Interventions for the management of abdominal pain in Crohn's disease and inflammatory bowel disease

Vassiliki Sinopoulou; Morris Gordon; Anthony K Akobeng; Marco Gasparetto; Michael Sammaan; Jessica Vasiliou; Terence M Dovey

doi:10.1002/14651858.CD013531.pub2

. 2021 Nov 29;2021(11):CD013531. doi: 10.1002/14651858.CD013531.pub2

Interventions for the management of abdominal pain in Crohn's disease and inflammatory bowel disease

Vassiliki Sinopoulou ¹, Morris Gordon ¹, Anthony K Akobeng ^2,^✉, Marco Gasparetto ³, Michael Sammaan ⁴, Jessica Vasiliou ⁵, Terence M Dovey ⁶

Editor: Cochrane Gut Group

PMCID: PMC8629648 PMID: 34844288

Abstract

Background

Crohn's disease is a remitting and relapsing disorder that can affect the whole gastrointestinal tract. Active disease symptoms include abdominal pain, fatigue, weight loss, and diarrhoea. There is no known cure; however, the disease can be managed, and therefore places a huge financial burden on healthcare systems. Abdominal pain is a common and debilitating symptom of Crohn's and other inflammatory bowel diseases (IBDs), and is multifaceted. Abdominal pain in Crohn's disease could be a symptom of disease relapse or related to medication adverse effects, surgical complications and strictures or adhesions secondary to IBD. In the absence of these factors, around 20 to 50% of people with Crohn's in remission still experience pain.

Objectives

To assess the efficacy and safety of interventions for managing abdominal pain in people with Crohn's disease and IBD (where data on ulcerative colitis and Crohn's disease could not be separated).

Search methods

We searched CENTRAL, MEDLINE, three other databases, and clinical trials registries on 29 April 2021. We also searched the references of trials and systematic reviews for any additional trials.

Selection criteria

All published, unpublished, and ongoing randomised trials that compared interventions for the management of abdominal pain in the setting of Crohn's disease and IBD, with other active interventions or standard therapy, placebo, or no therapy were included. We excluded studies that did not report on any abdominal pain outcomes.

Data collection and analysis

Five review authors independently conducted data extraction and 'Risk of bias' assessment of the included studies. We analysed data using Review Manager 5. We expressed dichotomous and continuous outcomes as risk ratios and mean differences with 95% confidence intervals. We assessed the certainty of the evidence using GRADE methodology.

Main results

We included 14 studies (743 randomised participants).

Five studies evaluated participants with Crohn's disease; seven studies evaluated participants with IBD where the data on ulcerative colitis and Crohn's disease could not be separated; and two studies provided separate results for Crohn's disease participants. Studies considered a range of disease activity states. Two studies provided intervention success definitions, whilst the remaining studies measured pain as a continuous outcome on a rating scale. All studies except one measured pain intensity, whilst three studies measured pain frequency. Withdrawals due to adverse events were directly or indirectly reported in 10 studies.

No conclusions could be drawn about the efficacy of the majority of the interventions on pain intensity, pain frequency, and treatment success, except for the comparison of transcranial direct current stimulation to sham stimulation. The certainty of the evidence was very low in all but one comparison because of imprecision due to sparse data and risk of bias assessed as unclear or high risk.

Two studies compared a low FODMAP diet (n=37) to a sham diet (n=45) in IBD patients. The evidence on pain intensity was of very low certainty (MD ‐12.00, 95% CI ‐114.55 to 90.55). One study reported pain intensity separately for CD participants in the low FODMAP group [n=14, mean(SD)=24 (82.3)] and the sham group [n=12, mean(SD)=32 (69.3)]. The same study also reported pain frequency for IBD participants in the low FODMAP group [n=27, mean(SD)=36 (26)] and sham group [n=25, mean(SD)=38(25)] and CD participants in the low FODMAP group [n=14, mean(SD)=36 (138.4)] and sham group [n=12, mean(SD)=48 (128.2)]. Treatment success was not reported.

One study compared a low FODMAP diet (n=25) to high FODMAP/normal diet (n=25) in IBD patients. The data reported on pain intensity was unclear. Treatment success and pain frequency were not reported.

One study compared medicine‐separated moxibustion combined with acupuncture (n=51) versus wheat bran‐separated moxibustion combined with shallow acupuncture (n=51) in CD patients. The data reported on pain intensity and frequency were unclear. Treatment success was not reported.

One study compared mindfulness with CBT (n=33) versus no treatment (n=33) in IBD patients. The evidence is very uncertain about the effect of this treatment on pain intensity and frequency (MD ‐37.00, 95% CI ‐87.29 to 13.29). Treatment success was not reported.

One study compared soft non‐manipulative osteopathic treatment (n=16) with no treatment besides doctor advice (n=14) in CD patients. The evidence is very uncertain about the effect of this treatment on pain intensity (MD 0.01, 95% CI ‐1.81 to 1.83). Treatment success and pain frequency were not reported.

One study compared stress management (n=15) to self‐directed stress management(n=15) and to standard treatment (n=15) in CD patients. The evidence is very uncertain about the effect of these treatments on pain intensity (MD ‐30.50, 95% CI ‐58.45 to ‐2.55 and MD ‐34.30, 95% CI ‐61.99 to ‐6.61). Treatment success and pain frequency were not reported.

One study compared enteric‐release glyceryl trinitrate (n=34) with placebo (n=36) in CD patients. The data reported on pain intensity was unclear. Treatment success and pain frequency were not reported.

One study compared 100 mg olorinab three times per day (n=8) with 25 mg olorinab three times per day (n=6) in CD patients. Pain intensity was measured as a 30% reduction in weekly average abdominal pain intensity score for the 100mg group (n=5) and the 25mg group (n=6). The evidence is very uncertain about the effect of this treatment on pain intensity (RR 0.66, 95% CI 0.38 to 1.15). Treatment success and pain frequency were not reported.

One study compared relaxation training (n=28) to a waitlist (n=28) in IBD patients. The evidence is very uncertain about the effect of this treatment on pain intensity (MD ‐0.72, 95% CI ‐1.85 to 0.41). Treatment success and pain frequency were not reported.

One study compared web‐based education (n=30) with a book‐based education (n=30) in IBD patients. The evidence is very uncertain about the effect of this treatment on pain intensity (MD ‐0.13, 95% CI ‐1.25 to 0.99). Treatment success and pain frequency were not reported.

One study compared yoga (n=50) with no treatment (n=50) in IBD patients. The data reported on treatment success were unclear. Pain frequency and intensity were not reported.

One study compared transcranial direct current stimulation (n = 10) to sham stimulation (n = 10) in IBD patients. There may be an improvement in pain intensity when transcranial direct current is compared to sham stimulation (MD ‐1.65, 95% CI ‐3.29 to ‐0.01, low‐certainty evidence). Treatment success and pain frequency were not reported.

One study compared a kefir diet (Lactobacillus bacteria) to no intervention in IBD patients and provided separate data for their CD participants. The evidence is very uncertain about the effect of this treatment on pain intensity in IBD (MD 0.62, 95% CI 0.17 to 1.07) and CD (MD ‐1.10, 95% CI ‐1.67 to ‐0.53). Treatment success and pain frequency were not reported.

Reporting of our secondary outcomes was inconsistent.

The most adverse events were reported in the enteric‐release glyceryl trinitrate and olorinab studies. In the enteric‐release glyceryl trinitrate study, the adverse events were higher in the intervention arm. In the olorinab study, more adverse events were observed in the higher dose arm of the intervention. In the studies on non‐drug interventions, adverse events tended to be very low or zero. However, no clear judgements regarding adverse events can be drawn for any interventions due to the low number of events.

Anxiety and depression were measured and reported at the end of intervention in only one study; therefore, no meaningful conclusions can be drawn for this outcome.

Authors' conclusions

We found low certainty evidence that transcranial direct current stimulation may improve pain intensity compared to sham stimulation. We could not reach any conclusions on the efficacy of any other interventions on pain intensity, pain frequency, and treatment success. The certainty of the evidence was very low due to the low numbers of studies and participants in each comparison and clinical heterogeneity amongst the studies.

While no serious or total adverse events were elicited explicitly with any of the treatments studied, the reported events were very low. The certainty of the evidence for all comparisons was very low, so no conclusions can be drawn.

Plain language summary

Treatments for stomach pain in Crohn's disease

What is the aim of this review?

The aim of this Cochrane Review was to find out whether treatments in people with Crohn's disease can improve stomach pain.

We analysed data from 14 studies to answer this question.

Key messages

Based on low‐quality evidence, electrical brain stimulation may improve stomach pain compared to fake brain stimulation.

It is unclear whether there is any difference between a low FODMAP (a group of sugars found in food) diet and a diet that is not low in FODMAP in improving stomach pain.

It is unclear whether there is any difference between a stress management programme, self‐directed stress management, and standard treatment only, in improving stomach pain.

We were unable to draw any conclusions about the safety of any of the interventions.

It is unclear whether any of the treatments for the other comparisons under study are better or worse than another, as the evidence was limited due to the very low numbers of studies and participants and low quality of the reporting.

Further research that addresses the quality issues we have highlighted is needed.

What was studied in the review?

People with Crohn's disease commonly suffer stomach pain whether their disease is active or inactive.

Several types of therapies have been used to try to reduce pain in Crohn's disease, including diets, psychological therapies, alternative therapies, drugs, and exercise therapies.

There is currently no agreement amongst healthcare providers as to which therapy is better.

What are the main results of the review?

We searched for randomised controlled trials (studies in which participants are assigned to one of two or more treatment groups using a random method) comparing any treatment with any other treatment (such as dummy/placebo treatments) in people with Crohn's disease. We found 14 trials including a total of 743 participants who were aged 16 to 80 years old. We made the following conclusions.

• Electrical brain stimulation may be better than fake brain stimulation in improving pain, based on low‐quality evidence • It is unclear whether a low FODMAP diet or a diet that is not low in FODMAP is better in improving pain. • It is unclear whether a stress management programme, self‐directed stress management, or standard treatment only is better in improving pain. • It is unclear whether there is any difference between any of the other therapies in their effects on the management of pain. • It is unclear whether any therapy leads to a difference in major and minor side effects.

How up‐to‐date is this review?

This review is up‐to‐date as of April 2021.

Summary of findings

Background

Description of the condition

Inflammatory Bowel Disease (IBD) is a term for a group of disorders characterised by inflammation of the gut. The two main types of IBD are Crohn's Disease (CD) and Ulcerative Colitis (UC), which have several subtypes based on onset, disease location and clinical behaviour for CD, and extent for UC. There also exists a categorisation for the much rarer condition indeterminate colitis (Satsangi 2006).

