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Alimentary Pharmacology and Therapeutics

Review article: the treatment of functional abdominal bloating and distension


M. Schmulson* & L. Chang

*Laboratory of Liver, Pancreas and Motility (HIPAM), Department of Experimental Medicine-Faculty of Medicine, Universidad Nacional Autonoma de Mexico (UNAM), Mexico. Center for Neurobiology of Stress, Division of Digestive Diseases, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.

SUMMARY Background Abdominal bloating and distension are common symptoms in patients with functional gastrointestinal disorders (FGIDs), however, relatively little is known about their treatment. Aim To review the treatment trials for abdominal bloating and distension. Methods A literature review in Medline for English-language publications through February 2010 of randomised, controlled treatment trials in adults. Study quality was assessed according to Jadads score. Results Of the 89 studies reviewed, 18% evaluated patients with functional dyspepsia, 61% with irritable bowel syndrome (IBS), 10% with chronic constipation and 10% with other FGIDs. No studies were conducted in patients diagnosed with functional abdominal bloating. The majority of trials investigated the efcacy of prokinetics or probiotics, although studies are heterogeneous with respect to diagnostic criteria and outcome measures. In general, bloating and or distension were evaluated as secondary endpoints or as individual symptoms as part of a composite score rather than as primary endpoints. A greater proportion of IBS patients with constipation reported improvement in bloating with tegaserod vs. placebo (51% vs. 40%, P < 0.0001) and lubiprostone (P < 0.001). A greater proportion of nonconstipating IBS patients reported adequate relief of bloating with rifaximin vs. placebo (40% vs. 30%, P < 0.001). Bloating was signicantly reduced with the probiotics, Bidobacterium infantis 35624 (1 108 dose vs. placebo: )0.71 vs. )0.44, P < 0.05) and B. animalis (live vs. heat-killed: )0.56 1.01 vs. )0.31 0.87, P = 0.03). Conclusions Prokinetics, lubiprostone, antibiotics and probiotics demonstrate efcacy for the treatment of bloating and or distension in certain FGIDs, but other agents have either not been studied adequately or have shown conicting results. Aliment Pharmacol Ther 2011; 33: 10711086

Correspondence to: Dr L. Chang, Center for Neurobiology of Stress, 10945 Le Conte Avenue, PVUB 2114, Los Angeles, CA 90095-6949, USA. E-mail: linchang@ucla.edu

Publication data Submitted 4 October 2010 First decision 26 October 2010 Resubmitted 8 February 2011 Accepted 3 March 2011 EV Pub Online 29 March 2011 This commissioned review article was subject to full peer-review.

2011 Blackwell Publishing Ltd doi:10.1111/j.1365-2036.2011.04637.x

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M. Schmulson and L. Chang INTRODUCTION Bloating is a common symptom that is reported by 6% to 31% of the general population.13 It is usually considered the subjective sensation that is associated with abdominal distension, i.e. the visible increase in abdominal girth,4, 5 which is considered more of an objective sign. In a population-based study in Olmsted County in the United States, the age and gender-adjusted overall prevalence for bloating was 19% and 9% for visible abdominal distension.6 Bloating is a common complaint in patients with functional gastrointestinal disorders (FGIDs). In a U.S. study of a mixed population recruited from an academic university clinic and advertisement, of 542 patients with irritable bowel syndrome (IBS), 76% of patients reported abdominal bloating.7 Moreover, in a cross-sectional study among employees of a Veterans Affairs Health Care Center in the United States, of which 39% were men, bloating was reported by 35% of individuals with nonconstipating IBS, 23% with nondiarrhoea IBS and 42% with non-investigated dyspepsia.8 However, studies suggest that while bloating and distension are related, they are two separate symptoms. For example, in the above mentioned study in an academic university clinic, 24% reported having bloating only and 76% had both bloating and visible abdominal distension.7 IBS patients with bloating and distension had a higher female-to-male ratio, constipation predominance, symptom severity and less diurnal variation compared with those with bloating only. Patients with bloating with and without distension reported that symptoms progressively worsened during the day and were relieved by defecation or gas passage.7 Approximately 50% of the subjects fullling modied Rome II criteria for dyspepsia reported bloating, while almost half of this group also had visible abdominal distension. In addition, subjects with dyspepsia were two times more likely to have bloating alone or distension alone when compared with controls.6 In another U.S. study, distension dened by the presence of both bloating and visible abdominal distension was more prevalent than bloating alone in IBS and functional dyspepsia (FD), but bloating alone was more common than distension in functional constipation.6 Bloating has been considered a secondary criterion for IBS and FD according to the Rome I classication9 and a supportive symptom for IBS in the Rome II and III diagnostic criteria.10, 11 Despite being a common symptom of several FGIDs,12 the Rome classication includes Functional Bloating as an independent entity. The name
Table 1 | Rome III Diagnostic criteria for functional bloating11
Must include both of the following: 1. Recurrent feeling of bloating or visible distension at least 3 days a month in the last 3 months 2. Insufcient criteria for FD, IBS or other FGID Criteria fullled for the last 3 months with symptom onset at least 6 months prior to diagnosis.

has changed from Functional Abdominal Bloating both in Rome I and II9, 10 to Functional Bloating in Rome III (Table 1).11 This diagnosis is made in patients with symptoms of bloating who do not meet the diagnostic criteria of IBS, FD or other FGIDs. The pathophysiological mechanisms associated with abdominal bloating and distension are poorly understood. Bloating and distension together with eructation, aerophagia and atulence, have been attributed to excessive intestinal gas accumulation.13, 14 Other proposed underlying mechanisms include impaired small intestinal handling of gas,15 impaired clearance from the proximal colon,16 psychological factors,17 uid retention,18 food intolerance and carbohydrate malabsorption,4, 19 increase in lumbar lordosis,5, 20 weakness of abdominal wall musculature,21 altered sensorimotor function,22 small intestinal bacterial overgrowth and altered gut microora.23 Although bloating and distension are very common symptoms, they are considered challenging to treat in clinical practice. Relatively little is known about the efcacy of treatments for these symptoms. Therefore, we reviewed the literature of treatment interventions for bloating and distension in patients with FGIDs.

METHODS A literature search was performed on PubMed in the Medline database using the following terms: bloating syndrome, functional abdominal bloating, abdominal bloating, bloating, abdominal distension, atulence and gases. These were combined using the AND operator, with studies identied with the following terms: therapeutics, combined modality therapy, complementary therapies, drug therapy, therapies, investigational, psychotherapy, behavior therapy, cognitive therapy, surfactants, antifoaming agents, anti-bacterial agents, antibiotics, probiotics, prebiotics, dietary supplements, pancreatic enzymes, antispasmodics and parasympatholytics. Searching limits included humans, men and women, randomised controlled trials, all adults

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Aliment Pharmacol Ther 2011; 33: 10711086 2011 Blackwell Publishing Ltd

Review: treatment of bloating and distension


aged 18 or older and English language. The search included all articles published in the past (no starting date restrictions) to a publication cut-off date of February 2010. A total of 167 articles were retrieved. The titles and abstracts were reviewed by the authors to select only those articles that analysed the effect of treatment on bloating and or distension in FGIDs, excluding those that did not meet eligibility. We also performed manual searches of reference lists from relevant articles to identify other manuscripts which may have been missed by the search strategy. Eighty-ve articles were reviewed in detail. Of these, ve were not included: one was a duplicate publication,24 two did not report the treatment response on bloating25, 26 and two could not be retrieved in full text.27, 28 There were two recently published articles that were not identied by the search, but that analysed the efcacy of renzapride and linaclotide on bloating and were therefore added.29, 30 Three additional articles were identied by manual search of references from other articles.3133 Moreover, two multicentre, placebo-controlled trials that were recently published in abstract form were also reviewed.3436 Thus, a total of 87 articles were included in the review. Two of the studies were published in full text while preparing this article, therefore their references were updated.30, 36 Of the identied articles, 63% included patients with IBS, 16% with dyspepsia, 10% with chronic constipation and 10% with symptoms of other FGIDs. There were no studies conducted in patients specically diagnosed with Functional Abdominal Bloating or Functional Bloating. We also did not identify any psychological or behavioural treatment studies that measured their efcacy on bloating or distension. The quality of reporting of each clinical trial was graded according to Jadads scale from 0 to 5.37 A score of 4 was considered to be of high quality. Accordingly, each article was assessed based on three methodological items: randomisation, concealment of treatment and intention-to-treat analysis and withdrawals. In the case of articles published in abstract form, we did not include the Jadads scale, as these formats do not provide all the necessary information. Disacharides, Monosacharides and Polyols (FODMAPs).33 Patients with IBS and fructose malabsorption who had reported symptomatic relief to a low FODMAPs diet, were re-challenged with one of four test substances: fructans, fructose, fructans and fructose, or glucose in low, medium or high doses in a crossover design study (supplementary Table S1). Bloating severity scores increased with fructans, fructose and a mixture of both in a dose dependent manner and were signicantly greater than that with glucose, suggesting the benet of the low FODMAPs diet for bloating in IBS. Antifoaming surfactants One of the earliest pharmacological treatments used to relieve bloating and distension was antifoaming agents, which are thought to alter the elasticity of the gas bubbles and ease the passage of atus (supplementary Table S1). A very small study in 41 patients with upper GI symptoms, such as heartburn, feeling fullness, bloating, gas and upset stomach, reported that simethicone was signicantly superior to placebo in decreasing the frequency and severity of gas, distension stiffness and bloating.39 A recent multicentre trial evaluated the combination of simethicone and activated charcoal in patients consulting general practitioners for abdominal fullness, bloating, nausea and slow digestion.40 Patients with diagnostic symptoms of gastro-oesophageal reux or IBS were included as long as these symptoms were not the predominant ones. However, patients with longstanding dyspepsia who had undergone endoscopic or imaging explorations within the previous 2 years were excluded. Compared with placebo, the intensity of fullness, bloating and sensation of slow digestion were signicantly decreased after 90 days with the active treatment. Antispasmodics Smooth muscle spasm has been thought to contribute to symptom generation in FGIDs and therefore antispasmodics have been used.40, 41 In many parts of the world, these agents remain the rst-line treatment for FGIDs.42 Trimebutine has been traditionally considered an antispasmodic, but its mechanism of action is not well understood. It is an opioid agonist that acts on j, l and d receptors of the enteric nervous system and modulates the release of motilin and other peptides.43 Two studies evaluated its effect on bloating in IBS (supplementary Table S1).44, 46 The rst study reported data from three trials. Two of the trials were crossover, placebo-controlled trials, but treatment durations lasted only 3 days
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RESULTS
Dietary interventions The osmotic load within the bowel lumen may contribute to abdominal distension38 and candidate substrates that are highly fermentable are poorly absorbed short chain carbohydrates called Fermentable Oligosaccharides,
Aliment Pharmacol Ther 2011; 33: 10711086 2011 Blackwell Publishing Ltd

