Aliment Pharmacol Ther 2011; 33: 1071–1086
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 Jadad’s 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 efficacy 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 significantly reduced with the probiotics, Bifidobacterium 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 efficacy for the treatment of bloating and/or distension in certain FGIDs, but other agents have either not been studied adequately or have shown conflicting results.
Bloating is a common symptom that is reported by 6% to 31% of the general population.1–3 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 fulfilling modified 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 defined 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 classification9 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 classification includes Functional Bloating as an independent entity. The name 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.
|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. Insufficient criteria for FD, IBS or other FGID|
The pathophysiological mechanisms associated with abdominal bloating and distension are poorly understood. Bloating and distension together with eructation, aerophagia and flatulence, 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 fluid 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 microflora.23
Although bloating and distension are very common symptoms, they are considered challenging to treat in clinical practice. Relatively little is known about the efficacy of treatments for these symptoms. Therefore, we reviewed the literature of treatment interventions for bloating and distension in patients with FGIDs.
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’, ‘flatulence’ and ‘gases’. These were combined using the AND operator, with studies identified 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 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-five articles were reviewed in detail. Of these, five 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 identified by the search, but that analysed the efficacy of renzapride and linaclotide on bloating and were therefore added.29, 30 Three additional articles were identified by manual search of references from other articles.31–33 Moreover, two multicentre, placebo-controlled trials that were recently published in abstract form were also reviewed.34–36 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 identified 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 specifically diagnosed with Functional Abdominal Bloating or Functional Bloating. We also did not identify any psychological or behavioural treatment studies that measured their efficacy on bloating or distension.
The quality of reporting of each clinical trial was graded according to Jadad’s 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 Jadad’s scale, as these formats do not provide all the necessary information.
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, 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 significantly greater than that with glucose, suggesting the benefit of the low FODMAPs diet for bloating in IBS.
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 flatus (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 significantly 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 reflux or IBS were included as long as these symptoms were not the predominant ones. However, patients with long-standing 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 significantly decreased after 90 days with the active treatment.
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 first-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 κ, μ and δ 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 first study reported data from three trials. Two of the trials were crossover, placebo-controlled trials, but treatment durations lasted only 3 days with a trimebutine dose of 100 or 200 mg three times daily respectively. In the first 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 study’s 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 significantly 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 significant 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 significantly 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 fibre diet with a 20-g fibre diet plus 10-g bran supplement without OB over 24 months. A greater reduction in distension was demonstrated in the OB with fibre 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 first 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 significantly more with OB than with placebo.34 The adverse event profile 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 influx blocking effect.52 Two studies evaluated the efficacy of enteric coated peppermint in IBS (supplementary Table S1). One study included predominantly men (60%) with IBS and demonstrated a significant reduction in abdominal distension in 83% of patients on peppermint oil compared to 29% of those on placebo.52 The second placebo-controlled study was conducted in IBS patients with negative lactose and lactulose breath tests and coeliac serologies and reported a significant decrease in bloating and distension after 4 weeks of treatment for both groups, but a significantly greater improvement with peppermint oil.53
In summary, antispasmodics have shown some efficacy in the treatment of bloating, but most of the trials included small sample sizes and analyssed the efficacy 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 difficult to make definitive conclusions on the efficacy 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 have been traditionally used as first-line therapy in IBS and chronic constipation. The efficacy of ispaghula husk (psyllium) was studied in IBS patients, of which half were classified 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 efficacy 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 significant differences in the bloating severity scores between those taking polycarbophil and placebo.55
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 short-term treatment of chronic constipation.56 Improvement of constipation would be expected to help reduce bloating and distension. The efficacy 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 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 fluid secretion
Lubiprostone enhances fluid 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 significance.60 Results of two phase 3 trials in IBS-C (supplementary Table S2), reported a significantly 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 significant 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 fluid 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 significantly 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 ‘floor-effect’. Two phase 3 clinical trials conducted in 1272 patients with modified 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 significantly decreased from baseline with both the 133 and 266 mcg doses of linaclotide, but not with placebo.35
In summary, in studies of high quality of reporting, lubiprostone demonstrated efficacy in bloating in FGIDs with constipation. More information is needed regarding the efficacy 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.