CD is a remitting and relapsing disease of the gastrointestinal tract that affects over 3.5 million young people and adults in the USA and Europe (Kaplan 2015), and more than 6.8 million globally (Alatab 2020). Active CD symptoms include abdominal pain, fatigue, weight loss, and diarrhoea. There is no known cure; however, the disease can be managed via lifelong treatment and care, and therefore places a huge financial burden on healthcare systems. The annual care costs of inflammatory bowel disease (IBD) to the National Health Service (NHS) was estimated at over GBP 1000 million in 2010 (RCP 2012). For CD alone, this amounts to over GBP 6000 per patient annually (Ghosh 2015). Treatment of the disease may involve surgical intervention or immunosuppression using thiopurines and anti‐tumour necrosis factor (anti‐TNF) medications (Gjuladin‐Hellon 2019). These interventions aim to induce remission, maintain remission, and manage symptoms (Greenley 2013).

Abdominal pain is a common and debilitating symptom of CD and other IBDs, which is multifaceted, with multiple causes and contributors, such as a symptom of disease relapse, an adverse effect of medication, surgical complication, or due to problems related to CD itself, such as strictures or adhesions secondary to IBD (Srinath 2012). The pain may also vary between adults and children and may also be influenced by disease activity. Even in the absence of the aforementioned factors, around 20% to 50% of people with CD in remission still experience pain (Bielefeldt 2009). This has been attributed to functional abdominal pain disorders (FAPD) such as irritable bowel syndrome (IBS), abdominal migraine, and functional dyspepsia (Odes 2017), although the definition of such disorders involves explicit exclusion of pathology such as IBD. Evidence is lacking to indicate whether there is a specific variant of functional pain coexisting within people with IBD, or a separate pain disorder that can be attributed to IBD pathologic mechanisms. The aetiology and management of abdominal pain in CD may therefore vary in ways that cannot be fully explained. A common suggestion is that the inflammation in the intestinal wall can lead to the perception of abdominal pain (Docherty 2011).

Description of the intervention

Pharmacological interventions

Medication for CD can reduce inflammation and associated pain by inducing remission. Where pain persists in the absence of inflammation, it has been managed with a variety of agents, including pain‐relieving medication such as antispasmodics, non‐steroidal anti‐inflammatory drugs (NSAIDs), laxatives, antidepressants, antiemetic agents, cyclo‐oxygenase‐2 (COX‐2) inhibitors, and psychoactive drugs such as cannabis and opioids (Srinath 2012). Due to the potential adverse effects of some of these drugs, short‐term use is advised.

Non‐pharmacological interventions

Non‐pharmacological interventions used in managing pain may include dietary, psychological, lifestyle advice, and alternative medicine. These interventions are considered by some as less invasive and may be used as adjuvant treatment. Cognitive behavioural therapy (CBT), stress management, and coping skills training are the most commonly used psychological interventions. These therapies can be very heterogeneous, therefore it is key to consider the specific evidence and conceptual alignment of the approach delivered to understand 'what' the therapy was, as well as 'whether' it was effective. Alternative treatments such as acupuncture and transcutaneous electrical nerve stimulation, which have been used in other conditions such as IBS, are increasingly used in people with IBD, albeit based on limited evidence (Srinath 2012). Dietary interventions studied include the avoidance of FODMAP (fermentable oligo‐, di‐, monosaccharides and polyols) and the use of supplements with prebiotic properties; however, the evidence on their effectiveness appears to be weak and conflicting (Norton 2017).

Whilst some interventions such as neurochemicals and acupuncture have mostly been used in conditions such as IBS, others such as COX‐2 inhibitors have been associated with little to no effect in IBD (Paiotti 2012).

How the intervention might work

The mechanism of action of different interventions depends on the nature or cause of the abdominal pain.

Antispasmodics suppress intestinal spasms which cause pain from inflammation or obstruction (Srinath 2012). Pain related to strictures can be improved by following a low‐residue diet, which can pass through with ease, thereby preventing intestinal pain (Srinath 2012). A low FODMAP diet also aims to limit the intake of non‐absorbable nutrients, and has recently gained considerable attention in the management of IBS (Prince 2016).

Psychological techniques such as CBT, mindfulness, and stress management tend to help people with CD change negative behaviours that might be worsening their pain and provide coping mechanisms (Norton 2017). Yoga‐based programmes are thought to work by improving depression and anxiety (Ewais 2019). Other complementary or alternative therapies, such as the use of herbal and dietary supplements, traditional Chinese practices, and mind‐body techniques, have been proposed to have anti‐inflammatory, stress‐reducing, or other therapeutic modes of action (Lin 2018).

Why it is important to do this review

Abdominal pain in people with CD can lead to depressive symptoms, reduced quality of life, and an increase in the use of healthcare facilities (Srinath 2012). Effective pain management is therefore vital.

There are concerns regarding the safety of pharmacological interventions, such as the relative inefficacy of currently available analgesics and their potential toxicity. Opioids can offer short‐term relief; however, they are associated with such problems as narcotic bowel syndrome and other symptoms like constipation (Thapa 2019). Furthermore, there may be concern amongst people with IBD about the stigma of addiction associated with the use of opioids. The use of opioids in chronic pain can lead to people exhibiting withdrawal symptoms that are similar to CD symptoms (Pauly 2017), which can further complicate treatment. There are also concerns about the use of NSAIDs, which can have effects that mimic or potentially exacerbate CD activity (Long 2016).

Pain management has been highlighted as a priority topic for research by IBD patient groups and charities, but is currently not covered in the National Institute for Health and Care Excellence guidelines (NICE 2019), European Crohn's and Colitis Organisation guidelines (ECCO 2010), or Crohn's and Colitis Foundation guidance. Whilst several non‐Cochrane systematic reviews have assessed interventions for pain management in IBD, none has currently assessed the efficacy and safety of these interventions in Crohn's disease. Although this review covers interventions that have been previously assessed in published Cochrane Reviews in the group portfolio (Iheozor‐Ejiofor 2019; Kafil 2018; Limketkai 2019; Timmer 2011), the focus of this review was only on studies that have been conducted for the purpose of providing relief for abdominal pain.

Objectives

To assess the efficacy and safety of interventions for managing abdominal pain in people with Crohn's disease and IBD (where data on ulcerative colitis and Crohn's disease could not be separated).

Methods

Criteria for considering studies for this review

Types of studies

All published, unpublished, and ongoing randomised controlled trials (RCTs) that compared interventions for the management of abdominal pain in the setting of CD and IBD, with other active interventions or standard therapy, placebo, or no therapy. We excluded studies that did not report on any abdominal pain outcomes.

Types of participants

Adults and children with Crohn's disease or IBD who are experiencing abdominal pain. If studies included participants with ulcerative colitis as well as those with CD, these studies were included, and separate data sought for analysis. Where separate data could not be obtained, IBD patients were included as a whole.

Types of interventions

Pain‐relieving drugs such as antispasmodics, antidepressants, laxatives, antidiarrhoeal agents, antibiotics, analgesics, antireflux agents, antiemetic agents, antimigraine agents, antihistaminic agents, serotonergic agents, and psychoactive drugs.
Behaviour therapy, e.g. cognitive behavioural therapy (CBT), hypnotherapy.
Lifestyle advice, e.g. advice on physical activity including exercise.
Dietary interventions such as reduced intake of FODMAP; additional fibre intake; decrease in gas‐producing foods; extra fluid intake; lactulose‐, gluten‐, and histamine‐free diet.
Pre‐ and probiotics.
Other alternative therapies, e.g. acupuncture, homeopathy, body‐oriented therapy, musculoskeletal therapy (osteopathy/chiropractic), yoga.

Types of outcome measures

Both dichotomous and continuous outcomes were valid for inclusion.

Primary outcomes

Treatment success as defined by the authors.
Abdominal pain frequency or change in frequency of pain using any validated scale.
Abdominal pain intensity or change in pain intensity using any validated scale.
Withdrawal due to adverse events.

Secondary outcomes

Anxiety/depression using any validated scale.
Adverse events (total number of participants with any event).
Serious adverse events (as defined by the authors within the primary study)

Search methods for identification of studies

Electronic searches

We searched the following sources from the inception of each database to the date of search on 29 April 2021:

the Cochrane Central Register of Controlled Trials (CENTRAL) (via Ovid EBMR) (inception to Issue 03, 2021);
MEDLINE (via Ovid) (1946 to 29 April 2021);
PsycINFO (via Ovid) (1987 to 29 April 2021);
AMED (via Ovid) (Allied and Complementary Medicine) (1985 to 29 April 2021);
CINAHL (via EBSCO) (Cumulative Index to Nursing and Allied Health Literature) (1984 to 29 April 2021).

We also searched the following trial registers on 29 April 2021:

US National Institutes of Health Ongoing Trials Register ClinicalTrials.gov (www.clinicaltrials.gov);
World Health Organization International Clinical Trials Registry Platform (WHO ICTRP) (www.who.int/trialsearch/).

We placed no restrictions on language of publication. For detailed search strategies, see Appendix 1.

Searching other resources

As complementary search methods, we carefully checked relevant systematic reviews for potentially eligible studies. We also scrutinised the references of included studies. We sought unpublished trials by contacting experts in the field, and scanned the Internet and abstracts submitted to major international congresses from the three years prior to the search to capture any studies presented but not yet published in full.

In the case of foreign language papers, we planned to obtain translations of papers if necessary.

Data collection and analysis

We carried out data collection and analysis according to the methods recommended in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2021).

Selection of studies

Five review authors independently screened the titles and abstracts identified by the literature search, excluding studies that based on title and abstract did not meet our inclusion criteria. We obtained the full reports of studies deemed potentially eligible. Five review authors independently assessed the full texts for inclusion in the review. Any disagreements were resolved by discussion or by consulting another review author if necessary. We recorded the studies excluded at this or subsequent stages, and the main reason for their exclusion, in the 'Characteristics of excluded studies' tables.

Where there were multiple publications for a given study, we collated the reports of the same study so that each study, rather than each report, was the unit of interest in the review; such studies have a single identifier with multiple references.

Studies that had the primary goal of inducing or maintaining remission in IBD were excluded, regardless as to whether they reported pain outcomes. This reflected the fact that any such pain imporvement was as a result of disease state and not an indepedent pain intervention and all such interventions are considered in seperate reviews. Such studies were excluded at the title and abstract screening stage. Studies that did not report any abdominal pain related outcomes, were excluded at the full text screening stage, and only after contact with the authors whenever the reporting of pain related outcomes was unclear.