M. Schmulson and L. Chang


with a trimebutine dose of 100 or 200 mg three times daily respectively. In the rst trial, bloating decreased with trimebutine but not with placebo and patients reported higher satisfaction with trimebutine. However, in the second trial, there was no difference in the patients preference for trimebutine or placebo, which was the studys main outcome assessment.44 The third trial compared 2 weeks of trimebutine and mebeverine (another antispasmodic with anticholinergic properties)45 in patients with mostly moderate to severe abdominal distension. Both groups reported equal improvement in abdominal distension.44 Another very small study also showed that trimebutine, but not placebo, decreased bloating and the patients treatment satisfaction scores.46 Octilonium bromide (OB) is a quaternary ammonium compound selectively acting on the smooth muscle of the distal GI tract by interfering with the Ca2+ ions necessary for the electromechanical coupling.47 An earlier, very small study found that OB signicantly reduced the severity of bloating during the 4-week treatment period compared wity placebo, but the difference was marginal at the end of the study (supplementary Table S1).48 A larger, 15-week study reported signicant but comparable reductions in distension scores for both the OB and placebo groups.49 The authors subsequently published a supplementary post hoc analysis of the same data, reporting that OB was signicantly superior to placebo in the rates of monthly (at least 2 of 4 weeks month) and weekly responses of abdominal gas and distension relief.50 Another study compared the combination of OB and a 10 to 15-g bre diet with a 20-g bre diet plus 10g bran supplement without OB over 24 months. A greater reduction in distension was demonstrated in the OB with bre group, but this was not sustained during the follow-up period.51 However, this study did not clearly state whether patients received treatment during the rst 12 months of the study and the number of patients who remained in the study during the follow-up period. A recent multinational trial in patients with IBS reported that bloating severity decreased signicantly more with OB than with placebo.34 The adverse event prole was similar in both groups and tolerability was excellent. Peppermint oil is a natural volatile oil that is considered a spasmolytic agent due to its calcium inux blocking effect.52 Two studies evaluated the efcacy of enteric coated peppermint in IBS (supplementary Table S1). One study included predominantly men (60%) with IBS and demonstrated a signicant reduction in abdominal distension in 83% of patients on peppermint oil com1074

pared to 29% of those on placebo.52 The second placebocontrolled study was conducted in IBS patients with negative lactose and lactulose breath tests and coeliac serologies and reported a signicant decrease in bloating and distension after 4 weeks of treatment for both groups, but a signicantly greater improvement with peppermint oil.53 In summary, antispasmodics have shown some efcacy in the treatment of bloating, but most of the trials included small sample sizes and analyssed the efcacy within each treatment group rather than between active treatment and placebo. In addition, the majority of these articles were of low quality. Therefore, it is difcult to make denitive conclusions on the efcacy of this family of agents. Moreover, the mechanism by which these agents can improve bloating and distension is unclear, but it is possible that they may have an analgesic effect by decreasing intestinal smooth muscle contractility. Larger studies are warranted. Bulking agents Bulking agents have been traditionally used as rst-line therapy in IBS and chronic constipation. The efcacy of ispaghula husk (psyllium) was studied in IBS patients, of which half were classied as IBS-C (supplementary Table S1). After 3 months, both ispaghula and placebo similarly decreased the frequency and severity of bloating. However, whole gut transit time decreased only with ispaghula.54 The efcacy of calcium polycarbophil, a synthetic hydrophilic colloid, was compared with placebo in a small crossover study in IBS (supplementary Table S1). At the end of the study, patients were asked to express an overall preference, and those with bloating favoured polycarbophil more strongly than placebo. However, there were no signicant differences in the bloating severity scores between those taking polycarbophil and placebo.55 Osmotic laxatives With regard to osmotic laxatives, polyethylene glycol (PEG) 3350 is an inert polymer that has shown to be nontoxic, absorbed only in trace amounts and is water soluble.56 PEG 3350 has been approved for the shortterm treatment of chronic constipation.56 Improvement of constipation would be expected to help reduce bloating and distension. The efcacy of PEG for bloating was studied in one high quality trial that included patients with chronic constipation who met Rome II criteria but were also taking medications associated with at least a 3% incidence of constipation.57 Both PEG and placebo
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relieved bloating in a similar fashion, despite the fact that 78% of the PEG-treated patients no longer met the symptom criteria for constipation vs. 39% of those on placebo (supplementary Table S2).57 Stimulants of uid secretion Lubiprostone enhances uid secretion into the gut lumen by activating the type-2 chloride channels (ClC-2) located in the apical area of the enteric epithelial cells. The activation of the ClC-2 induces the negatively charged chloride ions to enter the lumen and the positively charged sodium ions passively diffuse through the intracellular spaces to balance chloride, allowing water to follow passively into the lumen.58 Although lubiprostone at a dose of 24 mcg twice daily was shown to accelerate small intestinal and colonic transit in healthy volunteers,59 a dose of 24 mcg once daily increased the colonic motor function without a statistical signicance.60 Results of two phase 3 trials in IBS-C (supplementary Table S2), reported a signicantly greater improvement in the bloating severity score compared with baseline in the lubiprostone group than that observed in the placebo group at month 2.32 Five percent of the subjects reported nausea as an adverse event. As for chronic constipation (supplementary Table S2), patients treated with lubiprostone for 4 weeks reported signicant improvements in bloating at weeks 2 and 3 compared with those taking placebo.61 Linaclotide (MD-1100) is a novel agonist of the guanylate cyclase-C receptors on the luminal surface of intestinal enterocytes that is minimally absorbed and has shown to increase uid secretion and transit in animal models.30 Linaclotide was shown to accelerate ascending colon emptying half-time and overall colonic transit at 48 h but not overall transit at 24 h.62 In a dose-ranging, phase 2b study in chronic constipation, linaclotide significantly improved the severity of bloating.30 In addition, there was a signicantly greater proportion of patients taking linaclotide who reported a decrease in bloating compared with placebo (supplementary Table S2). However, there was not a dose-dependent effect, perhaps due to relatively low baseline scores, which decreases the ability of linaclotide to improve bloating, i.e. a oor-effect. Two phase 3 clinical trials conducted in 1272 patients with modied Rome II criteria for functional constipation that were recently published in abstract form performed within group comparisons for change in bloating severity.35 Bloating severity signicantly decreased from baseline with both the 133 and 266 mcg doses of linaclotide, but not with placebo.35
Aliment Pharmacol Ther 2011; 33: 10711086 2011 Blackwell Publishing Ltd

