Opioid-induced bowel dysfunction: epidemiology, pathophysiology, diagnosis, and initial therapeutic approach.

Opioids affect motor and sensory function throughout the gastrointestinal tract, and are frequently associated with a number of gastrointestinal symptoms including constipation, which impairs the quality of life and may limit the dose of opioid or result in discontinuation altogether. Patients with opioid-induced constipation should be assessed by careful history and physical examination, and in some cases where the diagnosis is unclear with select diagnostic tests. Few clinical studies have been conducted to assess the efficacy of various treatments. However, it is generally recommended that first-line therapy begin with opioid rotation, as well as with low-cost and low-risk approaches such as lifestyle changes, consumption of fiber-rich food, stool softeners, and laxatives.

IBS with constipation, functional constipation, painful and non-painful constipation: e Pluribus Plures?

IBS with constipation (IBS-C) and chronic constipation (CC) can be difficult to distinguish clinically. The Rome III criteria create mutual exclusion between IBS-C and CC, based on the presence of abdominal pain, which is a defining criterion for IBS-C. Previous surveys found that up to 45% of CC patients have abdominal pain and other IBS features. A Spanish general population study proposes a subclassification of patients with CC based on abdominal pain and other features of IBS. As the Rome criteria evolve, these and other observations provide the basis for further efforts in discerning key features of IBS-C and CC.

Effects of linaclotide in patients with irritable bowel syndrome with constipation or chronic constipation: a meta-analysis.

BACKGROUND & AIMS: Linaclotide is a minimally absorbed, 14-amino acid peptide used to treat patients with irritable bowel syndrome with constipation (IBS-C) or chronic constipation (CC). We performed a meta-analysis to determine the efficacy of linaclotide, compared with placebo, for patients with IBS-C or CC. METHODS: MEDLINE, EMBASE, and the Cochrane central register of controlled trials were searched for randomized, placebo-controlled trials examining the effect of linaclotide in adults with IBS-C or CC. Dichotomous results were pooled to yield a relative risk (RR), 95% confidence intervals (CIs), and number needed to treat (NNT). RESULTS: The search identified 7 trials of linaclotide in patients with IBS-C or CC; 6 were included in the analysis. Two of 3 trials of IBS-C used the end point recommended by the U.S. Food and Drug Administration: an increase from baseline of 1 or more complete spontaneous bowel movement (CSBM)/week and a 30% or more reduction from baseline in the weekly average of daily worst abdominal pain scores for 50% of the treatment weeks. On the basis of this end point, the RR for response to treatment with 290 µg linaclotide, compared with placebo, was 1.95 (95% CI, 1.3-2.9), and the NNT was 7 (95% CI, 5-11). For CC, on the basis of data from 3 trials of patients with CC, the RR for the primary end point (more than 3 CSBMs/week and an increase in 1 or more CSBM/week, for 75% of weeks) was 4.26 for 290 µg linaclotide vs placebo (95% CI, 2.80-6.47), and the NNT was 7 (95% CI, 5-8). Linaclotide also improved stool form and reduced abdominal pain, bloating, and overall symptom severity in patients with IBS-C or CC. CONCLUSIONS: On the basis of a meta-analysis, linaclotide improves bowel function and reduces abdominal pain and overall severity of IBS-C or CC, compared with placebo.

A critical appraisal of lubiprostone in the treatment of chronic constipation in the elderly.

Chronic constipation is a common disorder in the general population, with higher prevalence in the elderly, and is associated with worse quality of life and with greater health care utilization. Lubiprostone is an intestinal type-2 chloride channel activator that increases intestinal fluid secretion, small intestinal transit, and stool passage. Lubiprostone is currently approved by the US Food and Drug Administration for the treatment of chronic idiopathic constipation and of irritable bowel syndrome with predominant constipation. This review outlines current approaches and limitations in the treatment of chronic constipation in the elderly and discusses the results, limitations, and applicability of randomized, controlled trials of lubiprostone that have been conducted in the general and elderly population, with additional focus on the use of lubiprostone in constipation in Parkinson's disease and in opioid-induced constipation, two clinical entities that can be comorbid in elderly patients.

Rifaximin for the treatment of irritable bowel syndrome.

INTRODUCTION: Few therapeutic options are available for irritable bowel syndrome (IBS). Lubiprostone is approved by the FDA for IBS with constipation, and alosetron in IBS with diarrhea (IBS-D). It has been proposed that alterations in the bowel microflora may play a role in the pathophysiology of IBS, and that modulation of the microflora holds therapeutic potential. Rifaximin is a nonsystemic antibiotic that has shown efficacy in IBS. AREAS COVERED: This narrative review covers the treatment options available for IBS-D and focuses on rifaximin. Rifaximin pharmacodynamics, clinical pharmacology and results of clinical studies from proof of concept to the latest Phase III and retreatment studies in IBS are summarized. Challenges to rifaximin use, safety issues and regulatory data are also discussed. EXPERT OPINION: The evidence supports rifaximin as an emerging treatment for IBS. Strategies for appropriate patient selection need to be further developed, and continued efficacy of rifaximin over repeated treatment courses needs to be better characterized.

