What do Cochrane systematic reviews say about the management of irritable bowel syndrome?

ABSTRACT BACKGROUND: Irritable bowel syndrome (IBS) is a clinical disorder associated with high socioeconomic burden. Despite its importance, management of IBS remains difficult and several interventions have been hypothesized as beneficial for this condition. This study identified and summarized all Cochrane systematic reviews (SRs) about the effects of interventions for managing IBS patients. DESIGN AND SETTING: Review of systematic reviews, carried out in the Discipline of Evidence-Based Medicine, Escola Paulista de Medicina (EPM), Universidade Federal de São Paulo (UNIFESP). METHODS: Review of Cochrane SRs addressing interventions for IBS. RESULTS: We included six SRs assessing acupuncture, bulking agents, antispasmodics, antidepressants, herbal medicines, homeopathy, hypnotherapy and psychological therapy for IBS. The certainty of evidence ranged from unknown to moderate, mainly due to imprecision in the estimates and high risk of bias from the primary studies included. There was moderate certainty of evidence that acupuncture had no important benefit regarding improvement of symptoms and quality of life, compared with sham acupuncture. There was also very low certainty of evidence that homeopathic asafoetida, used alone or in association with nux, was better than placebo regarding self-reported overall improvement. CONCLUSION: There was moderate certainty of evidence that acupuncture had no important benefit regarding improvement of symptoms and quality of life. Further well-designed and well-conducted randomized clinical trials are needed in order to reduce the uncertainties regarding the most commonly used interventions for patients with IBS.

interventions. 9 In some cases, practical recommendations are made on the basis of low levels of clinical evidence, relating only to hypothesized aspects of the pathophysiology of the condition. 9 Since IBS is a highly prevalent condition associated with a heavy socioeconomic burden, systematic reviews addressing interventions for treating this condition are needed in order to guide decision-making. Cochrane systematic reviews are considered to provide reliable evidence and are a useful tool for healthcare providers and patients.

OBJECTIVE
To summarize and present the evidence from Cochrane systematic reviews assessing interventions for management of irritable bowel syndrome patients.

Design and setting
This was a review of Cochrane systematic reviews (SRs) car-

Types of studies
We included only the latest published version of Cochrane systematic reviews (SRs). We excluded all protocols, or any SR marked as "withdrawn" in the Cochrane Database of Systematic Reviews (CDSR).

Types of participants
We considered any participant who had been diagnosed with irritable bowel syndrome, as determined through the criteria of the original review authors. Reviews addressing irritable bowel syndrome and also other clinical situations were included only if the subset of data relating to irritable bowel syndrome participants was provided separately.

Types of intervention
We considered any pharmacological or non-pharmacological intervention for therapeutic purposes, compared with placebo, no intervention or any other intervention.

Type of outcomes
We considered the clinical and laboratory outcomes that had already been considered by the SR authors. When multiple outcomes were presented, we chose the primary safety and effectiveness outcomes or the most clinically relevant outcomes, to present in the current review.

Search for reviews
We performed a systematic search in the Cochrane Database of Systematic Reviews (via Wiley) on December 4, 2018. The search strategy is fully depicted in Table 1.

Selection of systematic reviews
The selection process was performed by two authors, who independently screened all titles and abstracts retrieved through the electronic search. The authors checked whether the abstracts thus retrieved fulfilled the inclusion criteria and decided whether to include or exclude them. Any disagreements in the selection process were resolved through reaching a consensus.

Presentation of the results
We produced a synthesis and presented the following characteristics relating to the reviews that were included: PICOs (population, intervention, comparator and outcomes), objectives, methods, main results, risk of bias from the original studies and certainty of evidence through the GRADE approach; 10 along with the conclusions from the authors of the SRs that were included.