In summary, in studies of high quality of reporting, lubiprostone demonstrated efcacy in bloating in FGIDs with constipation. More information is needed regarding the efcacy of linaclotide on bloating compared with placebo. It is possible that the secretory properties and the ability to accelerate intestinal transit play a role in their effect on bloating symptoms. Prokinetics Disturbances in GI motility may contribute to the pathogenesis of bloating and distension by interfering with the movement of gas.5 Hence, there is a rationale for the use of prokinetics for the treatment of these symptoms. Cholinergic pathways are the main ones implicated in regulating GI motility. Neurotransmitters such as serotonin (5-HT) via 5-HT4 receptors and others acting through dopamine and motilin receptors have also been implicated.63 Dopamine antagonists. Three dopamine antagonists have been studied in dyspepsia (supplementary Table S3): (i) metoclopramide, a centrally acting dopamine antagonist that enhances the local effect of acetylcholine on the gastric smooth muscle, (ii) levosulpiride, an antagonist of central and peripheral dopamine receptors and (iii) domperidone, a peripheral dopamine antagonist.64 In a small trial in patients with dyspeptic symptoms, metoclopramide had no effect on abdominal distension.65 In patients with dysmotility-like FD, both levosulpiride and cisapride (another prokinetic agent with 5-HT4 properties), signicantly improved bloating at doses that accelerate gastric emptying in FD and gastroparesis.66 Side effects were more common with levosulpiride, but more patients with cisapride had to withdraw from the study because of side effects such as anxiety, tachycardia, dizziness and even bloating. Domperidone demonstrated a signicant improvement in the postprandial atulence symptom cluster (i.e. abdominal swelling, feeling full after a heavy meal, and eructation) when compared with baseline in patients with dyspepsia and IBS symptoms (supplementary Table S3).67 By contrast, another study conducted in IBS patients, who had symptoms that persisted for at least 6 months and were present on at least 3 days per week, reported more days per week with distension on domperidone but not with placebo. Domperidone had no signicant effect on gastric emptying, small bowel or whole gut transit times.68 Muscarinic antagonists. Acotiamide hydrochloride trihydrate is a novel gastric motility modulator that partly exerts
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its prokinetic effect by enhancing acetylcholine release via antagonism of the M1 and M2 muscarinic receptors in addition to inhibiting acetylcholinesterase activity.69 In patients with Rome II positive FD, improvement in bloating severity with acotiamide was not related to enhanced gastric emptying or accommodation or to decreased gastric sensitivity (supplementary Table S3) and therefore the underlying mechanism responsible for the effect on bloating needs to be determined.70 Two serious adverse events reported with the 50 mg three times daily dosage were biliary colic and angina pectoris. Both resolved at the end of the study and were considered unlikely related to the medication.70 5HT4 agonists. Cisapride exerts its prokinetic effect by enhancing the release of acetylcholine at the myenteric plexus and acting on 5-HT4 receptors.71, 72 It also has 5HT2 and 5-HT3 antagonist effects. Five placebo-controlled studies conducted in patients with dyspepsia in several countries,7175 evaluated the efcacy of cisapride on bloating (supplementary Table S3). Overall, cisapride appears to reduce bloating in patients with symptoms of FD. However, none of the studies were rated to be of high quality. In IBS, the efcacy of cisapride on bloating symptoms is inconsistent (supplementary Table S3). In IBS-C patients treated with cisapride 5 mg three times daily with an increase to 10 mg three times daily if there was no improvement, no differences were found in the severity of bloating compared with placebo.76 This study was rated to be of higher quality than two other studies, both of which demonstrated efcacy with cisapride. One of the two studies found that patients reported a signicant but similar improvement in bloating severity both with cisapride and placebo, but there was a greater proportion of patients without bloating with cisapride.76 The other trial in IBS-C found that distension improved with both cisapride and placebo. However, the improvement was signicantly greater with cisapride, mainly due to a greater reduction in the frequency of complete disappearance of distension.78 Taken together, cisapride appears to reduce bloating and distension in patients with FD, but there is conicting evidence on its effect on bloating in IBS-C. Tegaserod, is a selective 5-HT4 receptor partial agonist that has been shown to accelerate orocecal transit times in IBS-C patients.79 Two identical placebo-controlled trials were conducted in women with dyspepsia symptoms consisting of mid-upper abdominal discomfort characterised by at least two of the following symptoms: postprandial fullness, early satiety and or bloating.80 There was a
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signicant improvement in bloating with tegaserod vs. placebo in one of the trials but a trend for an effect in the other one (supplementary Table S3). Four placebo-controlled high quality studies8184 evaluated the efcacy of tegaserod in patients with IBS-C or IBS without diarrhoea (supplementary Table S3). These studies reported either a trend82, 83 or a signicant81, 84 improvement in bloating with tegaserod. Another study evaluated the efcacy and safety of tegaserod given during an initial and subsequent repeated treatment period in women with IBS-C.84 Patients with at least a partial response (satisfactory relief of either overall IBS symptoms or abdominal discomfort pain for 2 of the rst 4 treatment weeks) during the initial treatment period entered a treatment-free interval. During this treatmentfree interval, a gradual recurrence of symptoms occurred in some patients after both tegaserod and placebo. Patients who experienced symptom recurrence entered a repeated treatment period. Those previously treated with tegaserod were re-randomised to tegaserod or placebo for one additional month and those previously on placebo were mock randomised to tegaserod. Tegaserod was superior to placebo in relieving overall symptoms, abdominal pain discomfort and bloating during both treatment periods.84 With regard to chronic constipation, studies were more consistent in demonstrating a signicant decrease in the bothersomeness of bloating with tegaserod, but not with placebo (supplementary Table S3).8587 However, bloating and distension were also reported as adverse events in both treatment groups.86, 87 In summary, tegaserod appears to have some efcacy on bloating symptoms in various FGIDs, but the results less consistent in FD and nondiarrhoea predominant IBS as they are in chronic constipation. All of the studies were of high quality. It is important to note that tegaserod is unavailable in many parts of the world because of cardiovascular safety concerns and it is only available in certain countries under a restricted access program.88, 89 Macrolides. In patients with FD and delayed gastric emptying, an intravenous one-time dose of erythromycin (supplementary Table S3) enhanced gastric emptying for solids and liquids compared with saline. Bloating was the only meal induced symptom that improved.90 Colchicine. This agent has been evaluated in chronic constipation due to its side effect of diarrhoea. It accelerates GI motility and increases secretion.91 In a crossover design, placebo-controlled study in 16 patients with
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chronic idiopathic constipation refractory to standard medical therapy (supplementary Table S3), an increase in the number of spontaneous bowel movements with acceleration of the colonic transit was found with colchicine, but there were no differences in bloating scores compared with placebo.91 Other serotonergic agents Serotonin (5-HT) is an important neurotransmitter that modulates gut function and more than 95% in the human body is present in the enteric nervous system.63 It is considered to be involved not only in GI motility and secretion but also in visceral perception.92 Therefore, it may be related to the generation of abdominal distension and bloating. There are at least four 5-HT receptors that have been associated with the GI physiology in humans, including 5-HT1, 5-HT2, 5-HT3 and 5-HT4. In addition, several agents that target these receptors have been developed for functional and motility disorders of the GI tract.93 5-HT1 agonists. Sumatriptan is a specic 5-HT1 receptor agonist that induces relaxation of the gastric fundus in FD. In a study of 30 patients with dyspeptic symptoms and negative upper GI endoscopy, an acute subcutaneous dose with sumatriptan or placebo, administered twice 48 h apart, concluded that sumatriptan improved the gastric distension-induced nausea in both dyspeptic patients and controls, but did not reduce bloating, pain or heartburn.94 In a recent 4-week study in patients with FD and visceral hypersensitivity to gastric distension or with impaired accommodation, the 5-HT1A receptor agonist R-13769695 failed to relieve bloating (supplementary Table S4). Both studies were of low quality. 5-HT3 antagonists and others. Although 5-HT3 antagonists have demonstrated efcacy in nonconstipating IBS, they have not been shown to improve bloating.96 Ondansetron is a highly selective 5-HT3 antagonist that was assessed in patients with IBS-D (n = 28) and IBS-C (n = 20) and demonstrated no signicant effect on abdominal distension.97 In addition, three alosetron studies98100 did not show any signicant efcacy of the secondary variable of bloating in IBS patients with predominantly diarrhoea symptoms (supplementary Table S4). However, bloating is not reported to be a predominantly bothersome or severe symptom by IBS-D patients compared with IBS-C patients.101 The efcacy and safety of renzapride, a full 5-HT4 agonist, 5-HT3 antagonist and a weak partial 5-HT2b antagonist, was
Aliment Pharmacol Ther 2011; 33: 10711086 2011 Blackwell Publishing Ltd

recently assessed in a high quality, 12-week, phase 3, dose-ranging multinational trial in 1798 women with IBS-C.29 The sensation of bloating improved in all groups with a limited superiority of the 2 mg twice daily dose of renzapride over placebo (supplementary Table S4). Selective serotonin reuptake inhibitors On the basis that both psychological factors and serotonin receptors as mediators of visceral hypersensitivity and motor function are involved in the pathogenesis of FGIDs, it is plausible to believe that selective serotonin reuptake inhibitors (SSRIs) can be effective as visceral analgesics and therefore improve symptoms such as bloating.102, 103 Two high-quality, but small studies compared uoxetine with placebo in patients with IBS (supplementary Table S4). The rst study did not nd any signicant differences in the proportion of patients reporting bloating after 6 weeks of treatment compared with baseline within the uoxetine and placebo groups.102 The second one demonstrated a signicant decrease in the proportion that reported bloating interfering with daily activities with uoxetine but not placebo.103 Paroxetine was also evaluated in IBS patients who did not respond to a high bre diet. Paroxetine was considered to be effective a priori if there was the presence of at least 30% difference in the proportion of patients who reported a decrease in bloating. No difference was found with paroxetine compared with placebo.104 However, in a small randomised, crossover designed study, citalopram signicantly decreased the number of days with bloating after 3 and 6 weeks of treatment as well as the severity of bloating compared with placebo.31 Although all of these studies had a high quality of reporting, larger studies with SSRIs together with better trial designs are needed to determine the effectiveness of these agents for the treatment of bloating and distension. Notably, there were no studies identied that assessed the effect of tricyclic antidepressants on bloating distension and this needs to be explored. Opioid agents Endogenous opioids have been shown to regulate GI motility and can modulate visceral sensitivity along the digestive tract.105 In addition, opioid receptors closely interact with the 5-HT4 receptors in the enteric nervous system and opioid antagonists have synergistic effects with 5-HT4 agonists on bowel motility.106, 107 Fedotozine, a peripheral kappa receptor agonist, was studied in a dose-ranging trial in patients with FD symptoms for 6
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weeks. Compared with placebo, fedotozine at doses of 30 and 70 mg tid signicantly decreased postprandial fullness and bloating scores (supplementary Table S5).108 In a dose-ranging, placebo-controlled study in patients with IBS symptoms, 30 mg of fedotozine was superior to placebo in relieving maximal daily abdominal bloating measured as a secondary variable (supplementary Table S5).109 Naloxone is a high afnity l-opioid receptor competitive antagonist with a lower afnity for j- and d receptors. In a very small, placebo-controlled trial in IBS-C and IBS-A patients, naloxone was not associated with a signicant change in bloating scores compared with placebo (supplementary Table S5).110 The quality of reporting of these studies was good. Antidiarrhoeal agents The efcacy of antidiarrhoeals has been assessed for the treatment of IBS symptoms including bloating. For example, lidamidine is an agonist of the alpha-2 receptors located presynaptically on colonic nerves, inhibiting the release of acetylcholine. However, its main effect appears to be the inhibition of secretion rather than motility.111 A small crossover study of lidamidine vs. placebo in 62 patients with IBS and distension (IBS-D: 26%, IBS-C: 33%, IBS-A: 41%) reported no change in abdominal distension in either group (supplementary Table S5).112 Another small trial in Romania compared the efcacy of diosmectite, a natural silicate of aluminium and magnesium used as an intestinal adsorbent, with the mu receptor agonist loperamide, in patients with functional diarrhoea. Diosmectite, but not loperamide, reduced bloating severity (supplementary Table S5).113 Antibiotics Based on the presumption that the production of the so called gas-related symptoms is either from bacterial fermentation of carbohydrates in the colon, altered gut ora or small bowel bacterial overgrowth (SIBO), it is reasonable to hypothesise that antibiotics can relieve bloating and distension.4 Rifaximin is an antibiotic that lacks intestinal absorption and is highly active even against anaerobes.114 The efcacy of rifaximin vs. activated charcoal was tested in a group of 34 patients with FGIDs according to Rome I criteria. Although the specic disorders were not described, the patients complained of excessive passage of atus, bloating, abdominal discomfort or pain not explained by structural or biochemical abnormalities.115 Rifaximin at a dose of 400 mg twice daily, but not charcoal, signicantly reduced the H2 excretion on the lactulose hydrogen breath test and over1078

