Susan L. Lucak

Use of probiotics in gastrointestinal disorders: what to recommend?

Perturbation of bacterial microflora of the gastrointestinal (GI) tract may play an important role in the pathophysiology of some GI disorders. Probiotics have been used as a treatment modality for over a century. They may restore normal bacterial microflora and effect the functioning of the GI tract by a variety of mechanisms. Probiotics are not currently regulated and only few randomized controlled trials exist investigating their efficacy in different GI disorders. They are available in a variety of formulations and delivery systems making interpretation and comparison of studies even more difficult. The efficacy of probiotics, either as a single strain or a combination of probiotics, has been tested in antibiotic-associated diarrhea, Clostridium difficile colitis, infectious diarrhea, ulcerative colitis, Crohn’s disease, pouchitis, and irritable bowel syndrome, among other disorders. Results of the studies are reviewed in this article and recommendations for probiotic use in these disorders are made. Although probiotics appear to be generally safe in an outpatient setting, the situation may be different in immunocompromised, hospitalized patients who may be at a greater risk of developing probiotic sepsis. No studies exist addressing the issue of safety specifically. Many questions regarding use of probiotics in GI disorders remain to be answered in future studies, such as most optimal doses, duration of treatment, physiological and immunological effects, efficacy of specific probiotics in specific disease states, and safety in debilitated patients.

Measuring irritable bowel syndrome patient‐reported outcomes with an abdominal pain numeric rating scale

Background  Controversy exists on how to measure patient‐reported outcomes in irritable bowel syndrome (IBS) clinical trials effectively. Pain numeric rating scales (NRS) are widely used in the non‐IBS pain literature. The Food and Drug Administration has proposed using the NRS in IBS.

Measuring symptoms in the irritable bowel syndrome: development of a framework for clinical trials

Aliment Pharmacol Ther 2010; 32: 1275–1291

Developing Valid and Reliable Health Utilities in Irritable Bowel Syndrome: Results from The IBS PROOF Cohort

OBJECTIVES:A “utility” is a measure of health-related quality of life (HRQOL) that ranges between 0 (death) and 1 (perfect health). Disease-targeted utilities are mandatory to conduct cost–utility analyses. Given the economic and healthcare burden of irritable bowel syndrome (IBS), cost–utility analyses will play an important role in guiding health economic decision-making. To inform future cost–utility analyses in IBS, we measured and validated the IBS utilities.METHODS:We analyzed data from Rome III IBS patients in the Patient Reported Observed Outcomes and Function (PROOF) Cohort—a longitudinal multi-center IBS registry. At entry, the patients completed a multi-attribute utility instrument (EuroQOL), bowel symptom items, IBS severity measurements (IBS Severity Scale (IBSSS), Functional Bowel Disease Severity Index (FBDSI)), HRQOL indexes (IBS quality-of-life instrument (IBS-QOL), Center for disease control-4 (CDC-4)), and the Worker Productivity Activity Index for IBS (WPAI). We repeated assessments at 3 months.RESULTS:There were 257 patients (79% women; age=43±15 years) at baseline and 85 at 3 months. The mean utilities in patients with severe vs. non-severe IBS were 0.70 and 0.80, respectively (P<0.001). There were no differences in utilities among IBS with constipation (IBS-C), IBS with diarrhea (IBS-D), and mixed IBS (IBS-M) subgroups. EuroQOL utilities correlated with FBDSI (r=0.31; P<0.01), IBSSS (r=0.36; P<0.01), IBS-QOL (r=0.36; P<0.01), CDC-4 (r=0.44; P<0.01), WPAI presenteeism (r=0.16; P<0.01), abdominal pain (r=0.43; P<0.01), and distension (r=0.18; P=0.01). The utilities in patients reporting “considerable relief” of symptoms at 3 months vs. those without considerable relief were 0.78 and 0.73, respectively (P=0.02).CONCLUSIONS:EuroQOL utilities are valid and reliable in IBS. The utility of severe IBS (0.7) is similar to Class III congestive heart failure and rheumatoid arthritis. These validated utilities can be employed in future IBS cost–utility analyses.