Search results
The initial search retrieved 78 abstracts of systematic reviews (SRs). After the selection process, six SRs were found to fulfill our inclusion criteria and were included in the analysis. [11][12][13][14][15][16] Results from systematic reviews The six SRs included assessed the effects of conventional interventions (bulking agents, antispasmodics and antidepressants) and non-conventional interventions (acupuncture, herbal medicines, homeopathy, psychological therapy and hypnotherapy) for participants with irritable bowel syndrome (IBS). The main findings from the SRs included, and the quality of the evidence (based on the GRADE approach), 10 are detailed in Table 2. A brief summary of each SR is presented below.

Acupuncture
It has been hypothesized that acupuncture may have effects on the visceral system through stimulating the somatic system, thereby improving symptoms in patients with IBS. This SR 11 assessed the effects of acupuncture on IBS and included 17 randomized clinical trials (RCTs) with 1806 participants. Acupuncture was compared with no intervention, sham intervention (placebo for acupuncture) and pharmacological interventions.

Acupuncture versus pharmacological treatment
• Proportion of participants with symptom improvement: higher for acupuncture group (risk ratio, RR 1.28; 95% CI 1.12 to 1.45; 5 RCTs; 449 participants; low certainty of evidence). This outcome was assessed through dichotomization of the scales considered in each RCT, in which a cutoff point was established to decide whether participants had experienced an "improvement". Likewise, the SR authors found an improvement in this same outcome favoring acupuncture over no specific treatment (RR 2.11; 95% CI 1.18 to 3.79; two RCTs; 118 participants).
Adverse events were reported in nine RCTs. In one RCT, it was reported that one participant had withdrawn due to syncope, while in eight RCTs, no serious adverse events were reported.
The authors of this SR concluded that acupuncture did not provide any benefit for treating IBS patients, compared with sham treatment. Acupuncture seemed to be better than pharmacological interventions or no intervention, but this finding would need to be interpreted with caution and would need to be explored through further RCTs. The fact that the trials were not blinded increased the risk of bias in subjective outcomes such as "symptom improvement". For further details and to access all the analyses, refer to the original abstract, available from: https://www. cochranelibrary.com/cdsr/doi/10.1002/14651858.CD005111.pub3/full.

Bulking agents, antispasmodics and antidepressants
This SR 12    Continue... *GRADE (Grading of Recommendations Assessment, Development and Evaluation) has the aim of assessing the certainty of the body of evidence. From this, the outcomes are classified as having high certainty (high confidence that the estimated effect is close to the true effect); moderate certainty (likely that the estimated effect is close to the real effect, but there is a possibility that it is not); low certainty (limited confidence in the effect estimate) or very low certainty (the true effect is likely to be substantially different from the estimate effect). **For further information about specific types of herbal therapy, refer to the relevant text in the "Results" section of this paper. IBS = irritable bowel syndrome; NA = not assessed; RCTs = randomized clinical trials. Subgroup analyses for different types of antispasmodics found that use of cimetropium/dicyclomine, peppermint oil, pinaverium and trimebutine presented statistically significant benefits.

Herbal medicines
Herbal therapies are commonly used for many clinical conditions and it has been hypothesized that these could have benefits for IBS patients. This SR 13 assessed the effects of herbal medicines on management of IBS and included 75 RCTs (7957 participants). The methodological quality of three RCTs was high, but the overall quality of the remaining RCTs was low. Seventy-one different herbal medicines were tested alone or in combination with conventional therapy, and were compared with placebo or conventional pharmacological therapy.

Herbal medicines versus conventional therapy
In 65 RCTs in which 51 different herbal medicines were tested, 22 herbal medicines resulted in statistically significant symptom improvement and 29 herbal medicines were not significantly different from conventional therapy.

Herbal medicines combined with conventional therapy versus conventional therapy alone
In nine RCTs in which herbal medicine combined with conventional therapy was evaluated, six showed that there was additional benefit from the combination therapy, compared with conventional monotherapy.

Homeopathy
This SR 14 assessed the effects of homeopathy for treating IBS patients and included three RCTs (213 participants).

