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*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.
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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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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,
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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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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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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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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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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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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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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.
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