Yolanda Scarlett

Biofeedback treatment of fecal incontinence: a critical review.

PURPOSE: The aims of this review are 1) to critically evaluate the literature on the efficacy of biofeedback treatment for fecal incontinence, 2) to compare different types of biofeedback, and 3) to identify patient characteristics which predict a successful outcome. METHODS: The MEDLINE database was searched for articles published between 1973 and 1999 which included the terms “biofeedback” and “fecal incontinence.” Pediatric and adult articles in any language were screened. Inclusion for review required that the study be prospective, have five or more subjects, and have a description of the treatment protocol. RESULTS: Thirty-five studies were reviewed. Only six studies used a parallel treatment design and just three of those randomized subjects to treatment groups. A meta-analysis (weighted by subjects) was performed to compare the results of two treatment protocols that dominate the literature. The mean success rate of studies usingCoordination training (i.e., coordinating pelvic floor muscle contraction with the sensation of rectal filling) was 67 percent, while the mean success rate for studies usingStrength training (i.e., pelvic floor muscle contraction) was 70 percent. Furthermore, the mean success rate for thoseStrength training studies using electromyographic biofeedback was 74 percent, while the mean success rate for studies using anal canal pressure biofeedbackStrength training was 64 percent. However, these conclusions are limited by the absence of clearly identified criteria for determining success. There are also inconsistencies in the literature regarding the patient selection criteria, severity and cause of symptoms, amount of treatment, as well as the type of biofeedback protocols and instrumentation used. Finally, no patient characteristics were identified that would assist in predicting successful outcome. CONCLUSION: Although most studies report positive results using biofeedback to treat fecal incontinence, quality research is lacking. Recommendations are made for future investigations to 1) improve experimental design, 2) include long term follow-up data, and 3) to use an adequate sample size that allows for meaningful analysis.

Randomized controlled trial shows biofeedback to be superior to pelvic floor exercises for fecal incontinence.

PURPOSE: This study aimed to compare manometric biofeedback with pelvic floor exercises for the treatment of fecal incontinence in a randomized controlled trial controlling for nonspecific treatment effects. METHODS: After excluding patients who were adequately treated with medication, education, and behavioral strategies (21%), 108 patients (83 females; average age, 59.6 years) underwent either pelvic floor exercises alone (n = 63) or manometric biofeedback plus pelvic floor exercises (n = 45). Patients in both groups were taught behavioral strategies to avoid incontinence. RESULTS: At three-month follow-up, biofeedback patients had significantly greater reductions on the Fecal Incontinence Severity Index (P = 0.01) and fewer days with fecal incontinence (P = 0.083). Biofeedback training increased anal canal squeeze pressure more than pelvic floor exercises did (P = 0.014) and with less abdominal tension during squeeze (P = 0.001). Three months after training 76% of patients treated with biofeedback vs. 41% patients treated with pelvic floor exercises (chi-squared = 12.5, P < 0.001) reported adequate relief. Before treatment, the groups did not differ on demographic, physiologic, or psychologic variables, symptom severity, duration of illness, quality-of-life impact, or expectation of benefit. At 12-month follow-up, biofeedback patients continued to show significantly greater reduction in Fecal Incontinence Severity Index scores (F = 4.83, P = 0.03), and more patients continued to report adequate relief (chi-squared = 3.64, P = 0.056). CONCLUSION: This investigation provides definitive support for the efficacy of biofeedback. Biofeedback training resulted in greater reductions in fecal incontinence severity and days with fecal incontinence. Biofeedback was also more effective than pelvic floor exercises alone in producing adequate relief of fecal incontinence symptoms in patients for whom conservative medical management had failed.

Increased colonic pain sensitivity in irritable bowel syndrome is the result of an increased tendency to report pain rather than increased neurosensory sensitivity

Objective: The aim was to determine whether lower visceral pain thresholds in irritable bowel syndrome (IBS) primarily reflect physiological or psychological factors. Methods: Firstly, 121 IBS patients and 28 controls underwent balloon distensions in the descending colon using the ascending methods of limits (AML) to assess pain and urge thresholds. Secondly, sensory decision theory analysis was used to separate physiological from psychological components of perception: neurosensory sensitivity (p(A)) was measured by the ability to discriminate between 30 mm Hg vs 34 mm Hg distensions; psychological influences were measured by the report criterion—that is, the overall tendency to report pain, indexed by the median intensity rating for all distensions, independent of intensity. Psychological symptoms were assessed using the Brief Symptom Inventory (BSI). Results: IBS patients had lower AML pain thresholds (median: 28 mm Hg vs 40 mm Hg; p<0.001), but similar neurosensory sensitivity (median p(A): 0.5 vs 0.5; p = 0.69; 42.6% vs 42.9% were able to discriminate between the stimuli better than chance) and a greater tendency to report pain (median report criterion: 4.0 (“mild” pain) vs 5.2 (“weak” pain); p = 0.003). AML pain thresholds were not correlated with neurosensory sensitivity (r = −0.13; p = 0.14), but were strongly correlated with report criterion (r = 0.67; p<0.0001). Report criterion was inversely correlated with BSI somatisation (r = −0.26; p = 0.001) and BSI global score (r = −0.18; p = 0.035). Similar results were seen for the non-painful sensation of urgency. Conclusion: Increased colonic sensitivity in IBS is strongly influenced by a psychological tendency to report pain and urge rather than increased neurosensory sensitivity.