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), significantly 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 significant improvement in the ‘postprandial flatulence’ 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 significant 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 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 5-HT2 and 5-HT3 antagonist effects. Five placebo-controlled studies conducted in patients with dyspepsia in several countries,71–75 evaluated the efficacy 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 efficacy 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 efficacy with cisapride. One of the two studies found that patients reported a significant 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 significantly 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 conflicting 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 significant 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 studies81–84 evaluated the efficacy of tegaserod in patients with IBS-C or IBS without diarrhoea (supplementary Table S3). These studies reported either a trend82, 83 or a significant81, 84 improvement in bloating with tegaserod. Another study evaluated the efficacy 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 first 4 treatment weeks) during the initial treatment period entered a treatment-free interval. During this treatment-free 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 significant decrease in the bothersomeness of bloating with tegaserod, but not with placebo (supplementary Table S3).85–87 However, bloating and distension were also reported as adverse events in both treatment groups.86, 87
In summary, tegaserod appears to have some efficacy 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 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 specific 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 efficacy 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 significant effect on abdominal distension.97 In addition, three alosetron studies98–100 did not show any significant efficacy 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 efficacy and safety of renzapride, a full 5-HT4 agonist, 5-HT3 antagonist and a weak partial 5-HT2b antagonist, was 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 fluoxetine with placebo in patients with IBS (supplementary Table S4). The first study did not find any significant differences in the proportion of patients reporting bloating after 6 weeks of treatment compared with baseline within the fluoxetine and placebo groups.102 The second one demonstrated a significant decrease in the proportion that reported bloating interfering with daily activities with fluoxetine but not placebo.103 Paroxetine was also evaluated in IBS patients who did not respond to a high fibre 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 significantly 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 identified that assessed the effect of tricyclic antidepressants on bloating/distension and this needs to be explored.
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 weeks. Compared with placebo, fedotozine at doses of 30 and 70 mg tid significantly 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 affinity μ-opioid receptor competitive antagonist with a lower affinity for κ- and δ receptors. In a very small, placebo-controlled trial in IBS-C and IBS-A patients, naloxone was not associated with a significant change in bloating scores compared with placebo (supplementary Table S5).110 The quality of reporting of these studies was good.
The efficacy 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 efficacy 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
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 flora 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 efficacy of rifaximin vs. activated charcoal was tested in a group of 34 patients with FGIDs according to Rome I criteria. Although the specific disorders were not described, the patients complained of excessive passage of flatus, 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, significantly reduced the H2 excretion on the lactulose hydrogen breath test and overall severity of symptoms (supplementary Table S6). While rifaximin was associated with a reduction in the mean number of flatus 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 flatulence with negative lactulose hydrogen breath tests, rifaximin at a dose of 400 mg twice daily was associated with significant global symptom relief and reduction in bloating scores compared with placebo (supplementary Table S6). In the subset of seventy patients who fulfilled 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 efficacy 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 significantly 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, modification of the microbiota may improve gas-related symptoms. Probiotics are defined by the World Health Organization as live micro-organisms that when administered in adequate amounts confer a health benefit 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 beneficially affect the host by promoting the growth and improving survival of probiotics residing in the colon. Prebiotics include oligosaccharides (OS) and fructooligosaccharides (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 efficacy for bloating and distension.