all severity of symptoms (supplementary Table S6). While rifaximin was associated with a reduction in the mean number of atus episodes and abdominal girth, there was no change in bloating.115 By contrast, in a larger study by Sharara et al.116 of 124 patients with predominantly bloating and excessive atulence with negative lactulose hydrogen breath tests, rifaximin at a dose of 400 mg twice daily was associated with signicant global symptom relief and reduction in bloating scores compared with placebo (supplementary Table S6). In the subset of seventy patients who fullled criteria for IBS, rifaximin was also superior to placebo in relieving bloating. In a study conducted in IBS patients by Pimentel et al.,117 rifaximin at a dose of 400 mg three times daily for 10 days was superior to placebo in reducing the bloating severity score during the 10-week follow-up period (supplementary Table S6). This improvement remained after controlling for the higher baseline abdominal pain in the rifaximin group. Two recently completed phase 3 multicentre trials compared the efcacy of rifaximin at a dose of 550 mg three times daily and placebo for 14 days in patients with nonconstipating IBS.36 Adequate relief of IBS symptom of bloating was a key secondary endpoint. The pooled results showed that a signicantly greater proportion of patients taking rifaximin reported adequate relief of bloating than those taking placebo (40% vs. 30%). These studies suggest that rifaximin improves bloating in patients with FGIDs. Probiotics, prebiotics and symbiotics Colonic bacteria can generate intestinal gas through fermentation of undigested materials, therefore, an imbalance in gut microbiota may produce or exacerbate bloating or distension.118 Some bacterial groups are more prone to gas production than others, including Enterobacteriaceae and Clostridia,119 and to abnormal patterns of short chain fatty acids.120 Hence, modication of the microbiota may improve gas-related symptoms. Probiotics are dened by the World Health Organization as live micro-organisms that when administered in adequate amounts confer a health benet on the host.121 They are nonpathogenic microbial food supplements of human origin that enter the GI tract in an active form improving its intestinal microbial balance and can have positive effects on gut physiology and immunology.122 Prebiotics are nondigestible food ingredients that benecially affect the host by promoting the growth and improving survival of probiotics residing in the colon. Prebiotics include oligosaccharides (OS) and fructooligosaccharides
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(FOS). Finally, symbiotics are the combination of probiotics and prebiotics.123 Several probiotics, prebiotics and symbiotics have been evaluated in FGIDs and some studies have assessed their efcacy for bloating and distension. Probiotics Lactobacillus. One placebo-controlled study conducted in IBS patients showed a benecial effect on bloating, while three other studies did not (supplementary Table S6). Lactobacillus casei strain GG showed no effect vs. placebo in IBS patients complaining of abdominal distension.118 Similarly, L. plantarum administered in a rose-hip drink mixed with an oatmeal soup in patients with IBS reportedly had no effect on bloating, but the data were not shown.124 Lactobacillus reuteri, a major component of lactobacillus that can decrease the intestinal pH to a level that is unfavourable to most pathogenic bacteria, signicantly improved all analysed variables over time in IBS patients but there were no differences in bloating compared with placebo.125 Lactobacillus sporogenes Bacillus coagulans (Bc) has been used in food preparation products and it is classied as a lactic acid bacillus.126 IBS patients allocated to Bc GBI-30 6086, but not placebo, with higher baseline severity scores for bloating signicantly achieved improvement during all 7-weekly comparisons.127 Compared with placebo, L. casei Shirota failed to demonstrate differences in the occurrence or degree of bloating compared with baseline in patients with chronic constipation (supplementary Table S6).128 The same probiotic was studied in adults not fullling criteria for any GI diagnosis and found no difference in the Gastrointestinal Symptoms Rating Scale (GSRS)-atus score but there was a trend in the distension subscore (supplementary Table S6). There was also no difference in the Severity of Dyspepsia Assessment (SODA)-bloating subscore.129 Bidobacterium spp. Two studies have demonstrated the efcacy of B. infantis 35624 for bloating, atulence and or distension in IBS patients irrespective of the bowel habit subtype (supplementary Table S6).130, 131 Bidobacterium animalis DN-173 010 has been shown to decrease orocecal and colonic transit times.132 In a large scale, controlled, 6-week trial in 267 primary care patients with IBS-C, both live and heat-killed B. animalis DN-173 010 signicantly improved bloating; however, the effect was greater with live B. animalis DN-173 010 at the third week. The authors speculated that heat-killed
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probiotic may not be a true placebo and may have therapeutic properties that could have inuenced the high placebo response.133 Fermented milk containing B. lactis DN-173 010 was studied in women with minor GI symptoms but without any specic disorder.134 Compared with controls, the B. lactis DN-173 010 group reported greater improvements in the general well-being and frequency of atulence but not in bloating (supplementary Table S6). Probiotic mixtures. Kajander et al.135 hypothesised that a mixture of probiotics could show greater efcacy than a single probiotic in IBS, because of its multifactorial aetiology. They compared the efcacy of a mixture that included L. rhamnosus GG, L. rhamnosus LC705, B. breve 99 and Propionibacterium freudenreichii ssp. shermanii JS with placebo in IBS (supplementary Table S6). The benecial effects of these lactobacillus spp. includes immunomodulation and prevention and treatment of diarrhoea, while Propionibacterium can alleviate constipation.136, 137 During the 6-month treatment period, patients were allowed to continue their previous IBS medications (bre supplements, laxatives, antidiarrhoeals, antispasmodics, antiatulence agents and or antidepressants). At the end of the trial, the total symptom score that included abdominal pain, distension, atulence and borborygmi was signicantly lower with the probiotics vs. placebo, with a median reduction of 42% vs. 6% respectively. However, there was no difference in the individual symptom of distension (supplementary Table S6).135 Two studies evaluated the effectiveness of VSL#3, a mixture containing strains of three lyophilised species, Bidobacterium, Lactobacillus and Streptococcus (supplementary Table S6). In the rst study conducted in IBS-D patients, there was a signicant reduction in bloating scores compared with baseline with VSL#3, but there was only a trend compared with placebo.138 In a second study in patients with signicant bloating, there was no signicant difference in the reduction of bloating with VSL#3 or placebo.139 Because of the difculty in enrolling patients, only half completed the 8-week trial and a third completed only 4 weeks.139 In summary, the efcacy of probiotics on bloating symptoms has not been consistently demonstrated. Most of the studies are relatively small and there is variability in the quality of reporting. However, in high quality studies, B. infantis 35624 and B. animalis appear to have potential efcacy while Lactobacillus spp., B. lactis and VSL#3 do not.
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Prebiotics Fructooligosaccharides are nondigestible OS that are rapidly fermented into short-chain fatty acids in the colon, mainly by bidobacteria, promoting the growth of the bacteria and stimulating colonic peristalsis.140 Compared with placebo, FOS had no signicant effect on distension in IBS patients and those on FOS complained more of atulence.140 The quality of reporting in this study was good. A novel prebiotic, B-GOS, composed of transgalactooligosaccharide mixture produced from the activity of galactosyltransferase from B. bidum NCIMB 41171 on lactose, was recently evaluated in a pilot study in IBS. After 4 weeks, the prebiotic, particularly at the higher dose, signicantly enhanced faecal bidobacteria, evaluated by uorescent in situ hybridisation using synthetic oligonucleotide probes. Bloating improved with the 3.5 g day dose but worsened with 7.0 g day (supplementary Table S6). This study had a low quality of reporting.141 Symbiotics A study in IBS-A patients analysed the efcacy of SCMIII, a preparation of L. acidophilus, L. helveticus and bidobacteria in a vitamin and phytoextracts-enriched medium, compared with the same dosage of the heat inactivated symbiotic which served as the control.142 SCM-III signicantly improved the intensity of the bloating sensation compared with baseline and the control preparation at 6 weeks but was not distinguishable from the control arm at 12 weeks (supplementary Table S6). The quality of this study was rated as low. In patients with symptoms of FGIDs, but who did not meet criteria for any of the specic FGIDs diagnosis, the efcacy of ve combinations of intestinal microora fermented in substrates from whole plants, plants juices and minerals were explored, but no conclusive evidence on their efcacy could be made (supplementary Table S6).126 Complementary and alternative medicine Herbal remedies. Carmint, a herbal medicine that is thought to have antispasmodic, carminative and sedative effects, was studied in a relatively small, but high quality IBS study (supplementary Table S7). Although bloating severity and frequency decreased with carmint compared with placebo, the confounding effect of other medications was not taken into account in this trial.143 In another high quality study, Saito et al.144 compared the efcacy of the herbal remedy St Johns Wort and placebo on bloating in IBS patients. The effect of St. Johns Wort on bloating was not signicantly different than placebo. Also, a Tibetan blend of 15 herbs was studied in IBS and
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showed a within group improvement in the percentage of patients reporting moderate to severe abdominal distension at 12 weeks with this formula, but there was no difference compared with placebo.145 Finally, moxibustion is a traditional Chinese medicine in which the moxa leaf is pulverised and processed into a stick and then lit and held over specic acupuncture points to warm them and stimulate blood ow and energy. It was used in conjunction with acupuncture in a small study in IBS.146 A composite score that included bloating improved 52% with moxibustion vs. 1.7% with sham placebo.146 Although this study was designed according to the 2001 version of the Consolidated Standards of Reporting Trials (CONSORT)147 and the 2002 Standards for Reporting Interventions in Controlled Trial of Acupunture (STRICTA) guidelines,148 it only had an intermediate quality of reporting (supplementary Table S7). Other therapies Melatonin is a sleep promoting agent that is largely secreted in the GI tract.149, 150 It is involved in the digestive pathophysiology, but the exact mechanism of action by which it regulates the gastrointestinal motility is not well understood.151 Because sleep disturbances are common in IBS and melatonin can regulate sleep as well as the bowel function, it has been studied in this disorder. However, melatonin did not produce any effects on bloating in patients with IBS and sleep disturbances, although it decreased abdominal pain and increased the rectal pain thresholds without inuencing the sleep parameters.152 In addition, a pilot study in IBS showed that hypnotherapy was superior to placebo in improving the mean weekly distension score. This difference reached signicance by the fourth week of treatment.153 Taking into consideration the higher female prevalence of FGIDs such as FD, IBS and constipation-related symptoms,154, 155 and increased bloating at the time of menses,156 it has been suggested that ovarian hormones play a role in these symptoms. The efcacy of leuprolide acetate, a gonadotropin-releasing hormone, in relieving GI symptoms including bloating was assessed in two studies comparing 3 or 4 months treatment with 3.75 mg intramuscular administration vs. placebo.157, 158 The studies were conducted in women with symptoms of nausea, vomiting, early satiety, anorexia, bloating and distension that were unresponsive to conventional therapies. The rst trial reported that leuprolide signicantly improved the bloating score compared with baseline while placebo did not. The second trial showed similar improvements in both groups (supplementary Table S7).
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Review: treatment of bloating and distension CONCLUSIONS To the best of our knowledge, this is the rst comprehensive review on the treatment of bloating and distension. We have found that at least two-thirds of the studies were conducted in IBS patients in whom these symptoms were evaluated as secondary variables. Less than 5% of the treatment trials were performed in patients specically complaining of bloating and or distension. Therefore, the studies may not have been sufciently powered to detect signicant differences in bloating and distension. In addition, many of the earlier trials performed within group analyses of efcacy and not between group analyses and therefore no denitive conclusions can be drawn from their results. More importantly, the optimal patient reported outcome measures to detect a treatment response for bloating and visible abdominal distension have yet to be determined. Moreover, it seems highly likely that there is publication bias and negative trials are less likely to be published, particularly with respect to symptoms that are subjective and secondary outcome measures such as bloating and distension. The large majority of trials investigated the efcacy of prokinetics and probiotics and the studies are heterogeneous in terms of the patient population, diagnostic criteria for the FGIDs and outcome measures. The available evidence suggests that currently there is no treatment that has unequivocally proven to be effective for abdominal bloating or distension. Overall, some efcacy has been demonstrated with 5HT4 agonists (cisapride in FD and tegaserod in chronic constipation and IBS-C), lubiprostone in both chronic constipation and IBS-C, rifaximin in patients with predominantly bloating, as well as in IBS and certain probiotics such as Bifantis 35624 and B. animalis. While there are inconsistent results with the other therapies, most have not been evaluated in welldesigned, appropriately sized trials that have employed rigorous statistical analyses or in well-characterised patient populations. Future studies need to develop valid patient reported endpoints for bloating and distension, evaluate these symptoms as primary outcome measures and determine predictors of treatment response. ACKNOWLEDGEMENTS Declaration of personal interests: Dr Schmulson has served as a consultant for Procter and Gamble, Novartis and Schering-Plough. He has served as a speaker for Nycomed, Schering-Plough, Novartis and Mayoli-Spindler, and has received research funding from Nycomed and Nestle. Dr Chang has served as a consultant for Takeda, Forest, Rose Pharma, GlaxoSmithKline, Ironwood, Salix, Ocera and Movetis. She has received research funding from Takeda, Rose Pharma and Prometheus. Declaration of funding interests: This study was supported in part by grant PAPIIT, IN-210010 of DGAPA, Universidad Nacional Autonoma de Mexico (UNAM). SUPPORTING INFORMATION Additional Supporting Information may be found in the online version of this article: Table S1. Dietary interventions, antifoaming and bulking agents for the treatment of bloating and distension. Table S2. Osmotic laxatives and stimulants of uid secretion for the treatment of bloating and distension. Table S3. Prokinetics for the treatment of bloating and distension. Table S4. Other serotoninergic agents and SSRIs for the treatment of bloating and distension. Table S5. Opioid agonists and antidiarrhoeal agents for the treatment of bloating and distension. Table S6. Antibiotics, probiotics, prebiotics and symbiotics for the treatment of bloating and distension. Table S7. Complementary and alternative medicine and other therapies for the treatment of bloating and distension. Please note: Wiley-Blackwell are not responsible for the content or functionality of any supporting materials supplied by the authors. Any queries (other than missing material) should be directed to the corresponding author for the article.

