amy Kavanagh, MSN, RN-BC, Amie Kawasaki, MD, Shantae McLean, MD, Tracey O'Dowd, RN, John Owens, MSN, RN, Nazema Y. Siddiqui, MD, MHSc, Katelyn C. Smith, FNP-C, and Alison C. Weidner, MD, MMCi. University of Pennsylvania: Uduak Andy, Yelizaveta Borodyanskaya, Lorraine Flick, Heidi Harvie, and Zandra Kennedy. University of Pittsburgh Magee-Womens Hospital: Mary Ackenbom, Kara Albrecht, Lindsey Baranski, Michael Bonidie, Megan Bradley, Alexus Bushee, Pamela Fairchild, Judy Gruss, Beth Klump, Lauren Kunkle, Jacqueline Noel, Pamela Moalli, and Margaret Rajkovic. University of Texas Southwestern: Shanna Atnip, WHNP, Sunil Balgobin, MD, Juanita Bonilla, Agnes Burris, RN, Marlene Corton, MD, Maria Florian-Rodriguez, MD, Christy Hegan, WHNP, Priscilla Reynolds, WHNP, Joseph Schaffer, MD, Alison Schmitt, WHNP, and Clifford Wai, MD. RTI International: Andrew Burd, Kate Burdekin, Kendra Glass, Brenda Hair, Michael Ham, Pooja Iyer, James Pickett, Peter Robbins, Amanda Shaffer, Taylor Swankie, Yan Chen Tang, Sonia Thomas, Kevin Wilson, and Dennis Wallace. PFDN Data Safety and Monitoring Board members: Paul Tulikangas, University of Connecticut Hartford Hospital, Jenifer D. Ihm, Patient Advocate, Lan Kong, Penn State University College of Medicine, Donna McClish, Virginia Commonwealth University, Katharine O'Dell, UMass Memorial Medical Center, Lea Perez, KLP Consulting LLC, Leslie Rickey, Yale New Haven Hospital, David Shade, The Johns Hopkins University, Ashok Tuteja, University of Utah, and Susan Yount, Frontier Nursing University, Lexington, KY.
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