Data extraction and management

Five review authors independently performed data extraction using piloted data extraction forms. We extracted the following data from the included studies:

trial setting: country and number of trial centres;
methods: study design, total study duration and date;
participant characteristics: age, sociodemographics, ethnicity, diagnostic criteria, pain location, and total number of participants;
eligibility criteria: inclusion and exclusion criteria;
intervention and comparator;
outcomes: outcome definition, unit of measurement, and time of collection;
results: number of participants allocated to each group, missing participants, and sample size;
funding source.

All treatment arms are described in the 'Characteristics of included studies' tables.

Assessment of risk of bias in included studies

Five review authors independently assessed risk of bias in the included studies based on the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2021). We assessed the following 'Risk of bias' domains:

sequence generation (selection bias);
allocation concealment (selection bias);
blinding of participants and personnel (performance bias);
blinding of outcome assessment (detection bias);
incomplete outcome data (attrition bias);
selective reporting (reporting bias);
other bias such as imbalance in participants' baseline characteristics.

We judged the studies to be at low, high, or unclear risk of bias for each domain assessed, based on the guidance in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2021).

After data extraction, the five review authors compared the extracted data, discussing and resolving any discrepancies before transfer of data into the 'Characteristics of included studies' tables.

Measures of treatment effect

We expressed treatment effect as risk ratios (RR) with corresponding 95% confidence intervals (CI) for dichotomous outcomes, and mean difference (MD) with 95% CI for continuous outcomes. Where endpoint and change score were both reported, we used endpoint scores for data analysis. However, if the studies assessed the same continuous outcome in different ways, we estimated the treatment effect using the standardised mean difference (SMD) (Cohen 1988).

Unit of analysis issues

The unit of analysis was the participant. For studies comparing more than two intervention groups, we planned to make multiple pair‐wise comparisons between all possible pairs of intervention groups. To avoid double counting, we would divide shared intervention groups evenly amongst the comparisons. For dichotomous outcomes, we planned to divide both the number of events and the total number of participants. For continuous outcomes, we would only divide the total number of participants, and leave the means and standard deviations (SDs) unchanged. We planned to include cross‐over studies for quantitative analysis only if data were separately reported before and after cross‐over, and use only pre‐cross‐over data. We did not anticipate finding any cluster‐RCTs; we would only use study data from such trials if the authors employed appropriate statistical methods in taking the clustering effect into account. We would also exclude cluster‐RCTs in a sensitivity analysis to assess their impact on the results.

Dealing with missing data

We contacted study authors in the case of missing data or studies that did not report data in sufficient detail. We attempted to estimate missing SDs using relevant statistical tools and calculators available in Review Manager 5 if studies reported standard errors (Review Manager 2020). Studies that failed to report measures of variance were judged as at high risk of reporting bias.

Assessment of heterogeneity

We assessed the included studies to determine their homogeneity in terms of participants, intervention, comparator, and outcome. To test for statistical heterogeneity, we employed a Chi² test using a P value of less than 0.1 to give an indication of the presence of heterogeneity. Inconsistency was quantified and represented by the I² statistic. We interpreted the thresholds as follows (Higgins 2021):

0% to 40%: might not be important;
30% to 60%: may represent moderate heterogeneity;
50% to 90%; may represent substantial heterogeneity;
75% to 100%: considerable heterogeneity.

Assessment of reporting biases

Most reporting biases were minimised by using an inclusive search strategy. We planned to investigate publication bias using a funnel plot if there were 10 or more studies. The magnitude of publication bias would be determined by visual inspection of the asymmetry of the funnel plot. In addition, we would test funnel plot asymmetry by performing a linear regression of intervention effect estimate against its standard error, weighted by the inverse of the variance of the intervention effect estimate (Egger 1997).

Data synthesis

To summarise the study characteristics, we conducted a narrative synthesis of all the included studies. We then carried out a meta‐analysis if two or more studies assessed similar populations, interventions, and outcomes. We planned to analyse studies of children, adults, and different sub‐intervention types separately. We used Review Manager 5 (Review Manager 2020). We synthesised study data using the random‐effects model if there was statistical heterogeneity (I² > 0%); otherwise, we used the fixed‐effect model. We combined effect estimates of studies that reported data in a similar way in the meta‐analysis. We pooled RRs for dichotomous outcomes, and MDs or SMDs for continuous outcomes, alongside 95% CIs. Where we were unable to carry out a meta‐analysis (e.g. due to lack of uniformity in data reporting), we presented a narrative summary of the included studies.

Subgroup analysis and investigation of heterogeneity

If we identified heterogeneity, we investigated possible causes and addressed them using the methods described in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2021). We planned to undertake subgroup analyses of potential effect modifiers if sufficient data were available. We identified several potential modifiers of effect:

disease activity (active versus inactive disease);
pain location;
disease location.

Sensitivity analysis

We planned to undertake a sensitivity analysis on the primary outcome of treatment success in order to assess whether the findings of the review were robust to decisions made during the review process. In particular, we planned to exclude studies at high or unclear risk of bias from analyses. Where data analyses included studies with reported and estimated SDs, we excluded studies with estimated SDs to assess whether this affected the findings of the review. We investigated whether the choice of model (fixed‐effect versus random‐effects) affected the results.

Summary of findings and assessment of the certainty of the evidence

We have presented our primary outcomes results in 'Summary of findings' tables. Each comparison and primary outcome was exported to GRADEpro GDT software for quality assessment (GRADEpro GDT). Based on risk of bias, inconsistency, imprecision, indirectness, and publication bias, we graded the quality of the evidence for each outcome as high, moderate, low, or very low. These ratings have been defined as follows:

high: further research is very unlikely to change our confidence in the estimate of effect;
moderate: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate;
low: further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate;
very low: any estimate of effect is very uncertain.

We justified all decisions to downgrade the quality of studies using footnotes, and made comments to aid the reader's understanding of the review where necessary.

Results

Description of studies

Information on the results of the search, included and excluded studies, and 'Risk of bias' assessment is provided below.

Results of the search

We completed our literature search on 29 April 2021 (Appendix 1), identifying a total of 3654 records through database searching and 13 additional records from alternative sources. After removal of duplicates, 3282 unique records remained. Title and abstract screening revealed 63 records for full‐text review. After assessing all 63 records, we identified 22 records of 14 studies that met the inclusion criteria and were included in the review. We also identified 9 records of 9 ongoing studies and 24 records of 19 studies awaiting classification. We excluded 8 records of 8 studies for various reasons (see Characteristics of excluded studies). The results of the search are presented in a PRISMA flow diagram (Figure 1). There are two fully published RCTs (Bao 2021; Lee 2021) which are under awaiting classification and not included in our results and meta‐analyses, as they were identified during our updated search. They will be included in future updated of this review.

Included studies

Setting

Fourteen RCTs involving a total of 743 participants met our inclusion criteria. One study was conducted in China (Bao 2016), three in the UK (Berrill 2014; Cox 2020; Hawkes 2001), two in Spain (Espi Lopez 2018; Garcia‐Vega 2004), one in the USA (Higgins 2019), two in Turkey (Ozgursoy Uran 2019; Yilmaz 2019), one in India (Sharma 2015), one in Israel (Mizrahi 2012), two in Italy (Tapete 2018; Tapete 2019), and one in Germany (Volz 2016). All of the included studies were conducted in hospitals, medical centres, and gastroenterology units, except Sharma 2015, which was conducted in an institute of medical science, and three studies for which no information was provided about setting (Tapete 2018; Tapete 2019; Yilmaz 2019). Seven studies were single‐centre (Espi Lopez 2018; Garcia‐Vega 2004; Mizrahi 2012; Ozgursoy Uran 2019; Sharma 2015; Volz 2016; Yilmaz 2019); five were multicentre (Bao 2016; Berrill 2014; Cox 2020; Hawkes 2001; Higgins 2019); and two studies did not provide this information (Tapete 2018; Tapete 2019).

Participants

All studies reported age in mean (SD), except for two studies that did not report it at all (Tapete 2018; Tapete 2019); one study that reported mean and range of ages (Yilmaz 2019); and one study that only mentioned their accepted age range for participants (Sharma 2015). The average age of participants ranged from 31.7, in Garcia‐Vega 2004, to 44.9, in Berrill 2014. The lowest accepted age was 16 years (Hawkes 2001; Sharma 2015), and the highest 80 years (Higgins 2019; Volz 2016); 4 studies did not have an upper age limit (Cox 2020; Hawkes 2001; Mizrahi 2012; Ozgursoy Uran 2019). Four studies did not mention age in their inclusion/exclusion criteria (Bao 2016; Garcia‐Vega 2004; Tapete 2018; Tapete 2019).

Five studies examined exclusively CD populations (Bao 2016; Espi Lopez 2018; Garcia‐Vega 2004; Hawkes 2001; Higgins 2019), whilst the remaining studies examined a mix of IBD patients (Berrill 2014; Cox 2020; Mizrahi 2012; Ozgursoy Uran 2019; Sharma 2015; Tapete 2018; Tapete 2019; Volz 2016; Yilmaz 2019). Cox 2020 reported separate CD results. We contacted the authors of the other studies providing mixed IBD results to ask for separate outcome results for their CD participants, and one was able to provide this information (Yilmaz 2019).

Four studies examined participants in an active stage of the disease (Bao 2016; Hawkes 2001; Mizrahi 2012; Volz 2016); six studies participants in an inactive stage of the disease (Berrill 2014; Cox 2020; Garcia‐Vega 2004; Sharma 2015; Tapete 2018; Tapete 2019); one study participants in an inactive or mild stage of the disease (Higgins 2019); one study participants in inactive to moderate stages of the disease (Yilmaz 2019); and one study participants with a mix of inactive and active disease (Ozgursoy Uran 2019). One study did not report on activity of the disease (Espi Lopez 2018).

Nine studies reported disease duration (Bao 2016; Cox 2020; Garcia‐Vega 2004; Hawkes 2001; Higgins 2019; Ozgursoy Uran 2019; Volz 2016; Yilmaz 2019). All of these studies presented disease duration in mean (SD) except Cox 2020, which only provided the mean; Ozgursoy Uran 2019, which reported disease duration in incremental ranges in months; and Yilmaz 2019, which provided the mean and range. Average disease duration ranged from 3 years, in Yilmaz 2019, to 12 years, in Higgins 2019.

Interventions

The following interventions were assessed in the included trials.