REFERENCES
1. Heaton KW, ODonnell LJ, Braddon FE, Mountford RA, Hughes AO, Cripps PJ. Symptoms of irritable bowel syndrome in a British urban community: consulters and nonconsulters. Gastroenterology 1992; 102: 19627.
Aliment Pharmacol Ther 2011; 33: 10711086 2011 Blackwell Publishing Ltd

2. Sandler RS, Stewart WF, Liberman JN, Ricci JA, Zorich NL. Abdominal pain, bloating, and diarrhea in the United States: prevalence and impact. Dig Dis Sci 2000; 45: 116671.

3. Talley NJ, Boyce P, Jones M. Identication of distinct upper and lower gastrointestinal symptom groupings in an urban population. Gut 1998; 42: 6905.

1081

M. Schmulson and L. Chang


4. Zar S, Benson MJ, Kumar D. Review article: bloating in functional bowel disorders. Aliment Pharmacol Ther 2002; 16: 186776. 5. Azpiroz F, Malagelada JR. Abdominal bloating. Gastroenterology 2005; 129: 106078. 6. Jiang X, Locke GR 3rd, Choung RS, Zinsmeister AR, Schleck CD, Talley NJ. Prevalence and risk factors for abdominal bloating and visible distention: a population-based study. Gut 2008; 57: 75663. 7. Chang L, Lee OY, Naliboff B, Schmulson M, Mayer EA. Sensation of bloating and visible abdominal distension in patients with irritable bowel syndrome. Am J Gastroenterol 2001; 96: 33417. 8. Tuteja AK, Talley NJ, Joos SK, Tolman KG, Hickam DH. Abdominal bloating in employed adults: prevalence, risk factors, and association with other bowel disorders. Am J Gastroenterol 2008; 103: 12418. 9. Thompson WG, the working team for Functional Gastrointestinal Disorders. Functional bowel disorders and functional abdominal pain. In: Drossman DA, Richter JE, Talley NJ, Thompson WG, Corazziari E, Whitehead WE, eds. The Functional Gastrointestinal Disorders, 1st ed. Boston New York Toronto London: Little, Brown and Co, 1994; 11573. 10. Thompson WG, Longstreth GF, Drossman DA, et al. Functional bowel disorders and functional abdominal pain. Gut 1999; 45(Suppl. 2): II437. 11. Longstreth GF, Thompson WG, Chey WD, Houghton LA, Mearin F, Spiller RC. Functional bowel disorders. In: Drossman DA, Corazziari E, Delvaux M, Spiller RC, Talley NJ, Thompson WG, Whitehead WE, eds. Rome III: The Functional Gastrointestinal Disorders, 3rd ed. Lawrence, KS: Allen Press, Inc., 2006; 487556. 12. Drossman DA, Li Z, Andruzzi E, et al. US householder survey of functional gastrointestinal disorders. Prevalence, sociodemography, and health impact. Dig Dis Sci 1993; 38: 156980. 13. Jones M. Bloating and intestinal gas. Curr Treat Options Gastroenterol 2005; 8: 3118. 14. Serra J, Azpiroz F, Malagelada JR. Mechanisms of intestinal gas retention in humans: impaired propulsion versus obstructed evacuation. Am J Physiol Gastrointest Liver Physiol 2001; 281: G13843. 15. Serra J, Azpiroz F, Malagelada JR. Impaired transit and tolerance of intestinal gas in the irritable bowel syndrome. Gut 2001; 48: 149. 16. Hernando-Harder AC, Serra J, Azpiroz F, et al. Colonic responses to gas loads in subgroups of patients with abdominal bloating. Am J Gastroenterol 2010; 10: 87682. 17. Song JY, Merskey H, Sullivan S, Noh S. Anxiety and depression in patients with abdominal bloating. Can J Psychiatry 1993; 38: 4759. 18. Sullivan SN. Functional abdominal bloating. J Clin Gastroenterol 1994; 19: 237. 19. Haderstorfer B, Psycholgin D, Whitehead WE, Schuster MM. Intestinal gas production from bacterial fermentation of undigested carbohydrate in irritable bowel syndrome. Am J Gastroenterol 1989; 84: 3758. 20. Maxton DG, Martin DF, Whorwell PJ, Godfrey M. Abdominal distension in female patients with irritable bowel syndrome: exploration of possible mechanisms. Gut 1991; 32: 6624. 21. Accarino A, Perez F, Azpiroz F, Quiroga S, Malagelada JR. Abdominal distention results from caudo-ventral redistribution of contents. Gastroenterology 2009; 136: 154451. 22. Houghton LA, Whorwell PJ. Towards a better understanding of abdominal bloating and distension in functional gastrointestinal disorders. Neurogastroenterol Motil 2005; 17: 50011. 23. Lin HC. Small intestinal bacterial overgrowth: a framework for understanding irritable bowel syndrome. JAMA 2004; 292: 8528. 24. Baldi F, Longanesi A, Blasi A, et al. Octylonium bromide in the treatment of the irritable bowel syndrome: a clinicalfunctional study. Hepatogastroenterology 1992; 39: 3925. 25. Fidelholtz J, Smith W, Rawls J, et al. Safety and tolerability of tegaserod in patients with irritable bowel syndrome and diarrhea symptoms. Am J Gastroenterol 2002; 97: 117681. 26. Mangel AW, Chaturvedi P. Evaluation of Crofelemer in the treatment of diarrheapredominant irritable bowel syndrome patients. Digestion 2008; 78: 1806. 27. Corazza GR, Biagi F, Albano O, et al. Levosulpiride in functional dyspepsia: a multicentric, double-blind, controlled trial. Ital J Gastroenterol 1996; 28: 317 23. 28. Piai G, Mazzacca G. Prinium bromide in the treatment of the irritable colon syndrome. Gastroenterology 1979; 77: 5002. 29. Lembo AJ, Cremonini F, Meyers N, Hickling R. Clinical trial: renzapride treatment of women with irritable bowel syndrome and constipation a double-blind, randomized, placebo-controlled, study. Aliment Pharmacol Ther 2010; 31: 97990. 30. Lembo AJ, Kurtz CB, Macdougall JE, et al. Efcacy of linaclotide for patients with chronic constipation. Gastroenterology 2010; 138: 88695. 31. Tack J, Broekaert D, Fischler B, Van Oudenhove L, Gevers AM, Janssens J. Acontrolled crossover study of the selective serotonin reuptake inhibitor citalopram in irritable bowel syndrome. Gut 2006; 55: 1095103. 32. Drossman DA, Chey WD, Johanson JF, et al. Clinical trial: lubiprostone in patients with constipation-associated irritable bowel syndrome results of two randomized, placebo-controlled studies. Aliment Pharmacol Ther 2009; 29: 32941. 33. Shepherd SJ, Parker FC, Muir JG, Gibson PR. Dietary triggers of abdominal symptoms in patients with irritable bowel syndrome: randomized placebocontrolled evidence. Clin Gastroenterol Hepatol 2008; 6: 76571. 34. Tack OB. Otilonium bromide improves and delays time to post-treatment relapse in irritable bowel syndrome. Gastroenterology 2010; 138(Suppl. 1): S223. 35. Lembo A, Schneider H, Lavins BJ, et al. Efcacy and safety of once daily linaclotide administered orally for 12 weeks in patients with chronic constipation: results from 2 randomized, double blind, placebo-controlled phase 3 trials. Gastroenterology 2010; 138(Suppl. 1): S534. 36. Pimentel M, Lembo A, Chey WD, et al. Rifaximin therapy for patients with irritable bowel syndrome without constipation. N Engl J Med 2011; 364: 2232. 37. Jadad AR, Moore RA, Carroll D, et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials 1996; 17: 112. 38. Robayo-Torres CC, Quezada-Calvillo R, Nichols BL. Disaccharide digestion: clinical and molecular aspects. Clin Gastroenterol Hepatol 2006; 4: 27687. 39. Bernstein JE, Kasich AM. A doubleblind trial of simethicone in functional disease of the upper gastrointestinal tract. J Clin Pharmacol 1974; 14: 617 23. 40. Lecuyer M, Cousin T, Monnot MN, Cofn B. Efcacy of an activated charcoal-simethicone combination in dyspeptic syndrome: results of a randomized prospective study in general practice. Gastroenterol Clin Biol 2009; 33: 47884. 41. Ford AC, Talley NJ, Spiegel BM, et al. Effect of bre, antispasmodics, and peppermint oil in the treatment of irritable bowel syndrome: systematic review and meta-analysis. BMJ 2008; 337: A2313.