Obesity does not increase effects of synthetic ghrelin on human gastric motor functions.

BACKGROUND & AIMS: Ghrelin is secreted by the stomach and stimulates food intake. Obese individuals have lower fasting plasma ghrelin levels but increased appetite, suggesting greater responses to endogenous ghrelin in obesity. The aim of this study was to compare effects of exogenous ghrelin (at a dose that stimulates growth hormone [GH] release in the physiologic range) versus placebo on gastric emptying, gastric volume, and postprandial symptoms and determine whether body mass (ranging from normal weight to obesity) influences responses to ghrelin. METHODS: After intravenous bolus synthetic human ghrelin (0.33 mug/kg) or saline, we measured plasma GH, gastric volume, and gastric emptying by combined (99m)Tc-single-photon emission computed tomography and scintigraphy ((111)In egg meal, 300 kcal) and postprandial symptoms using visual analogue scales. RESULTS: In 25 obese subjects (5 men and 20 women; body mass index [BMI], 36 +/- 4 kg/m(2)) and 13 female normal-weight (BMI, 22 +/- 2 kg/m(2)) subjects of similar ages, ghrelin increased GH levels (15.0 +/- 2.4 ng/mL) at 40 minutes postinjection and tended to decrease fasting gastric volumes compared with placebo (P = .059). There were no effects of BMI on treatment response and no differences between ghrelin and saline on postprandial (P = .09) or change in (postprandial minus fasting) gastric volumes, gastric emptying, or aggregate postprandial symptoms. Effects of ghrelin did not differ between obese and normal-weight participants. CONCLUSIONS: At doses that stimulate physiologic GH plasma levels, synthetic ghrelin tended to decrease fasting gastric volumes without altering postprandial volumes or gastric emptying in a predominantly female cohort. The data are not consistent with the hypothesis that higher body mass is associated with increased gastric responsiveness to ghrelin.

Levofloxacin-based triple therapy in first-line treatment for Helicobacter pylori eradication.

BACKGROUND: The standard first-line therapies for Helicobacter pylori eradication are based on clarithromycin and amoxicillin or metronidazole. Recent studies suggested levofloxacin as an alternative option for both first-and second-line H. pylori eradication treatment. AIMS: To compare efficacy and tolerability of two different 7-day standard triple therapies versus 7-day levofloxacin-based triple therapy in first-line treatment for H. pylori infection. METHODS: Three hundred consecutive H. pylori positive patients were randomized to receive: clarithromycin, amoxicillin, esomeprazole (Group A: N = 100); clarithromycin, metronidazole, esomeprazole (Group B: N = 100); or clarithromycin, levofloxacin, esomeprazole (Group C: N = 100). H. pylori status was rechecked by (13)C urea breath test 6 wk after the end of therapy. RESULTS: Sixteen out of 300 patients discontinued treatment because of the occurrence of side effects (Group A, 5; Group B, 7; Group C, 4). The eradication rates in intention to treat (ITT) and per protocol (PP) analyses were: Group A, 75% and 79%; Group B, 72% and 77.4%; and Group C, 87% and 90.6%. The eradication rate achieved with levofloxacin-based triple therapy was significantly higher than that with standard therapies in either ITT (87%vs 75%, p <0.05; 87%vs 72%, p <0.01;) or PP analysis (90.6%vs 79%, p <0.05; 90.6 vs 77.4, p <0.05). No difference was found between standard triple therapies. The incidence of side effects was similar among groups. CONCLUSIONS: A 7-day levofloxacin-based triple therapy can achieve higher H. pylori eradication rates than standard regimens. These data suggest levofloxacin-based regimens can be the most effective in first-line anti-H. pylori therapy, at least in the Italian population.

Treatments targeting putative mechanisms in irritable bowel syndrome.

The pathophysiology of irritable bowel syndrome (IBS) is heterogeneous; it is possible for several mechanisms to be disturbed in the same patient. Isolating a single target for pharmacological manipulation is also difficult because of the complexity and overlap of the neural circuitry in the enteric and central nervous system. This review summarizes the rationale and efficacy of current and future therapies for IBS, on the basis of putative pathophysiological models. The modulation of gastrointestinal sensorimotor function, intestinal gas handling, the gastrocolonic reflex, neurohormonal stress responses, central processing of afferent information, and microbial flora are the current frontiers for experimental therapeutics for IBS. Patients presumed to have POSTINFECTIOUS IBS have also been targeted as a distinct group. In the very near future, it is unlikely that a single drug will come to the fore as a suitable and successful treatment for everyone with IBS, but new data on potential therapeutic targets lend hope for the improved long-term management of IBS. Disease modification rather than just symptom-based treatments must remain the goal.