Characterizing abdominal pain in IBS: guidance for study inclusion criteria, outcome measurement and clinical practice

Aliment Pharmacol Ther 2010; 32: 1192–1202

Current and emergent pharmacologic treatments for irritable bowel syndrome with diarrhea: evidence-based treatment in practice:

Irritable bowel syndrome with diarrhea (IBS-D) is a common, chronic functional gastrointestinal disorder with symptoms that can be distressing for patients and often result in substantially impaired quality of life. This review focuses on providing clinicians with information on practical, evidence-based treatment for IBS-D. Current therapies commonly used for the treatment of IBS-D, including pharmacologic and nonpharmacologic interventions, are briefly reviewed, followed by discussion of the emergent pharmacologic treatments (rifaximin and eluxadoline) and medical foods (IBgard® and EnteraGam®). Given the lack of a standard treatment algorithm for IBS-D and the emergence of new pharmacologic therapies, treatment needs to be tailored to the individual patient and take into account the severity of disease. In this context, the latter part of this manuscript examines how treatments for IBS-D can be used in clinical practice by presenting three patient case scenarios with varying degrees of IBS-D severity. For each case, the patient’s medical history and clinical presentation are related to the Rome Foundation multidimensional clinical profile (MDCP) and potential treatment options with current and emergent therapies are reviewed. The interplay of gastrointestinal symptoms and their psychosocial impact, as well as the importance of a patient-centered approach to therapy, are discussed. Consideration is given to the potential need for combination therapies and how emergent treatments could fit into the treatment pathway for mild, moderate, and severe cases of IBS-D in clinical practice.

Irritable bowel syndrome and ischemic colitis: evidence supporting the increased use of alosetron

Alosetron, a 5-hydroxytryptamine 3 (5-HT3) receptor antagonist, was approved by the US Food and Drug Administration (FDA) for the treatment of diarrhea-predominant irritable bowel syndrome (IBS-D) in women in February 2000. Initial clinical trials demonstrated significant efficacy, particularly in improving fecal urgency, stool frequency and consistency [Camilleri et al. 2001]. In a recent review and systematic meta-analysis of eight alosetron clinical trials, the number needed to treat (NNT) was reported to be 7.5 [Shah et al. 2012]. Although its efficacy was never questioned, safety became a concern as cases of ischemic colitis (IC) were reported, leading to voluntary withdrawal of alosetron by GlaxoSmithKline in November 2000. Alosetron was reintroduced in 2002 as a result of patient advocacy, with a risk management plan (RMP) designed to limit availability to women with severe IBS-D [Chang et al. 2010; Lewis, 2011].

An Open-Label Pilot Study of Duloxetine in Patients With Irritable Bowel Syndrome and Comorbid Major Depressive Disorder.

Abstract Major depressive disorder (MDD) and irritable bowel syndrome (IBS) frequently co-occur, yet treating their comorbid presentation is challenging. Low-dose tricyclic antidepressants are efficacious for IBS, but higher doses to treat depressive symptoms present tolerability problems, whereas selective serotonin reuptake inhibitors are more tolerable but show inconsistent efficacy for IBS. If efficacious, serotonin-norepinephrine reuptake inhibitors like duloxetine would provide a useful alternative. We explored efficacy, tolerability, and time to onset of action of duloxetine in comorbid IBS-MDD in an open-label, 12-week trial. Repeated-measures mixed-effects regression analysis with the intent-to-treat sample assessed rate of change of the clinician-administered Gastrointestinal Symptoms Rating Scale, Montgomery-Åsberg Depression Rating Scale, and other clinician-administered and self-report scales. Seventeen Hispanic adults with current MDD and comorbid IBS meeting Rome III criteria entered the study. Medical and laboratory assessment ruled out alarm symptoms and signs inconsistent with IBS. Duloxetine led to significant improvement in Gastrointestinal Symptoms Rating Scale and Montgomery-Åsberg Depression Rating Scale scores and 71.4% and 64.3% intent-to-treat response rates for IBS and MDD, respectively. Abdominal pain severity decreased by 56%. Contrary to expectation of rapid analgesic effects, based on duloxetine studies for neuropathic pain, both IBS and MDD symptoms improved gradually; differences in slopes of improvement were nonsignificant. Duloxetine was moderately well tolerated at a mean endpoint dose of 60 mg/d. Study limitations include the lack of placebo control, modest sample size, single ethnic group, and high attrition rate. Duloxetine efficacy for comorbid IBS-MDD should be studied under placebo-controlled conditions with larger and more diverse samples.