1082

Aliment Pharmacol Ther 2011; 33: 10711086 2011 Blackwell Publishing Ltd

Review: treatment of bloating and distension


42. Quigley E, Fried M, Gwee KA, et al. Irritable Bowel Syndrome: A Global Perspective. World Gastroenterology Organization Global Guidelines. Available at: http://www.worldgastroenterology.org/ irritable-bowel-syndrome.html. 43. Delvaux M, Wingate D. Trimebutine: mechanism of action, effects on gastrointestinal function and clinical results. J Int Med Res 1997; 25: 22546. 44. Luttecke K. A three-part controlled study of trimebutine in the treatment of irritable colon syndrome. Curr Med Res Opin 1980; 6: 43743. 45. Darvish-Damavandi M, Nikfar S, Abdollahi M. A systematic review of efcacy and tolerability of mebeverine in irritable bowel syndrome. World J Gastroenterol 2010; 16: 54753. 46. Dumitrascu DL, Stanculete M. The effect of trimebutine on the psychosocial adjustment to illness in the irritable bowel syndrome. Rom J Intern Med 2006; 44: 27380. 47. Maggi CA, Manzini S, Meli A. Octylonium bromide: a smooth muscle relaxant which interferes with calcium ions mobilization. Arch Int Pharmacodyn Ther 1983; 264: 30523. 48. Baldi F, Longanesi A, Blasi A, et al. Clinical and functional evaluation of the efcacy of otilonium bromide: a multicenter study in Italy. Ital J Gastroenterol 1991; 23(Suppl. 1): 603. 49. Battaglia G, Morselli-Labate AM, Camarri E, et al. Otilonium bromide in irritable bowel syndrome: a double-blind, placebo-controlled, 15-week study. Aliment Pharmacol Ther 1998; 12: 100310. 50. Glende M, Morselli-Labate AM, Battaglia G, Evangelista S. Extended analysis of a double-blind, placebo-controlled, 15-week study with otilonium bromide in irritable bowel syndrome. Eur J Gastroenterol Hepatol 2002; 14: 13318. 51. Villagrasa M, Boix J, Humbert P, Quer JC. Aleatory clinical study comparing otilonium bromide with a ber-rich diet in the treatment of irritable bowel syndrome. Ital J Gastroenterol 1991; 23(Suppl. 1): 6770. 52. Liu JH, Chen GH, Yeh HZ, Huang CK, Poon SK. Enteric-coated peppermint-oil capsules in the treatment of irritable bowel syndrome: a prospective, randomized trial. J Gastroenterol 1997; 32: 7658. 53. Cappello G, Spezzaferro M, Grossi L, Manzoli L, Marzio L. Peppermint oil (Mintoil) in the treatment of irritable bowel syndrome: aprospective double blind placebo-controlled randomized trial. Dig Liver Dis 2007; 39: 5306. 54. Prior A, Whorwell PJ. Double blind study of ispaghula in irritable bowel syndrome. Gut 1987; 28: 15103. 55. Toskes PP, Connery KL, Ritchey TW. Calcium polycarbophil compared with placebo in irritable bowel syndrome. Aliment Pharmacol Ther 1993; 7: 8792. 56. DiPalma JA, DeRidder PH, Orlando RC, Kolts BE, Cleveland MB. A randomized, placebo-controlled, multicenter study of the safety and efcacy of a new polyethylene glycol laxative. Am J Gastroenterol 2000; 95: 44650. 57. DiPalma JA, Cleveland MB, McGowan J, Herrera JL. A comparison of polyethylene glycol laxative and placebo for relief of constipation from constipating medications. South Med J 2007; 100: 108590. 58. Cuppoletti J, Malinowska DH, Tewari KP, et al. SPI-0211 activates T84 cell chloride transport and recombinant human ClC-2 chloride currents. Am J Physiol Cell Physiol 2004; 287: C117383. 59. Camilleri M, Bharucha AE, Ueno R, et al. Effect of a selective chloride channel activator, lubiprostone, on gastrointestinal transit, gastric sensory, and motor functions in healthy volunteers. Am J Physiol Gastrointest Liver Physiol 2006; 290: G9427. 60. Sweetser S, Busciglio IA, Camilleri M, et al. Effect of a chloride channel activator, lubiprostone, on colonic sensory and motor functions in healthy subjects. Am J Physiol Gastrointest Liver Physiol 2009; 296: G295301. 61. Johanson JF, Morton D, Geenen J, Ueno R. Multicenter, 4-week, doubleblind, randomized, placebo-controlled trial of lubiprostone, a locally-acting type-2 chloride channel activator, in patients with chronic constipation. Am J Gastroenterol 2008; 1031: 1707. 62. Andresen V, Camilleri M, Busciglio IA, et al. Effect of 5 days linaclotide on transit and bowel function in females with constipation-predominant irritable bowel syndrome. Gastroenterology 2007; 133: 7618. 63. Sanger GJ. Translating 5-HT receptor pharmacology. Neurogastroenterol Motil 2009; 21: 12358. 64. Tonini M, Cipollina L, Poluzzi E, Crema F, Corazza GR, De Ponti F. Review article: clinical implications of enteric and central D2 receptor blockade by antidopaminergic gastrointestinal prokinetics. Aliment Pharmacol Ther 2004; 19: 37990. 65. Johnson AG. Controlled trial of metoclopramide in the treatment of atulent dyspepsia. Br Med J 1971; 2: 256. 66. Mearin F, Rodrigo L, Perez-Mota A, et al. Levosulpiride and cisapride in the treatment of dysmotility-like functional dyspepsia: a randomized, doublemasked trial. Clin Gastroenterol Hepatol 2004; 2: 3018. 67. Milo R. Use of the peripheral dopamine antagonist, domperidone, in the management of gastro-intestinal symptoms in patients with irritable bowel syndrome. Curr Med Res Opin 1980; 6: 57784. 68. Cann PA, Read NW, Holdsworth CD. Oral domperidone: double blind comparison with placebo in irritable bowel syndrome. Gut 1983; 24: 113540. 69. Doi Y, Murasaki O, Kaibara M, et al. Characterization of functional effects of Z-338, a novel gastroprokinetic agent, on the muscarinic M1, M2, and M3 receptors expressed in Xenopus oocytes. Eur J Pharmacol 2004; 505: 315. 70. Tack J, Masclee A, Heading R, et al. A dose-ranging, placebo-controlled, pilot trial of Acotiamide in patients with functional dyspepsia. Neurogastroenterol Motil 2009; 21: 27280. 71. Champion MC, MacCannell KL, Thomson AB, et al. A double-blind randomized study of cisapride in the treatment of nonulcer dyspepsia. The Canadian Cisapride Nud Study Group. Can J Gastroenterol 1997; 11: 12734. 72. Kellow JE, Cowan H, Shuter B, et al. Efcacy of cisapride therapy in functional dyspepsia. Aliment Pharmacol Ther 1995; 9: 15360. 73. Chung JM. Cisapride in chronic dyspepsia: results of a double-blind, placebocontrolled trial. Scand J Gastroenterol Suppl 1993; 195: 114. 74. Al-Quorain A, Larbi EB, al-Shedoki F. A double-blind, randomized, placebocontrolled trial of cisapride in Saudi Arabs with functional dyspepsia. Scand J Gastroenterol 1995; 30: 5314. 75. Chen JD, Ke MY, Lin XM, Wang Z, Zhang M. Cisapride provides symptomatic relief in functional dyspepsia associated with gastric myoelectrical abnormality. Aliment Pharmacol Ther 2000; 14: 10417. 76. Farup PG, Hovdenak N, Wetterhus S, Lange OJ, Hovde O, Trondstad R. The symptomatic effect of cisapride in patients with irritable bowel syndrome and constipation. Scand J Gastroenterol 1998; 33: 12831. 77. Schutze K, Brandstatter G, Dragosics B, Judmaier G, Hentschel E. Double-blind study of the effect of cisapride on constipation and abdominal discomfort as components of the irritable bowel syndrome. Aliment Pharmacol Ther 1997; 11: 38794. 78. Van Outryve M, Milo R, Toussaint J, Van Eeghem P. Prokinetic treatment of constipation-predominant irritable bowel syndrome: a placebo-controlled study of cisapride. J Clin Gastroenterol 1991; 13: 4957.