Effect of somatostatin analog on postprandial satiation in obesity.

OBJECTIVE: Altered satiation may impact postprandial symptoms and potentially change food intake in obesity. Our aim was to compare effects of octreotide and placebo on postprandial symptoms, satiation, and gastric volumes in obesity. RESEARCH METHODS AND PROCEDURES: In a randomized, parallel-group, double-blind, placebo-controlled study, 26 obese but otherwise healthy participants received 100 mug of octreotide or placebo subcutaneously 30 minutes before each study. Studies were performed on 2 separate days and included validated non-invasive techniques: (99m)Tc-single photon emission computed tomography imaging to measure fasting stomach volume and gastric volume changes after 90 mL of water and 240 mL of Ensure and a standardized nutrient drink test to measure the maximum tolerated volume and postprandial symptoms. RESULTS: Relative to placebo, octreotide increased gastric volume after 90 mL of water; however, fasting and gastric volume change post-Ensure and maximum tolerated volume of Ensure were not different. Octreotide decreased sensations of fullness (p = 0.035) and bloating (p = 0.05) and tended to reduce aggregate symptoms (p = 0.07) after the fully satiating meal. DISCUSSION: In obese individuals, somatostatin analog significantly reduced postprandial sensations after a satiating meal without altering maximum tolerated meal volume or postnutrient gastric volume, suggesting an effect on upper gut sensation. The role of somatostatin as a permissive factor in the development of obesity by reducing postprandial sensations deserves further study.

Effect of gastric volume or emptying on meal-related symptoms after liquid nutrients in obesity: a pharmacologic study.

BACKGROUND & AIMS: Altered postprandial satiation influences food intake in obesity. The aim of this study was to evaluate the contribution of gastric motor functions to intra- and postprandial symptoms in obese, otherwise healthy, people. METHODS: In a randomized, parallel-group, double-blind design, 40 obese (body mass index>30 kg/m2) healthy volunteers (n=10/group) received intravenous saline (placebo), atropine (.02 mg/kg), or erythromycin (1 or 3 mg/kg) to alter gastric volume and emptying after liquid nutrient meals, measured by validated imaging methods. The nutrient drink test assessed the volume ingested at maximum satiation, and intra- and early postprandial symptoms. Relationships between gastric motor functions, meal size, and symptoms were assessed by using multiple regression. Circulating levels of candidate upper-gut hormones involved in satiation were measured. RESULTS: Relative to placebo, atropine retarded gastric emptying and increased gastric volumes; erythromycin accelerated gastric emptying and reduced gastric volumes during fasting. Although similar maximal tolerated volumes were recorded across treatments, intra- and immediate postprandial symptoms were increased by these perturbations, particularly nausea and bloating. Upper-gut hormonal profiles generally reflected changes in gastric emptying. Regression analysis showed that fasting predrug gastric volume was a significant predictor of intra- and postprandial bloating. Change in gastric volume postdrug or postmeal did not contribute additionally to predicting intra- or postprandial symptoms. There was significant (negative) association between gastric emptying and fullness score, and significant (positive) association with hunger score 30 minutes postprandially. CONCLUSIONS: In obese individuals, fasting gastric volumes and gastric emptying, but not postprandial gastric volumes, were associated with intra- and postprandial symptoms. Understanding the determinants of gastric volume may provide insights on mechanisms controlling satiation.

Idiopathic chronic urticaria and celiac disease.

Idiopathic chronic urticaria (ICU) is a chronic relapsing cutaneous disease. Some case reports or studies on small series of celiac disease (CD) patients have suggested a possible association between CD and ICU. The aim of this study was to assess the prevalence of CD in a population of adults ICU patients with respect to healthy controls. We consecutively enrolled 80 patients affected by ICU and 264 blood donors as the control population without a history of ICU. Serum anti-transglutaminase IgG and anti-endomysium IgA antibodies were evaluated in all subjects. In the case of positivity to serology, diagnosis was confirmed by duodenal biopsy. One of 80 (1.25%) ICU patients were positive to both anti-transglutaminase and anti-endomysium antibodies. Duodenal biopsy showed partial villous atrophy. One control of 264 (0.38%) had CD. No statistical difference was found in the prevalence of CD between the two groups. ICU patients do not seem to bear a greater risk for CD compared to the general population.

Frontiers in functional dyspepsia.