Review: Optimizing outcomes with alosetron hydrochloride in severe diarrhea-predominant irritable bowel syndrome

Irritable bowel syndrome (IBS) is a highly prevalent functional gastrointestinal disorder that causes a range of symptoms. Currently, alosetron hydrochloride (Lotronex®), a selective serotonin type 3 receptor antagonist, is the only medication approved for the treatment of severe diarrhea-predominant irritable bowel syndrome (IBS-D) in women who have inadequately responded to conventional therapy. Alosetron has demonstrated efficacy compared with placebo in clinical trials and has been shown to improve overall health-related quality of life (HRQoL). However, rare instances of ischemic colitis and severe complications of constipation have been reported. As a result, in 2000 alosetron was voluntarily withdrawn from the market but was reintroduced in 2002 with a more restricted indication and a requirement that clinicians and patients follow a prescribing program. Although the efficacy and benefit of alosetron has been clearly demonstrated, it has been used sparingly since its reintroduction. This brief review describes the history of alosetron, efficacy of alosetron in the treatment of IBS, the impact of severe IBS on HRQoL, safety considerations, the risk evaluation and mitigation strategy program under which alosetron is now prescribed, and an update on postmarketing surveillance data.

PTU-133 Effect of Eluxadoline on Abdominal and Bowel Symptoms Over Time in Phase 3 Clinical Trials in Patients with Irritable Bowel Syndrome with Diarrhoea (IBS-D)

Introduction Eluxadoline (ELX) is a mixed µ- and κ-opioid receptor (OR) agonist and δ-OR antagonist. It is locally active and approved for the treatment of IBS-D. Effects of ELX on abdominal pain and stool consistency have been reported based on a composite response; effects on other abdominal and bowel symptoms were evaluated over time. Methods Two double-blind, placebo (PBO)-controlled, Phase 3 trials (IBS-3001 and IBS-3002) randomised patients (pts) meeting Rome III criteria for IBS-D to twice-daily treatment with ELX 75 or 100 mg or PBO. Pts completed an electronic diary and rated daily IBS symptoms of abdominal discomfort and bloating (both on a 0–10 scale), and recorded numbers of bowel movements (BMs) and episodes of urgency and fincontinence daily through 26 weeks (wks). To assess trajectories of treatment effects over time, daily symptom scores and counts of BMs and episodes of urgency and incontinence were mwith longitudinal analyses. Treatment effect estimates from the models were evaluated at Wks 4, 8, 12, 16, 20, and 24 based on estimated least squares (LS) mean differences (symptom scores) and risk ratios (frequency data). Results 2428 pts with IBS-D were enrolled across both trials. In both studies, daily abdominal discomfort and bloating scores decreased from baseline within the first wk, with greater reductions seen for ELX. Abdominal discomfort scores were significantly lower (p < 0.05) than PBO for ELX 100 mg at all time points through Wk 24 in both studies (except Wk 4 in IBS-3002), while bloating was significantly lower (p < 0.05) than PBO for ELX 100 mg from Wk 16 onward in both studies (Table). BM frequency and episodes of urgency and incontinence were also reduced from baseline. Both ELX doses significantly reduced (p < 0.05) episodes of urgency compared with PBO at all time points through Wk 24 in both studies. Similarly, ELX significantly reduced BM frequency compared with PBO through 24 wks (data not shown). Episodes of incontinence were significantly lower (p < 0.05) than PBO for both ELX doses from Wk 16 onward in IBS-3002.Abstract PTU-133 Table 1 Longitudinal analysis of abdominal discomfort and bloating Conclusion ELX significantly improves abdominal discomfort and bloating, and significantly reduces BM frequency and episodes of urgency and incontinence; effects are sustained through 6 months of treatment. Reference 1 Previously presented at ACG 2015. Abstract #1761. Am J Gastroenterol 2015;110:S739–S766. doi:10.1038/ajg.2015.275. Disclosure of Interest L. Harris Grant/research support from: Alvine, Rhythm Pharmaceuticals, Consultant for: Allergan plc, QoL, Ironwood, Conflict with: Ironwood, Allergan plc, S. Lucak Consultant for: Allergan plc, Takeda, Salix, Ironwood, Prometheus, Speaker bureau with: Allergan plc, Takeda, Salix, Ironwood, Conflict with: Allergan plc, Takeda, Salix, Ironwood, L. Chang Conflict with: Ironwood, Allergan plc, Valeant, QOL Medical, Takeda, Ardelyx, Commonwealth Laboratories, AstraZeneca, Synergy, L. Dove Consultant for: Allergan plc, P. Covington: None Declared