Low FODMAP (fermentable oligo‐, di‐, monosaccharides and polyols) diet versus sham diet (Cox 2020; Tapete 2018).
Low FODMAP diet versus high FODMAP/normal diet (Tapete 2019).
Medicine‐separated moxibustion combined with acupuncture versus wheat bran‐separated moxibustion combined with shallow acupuncture (Bao 2016).
Mindfulness with cognitive behavioural therapy (CBT) versus no treatment (both groups received standard medical therapy) (Berrill 2014).
Soft non‐manipulative osteopathic versus no treatment besides doctor advice (Espi Lopez 2018).
Stress management versus self‐directed stress management (it is unclear whether these interventions replaced standard treatment or were added to standard treatment) versus standard treatment (Garcia‐Vega 2004).
Enteric‐release glyceryl trinitrate versus placebo (Hawkes 2001).
100 mg olorinab three times per day versus 25 mg olorinab three times per day (Higgins 2019).
Relaxation training versus waitlist (Mizrahi 2012).
Web‐based education versus standard book‐based education (Ozgursoy Uran 2019).
Yoga intervention versus no treatment (both groups received standard medical therapy) (Sharma 2015).
Transcranial direct current stimulation versus sham stimulation (Volz 2016).
Kefir diet (Lactobacillus bacteria) versus no intervention (Yilmaz 2019).

Outcomes

The length of the interventions ranged from 5 days, in Volz 2016, to 12 months, in Berrill 2014.

Primary outcomes

Treatment success as defined by the authors

Only two studies clearly defined their criteria for treatment success: Sharma 2015, which measured pain as a dichotomous outcome (presence or absence of pain), and Higgins 2019, which defined success as achieving ≥ 30% reduction in weekly average abdominal pain from baseline to week 8. Treatment success was not explicitly mentioned in the remaining studies. Study authors reported pain as a continuous outcome and did not report numbers of responders for their interventions per any definition.

Abdominal pain frequency or change in frequency of pain

Three studies measured pain frequency. Bao 2016 evaluated pain frequency using Traditional Chinese Medicine (TCM) symptom scores on an adapted pain intensity scale of 0 to 3: 0 (none), 1 (light), 2 points (moderate), 3 points (severe). The wording of the adapted scale for pain frequency was not mentioned. Cox 2020 measured pain frequency in days using the Irritable Bowel Syndrome Severity Scoring System (IBS‐SSS) 0‐to‐100 scoring scale, and in days where pain was reported as moderate or severe using the Gastrointestinal Symptom Rating Scale (GSRS). Berrill 2014 used the total IBS‐SSS scores, which measure frequency and severity of abdominal discomfort, severity of abdominal bloating, satisfaction with bowel habit, and impact of symptoms on life in general. Each domain is scored 0 to 100, and an overall score of 0 to 500 is obtained. A higher score is indicative of more severe symptoms.

Abdominal pain intensity or change in pain intensity using any validated scale

All studies except Sharma 2015 measured pain intensity. Five studies used a 0‐to‐100‐millimetre visual analogue scale (VAS), where 0 indicates no pain and 100 (or 10 if measured in centimetres) the worst pain possible (Espi Lopez 2018; Mizrahi 2012; Tapete 2018; Tapete 2019; Volz 2016). One study, Ozgursoy Uran 2019, used the 0‐to‐100‐millimetre VAS to separate participants into groups that experienced no pain, pain from 1 to 5, and pain from 6 to 10. Four studies used scoring scales between 0 and 3. Bao 2016 evaluated pain intensity using TCM symptom scores on a scale of 0 to 3, where 0 = none, 1 = light, 2 = moderate, 3 = severe; Hawkes 2001 used scores that represented the sum of a 7‐day diary card score on a scale of 0 = no pain to 3 = severe pain; Yilmaz 2019 used a symptoms diary where participants rated their pain on a scale of 0 to 3, where 0 = none, 1 = mild, 2 = moderate, and 3 = severe; and Cox 2020 used the IBS‐SSS 0‐to‐100 scale and the GSRS, which measures severity of pain on a 0‐to‐3 scale. Garcia‐Vega 2004 used a symptom diary where participants rated the severity of their daily pain on a scale of 1 to 3 (1 = mild, 2 = moderate, 3 = severe) and devised their own formulas based on diary card scores to calculate their results. Berrill 2014 used the total IBS‐SSS scores, which measure frequency and severity of abdominal discomfort, severity of abdominal bloating, satisfaction with bowel habit, and impact of symptoms on life in general. Each domain is scored 0 to 100, and an overall score of 0 to 500 is obtained. A higher score is indicative of more severe symptoms. Higgins 2019 used a weekly Average Abdominal Pain Score (AAPS), which was the daily pain scores averaged over one week that were larger than 4 on a scale of 0 (no pain) to 10 (worst ever).

Withdrawal due to adverse events

This was reported or could be extracted based on the text in 10 studies (Bao 2016; Berrill 2014; Cox 2020; Espi Lopez 2018; Hawkes 2001; Higgins 2019; Ozgursoy Uran 2019; Sharma 2015; Volz 2016; Yilmaz 2019).

Secondary outcomes

Anxiety/depression

Five studies mentioned having measured anxiety or depression, or both (Berrill 2014; Espi Lopez 2018; Mizrahi 2012; Sharma 2015; Volz 2016). Two of these studies used the Hospital Anxiety and Depression Scale (HADS) (Berrill 2014; Espi Lopez 2018); however, Berrill 2014 only reported baseline scores, and Espi Lopez 2018 did not report any scores. Mizrahi 2012 used Spielberger’s State‐Trait Anxiety Inventory to measure anxiety and the 0‐to‐10‐centimetre VAS to measure depression; Sharma 2015 also used Spielberger’s State‐Trait Anxiety Inventory to measure anxiety. Volz 2016 used the Beck Depression Inventory to measure depression, but only reported baseline scores.

Adverse events (total number of participants with any event)

Six studies reported the total number of participants with adverse events (Bao 2016; Cox 2020; Espi Lopez 2018; Hawkes 2001; Higgins 2019; Sharma 2015). Volz 2016 reported total occurrences of adverse events, but not the number of participants with adverse events.

Serious adverse events (as defined by the authors within the primary study )

The same six studies that reported numbers of participants with adverse events also reported numbers of participants with serious adverse events (Bao 2016; Cox 2020; Espi Lopez 2018; Hawkes 2001; Higgins 2019; Sharma 2015).

Funding sources and conflicts of interest

Eight studies reported their sources of funding (Berrill 2014; Cox 2020; Hawkes 2001; Higgins 2019; Ozgursoy Uran 2019; Sharma 2015; Volz 2016; Yilmaz 2019). Three studies were funded via government grants (Berrill 2014; Sharma 2015; Volz 2016), two by private foundations (Cox 2020; Hawkes 2001), one by an industrial partner (Higgins 2019), and two studies reported having received no funding (Ozgursoy Uran 2019; Yilmaz 2019).

Eight studies made declarations on conflicts of interest (Berrill 2014; Cox 2020; Espi Lopez 2018; Higgins 2019; Ozgursoy Uran 2019; Sharma 2015; Volz 2016; Yilmaz 2019). Six studies declared no conflicts of interest (Berrill 2014; Espi Lopez 2018; Ozgursoy Uran 2019; Sharma 2015; Volz 2016; Yilmaz 2019); one study declared industry connections and ownership of an invention connected to their intervention (Cox 2020); and one study declared that one of the authors is an employee of the industrial partner that provided funding (Higgins 2019).

Excluded studies

We excluded eight studies for various reasons. The reasons for exclusion of each study are presented in the Characteristics of excluded studies table and are summarised below.

Wrong outcomes (3 studies) (ACTRN12617000876392; Engel 2016; Tripp 2017).
Wrong interventions (2 studies) (Forbes 2019; Gearry 2009).
Not RCTs (2 studies) (McCormick 2010; Spagnuolo 2017).
Wrong indication (1 study) (ISRCTN98226923).

Risk of bias in included studies

The results of our ‘Risk of bias’ assessment are presented below (Figure 2; Figure 3). Further details can be found in the ‘Risk of bias’ tables in the Characteristics of included studies tables.

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

Allocation

Randomisation was described clearly in nine studies, which we rated as at low risk of bias (Bao 2016; Berrill 2014; Cox 2020; Espi Lopez 2018; Hawkes 2001; Ozgursoy Uran 2019; Sharma 2015; Volz 2016; Yilmaz 2019), and insufficiently described in five studies, which were assessed as at unclear risk of bias (Garcia‐Vega 2004; Higgins 2019; Mizrahi 2012; Tapete 2018; Tapete 2019).

Four studies were assessed as at low risk of allocation concealment bias (Berrill 2014; Cox 2020; Espi Lopez 2018; Sharma 2015), as allocation concealment was judged to be adequately described. We rated the other 10 studies as at unclear risk of bias for allocation concealment (Bao 2016; Garcia‐Vega 2004; Hawkes 2001; Higgins 2019; Mizrahi 2012; Ozgursoy Uran 2019; Tapete 2018; Tapete 2019; Volz 2016; Yilmaz 2019), as they provided insufficient or no information.

Blinding

We rated two studies as having a low risk of performance bias since they used as control a placebo that was identical to the intervention product, Hawkes 2001, or a sham procedure that could not be differentiated from the intervention, Volz 2016. We rated Bao 2016 as at unclear risk of performance bias as there was no information about blinding, and we received no response to our enquiries to the author. We assessed the other 11 studies as at high risk of performance bias, as neither participants nor study personnel were blinded to the interventions, or the studies were open‐label (Berrill 2014; Cox 2020; Espi Lopez 2018; Garcia‐Vega 2004; Higgins 2019; Mizrahi 2012; Ozgursoy Uran 2019; Sharma 2015; Tapete 2018; Tapete 2019; Yilmaz 2019); however, Cox 2020 used a sham diet to blind their participants to the intervention, which is not typical in diet RCTs due to the difficulty it entails.

Five studies provided sufficient information about blinding of outcome assessment and were assessed as at low risk of detection bias (Espi Lopez 2018; Garcia‐Vega 2004; Ozgursoy Uran 2019; Volz 2016; Yilmaz 2019). The remaining nine studies provided insufficient information for judgement and were judged to be at unclear risk of detection bias (Bao 2016; Berrill 2014; Cox 2020; Hawkes 2001; Higgins 2019; Mizrahi 2012; Sharma 2015; Tapete 2018; Tapete 2019).

Incomplete outcome data

Ten studies provided sufficient information for judgement and were assessed as at low risk of attrition bias (Bao 2016; Cox 2020; Espi Lopez 2018; Hawkes 2001; Higgins 2019; Mizrahi 2012; Ozgursoy Uran 2019; Sharma 2015; Tapete 2018; Tapete 2019). We assessed three studies as at unclear risk of bias for this domain (Garcia‐Vega 2004; Tapete 2018; Tapete 2019), and one study as at high risk of attrition bias (Berrill 2014).