Lactobacillus. One placebo-controlled study conducted in IBS patients showed a beneficial 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.124Lactobacillus reuteri, a major component of lactobacillus that can decrease the intestinal pH to a level that is unfavourable to most pathogenic bacteria, significantly improved all analysed variables over time in IBS patients but there were no differences in bloating compared with placebo.125Lactobacillus sporogenes/Bacillus coagulans (Bc) has been used in food preparation products and it is classified as a lactic acid bacillus.126 IBS patients allocated to Bc GBI-30 6086, but not placebo, with higher baseline severity scores for bloating significantly 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 fulfilling criteria for any GI diagnosis and found no difference in the Gastrointestinal Symptoms Rating Scale (GSRS)-flatus 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
Bifidobacterium spp. Two studies have demonstrated the efficacy of B. infantis 35624 for bloating, flatulence and/or distension in IBS patients irrespective of the bowel habit subtype (supplementary Table S6).130, 131Bifidobacterium 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 significantly improved bloating; however, the effect was greater with live B. animalis DN-173 010 at the third week. The authors speculated that heat-killed probiotic may not be a true placebo and may have therapeutic properties that could have influenced the high ‘placebo’ response.133 Fermented milk containing B. lactis DN-173 010 was studied in women with minor GI symptoms but without any specific disorder.134 Compared with controls, the B. lactis DN-173 010 group reported greater improvements in the general well-being and frequency of flatulence but not in bloating (supplementary Table S6).
Probiotic mixtures. Kajander et al.135 hypothesised that a mixture of probiotics could show greater efficacy than a single probiotic in IBS, because of its multifactorial aetiology. They compared the efficacy 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 beneficial 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 (fibre supplements, laxatives, antidiarrhoeals, antispasmodics, antiflatulence agents and/or antidepressants). At the end of the trial, the total symptom score that included abdominal pain, distension, flatulence and borborygmi was significantly 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, Bifidobacterium, Lactobacillus and Streptococcus (supplementary Table S6). In the first study conducted in IBS-D patients, there was a significant 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 significant bloating, there was no significant difference in the reduction of bloating with VSL#3 or placebo.139 Because of the difficulty in enrolling patients, only half completed the 8-week trial and a third completed only 4 weeks.139
In summary, the efficacy 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 efficacy while Lactobacillus spp., B. lactis and VSL#3 do not.
Fructooligosaccharides are nondigestible OS that are rapidly fermented into short-chain fatty acids in the colon, mainly by bifidobacteria, promoting the growth of the bacteria and stimulating colonic peristalsis.140 Compared with placebo, FOS had no significant effect on distension in IBS patients and those on FOS complained more of flatulence.140 The quality of reporting in this study was good. A novel prebiotic, B-GOS, composed of trans-galactooligosaccharide mixture produced from the activity of galactosyltransferase from B. bifidum NCIMB 41171 on lactose, was recently evaluated in a pilot study in IBS. After 4 weeks, the prebiotic, particularly at the higher dose, significantly enhanced faecal bifidobacteria, evaluated by fluorescent 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
A study in IBS-A patients analysed the efficacy of SCM-III, a preparation of L. acidophilus, L. helveticus and bifidobacteria 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 significantly 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 specific FGIDs diagnosis, the efficacy of five combinations of intestinal microflora fermented in substrates from whole plants, plants juices and minerals were explored, but no conclusive evidence on their efficacy 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 efficacy of the herbal remedy St John’s Wort and placebo on bloating in IBS patients. The effect of St. John’s Wort on bloating was not significantly different than placebo. Also, a Tibetan blend of 15 herbs was studied in IBS and 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 specific acupuncture points to warm them and stimulate blood flow 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).
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 influencing 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 significance 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 efficacy 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 first trial reported that leuprolide significantly improved the bloating score compared with baseline while placebo did not. The second trial showed similar improvements in both groups (supplementary Table S7).
To the best of our knowledge, this is the first 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 specifically complaining of bloating and/or distension. Therefore, the studies may not have been sufficiently powered to detect significant differences in bloating and distension. In addition, many of the earlier trials performed within group analyses of efficacy and not between group analyses and therefore no definitive 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 efficacy 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 efficacy 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 well-designed, 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.
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 Autónoma de México (UNAM).