Functional dyspepsia (FD) refers to unexplained pain or discomfort in the upper abdomen and is commonly seen in gastroenterology practice. The underlying pathophysiologic mechanisms associated with FD are unclear, although traditionally, delayed gastric emptying, visceral hypersensitivity to acid or mechanical distention, and impaired gastric accommodation have been implicated as putative physiologic disturbances. It also remains uncertain whether FD and irritable bowel syndrome are different presentations of the same disorder. Recent data on pathophysiologic mechanisms of FD have focused on postprandial motor disturbances (accelerated gastric emptying, antral-fundic incoordination, and abnormal phasic contractions), alterations of neurohormonal mechanisms in response to a meal, and previous acute infection. Pharmacologic therapies for FD may be guided by these novel mechanisms, as current available therapeutic options are limited. Novel prokinetics and gastric accommodation modulators, visceral analgesics, and agents targeting the neurohormonal response to food ingestion are the next therapeutic frontiers in FD. This review summarizes traditional knowledge and more recent advances in the pathophysiology of FD and potential therapeutic opportunities.

Can 13C urea breath test predict resistance to therapy in Helicobacter pylori infection?

BACKGROUND/AIMS: Results of 13C urea breath test (UBT), a noninvasive test for detecting active H. pylori infection, have been regarded also numerically for a possible predictive value on bacterial load and entity of mucosal inflammation. In the present study we wished to determine whether there is a particular value of Delta Over Baseline (DOB) result which could predict resistance to anti-H. pylori therapy. METHODOLOGY: 570 subjects from 1376 tested received a standard triple anti-H. pylori regimen. After a minimum of 6 weeks subjects underwent control UBT testing. Correlation of DOB values at diagnostic and control UBT and sensitivity of different DOB levels to predict resistance to therapy were calculated using simple linear correlation and Bayes' theorem, respectively. RESULTS: Modest linear correlation was observed between DOB values (r2=0.28). The value of 13.0 at diagnostic UBT showed a sensitivity of 65.5% to predict and further positivity at control testing. CONCLUSIONS: In our large series, UBT numerical DOB value weakly predicted resistance to first-line anti-H. pylori therapy.

Diagnostic and therapeutic use of proton pump inhibitors in non-cardiac chest pain: a metaanalysis.

OBJECTIVES: To assess (i) the efficacy of short-term proton pump inhibitors (PPIs) in non-cardiac chest pain (NCCP) and (ii) the performance of an empirical short-term treatment with PPI (PPI test) to establish a diagnosis of abnormal acid reflux in NCCP. METHODS: Metaanalysis of English language studies identified by searching MEDLINE (1966-May 2004), EMBASE (1980-May 2004), Cochrane Controlled Trials Register, and abstract books from major gastroenterology meetings (1993-2004). For the metaanalysis of PPI efficacy in NCCP, we selected randomized controlled trials (parallel group and crossover designs) comparing PPI therapy with placebo. For the metaanalysis of PPI test performance, we selected uncontrolled studies comparing the test with a standard reference. RESULTS: Eight studies were included in the PPI efficacy analysis. The pooled risk ratio for continued chest pain after PPI therapy was 0.54 (95% CI 0.41-0.71). The overall number needed to treat was 3 (95% CI 2-4). The pooled sensitivity, specificity, and diagnostic odds ratio for the PPI test versus 24-h pH monitoring and endoscopy were 80%, 74%, and 13.83 (95% CI 5.48-34.91), respectively. All studies were small and there was evidence of publication bias or other small study effects. CONCLUSION: PPI therapy reduces symptoms in NCCP and may be useful as a diagnostic test in identifying abnormal esophageal acid reflux.

Irritable bowel syndrome: epidemiology, natural history, health care seeking and emerging risk factors.

IBS is a common condition, affecting approximately 3% to 15% of the general population based on various diagnostic criteria. There seem to be differences in disease epidemiology between the eastern and the western world. As data from larger Asian epidemiological studies begin to surface,however, such differences appear to be less marked. The proportion of IBS patients who consult a physician for their symptoms is around 50%. Psychological factors and the presence and duration of abdominal pain are all significant predictors for health care seeking. The natural history of IBS is characterized by frequent fluctuation of symptoms and by an overlap with other functional GI disorders, some of which share a number of risk factors for IBS. Unnecessary abdominal surgery is performed in a high proportion of IBS sufferers. Along with the established role for psychosocial conditions in IBS, other risk factors are emerging. Evidence for postinfectious IBS is mounting, but the clinical usefulness of characterizing such patients remains unclear. Food sensitivities are frequently present in IBS, but more well-conducted trials of avoidance diets and desensitization are needed. Finally,genetic markers in IBS are an increasing focus of attention, but the amount of phenotypic variance explained by genetic variability remains to be established.