Asafoetida versus placebo
Asafoetida is a substance derived from the roots of perennial

Hypnotherapy
Hypnotherapy has been reported to have beneficial effects for managing symptoms. This SR 15 had the aim of assessing the effects of hypnotherapy for patients with IBS. Four RCTs (147 participants) were included, but no meta-analysis was performed, due to clinical and methodological heterogeneity between the studies.
No differences between the interventions were found in relation to frequency of bowel motions (12 months), proportion of subjects with bloating, frequency of bowel motion and abdominal pain.

Hypnotherapy plus pharmacological treatment versus pharmacological treatment alone
Combined therapy was superior regarding abdominal pain after three months (MD -14.4; 95% CI -24.69 to -4.11) and composite primary IBS symptoms (81 participants; one RCT). No differences between the interventions were found in relation to quality of life (after 12 months), constipation score (after 3 and 12 months), diarrhea score (after 3 and 12 months), overall symptom score (12 months) and abdominal pain (12 months).

Hypnotherapy versus psychotherapy plus placebo
There were benefits in the hypnotherapy group at three months in relation to abdominal pain, bowel habit, abdominal distension and general wellbeing (81 participants; one RCT). We entered into correspondence with the authors and found that the data were no longer available for analysis (their study was conducted more than 20 years ago).
No adverse events were reported in any of the trials. The results from these studies need to be interpreted with caution due to their poor methodological quality and small size. For further details and to access all the analyses, refer to the original abstract, available from: https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858. CD005110.pub2/full.

Psychological interventions
Physiological factors appear to be related to one of the pathophysiological aspects of IBS manifestation. There have been some indications of an association between IBS and psychiatric disorders. SR reported with very low certainty of evidence that homeopathic asafoetida, alone or in association with nux, was better than placebo regarding self-reported overall improvement. The other four SRs did not assess the certainty of evidence using the GRADE approach, and therefore future updates need to prioritize this assessment.
Our search strategy also retrieved four Cochrane SR protocols that might be included in a future update of this review. [20][21][22][23] The aims of these studies are to evaluate probiotic agents for diarrhea-predominant IBS, 20 probiotics for IBS in children, 21 biofeedback 22 and physical activity. 23 When published, these SRs will provide the current evidence from these increasingly used interventions for treating IBS and will help guide clinical practice. Also, the present review was restricted to data in the Cochrane Library. However, many SRs have been published by other scientific journals, and these may cover interventions that were not included here.
The fact that the RCTs included in each SR presented methodological and reporting limitations also reduced the certainty of the evidence found. Overall, heterogeneity relating to outcomes and low sample sizes were the most common shortcomings. These, respectively, prevented quantitative synthesis and magnified the imprecision of the findings.
Regarding practical implications, there were no solid conclusions that might reflect a strong recommendation for clinical practice. Healthcare providers and patients need to be aware that there is a lack of evidence from randomized clinical trials to support even the most commonly used interventions for treating IBS. Clinical practice may be individually guided through the results presented in Table 2, but future studies may change these results substantially.
Over the last few years, new classes of drugs have been introduced for management of those patients. However, few RCTs or SRs assessing their effects have been published. Linaclotide, which increases intestinal secretion through activation of guanylate cyclase C, is used for treating constipation and different presentations of diarrhea. 24 Eluxadoline, a mu-opioid receptor agonist, may likewise be useful for controlling abdominal pain, through regulating gastrointestinal motility, secretions and visceral sensation. 25 Although few studies have provided any support for a role for special diets in treating IBS, FODMAP diets (based on restriction of fermentable oligosaccharides, disaccharides, monosaccharides and polyols) are frequently used in clinical practice and need to be considered in further studies. 26 Fecal transplantation is another controversial topic, and upcoming RCTs and SRs need to encompass assessment of this intervention in future analyses. 27 In summary, it is not possible to provide full comprehension of IBS management through addressing only the published SRs. The major advances in drugs and alternative treatments that have been published recently make it imperative for updated and GRADE-guided 10 SRs to be produced. Future RCTs need to focus on the gaps in the evidence and consider clinically relevant outcomes.
Core outcome sets need to be developed within IBS research, and trialists should include these in their analyses.

CONCLUSION
This review included six Cochrane systematic reviews that eval-