Aliment Pharmacol Ther 2011; 33: 10711086 2011 Blackwell Publishing Ltd

1083

M. Schmulson and L. Chang


79. Prather CM, Camilleri M, Zinsmeister AR, McKinzie S, Thomforde G. Tegaserod accelerates orocecal transit in patients with constipation-predominant irritable bowel syndrome. Gastroenterology 2000; 118: 4638. 80. Vakil N, Laine L, Talley NJ, et al. Tegaserod treatment for dysmotility-like functional dyspepsia: results of two randomized, controlled trials. Am J Gastroenterol 2008; 103: 190619. 81. Muller-Lissner SA, Fumagalli I, Bard han KD, et al. Tegaserod, a 5-HT(4) receptor partial agonist, relieves symptoms in irritable bowel syndrome patients with abdominal pain, bloating and constipation. Aliment Pharmacol Ther 2001; 15: 165566. 82. Novick J, Miner P, Krause R, et al. A randomized, double-blind, placebocontrolled trial of tegaserod in female patients suffering from irritable bowel syndrome with constipation. Aliment Pharmacol Ther 2002; 16: 187788. 83. Kellow J, Lee OY, Chang FY, et al. An Asia-Pacic, double blind, placebo controlled, randomised study to evaluate the efcacy, safety, and tolerability of tegaserod in patients with irritable bowel syndrome. Gut 2003; 52: 6716. 84. Tack J, Muller-Lissner S, Bytzer P, et al. A randomised controlled trial assessing the efcacy and safety of repeated tegaserod therapy in women with irritable bowel syndrome with constipation. Gut 2005; 54: 170713. 85. Johanson JF, Wald A, Tougas G, et al. Effect of tegaserod in chronic constipation: a randomized, double-blind, controlled trial. Clin Gastroenterol Hepatol 2004; 2: 796805. 86. Kamm MA, Muller-Lissner S, Talley NJ, et al. Tegaserod for the treatment of chronic constipation: a randomized, double-blind, placebo-controlled multinational study. Am J Gastroenterol 2005; 100: 36272. 87. On Chan AO, Mo Hui W, Leung G, Hu WH, Lam SK, Wong BC. Efcacy of tegaserod for functional constipation in Chinese subjects: a randomized double-blind controlled trial in a single centre. Aliment Pharmacol Ther 2007; 25: 4639. 88. Brandt LJ. The FDAs decision-making process: isnt it time to temper the principle of protective paternalism? Am J Gastroenterol 2008; 103: 12267. 89. Thompson CA. Novartis suspends tegaserod sales at FDAs request. Am J Health Syst Pharm 2007; 64: 1020. 90. Arts J, Caenepeel P, Verbeke K, Tack J. Inuence of erythromycin on gastric emptying and meal related symptoms in functional dyspepsia with delayed gastric emptying. Gut 2005; 54: 45560.
1084

91. Verne GN, Eaker EY, Davis RH, Sninsky CA. Colchicine is an effective treatment for patients with chronic constipation: an open-label trial. Dig Dis Sci 1997; 42: 195963. 92. Bueno L, de Ponti F, Fried M, et al. Serotonergic and non-serotonergic targets in the pharmacotherapy of visceral hypersensitivity. Neurogastroenterol Motil 2007; 19(Suppl. 1): 89119. 93. Gershon M, Tack J. The serotonin signalling system: from basic understanding to drug development for functional GI disorders. Gastroenterology 2007; 132: 397414. 94. Malatesta MG, Fascetti E, Ciccaglione AF, et al. 5-HT1-receptor agonist sumatriptan modies gastric size after 500 ml of water in dyspeptic patients and normal subjects. Dig Dis Sci 2002; 47: 25915. 95. Tack J, Van Den Elzen B, Tytgat G, et al. A placebo-controlled trial of the 5-HT1A agonist R-137696 on symptoms, visceral hypersensitivity and on impaired accommodation in functional dyspepsia. Neurogastroenterol Motil 2009; 21: 61926. 96. Ford AC, Brandt LJ, Young C, Chey WD, Foxx-Orenstein AE, Moayyedi P. Efcacy of 5-HT3 antagonists and 5HT4 agonists in irritable bowel syndrome: systematic review and metaanalysis. Am J Gastroenterol 2009; 104: 183143. 97. Maxton DG, Morris J, Whorwell PJ. Selective 5-hydroxytryptamine antagonism: a role in irritable bowel syndrome and functional dyspepsia? Aliment Pharmacol Ther 1996; 10: 5959. 98. Camilleri M, Chey WY, Mayer EA, et al. A randomized controlled clinical trial of the serotonin type 3 receptor antagonist alosetron in women with diarrhea-predominant irritable bowel syndrome. Arch Intern Med 2001; 161: 173340. 99. Chey WD, Chey WY, Heath AT, et al. Long-term safety and efcacy of alosetron in women with severe diarrheapredominant irritable bowel syndrome. Am J Gastroenterol 2004; 99: 2195203. 100. Chang L, Ameen VZ, Dukes GE, McSorley DJ, Carter EG, Mayer EA. A dose-ranging, phase II study of the efcacy and safety of alosetron in men with diarrhea-predominant IBS. Am J Gastroenterol 2005; 100: 11523. 101. Schmulson M, Lee OY, Chang L, Naliboff B, Mayer EA. Symptom differences in moderate to severe IBS patients based on predominant bowel habit. Am J Gastroenterol 1999; 94: 292935. 102. Kuiken SD, Tytgat GN, Boeckxstaens GE. The selective serotonin reuptake inhibitor uoxetine does not change rectal sensitivity and symptoms in

patients with irritable bowel syndrome: a double blind, randomized, placebocontrolled study. Clin Gastroenterol Hepatol 2003; 1: 21928. 103. Vahedi H, Merat S, Rashidioon A, Ghoddoosi A, Malekzadeh R. The effect of uoxetine in patients with pain and constipation-predominant irritable bowel syndrome: a double-blind randomized-controlled study. Aliment Pharmacol Ther 2005; 22: 3815. 104. Tabas G, Beaves M, Wang J, Friday P, Mardini H, Arnold G. Paroxetine to treat irritable bowel syndrome not responding to high-ber diet: a doubleblind, placebo-controlled trial. Am J Gastroenterol 2004; 99: 91420. 105. Corazziari E. Role of opioid ligands in the irritable bowel syndrome. Can J Gastroenterol 1999; 13(Suppl. A): 71A5A. 106. De Luca A, Coupar IM. Insights into opioid action in the intestinal tract. Pharmacol Ther 1996; 69: 10315. 107. Foxx-Orenstein AE, Jin JG, Grider JR. 5HT4 receptor agonists and delta-opioid receptor antagonists act synergistically to stimulate colonic propulsion. Am J Physiol 1998; 275(5 Pt 1): G97983. 108. Fraitag B, Homerin M, Hecketsweiler P. Double-blind dose-response multicenter comparison of fedotozine and placebo in treatment of nonulcer dyspepsia. Dig Dis Sci 1994; 39: 10727. 109. Dapoigny M, Abitbol JL, Fraitag B. Efcacy of peripheral kappa agonist fedotozine versus placebo in treatment of irritable bowel syndrome. A multicenter dose-response study. Dig Dis Sci 1995; 40: 22449. 110. Hawkes ND, Rhodes J, Evans BK, Rhodes P, Hawthorne AB, Thomas GA. Naloxone treatment for irritable bowel syndrome a randomized controlled trial with an oral formulation. Aliment Pharmacol Ther 2002; 16: 164954. 111. Doherty NS, Hancock AA. Role of alpha-2 adrenergic receptors in the control of diarrhea and intestinal motility. J Pharmacol Exp Ther 1983; 225: 26974. 112. Prior A, Wilson KM, Whorwell PJ. Double-blind study of an alpha 2 agonist in the treatment of irritable bowel syndrome. Aliment Pharmacol Ther 1988; 2: 5359. 113. Dumitrascu DL, Stanculete M, Mitrea I, Dumitrascu DM, Farcas A. The effect of two antidiarrhoeal drugs on the psychosocial adjustment to illness in chronic functional diarrhoea. Rom J Intern Med 2004; 42: 1917. 114. Fumi AL, Trexler K. Rifaximin treatment for symptoms of irritable bowel syndrome. Ann Pharmacother 2008; 42: 40812. 115. Di Stefano M, Strocchi A, Malservisi S, Veneto G, Ferrieri A, Corazza GR. Nonabsorbable antibiotics for managing
Aliment Pharmacol Ther 2011; 33: 10711086 2011 Blackwell Publishing Ltd