Selective reporting

Nine studies reported all outcomes they set out to assess and were judged to be at low risk of reporting bias (Bao 2016; Berrill 2014; Cox 2020; Hawkes 2001; Mizrahi 2012; Ozgursoy Uran 2019; Tapete 2018; Volz 2016; Yilmaz 2019). Four studies provided insufficient information in the reports or protocols to permit a judgement as to whether all outcomes had been reported; these studies were assessed as at unclear risk of reporting bias (Garcia‐Vega 2004; Higgins 2019; Sharma 2015; Tapete 2019). We rated the remaining study as at high risk of bias for this domain (Espi Lopez 2018).

Other potential sources of bias

We rated eight studies as at low risk of other potential sources of bias (Berrill 2014; Cox 2020; Espi Lopez 2018; Ozgursoy Uran 2019; Sharma 2015; Tapete 2018; Volz 2016; Yilmaz 2019). We assessed two studies as at unclear risk of bias for this domain, as there were imbalances in the baseline characteristics of participants, and it is unclear how this may have influenced the results (Hawkes 2001; Tapete 2019). We rated four studies as having a high risk of other bias for the following reasons: significant differences in the baseline characteristics of participants that were highly likely to have affected the results (Garcia‐Vega 2004; Mizrahi 2012); the study declared that one or more authors were directly employed by the pharmaceutical companies funding the study (Higgins 2019); bias was detected in the way the efficacy of the studied intervention was presented in their introduction (Bao 2016).

Effects of interventions

See: Table 1; Table 2; Table 3; Table 4; Table 5; Table 6; Table 7; Table 8; Table 9; Table 10; Table 11; Table 12; Table 13

Summary of findings 1. Low FODMAP diet compared to sham diet for the management of abdominal pain in Crohn's disease and inflammatory bowel disease.

Low FODMAP diet compared to sham diet for the management of abdominal pain in Crohn's disease and inflammatory bowel disease
Patient or population: people with inflammatory bowel disease Setting: multicentre, 2 gastroenterology clinics in the UK and an unstated setting in Italy Intervention: low FODMAP diet Comparison: sham diet
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)
Outcomes	Risk with sham diet	Risk with low FODMAP diet	Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)
Treatment success as defined by the authors	‐	‐	‐	‐	Note measured
Pain frequency IBD (measured in days of pain on the IBS‐SSS questionnaire)	‐	MD 2 lower (15.86 lower to 11.86 higher)	‐	52 (1 study)	⊕⊝⊝⊝ very low ^{a b}
Pain frequency IBD (measured in days with moderate or severe pain on the GSRS questionnaire)	‐	MD 0.4 higher (0.44 lower to 1.24 higher)	‐	52 (1 study)	⊕⊝⊝⊝ very low ^{a b}
Pain frequency CD (measured in days of pain on the IBS‐SSS questionnaire)	‐	MD 12 lower (114.55 lower to 90.55 higher)	‐	26 (1 study)	⊕⊝⊝⊝ very low ^{a b}
Pain intensity IBD (0‐10cm visual analogue scale)	‐	MD 8.46 lower (15.76 lower to 1.16 lower)	‐	82 (2 studies)	⊕⊝⊝⊝ very low^{a b}
Pain intensity IBD (0‐3 point GSRS scale)	‐	MD 8 lower (66.27 lower to 50.27 higher)	‐	26 (1 study)	⊕⊝⊝⊝ very low ^{a b}
Pain intensity CD (0‐10cm visual analogue scale)	‐	MD 0.2 higher (8.67 lower to 9.07 higher)	‐	52 (1 study)	⊕⊝⊝⊝ very low ^{a b}
Withdrawal due to adverse events	4 per 1000	7.4 per 1000 (1 to 77)	RR 1.85 (0.18 to 19.19)	52 (1 study)	⊕⊝⊝⊝ very low^{a b}
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).  CD: Crohn's disease; CI: confidence interval; FODMAP: fermentable oligo‐, di‐, monosaccharides and polyols; GSRS: Gastrointestinal Symptom Rating Scale; IBD: inflammatory bowel disease; IBS‐SSS: Irritable Bowel Syndrome Severity Scoring System; MD: mean difference; RR: risk ratio
GRADE Working Group grades of evidence High certainty: We are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: We are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: Our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: We have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

Medicine‐separated moxibustion combined with acupuncture compared with wheat bran‐separated moxibustion combined with shallow acupuncture for the management of abdominal pain in Crohn's disease and inflammatory bowel disease
Patient or population: people with Crohn's disease Settings: Shanghai Acupuncture Meridian Institute Medical Clinic Acupuncture Inflammatory Bowel Disease Specialist Clinic, Zhongshan Hospital Affiliated Endoscopic Center, and Yueyang Hospital, Shanghai University of Traditional Chinese Medicine Intervention: medicine‐separated moxibustion combined with acupuncture Comparison: wheat bran‐separated moxibustion combined with shallow acupuncture
Outcomes	*Anticipated absolute effects (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)
Outcomes	Risk with wheat bran‐separated moxibustion combined with shallow acupuncture	Risk with medicine‐separated moxibustion combined with acupuncture	Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)
Treatment success as defined by the authors	‐	‐	‐	‐	Not measured
Abdominal pain frequency or change in frequency	‐	‐	‐	‐	Not measured
Abdominal pain intensity or change in intensity	‐	‐	‐	‐	Not measured
Withdrawals due to adverse events	0 per 1000	0 per 1000 (0 to 0)	Not estimable	102 (1 study)	⊕⊝⊝⊝ very low ^{a b}
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).  CI: confidence interval
GRADE Working Group grades of evidence High certainty: We are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: We are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: Our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: We have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

Soft non‐manipulative osteopathic treatment compared to no intervention for the management of abdominal pain in Crohn's disease and inflammatory bowel disease
Patient or population: people with Crohn's disease Setting: single centre, hospital in Spain Intervention: soft non‐manipulative osteopathic Comparison: no intervention
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)
Outcomes	Risk with no intervention	Risk with soft non‐manipulative osteopathic	Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)
Treatment success as defined by the authors	‐	‐	‐	‐	Not measured
Abdominal pain frequency or change in frequency	‐	‐	‐	‐	Not measured
Pain intensity (0‐10cm visual analogue scale)	‐	MD 0.01 higher (1.81 lower to 1.83 higher)	‐	30 (1 study)	⊕⊝⊝⊝ very low ^{a b}
Withdrawals due to adverse events	0 per 1000	0 per 1000 (0 to 0)	Not estimable	30 (1 study)	⊕⊝⊝⊝ very low ^{a b}
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).  CI: confidence interval; MD: mean difference
GRADE Working Group grades of evidence High certainty: We are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: We are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: Our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: We have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

Stress management (it is unclear whether these interventions replaced standard treatment or were added to standard treatment) versus standard treatment for the management of abdominal pain in Crohn's disease and inflammatory bowel disease
Patient or population: people with Crohn's disease Setting: single centre, Inflammatory Intestinal Disease Unit of Asturias Central Hospital, Spain Intervention: stress management Comparison: no stress management
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)
Outcomes	Risk with no stress management	Risk with stress management	Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)
Treatment success as defined by the authors	‐	‐	‐	‐	Not measured
Pain frequency or change in pain frequency	‐	‐	‐	‐	Not measured
Pain intensity (author‐derived formula based on a 1‐3 point scale)	‐	MD 34.3 lower (61.99 lower to 6.61 lower)	‐	30 (1 study)	⊕⊝⊝⊝ very low^{a b}
Withdrawals due to adverse events	‐	‐	‐	‐	Not measured
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).  CI: confidence interval; MD: mean difference
GRADE Working Group grades of evidence High certainty: We are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: We are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: Our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: We have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

Self‐directed stress management (it is unclear whether these interventions replaced standard treatment or were added to standard treatment) versus standard treatment for the management of abdominal pain in Crohn's disease and inflammatory bowel disease
Patient or population: people with Crohn's disease Setting: single centre, Inflammatory Intestinal Disease Unit of Asturias Central Hospital, Spain Intervention: stress management Comparison: no stress management
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)
Outcomes	Risk with no stress management	Risk with stress management	Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)
Treatment success as defined by the authors	‐	‐	‐	‐	Not measured
Pain frequency or change in pain frequency	‐	‐	‐	‐	Not measured
Pain intensity (author‐derived formula based on a 1‐3 point scale)	‐	MD 30.5 lower (58.45 lower to 2.55 lower)	‐	30 (1 study)	⊕⊝⊝⊝ very low^{a b}
Withdrawals due to adverse events	‐	‐	‐	‐	Not measured
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).  CI: confidence interval; MD: mean difference
GRADE Working Group grades of evidence High certainty: We are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: We are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: Our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: We have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

Enteric‐release glyceryl trinitrate compared to placebo for the management of abdominal pain in Crohn's disease and inflammatory bowel disease
Patient or population: people with Crohn's disease Setting: unstated (centres in the UK) Intervention: enteric‐release glyceryl trinitrate Comparison: placebo
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
	Risk with placebo	Risk with enteric‐release glyceryl trinitrate
Treatment success as defined by the authors	‐	‐	‐	‐	‐	Not measured
Abdominal pain frequency or change in frequency	‐	‐	‐	‐	‐	Not measured
Abdominal pain intensity or change in intensity	‐	‐	‐	‐	‐	Not measured
Withdrawal due to adverse events	Study population		RR 3.18 (0.94 to 10.76)	70 (1 study)	⊕⊝⊝⊝ very low ^{a b}	IG: Headache = 1, worsening clinical condition = 4, generalised rash = 1, mood change/irritability = 1, loss of consciousness/memory = 1 CG: Headache = 2, worsening clinical condition = 1
	83 per 1000	265 per 1000 (78 to 897)
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).  CI: confidence interval; RR: risk ratio
GRADE Working Group grades of evidence High certainty: We are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: We are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: Our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: We have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

100 mg olorinab 3 times/day compared to 25 mg olorinab 3 times/day for the management of abdominal pain in Crohn's disease and inflammatory bowel disease
Patient or population: people with Crohn's disease Setting: unstated (multicentre, USA) Intervention: 100 mg olorinab 3 times/day Comparison: 25 mg olorinab 3 times/day
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)
	Risk with 25 mg olorinab 3 times/day	Risk with 100 mg olorinab 3 times/day
Treatment success as defined by the authors	‐	‐	‐	‐	Not measured
Pain frequency or change in pain frequency	‐	‐	‐	‐	Not measured
Pain intensity (30% reduction in weekly AAPS)	Study population		RR 0.66 (0.38 to 1.15)	14 (1 study)	⊕⊝⊝⊝ very low ^{a b}
	1000 per 1000	660 per 1000 (380 to 1000)
Withdrawal due to adverse events	0 per 1000	0 per 1000 (0 to 0)	Not estimable	14 (1 study)	⊕⊝⊝⊝ very low ^{a b}
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).  CI: confidence interval; RR: risk ratio
GRADE Working Group grades of evidence High certainty: We are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: We are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: Our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: We have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