Physiologically Based Pharmacokinetic Modeling Framework for Quantitative Prediction of an Herb–Drug Interaction

Herb–drug interaction predictions remain challenging. Physiologically based pharmacokinetic (PBPK) modeling was used to improve prediction accuracy of potential herb–drug interactions using the semipurified milk thistle preparation, silibinin, as an exemplar herbal product. Interactions between silibinin constituents and the probe substrates warfarin (CYP2C9) and midazolam (CYP3A) were simulated. A low silibinin dose (160 mg/day × 14 days) was predicted to increase midazolam area under the curve (AUC) by 1%, which was corroborated with external data; a higher dose (1,650 mg/day × 7 days) was predicted to increase midazolam and (S)‐warfarin AUC by 5% and 4%, respectively. A proof‐of‐concept clinical study confirmed minimal interaction between high‐dose silibinin and both midazolam and (S)‐warfarin (9 and 13% increase in AUC, respectively). Unexpectedly, (R)‐warfarin AUC decreased (by 15%), but this is unlikely to be clinically important. Application of this PBPK modeling framework to other herb–drug interactions could facilitate development of guidelines for quantitative prediction of clinically relevant interactions.

Assessment of a Candidate Marker Constituent Predictive of a Dietary Substance–Drug Interaction: Case Study with Grapefruit Juice and CYP3A4 Drug Substrates

Dietary substances, including herbal products and citrus juices, can perpetrate interactions with conventional medications. Regulatory guidances for dietary substance–drug interaction assessment are lacking. This deficiency is due in part to challenges unique to dietary substances, a lack of requisite human-derived data, and limited jurisdiction. An in vitro–in vivo extrapolation (IVIVE) approach to help address some of these hurdles was evaluated using the exemplar dietary substance grapefruit juice (GFJ), the candidate marker constituent 6′,7′-dihydroxybergamottin (DHB), and the purported victim drug loperamide. First, the GFJ-loperamide interaction was assessed in 16 healthy volunteers. Loperamide (16 mg) was administered with 240 ml of water or GFJ; plasma was collected from 0 to 72 hours. Relative to water, GFJ increased the geometric mean loperamide area under the plasma concentration–time curve (AUC) significantly (1.7-fold). Second, the mechanism-based inhibition kinetics for DHB were recovered using human intestinal microsomes and the index CYP3A4 reaction, loperamide N-desmethylation (KI [concentration needed to achieve one-half kinact], 5.0 ± 0.9 µM; kinact [maximum inactivation rate constant], 0.38 ± 0.02 minute−1). These parameters were incorporated into a mechanistic static model, which predicted a 1.6-fold increase in loperamide AUC. Third, the successful IVIVE prompted further application to 15 previously reported GFJ-drug interaction studies selected according to predefined criteria. Twelve of the interactions were predicted to within the 25% predefined criterion. Results suggest that DHB could be used to predict the CYP3A4-mediated effect of GFJ. This time- and cost-effective IVIVE approach could be applied to other dietary substance–drug interactions to help prioritize new and existing drugs for more advanced (dynamic) modeling and simulation and clinical assessment.

A Modified Grapefruit Juice Eliminates Two Compound Classes as Major Mediators of the Grapefruit Juice-Fexofenadine Interaction: an In Vitro-In Vivo ‘Connect’

The grapefruit juice (GFJ)–fexofenadine interaction involves inhibition of intestinal organic anion transporting polypeptide (OATP)‐mediated uptake. Only naringin has been shown clinically to inhibit intestinal OATP; other constituents have not been evaluated. The effects of a modified GFJ devoid of furanocoumarins (∼99%) and polymethoxyflavones (∼90%) on fexofenadine disposition were compared to effects of the original juice. Extracts of both juices inhibited estrone 3‐sulfate and fexofenadine uptake by similar extents in OATP‐transfected cells (∼50% and ∼25%, respectively). Healthy volunteers (n = 18) were administered fexofenadine (120 mg) with water, GFJ, or modified GFJ (240 mL) by randomized, three‐way crossover design. Compared to water, both juices decreased fexofenadine geometric mean AUC and Cmax by ∼25% (P ≤ .008 and P ≤ .011, respectively), with no effect on terminal half‐life (P = .11). Similar effects by both juices on fexofenadine pharmacokinetics indicate furanocoumarins and polymethoxyflavones are not major mediators of the GFJ–fexofenadine interaction.

American Gastroenterological Association Institute Technical Review on the Medical Management of Opioid-Induced Constipation

Abbreviations used in this paper: AE, adverse event; AGA, American Gastroenterological Association; BFI, Bowel Function Index; BM, bowel movement; BSFS, Bristol Stool Form Scale; CI, confidence interval; FDA, Food and Drug Administration; GI, gastrointestinal; GRADE, Grading of Recommendations Assessment, Development and Evaluation; MD, mean difference; OIC, opioid-induced constipation; PAC-QOL, Patient Assessment of Constipation-Quality of Life; PAMORA, peripherally acting m-opioid receptor antagonist; PEG, polyethylene glycol; PICO, population, intervention, comparator, and outcomes; PROM, patient-reported outcome measure; QOL, quality of life; RCT, randomized controlled trial; RFBM, rescue-free bowel movement; RR, relative risk; SBM, spontaneous bowel movement.

S1830 Twelve Month Follow-Up for Patients with Pelvic Floor Dyssynergia-Type Constipation (PFD) Reporting Adequate Relief After a 4-Week Education and Medical Management Run-in Intervention

management intervention and 71% reported continued success at 12-month follow-up. These patients had an average of > 3 physician visits, specifically for FI, just in the previous 6 months. In addition to higher symptom severity and lower QOL measures, depression also predicted failure from run-in. Assessing patients with FI for depression may aid in developing an effective treatment plan that may include psychotherapy. [Supported by grants RO1 DK57048, R24 DK67674, and MO1 RR00046].