Review: treatment of bloating and distension


intestinal gas production and gas-related symptoms. Aliment Pharmacol Ther 2000; 14: 10018. 116. Sharara AI, Aoun E, Abdul-Baki H, Mounzer R, Sidani S, Elhajj I. A randomized double-blind placebo-controlled trial of rifaximin in patients with abdominal bloating and atulence. Am J Gastroenterol 2006; 101: 32633. 117. Pimentel M, Park S, Mirocha J, Kane SV, Kong Y. The effect of a nonabsorbed oral antibiotic (rifaximin) on the symptoms of the irritable bowel syndrome: a randomized trial. Ann Intern Med 2006; 17: 145. 118. OSullivan MA, OMorain CA. Bacterial supplementation in the irritable bowel syndrome. A randomized double-blind placebo-controlled crossover study. Dig Liver Dis 2000; 32: 294301. 119. King TS, Elia M, Hunter JO. Abnormal colonic fermentation in irritable bowel syndrome. Lancet 1998; 352: 11879. 120. Treem WR, Shoup ME, Hale DE, et al. Acute fatty liver of pregnancy, hemolysis, elevated liver enzymes, and low platelets syndrome, and long chain 3hydroxyacyl-coenzyme Adehydrogenase deciency. Am J Gastroenterol 1996; 91: 2293300. 121. FAO WHO (2002). Guidelines for the Evaluation of Probiotics in Food. Joint working group report on drafting guidelines for the evaluation of probiotics in food. Available at: http://www.who.int/ foodsafety/publications/fs_management/ probiotics2/en. 122. Schrezenmeir J, de Vrese M. Probiotics, prebiotics, and synbiotics approaching a denition. Am J Clin Nutr 2001; 73(Suppl. 2): 361S4S. 123. Gibson GR, Roberfroid MB. Dietary modulation of the human colonic microbiota: introducing the concept of prebiotics. J Nutr 1995; 125: 140112. 124. Nobaek S, Johansson ML, Molin G, Ah rne S, Jeppsson B. Alteration of intestinal microora is associated with reduction in abdominal bloating and pain in patients with irritable bowel syndrome. Am J Gastroenterol 2000; 95: 12318. 125. Niv E, Naftali T, Hallak R, Vaisman N. The efcacy of Lactobacillus reuteri ATCC 55730 in the treatment of patients with irritable bowel syndromea double blind, placebo-controlled, randomized study. Clin Nutr 2005; 24: 92531. 126. Kim LS, Hilli L, Orlowski J, Kupperman JL, Baral M, F Waters R. Efcacy of probiotics and nutrients in functional gastrointestinal disorders: a preliminary clinical trial. Dig Dis Sci 2006; 51: 213444. 127. Hun L. Bacillus coagulans signicantly improved abdominal pain and bloating in patients with IBS. Postgrad Med 2009; 121: 11924. 128. Koebnick C, Wagner I, Leitzmann P, Stern U, Zunft HJ. Probiotic beverage containing Lactobacillus casei Shirota improves gastrointestinal symptoms in patients with chronic constipation. Can J Gastroenterol 2003; 17: 6559. 129. Kalman DS, Schwartz HI, Alvarez P, Feldman S, Pezzullo JC, Krieger DR. A prospective, randomized, double-blind, placebo-controlled parallel-group dual site trial to evaluate the effects of a Bacillus coagulans-based product on functional intestinal gas symptoms. BMC Gastroenterol 2009; 9: 85. 130. Whorwell PJ, Altringer L, Morel J, et al. Efcacy of an encapsulated probiotic Bidobacterium infantis 35624 in women with irritable bowel syndrome. Am J Gastroenterol 2006; 101: 158190. 131. OMahony L, McCarthy J, Kelly P, et al. Lactobacillus and bidobacterium in irritable bowel syndrome: symptom responses and relationship to cytokine proles. Gastroenterology 2005; 128: 54151. 132. Pochart P, Marteau P, Bouhnik Y, Goderel I, Bourlioux P, Rambaud JC. Survival of Bidobacteria ingested via fermented milk during their passage through the human small intestine: an in vivo study using intestinal perfusion. Am J Clin Nutr 1992; 55: 7880. 133. Guyonnet D, Chassany O, Ducrotte P, et al. Effect of a fermented milk containing Bidobacterium animalis DN173 010 on the health-related quality of life and symptoms in irritable bowel syndrome in adults in primary care: a multicentre, randomized, doubleblind,controlled trial. Aliment Pharmacol Ther 2007; 26: 47586. 134. Guyonnet D, Schlumberger A, Mhamdi L, Jakob S, Chassany O. Fermented milk containing Bidobacterium lactis DN-173 010 improves gastrointestinal well-being and digestive symptoms in women reporting minordigestive symptoms: a randomised, double-blind, parallel, controlled study. Br J Nutr 2009; 102: 165462. 135. Kajander K, Hatakka K, Poussa T, Farkkila M, Korpela R. A probiotic mixture alleviates symptoms in irritable bowel syndrome patients: a controlled 6-month intervention. Aliment Pharmacol Ther 2005; 22: 38794. 136. Huang JS, Bousvaros A, Lee JW, Diaz A, Davidson EJ. Efcacy of probiotic use in acute diarrhea in children: a meta-analysis. Dig Dis Sci 2002; 47: 262534. 137. Ouwehand AC, Lagstrom H, Suomalainen T, Salminen S. Effect of probiotics on constipation, fecal azoreductase activity and fecal mucin content in the elderly. Ann Nutr Metab 2002; 46: 15962. 138. Kim HJ, Camilleri M, McKinzie S, et al. A randomized controlled trial of a probiotic, VSL#3, on gut transit and symptoms in diarrhoea-predominant irritable bowel syndrome. Aliment Pharmacol Ther 2003; 17: 895904. 139. Kim HJ, Vazquez Roque MI, Camilleri M, et al. A randomized controlled trial of a probiotic combination VSL# 3 and placebo in irritable bowel syndrome with bloating. Neurogastroenterol Motil 2005; 17: 68796. 140. Olesen M, Gudmand-Hoyer E. Efcacy, safety, and tolerability of fructooligosaccharides in the treatment of irritable bowel syndrome. Am J Clin Nutr 2000; 72: 15705. 141. Silk DB, Davis A, Vulevic J, Tzortzis G, Gibson GR. Clinical trial: the effects of a trans-galactooligosaccharide prebiotic on faecal microbiota and symptoms in irritable bowel syndrome. Aliment Pharmacol Ther 2009; 29: 50818. 142. Tsuchiya J, Barreto R, Okura R, Kawakita S, Fesce E, Marotta F. Single-blind followup study on the effectiveness of a symbiotic preparation in irritable bowel syndrome. Chin J Dig Dis 2004; 5: 16974. 143. Vejdani R, Shalmani HR, Mir-Fattahi M, et al. The efcacy of an herbal medicine, Carmint, on the relief of abdominal pain and bloating in patients with irritable bowel syndrome: a pilot study. Dig Dis Sci 2006; 51: 15017. 144. Saito YA, Rey E, Almazar-Elder AE, et al. A randomized, double-blind, placebo-controlled trial of St Johns Word for treating irritable bowel syndrome. Am J Gastroenterol 2010; 105: 1707. 145. Sallon S, Ben-Arye E, Davidson R, Shapiro H, Ginsberg G, Ligumsky M. A novel treatment for constipation-predominant irritable bowel syndrome using Padma Lax, a Tibetan herbal formula. Digestion 2002; 65: 16171. 146. Anastasi JK, McMahon DJ, Kim GH. Symptom management for irritable bowel syndrome: a pilot randomized controlled trial of acupuncture moxibustion. Gastroenterol Nurs 2009; 32: 24355. 147. Altman DG, Schulz KF, Moher D, et al. The revised CONSORT statement for reporting randomized trials: explanation and elaboration. Ann Intern Med 2001; 134: 66394. 148. MacPherson H, White A, Cummings M, et al. Standards for reporting interventions in controlled trials of acupuncture: the STRICTA recommendations. J Altern Complement Med 2002; 8: 859.

Aliment Pharmacol Ther 2011; 33: 10711086 2011 Blackwell Publishing Ltd

1085

M. Schmulson and L. Chang


149. Kunz D, Mahlberg R, Muller C, Til mann A, Bes F. Melatonin in patients with reduced REM sleep duration: two randomized controlled trials. J Clin Endocrinol Metab 2004; 89: 12834. 150. Bubenik GA. Thirty four years since the discovery of gastrointestinal melatonin. J Physiol Pharmacol 2008; 59(Suppl. 2): 3351. 151. Thor PJ, Krolczyk G, Gil K, Zurowski D, Nowak L. Melatonin and serotonin effects on gastrointestinal motility. J Physiol Pharmacol 2007; 58(Suppl. 6): 97103. 152. Song GH, Leng PH, Gwee KA, Moochhala SM, Ho KY. Melatonin improves abdominal pain in irritable bowel syndrome patients who have sleep disturbances: a randomised, double blind, placebo controlled study. Gut 2005; 54: 14027. 153. Whorwell PJ, Prior A, Faragher EB. Controlled trial of hypnotherapy in the treatment of severe refractory irritable-bowel syndrome. Lancet 1984; 2: 12324. 154. Schmulson M, Adeyemo M, GutierrezReyes G, et al. Differences in gastrointestinal symptoms according to gender in Rome II positive IBS and dyspepsia in a Latin American population. Am J Gastroenterol 2010; 105: 92532. 155. Adeyemo MA, Spiegel BM, Chang L. Meta-analysis: do irritable bowel syndrome symptoms vary between men and women? Aliment Pharmacol Ther 2010; 32: 73855. 156. Heitkemper MM, Chang L. Do uctuations in ovarian hormones affect gastrointestinal symptoms in women with irritable bowel syndrome? Gend Med 2009; 6(Suppl. 2): 15267. 157. Mathias JR, Clench MH, Reeves-Darby VG, et al. Effect of leuprolide acetate in patients with moderate to severe functional bowel disease. Double-blind, placebo-controlled study. Dig Dis Sci 1994; 39: 115562. 158. Mathias JR, Clench MH, Abell TL, et al. Effect of leuprolide acetate in treatment of abdominal pain and nausea in premenopausal women with functional bowel disease: a double-blind, placebocontrolled, randomized study. Dig Dis Sci 1998; 43: 134755.

1086

Aliment Pharmacol Ther 2011; 33: 10711086 2011 Blackwell Publishing Ltd