Relaxation training compared to waitlist for the management of abdominal pain in Crohn's disease and inflammatory bowel disease
Patient or population: people with inflammatory bowel disease Setting: Hadassah Medical Center in Jerusalem Intervention: relaxation training Comparison: waitlist
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)
Outcomes	Risk with waitlist	Risk with relaxation training	Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)
Treatment success as defined by the authors	‐	‐	‐	‐	Not measured
Pain frequency or change in pain frequency	‐	‐	‐	‐	Not measured
Pain intensity (0‐10cm visual analogue scale)	‐	MD 0.72 lower (1.85 lower to 0.41 higher)	‐	56 (1 study)	⊕⊝⊝⊝ very low ^{a b}
Withdrawals due to adverse effects	‐	‐	‐	‐	Not measured
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).  CI: confidence interval; MD: mean difference
GRADE Working Group grades of evidence High certainty: We are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: We are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: Our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: We have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

Web‐based education compared to standard book‐based education for the management of abdominal pain in Crohn's disease and inflammatory bowel disease
Patient or population: people with inflammatory bowel disease Setting: single centre, gastroenterology unit in Turkey Intervention: web‐based education Comparison: standard book‐based education
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)
Outcomes	Risk with standard book‐based education	Risk with web‐based education	Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)
Treatment success as defined by the authors	‐	‐	‐	‐	Not measured
Abdominal pain frequency or change in frequency	‐	‐	‐	‐	Not measured
Pain intensity (0‐10cm visual analogue scale)	‐	MD 0.13 lower (1.25 lower to 0.99 higher)	‐	60 (1 study)	⊕⊕⊝⊝ very low ^{a b}
Withdrawals due to adverse events	0 per 1000	0 per 1000 (0 to 0)	Not estimable	60 (1 study)	⊕⊝⊝⊝ very low^{a b}
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).  CI: confidence interval; MD: mean difference
GRADE Working Group grades of evidence High certainty: We are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: We are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: Our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: We have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

Yoga intervention compared to no treatment (both groups received standard medical therapy) for the management of abdominal pain in Crohn's disease and inflammatory bowel disease
Patient or population: people with inflammatory bowel disease Settings: single centre, All India Institute of Medical Science (AIIMS), New Delhi, India Intervention: yoga Comparison: no yoga
Outcomes	*Anticipated absolute effects (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)
Outcomes	Risk with standard medical therapy	Risk with yoga plus standard medical therapy	Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)
Treatment success as defined by the authors	‐	‐	‐	‐	Not measured
Abdominal pain frequency or change in frequency	‐	‐	‐	‐	Not measured
Abdominal pain intensity or change in intensity	‐	‐	‐	‐	Not measured
Withdrawal due to adverse events	0 per 1000	0 per 1000 (0 to 0)	Not estimable	100 (1 study)	⊕⊝⊝⊝ very low ^{a b}
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).  CI: confidence interval
GRADE Working Group grades of evidence High certainty: We are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: We are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: Our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: We have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

Transcranial direct current stimulation compared to sham stimulation for the management of abdominal pain in Crohn's disease and inflammatory bowel disease
Patient or population: people with inflammatory bowel disease Setting: single centre, Medical Department I (Gastroenterology, Infectious Diseases, Rheumatology) of the Charite‐Campus Benjamin Franklin, Germany Intervention: transcranial direct current stimulation Comparison: sham stimulation
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)
Outcomes	Risk with sham stimulation	Risk with transcranial direct current stimulation	Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)
Treatment success as defined by the authors	‐	‐	‐	‐	Not measured
Abdominal pain frequency or change in frequency	‐	‐	‐	‐	Not measured
Pain intensity (0‐10cm visual analogue scale)	‐	MD 1.65 lower (3.29 lower to 0.01 lower)	‐	20 (1 study)	⊕⊕⊝⊝ low ^a
Withdrawal due to adverse events	0 per 1000	0 per 1000 (0 to 0)	Not estimable	20 (1 study)	⊕⊕⊝⊝ low ^a
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).  CI: confidence interval; MD: mean difference; PPT: Pressure Pain Threshold
GRADE Working Group grades of evidence High certainty: We are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: We are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: Our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: We have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1.1 Pain frequency defined by days of pain by IBS‐SSS scores (0 to 100) for IBD	1	52	Mean Difference (IV, Random, 95% CI)	‐2.00 [‐15.86, 11.86]
1.2 Days with moderate or severe pain by GSRS scores for IBD (0 to 3) for IBD	1	52	Mean Difference (IV, Random, 95% CI)	0.40 [‐0.44, 1.24]
1.3 Pain frequency defined by days of pain by IBS‐SSS scores (0 to 100) for CD	1	26	Mean Difference (IV, Random, 95% CI)	‐12.00 [‐114.55, 90.55]
1.4 Pain intensity IBD (0 to 100)	2	82	Mean Difference (IV, Random, 95% CI)	‐8.46 [‐15.76, ‐1.16]
1.5 Pain intensity IBD (0 to 3)	1	52	Mean Difference (IV, Random, 95% CI)	0.20 [‐8.67, 9.07]
1.6 Pain intensity CD (0 to 100)	1	26	Mean Difference (IV, Random, 95% CI)	‐8.00 [‐66.27, 50.27]
1.7 Withdrawals due to adverse events	1	52	Risk Ratio (M‐H, Random, 95% CI)	1.85 [0.18, 19.19]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
4.1 Pain intensity	1	30	Mean Difference (IV, Random, 95% CI)	0.01 [‐1.81, 1.83]
4.2 Withdrawals due to adverse events	1	30	Odds Ratio (M‐H, Random, 95% CI)	Not estimable

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
8.1 Pain intensity	1	14	Risk Ratio (M‐H, Random, 95% CI)	0.66 [0.38, 1.15]
8.2 Withdrawals due to adverse events	1	14	Odds Ratio (M‐H, Random, 95% CI)	Not estimable

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
10.1 Pain intensity	1	60	Mean Difference (IV, Random, 95% CI)	‐0.13 [‐1.25, 0.99]
10.2 Withdrawals due to adverse events	1	60	Risk Ratio (M‐H, Random, 95% CI)	Not estimable

*Kefir (Lactobacillus* bacteria) compared to no intervention for the management of abdominal pain in Crohn's disease and inflammatory bowel disease**
Patient or population: people with inflammatory bowel disease Setting: unstated (single centre, Turkey) Intervention: kefir Comparison: no intervention
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)
Outcomes	Risk with no intervention	Risk with kefir	Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)
Treatment success as defined by the authors	‐	‐	‐	‐	Not measured
Abdominal pain frequency or change in frequency	‐	‐	‐	‐	Not measured
Pain intensity IBD (4‐point rating scale from 0 to 3)	‐	MD 0.62 higher (0.17 higher to 1.07 higher)	‐	48 (1 study)	⊕⊕⊝⊝ very low ^{a b}
Pain intensity CD (4‐point rating scale from 0 to 3)	‐	MD 1.10 lower (1.67 lower to 0.53 lower)	‐	20 (1 study)	⊕⊕⊝⊝ very low ^{a b}
Withdrawals due to adverse events	0 per 1000	0 per 1000 (0 to 0)	Not estimable	20 (1 study)	⊕⊝⊝⊝ very low ^{a b}
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).  CD: Crohn's disease; CI: confidence interval; IBD: inflammatory bowel disease; MD: mean difference
GRADE Working Group grades of evidence High certainty: We are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: We are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: Our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: We have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

Comparison	Study ID	Disease type	Disease activity	Length of intervention	Measurement of pain	Number of randomised participants
Low FODMAP diet vs sham diet	Cox 2020	CD/IBD	Inactive	4 weeks	Pain frequency and intensity: IBS‐SSS for pain rating scale 0 to 100, GSRS rating scale 0 to 3	52 (IG: 27; CG: 25)
Low FODMAP diet vs sham diet	Tapete 2018	IBD	Inactive	6 to 8 weeks	Pain intensity: VAS rating scale 0 to 10 cm	30 (IG: 10; CG: 20)
Low FODMAP diet vs high FODMAP/normal diet	Tapete 2019	IBD	Inactive	8 weeks cross‐over (4 weeks x 2)	Pain intensity: VAS rating scale 0 to 10 cm	50 (IG: 25; CG: 25)
Medicine‐separated moxibustion combined with acupuncture vs wheat bran‐separated moxibustion combined with shallow acupuncture	Bao 2016	CD	Mild to moderate	12 weeks	Pain frequency and intensity: Traditional Chinese Medicine rating scale 0 to 3	102 (IG: 51; CG: 51)
Mindfulness with CBT + standard medical therapy vs standard medical therapy	Berrill 2014	IBD	Inactive	12 months	Pain frequency and severity of abdominal discomfort, severity of abdominal bloating, satisfaction with bowel habit, and impact of symptoms on life in general. Each domain is scored 0 to 100, and an overall score of 0 to 500 is obtained.	66 (IG: 33; CG: 33)
Soft non‐manipulative osteopathic vs no intervention	Espi Lopez 2018	CD	Unclear	30 days	Pain intensity: VAS rating scale 0 to 10 cm	30 (IG: 16; CG: 14)
Stress management vs self‐directed stress management vs standard treatment	Garcia‐Vega 2004	CD	Inactive	8 weeks	Pain intensity: rating scale 1 to 3 and author formulas	45 (IG1: 15; IG2: 15; CG: 15)
Enteric‐release glyceryl trinitrate vs placebo	Hawkes 2001	CD	Moderate to severe	12 weeks	Pain intensity: rating scale 0 to 3	70 (IG: 34; CG: 36)
100 mg olorinab 3 times/day vs 25 mg olorinab 3 times/day	Higgins 2019	CD	Inactive to mild	8 weeks	Pain intensity: AAPS of 0‐to‐10 Likert scale	14 (IG: 8; CG: 6)
Relaxation training vs waitlist	Mizrahi 2012	IBD	Active	5 weeks	Pain intensity: VAS rating scale 0 to 10 cm	56 (IG: 28; CG: 28)
Web‐based education vs standard book‐based education	Ozgursoy Uran 2019	IBD	Mix of active and inactive	8 weeks	Pain intensity: VAS rating scale 0 to 10 cm	60 (IG: 10; CG: 10)
Yoga intervention + standard medical therapy vs standard medical therapy	Sharma 2015	IBD	Inactive	8 weeks	Presence or absence of pain	100 (IG: 50; CG: 50)
Transcranial direct current stimulation vs sham stimulation	Volz 2016	IBD	Active	5 days	Pain intensity: Pressure Pain Threshold taken with algometer, VAS rating scale 0 to 10 cm	20 (IG: 10; CG: 10)
Kefir diet (Lactobacillus bacteria) vs no intervention	Yilmaz 2019	CD/IBD	Inactive to moderate	4 weeks	Pain intensity: rating scale 0 to 3	48 (IG: 28; CG: 20)

