Talley, Nicholas J.

Summary Background Pregabalin is a calcium channel α2δ ligand that modifies visceral hypersensitivity in IBS patients. Clinical data for pregabalin in IBS are lacking. Aim To test the efficacy of pregabalin on gastrointestinal symptoms in IBS patients. Methods A double‐blind, placebo‐controlled trial was performed. Adults meeting IBS Rome III criteria with ≥3 pain attacks per month were randomised to pregabalin 225 mg vs placebo twice daily for 12 weeks. Questionnaires were completed weekly. The primary endpoint was average pain Bowel Symptom Scale (BSS) scores weeks 9‐12. An intention‐to‐treat analysis of covariance evaluated treatment effects on quantitative endpoints, adjusting for age and gender. Adequate relief and change in pain score were assessed using a chi‐squared test. Results Eighty‐five patients were recruited and randomised. Sample characteristics include: mean age 39.4 (SD = 14.6); 73 (86%) female; 37 (44%) IBS‐D, 29 (35%) IBS‐M, 18 (21%) IBS‐C. The pregabalin arm had lower average pain‐BSS scores weeks 9‐12 (25 vs 42, P = 0.008). Compared with placebo, the overall IBS BSS severity score was lower in the pregabalin arm (26 vs 42, P = 0.009). Differences were observed for the diarrhoea‐BSS and bloating‐BSS scores ( P = 0.049 and 0.016, respectively). No differences between groups were seen for constipation‐BSS scores. Adequate relief was not different between the two arms (46% vs 36%, P = 0.35). 63% pregabalin vs 45% placebo had a change in pain score ≥30 at week 12 from baseline ( P = 0.10). Post‐treatment IBS‐QoL scores did not differ between groups. Conclusion This trial suggests that pregabalin may be beneficial for IBS abdominal pain, bloating and diarrhoea.

Background and aims The functional gastrointestinal disorders (FGIDs) are extremely common conditions associated with a considerable personal, social and health economic burden. Managing FGIDs in clinical practice is challenging because of the uncertainty of symptom-based diagnosis, the high frequency of overlap between these conditions and the limited efficacy of available therapies. It has often been argued that successful drug development and management of FGIDs requires knowledge of the underlying pathophysiology. Numerous and highly variable candidate pathophysiological mechanisms have been implicated in the generation of FGID symptoms, but there is no current consensus on how to best define the relevance of these disturbances. Methods A group of international experts on FGIDs developed plausibility criteria that should be fulfilled by relevant pathophysiological mechanisms in FGIDs. Results Five criteria are proposed: (1) the presence of the abnormality in a subset of patients, (2) temporal association between proposed mechanism and symptom(s), (3) correlation between the level of impairment of the mechanism and symptom(s), (4) induction of the symptom(s) by provoking the pathophysiological abnormality in healthy subjects and (5) treatment response by a therapy specifically correcting the underlying disorder or congruent natural history of symptoms and dysfunction in the absence of specific therapy. Based on strength of evidence for these five criteria according to the Grading of Recommendations Assessment, Development and Evaluation system, a plausibility score can be calculated for each mechanism. Conclusion Evaluation of the strength of evidence for candidate pathophysiological abnormalities fulfilling these five plausibility criteria will help to identify the most relevant mechanisms to target for novel diagnostic approaches and for the development of new therapies.

Abstract Background: Palliative care guidelines recommend plain radiographs to assess constipation based on the presumption that visible fecal shadowing represents stool retention. Despite this, using plain radiographs in this way is not well validated. Objectives: This work's main aim was to compare clinicians' reports of fecal loading on radiographs. This study also compares clinicians' assessments with radio-opaque marker transit studies and patients' self-reported constipation symptoms. Methods: This study was conducted in a sample of 30 constipated palliative care patients taking laxatives who had all undergone colon transit studies and contemporaneous assessment of constipation symptoms with the Patient Assessment of Constipation Symptom (PAC-SYM) questionnaire. Four separate clinicians independently reported their opinions of fecal loading using a previously developed fecal loading scale. Participant details were summarized and pair-wise inter-rater agreement among all four raters were examined using the Bland-Altman approach. For the comparisons of the clinician-assigned fecal loading score between the radiographic assessment of the normal and slow colon transit time, the nonparametric approach of Mann-Whitney U tests were applied. Spearman's correlation analyses were employed to investigate the association between the clinician-assigned fecal loading score and the patient self-reported PAC-SYM score. Results: The results of this study are very similar to other studies conducted in functional constipation, highlighting systematic disagreement between observers. Further poor correlations were noted between fecal loading scores and colon transit times and with patient self-reported symptoms. Conclusion: These results, when considered with other work in chronic constipation, question the ongoing use of radiographs in the diagnosis of constipation.

ABSTRACTBackground:Although direct medical costs for constipation‐related medical visits are thought to be high, to date there have been no studies examining whether longitudinal resource use is persistently elevated in children with constipation. Our aim was to estimate the incremental direct medical costs and types of health care use associated with constipation from childhood to early adulthood.Methods:A nested case‐control study was conducted to evaluate the incremental costs associated with constipation. The original sample consisted of 5718 children in a population‐based birth cohort who were born during 1976 to 1982 in Rochester, MN. The cases included individuals who presented to medical facilities with constipation. The controls were matched and randomly selected among all noncases in the sample. Direct medical costs for cases and controls were collected from the time subjects were between 5 and 18 years of age or until the subject emigrated from the community.Results:We identified 250 cases with a diagnosis of constipation in the birth cohort. Although the mean inpatient costs for cases were $9994 (95% Confidence interval [CI] 2538–37,201) compared with $2391 (95% CI 923–7452) for controls (P = 0.22) during the time period, the mean outpatient costs for cases were $13,927 (95% CI 11,325–16,525) compared with $3448 (95% CI 3771–4621) for controls (P < 0.001) during the same time period. The mean annual number of emergency department visits for cases was 0.66 (95% CI 0.62–0.70) compared with 0.34 (95% CI 0.32–0.35) for controls (P < 0.0001).Conclusions:Individuals with constipation have higher medical care use. Outpatient costs and emergency department use were significantly greater for individuals with constipation from childhood to early adulthood.

Background. The ``gold-standard'' evidence of effectiveness for a clinical practice guideline is the randomized controlled trial (RCT), although RCTs have a limited ability to explore potential management strategies for a chronic disease where these interact over time. Modeling can be used to fill this gap, and models have become increasingly complex, with both dynamic sampling and representation of second-order uncertainty to provide more precise estimates. However, both simulation modeling and probabilistic sensitivity analysis are rarely used together. The objective of this study was to explore uncertainty in controversial areas of the 2005 American Gastroenterology Association position statement on the management of dyspepsia. Methods. Individual sampling model, incorporating a second-order probabilistic sensitivity analysis. Population. US adult patients presenting in primary care with dyspepsia. Interventions compared: empirical acid suppression, test and treat for Helicobacter pylori, initial endoscopy, acid suppression then endoscopy, test and treat then proton pump inhibitor (PPI) then endoscopy. Outcomes. Cost-effectiveness, quality-adjusted life years, and costs in US dollars from a societal perspective, measured over a 5-year period. Data sources: mainly Cochrane meta-analyses. Results. Endoscopy was dominated at all ages by other strategies. PPI therapy was the most cost-effective strategy in 30-year-olds with a low prevalence of H. pylori. In 60-year-olds, H. pylori test and treat was the most cost-effective option. Conclusions. Acid suppression alone was more cost-effective than either endoscopy or H. pylori test and treat in younger dyspepsia patients with a low prevalence of infection.