Comparison	Study ID	Treatment success end of study data IG/CG	Pain frequency end of study data IG/CG	Pain intenstiy end of study data IG/CG	Withdrawals due to adverse events IG/CG
Low FODMAP diet vs sham diet	Cox 2020	NR	IBS‐SSS all participants mean(SD) IG= 36(26); CG= 38(25) IBS‐SSS CD mean (SD) IG = 36(138.4); CG=48(128.2) GSRS all participants mean(SD) IG= 1.5(1.6); CG= 1.1(1.5)	IBS‐SSS all participants mean(SD) IG=22(15.6) ; CG=30(15) IBS‐SSS CD mean (SD) IG = 24(82.3); CG= 32(69.3) GSRS all participants mean(SD) IG=0.9(2.6) ; CG= 0.7(22.5)	IG: 2 CG: 1
Low FODMAP diet vs sham diet	Tapete 2018	NR	NR	mean(SD): IG=3.3 (1.9) CG= 4.3(2.2)	NR
Low FODMAP diet vs high FODMAP/normal diet	Tapete 2019	NR	NR	mean(SD): IG=1.1(1.6) CG=3.1(2.3) (unclear if average of both cross‐over arms or from the first or second phase of the cross‐over)	NR
Medicine‐separated moxibustion combined with acupuncture vs wheat bran‐separated moxibustion combined with shallow acupuncture	Bao 2016	NR	mean (no SD provided) IG=0 CG=0	mean (no SD provided) IG=2 CG=1	IG=0 CG=0
Mindfulness with CBT + standard medical therapy vs standard medical therapy	Berrill 2014	NR	Frequency and intensity measured together as part of the IBS‐SSS score mean(SD) IG= 187 (97) CG= 224 (111)		IG=0 CG=0
Soft non‐manipulative osteopathic vs no intervention	Espi Lopez 2018	NR	NR	mean(SD): IG=2.72(2.66) CG=2.71(2.43)	IG=0 CG=0
Stress management vs self‐directed stress management vs standard treatment	Garcia‐Vega 2004	NR	NR	mean(SD): IG=13.3(28) CG=47.6(47)	NR
Enteric‐release glyceryl trinitrate vs placebo	Hawkes 2001	NR	NR	mean(no SD presented) IG=8.1 CG=8.6	IG=9 CG=3
100 mg olorinab 3 times/day vs 25 mg olorinab 3 times/day	Higgins 2019	≥ 30% reduction in weekly AAPS IG: 5 CG: 6	NR	1.5 hours postdose mean(SD could not be calculated from figure) IG=1.9 CG= 1.9 Mean change in AAPS (no SD) IG= ‐4.6 CG= ‐4.6	IG=0 CG=0
Relaxation training vs waitlist	Mizrahi 2012	NR	NR	mean(SD): IG= 2.23(1.83) CG= 2.95(2.44)	NR
Web‐based education vs standard book‐based education	Ozgursoy Uran 2019	NR	NR	mean(SD): IG= 1.8(2.04) CG= 1.93(2.39)	IG=0 CG=0
Yoga intervention + standard medical therapy vs standard medical therapy	Sharma 2015	NR	NR	NR	IG=0 CG=0
Transcranial direct current stimulation vs sham stimulation	Volz 2016	NR	NR	mean(SD): IG= 2.8(2.3) CG= 4.45(1.3)	IG=0 CG=0
Kefir diet (Lactobacillus bacteria) vs no intervention	Yilmaz 2019	NR	NR	CD pain intensity mean(SD) IG= 0.2(0.63) CG= 1.3(0.67) IBD pain intensity mean(SD) IG= 0.9(0.97) CG= 0.28(0.61)	IG=0 CG=0

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
3.1 Pain frequency and severity of abdominal discomfort, severity of abdominal bloating, satisfaction with bowel habit, and impact of symptoms on life in general	1	66	Mean Difference (IV, Random, 95% CI)	‐37.00 [‐87.29, 13.29]
3.2 Withdrawals due to adverse events	1	66	Risk Ratio (M‐H, Random, 95% CI)	Not estimable

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
12.1 Pain intensity (0 to 100)	1	20	Mean Difference (IV, Random, 95% CI)	‐1.65 [‐3.29, ‐0.01]
12.2 Withdrawals due to adverse events	1	20	Odds Ratio (M‐H, Random, 95% CI)	Not estimable

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
13.1 CD pain intensity (0 to 3)	1	20	Mean Difference (IV, Random, 95% CI)	‐1.10 [‐1.67, ‐0.53]
13.2 IBD pain intensity (0 to 3)	1	48	Mean Difference (IV, Random, 95% CI)	0.62 [0.17, 1.07]
13.3 Withdrawals due to adverse events	1	20	Risk Ratio (M‐H, Random, 95% CI)	Not estimable

*Study characteristics*
Methods	RCT Setting: Shanghai Acupuncture Meridian Institute Medical Clinic Acupuncture Inflammatory Bowel Disease Specialist Clinic, Zhongshan Hospital Affiliated Endoscopic Center, and Yueyang Hospital, Shanghai University of Traditional Chinese Medicine Study period: January 2010 to December 2014
Participants	Inclusion criteria: 1. Patients with confirmed mild or moderate Crohn's disease (CDAI 151 ~ 350); 2. Patients who are not taking any drugs, or taking only salicylic acid drugs, and/or prednisone (dose < 15 mg and at least 1 month); 3. Patients who have not used immunosuppressants, anti‐tumour necrosis factor, or biologic within 3 months before entering the study; 4. Patients who agree and sign the informed consent form Exclusion criteria: 1. Patients during pregnancy or lactation; 2. Patients with serious heart, brain, liver, kidney, and haematopoietic system disease(s); 3. Patients with mental illness; 4. Patients with other serious diseases Age (mean ± SD): IG: 37 (15): CG: 33 (12) Sex (M/F): IG: 31/17; CG: 29/18 Site of disease: NS Use of concurrent medication: NS Disease duration (mean ± SD): IG: 4.7 (3.7) years; CG: 4.8 (4.4) years Disease activity: mild to moderate Number randomised: IG: 51; CG: 51 Number reaching end of study: IG: 48; CG: 47 Number analysed: IG: 48; CG: 47 Postrandomisation exclusion: IG: 3; CG: 4 ("Subjects who received less than 80% (29 times) of treatment units were considered to have dropped out")
Interventions	IG: The observation group was treated with medicine‐separated moxibustion combined with acupuncture, both of which were performed simultaneously. CG: The control group was treated with wheat bran‐separated moxibustion combined with shallow acupuncture, both of which were performed simultaneously.
Outcomes	Length of intervention: 12 weeks Primary outcomes: Abdominal pain frequency and intensity: Pain (extent, frequency, time) was evaluated using Traditional Chinese Medicine symptom scores which were divided into the following grades according to symptom severity: 0 (none), 1 (light), 2 points (moderate), 3 points (severe). Withdrawal due to adverse events Secondary outcomes: Serious adverse events Total adverse events
Notes	Funding source: NS Conflict of interest: NS Author contact details: wuhuangan@126.com Study was translated from Chinese by a translator.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Randomisation was done using random number tables.
Allocation concealment (selection bias)	Unclear risk	Not mentioned. Authors were contacted but provided no response.
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Not mentioned. Authors were contacted but provided no response.
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Not mentioned. Authors were contacted but provided no response.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Data were presented for all participants who completed the study; however, baseline values do not include dropouts.
Selective reporting (reporting bias)	Low risk	All prespecified outcomes are reported in the results.
Other bias	High risk	There are no declarations of conflicts of interest and funding, but the authors do not present a clear picture of the efficacy of acupuncture in their introduction. Also, the authors mention that there were no significant differences at baseline, but using a t‐test the baseline differences for gender are actually significant.

*Study characteristics*
Methods	RCT Setting: multicentre, hospitals in the UK Study period: February 2011 to May 2012 The study presents results for the IBD cohort as a whole, does not separate between CD and UC. Where separate data do exist they are presented below.
Participants	Inclusion criteria: age 18 to 65 years, diagnosis of UC or CD that was in remission based on a clinical index score and a C‐reactive protein level < 10 mg/L, and the presence of IBS‐type symptoms or a high perceived stress level Exclusion criteria: pregnancy, the presence of ileostomy or colostomy, previous colectomy, change in IBD medication (including use of steroids) within 3 months of study entry, change in psychotropic medication within 3 months of study entry, diagnosis of cognitive impairment, and previous psychological therapy Age (mean ± SD): IG: 44.4 +/‐ 11.7; CG: 45.4 +/‐ 10.6 Sex (M/F): IG: 8/25; CG: 7/26 Site of disease: CD: IG: ileal 2; ileo‐colonic 3; colonic 4 CG: ileal 4; ileo‐colonic 4; colonic 4 UC: IG: proctitis 6; left‐sided 14; pan‐colitis 4 CG: proctitis 5; left‐sided 14; pan‐colitis 2 Use of concurrent medication: IG: 5‐ASA 23; immunosuppressants 8; biologics 3 CG: 5‐ASA 22; immunosuppressants 13; biologics 0 Disease duration: NS Disease activity: remission. Clinical remission was assessed using SCCAI for UC and HBI for CD. Biochemical remission was assessed based on faecal calprotectin levels. Number randomised: IG: 33; CG: 33 (UC = 45, CD = 21) Number reaching end of study: IG: 16; CG: 28 Number analysed: ITT IG: 23; ITT CG: 28 PP IG: 16; PP CG: 30 Postrandomisation exclusion: IG: 14; CG: 1
Interventions	IG: multi‐convergent therapy combining mindfulness with cognitive behavioural therapy. The multi‐convergent therapy course consisted of 6 face‐to‐face sessions, each lasting 40 min, taking place over a 16‐week period. CG: no treatment Both groups received standard medical treatment throughout.
Outcomes	Length of intervention: 12 months Primary outcomes: Pain frequency and intensity: Improvement on the IBS‐SSS, which includes frequency and severity of abdominal discomfort, severity of abdominal bloating, satisfaction with bowel habit, and impact of symptoms on life in general. Each domain is scored 0 to 100, with an overall score of 0 to 500 obtained. A higher score is indicative of more severe symptoms. Withdrawal due to adverse events Secondary outcomes: Anxiety/depression: measured on the HADS
Notes	Funding source: National Institute for Social Care and Health Research (NISCHR) Conflict of interest: Authors declare there are no conflicts of interest. Author contact details: jamesberrill1@doctors.org.uk
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	A blocked randomisation process using random permuted blocks of sizes 4 and 6 (selected at random) was generated by the South East Wales Trials Unit.
Allocation concealment (selection bias)	Low risk	The sequences were put into sequentially numbered, sealed, opaque envelopes for use in the clinic.
Blinding of participants and personnel (performance bias) All outcomes	High risk	Not possible for this type of intervention
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	No mention of who performed the assessments or if they were blinded. We contacted the author for this information but received no response.
Incomplete outcome data (attrition bias) All outcomes	High risk	High number of participants in the IG discontinued the study.
Selective reporting (reporting bias)	Unclear risk	Primary outcome is reported on, but most outcomes outlined in the methods were not presented in the results. We contacted the authors but received no response.
Other bias	Low risk	No conflicts of interest and well‐balanced baseline characteristics, despite age differences

*Study characteristics*
Methods	RCT, single‐blind, placebo controlled Setting: multicentre, 2 gastroenterology clinics in the UK Study period: February 2016 to May 2017 The study presents results for the IBD cohort as a whole, does not separate between CD and UC. Where separate data do exist they are presented below.
Participants	Inclusion criteria: Eligible patients were 18 years of age, with quiescent CD or UC, experiencing ongoing gut symptoms and naïve to low FODMAP diet. Ongoing gut symptoms were required to meet the Rome III criteria for either diarrhoea predominant (IBS‐D), mixed subtype (IBS‐M), or unsubtyped IBS (IBS‐U), functional bloating, or functional diarrhoea, experiencing abdominal pain, bloating, and/or diarrhoea on 2 days during the baseline screening week and reporting inadequate relief of gastrointestinal symptoms. Exclusion criteria: Patients with dose changes of azathioprine, mercaptopurine, methotrexate, or biologics in the preceding 12 weeks; oral 5‐ASA in the preceding 4 weeks; or antibiotics, probiotics, or prebiotics in the preceding 8 weeks were excluded. Patients with pure perianal CD, a current stoma, previous extensive gastrointestinal resection, or a current stricture were excluded. Patients with established bile acid malabsorption were excluded because gut symptoms relating directly to bile acid malabsorption may not be modifiable by a low FODMAP diet. Patients with constipation‐predominant symptoms were excluded because these symptoms could be exacerbated by a low FODMAP diet. Patients with self‐reported lactose intolerance were included if they continued to experience gut symptoms despite low‐lactose diet. Patients were excluded if they had significant comorbidities, or if they were pregnant or lactating. Age (mean ± SD): IG: 33 (11); CG: 40 (13) Sex (M/F): IG: 10/17; CG: 13/12 Site of disease: IG: CD: ileal 4, colonic 4, ileocolonic 6; UC: proctitis: 6, left‐sided: 4, extensive: 3 CG: CD: ileal 2, colonic 4, ileocolonic 6; UC: proctitis: 3, left‐sided: 7, extensive: 3 Use of concurrent medication: IG: mesalamine 12, thiopurine 9, infliximab 10, adalimumab 2, vedolizumab 0, methotrexate 2 CG: mesalamine 11, thiopurine 12, infliximab 4, adalimumab 4, vedolizumab 1, methotrexate 1 Disease activity: quiescent. Quiescent IBD was defined by all of the following: physician global assessment, stable medications, no IBD flare in the previous 6 months, faecal calprotectin < 250 mg/g, and serum CRP < 10 mg/L. The threshold for faecal calprotectin was chosen according to evidence proposing optimal sensitivity and specificity for detecting endoscopically quiescent disease. Disease duration: IG: 7 years; CG: 11 years Number randomised: IG: 27 (UC: 13, CD: 14) CG: 25 (UC: 13, CD: 12) Number reaching end of study: (PP) IG: 24, IG: 22 Number analysed: (ITT) IG: 27, IG: 25 Postrandomisation exclusion: IG: 3 (1 withdrew consent, 1 antibiotics, 1 steroids); CG: 3 (1 withdrew consent, 1 pregnancy, 1 steroids)
Interventions	IG: low FODMAP diet. The diet involves the restriction of dietary fructans, galacto‐oligosaccharides, lactose, fructose in excess of glucose, and polyols, including sorbitol and mannitol. CG: sham diet. The selection of an appropriate control group and difficulties in masking intervention and control are challenging in dietary intervention studies, but for research on dietary advice (which most closely mimics clinical practice), 'sham' dietary advice is considered gold standard. The sham diet in this trial aimed to provide participants in the control group with an exclusion diet of similar intensity and burden to a low FODMAP diet, whilst not affecting nutrient, fibre, or FODMAP intakes. Dietary counselling for both low FODMAP diet and sham diet participants lasted approximately 20 minutes, and both groups received written information.
Outcomes	Length of intervention: 4 weeks Primary outcomes: Abdominal pain frequency and intensity: measured in days using the IBS‐SSS and in days where pain was reported as moderate or severe in GSRS at the final week of the diet (As the authors only presented SEM and not SD, we calculated the SD with the formula SD = SEM√randomised participants for the measurements below) Withdrawal due to adverse events Secondary outcomes:* Serious adverse events Total adverse events
Notes	Funding source: The study was funded by the Kenneth Rainin Foundation (Innovator and Breakthrough awards). The Kenneth Rainin Foundation had no role in the study design, data collection, data analysis, data interpretation, or writing of the manuscript. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication. Conflict of interest: Authors Kevin Whelan and Miranda C Lomer are the co‐inventors of a mobile application to assist patients following the low FODMAP diet. Kevin Whelan has received consultancy fees from Danone, and a research grant from Clasado. The remaining authors have no conflicts to disclose. Author contact details: kevin.whelan@kcl.ac.uk
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	A random allocation sequence was prepared online (www.sealedenvelope.com) by an independent researcher using block randomisation, with a 1:1 ratio of low FODMAP to placebo sham diet. Randomisation was stratified by diagnosis (CD or UC) and faecal calprotectin at screening (100 mg/g and 101 to 249 mg/g).
Allocation concealment (selection bias)	Low risk	Allocation sequences were sealed in opaque envelopes.
Blinding of participants and personnel (performance bias) All outcomes	High risk	"Participants were blinded to diet allocation and informed that both diets would change the types of carbohydrates consumed, but that one was the diet under investigation, whereas the other was a sham diet. The terms 'fermentable carbohydrates,' 'low FODMAP diet,' or the mechanisms of the diet were not mentioned to participants." However, personnel were unblinded.
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Not stated. We contacted the author for this information but received no response.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Data are presented for all participants.
Selective reporting (reporting bias)	Low risk	Outcomes were presented as per trial registration and methods.
Other bias	Low risk	Authors have disclosed conflicts of interest. Baseline characteristics are balanced.

*Study characteristics*
Methods	RCT, single‐blind Setting: single centre, hospital in Spain Study period: May 2016 to June 2016
Participants	Inclusion criteria: aged between 18 and 62 years, diagnosed with CD at least 1 year before, and presenting abdominal pain and receiving usual treatment with an adequate diet Exclusion criteria: non‐specific inflammatory bowel pain, abdominal tenderness, infection, ischaemia, physical damage, specific immunologic sensitivity, pregnancy, or breastfeeding mothers Age (mean ± SD): IG: 42.56 +/‐ 10.09; CG: 40.14 +/‐ 12.32 Sex (M/F): IG: 8/8; CG: 2/12 Site of disease: NS Use of concurrent medication: NS Disease activity: Data not shown, even though authors mention the data had been measured and used for their analysis. Disease duration: NS Number randomised: IG: 16; CG: 14 Number reaching end of study: IG: 16; CG: 14 Number analysed: IG: 16; CG: 14 Postrandomisation exclusion: IG: 0; CG:0
Interventions	IG: Soft non‐manipulative osteopathic including soft tissue techniques over 30 days. Participants were treated once every 10 days. The sessions lasted 45 minutes and were conducted by a physiotherapist who had extensive experience in manual therapy. The intervention included 6 techniques: frontal‐occipital cranial technique, cranial temporal rotation technique, neuro‐lymphatic reflexes technique, viscerosomatic reflexes technique, myofascial induction technique, visceral technique. Following the intervention, participants remained in supine position with a neutral head and neck position for 10 minutes, in order to obtain relaxation and diminish tension after treatment. CG: The CG only came to the evaluation sessions and received no treatment besides that recommended by the doctor.
Outcomes	Length of intervention: 30 days Primary outcomes: Abdominal pain intensity: Pain was assessed with the VAS, where participants marked their level of pain intensity on a 10‐centimetre horizontal line (0 = no pain to 10 = maximum pain) at the time the assessment was carried out. However, it is not clear if the VAS results were reported. Withdrawal due to adverse events Secondary outcomes: Serious adverse events Total adverse events
Notes	Funding source: NS Conflict of interest: The authors declare that they have no conflicts of interest. Author contact details: gemma.espi@uv.es
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Participants were randomly allocated to 2 different groups through computer software by an external assistant who was blinded to the study objectives.
Allocation concealment (selection bias)	Low risk	Participants were randomly allocated to 2 different groups through computer software by an external assistant who was blinded to the study objectives.
Blinding of participants and personnel (performance bias) All outcomes	High risk	Blinding is not possible for this type of intervention.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	1 physiotherapist performed the assessments and was unaware of the groups to which participants belonged. To reduce bias, participants were instructed not to tell the physiotherapist about the treatment they had received. The statistician was also blinded to the goals of the study.
Incomplete outcome data (attrition bias) All outcomes	Low risk	All reached study end
Selective reporting (reporting bias)	High risk	There is a lack of description of results in both text and table, and what is presented is unclear and different to what was originally planned.
Other bias	Low risk	The authors mention no significant difference between groups in pain baseline scores. There is no mention of funding, but authors declare no conflicts of interest.

PERMALINK

Interventions for the management of abdominal pain in Crohn's disease and inflammatory bowel disease

Vassiliki Sinopoulou

Morris Gordon

Anthony K Akobeng

Marco Gasparetto

Michael Sammaan

Jessica Vasiliou

Terence M Dovey

Abstract

Background

Objectives

Search methods

Selection criteria

Data collection and analysis

Main results

Authors' conclusions

Plain language summary

Summary of findings

Background

Description of the condition

Description of the intervention

Pharmacological interventions

Non‐pharmacological interventions

How the intervention might work

Why it is important to do this review

Objectives

Methods

Criteria for considering studies for this review

Types of studies

Types of participants

Types of interventions

Types of outcome measures

Primary outcomes

Secondary outcomes

Search methods for identification of studies

Electronic searches

Searching other resources

Data collection and analysis

Selection of studies

Data extraction and management

Assessment of risk of bias in included studies

Measures of treatment effect

Unit of analysis issues

Dealing with missing data

Assessment of heterogeneity

Assessment of reporting biases

Data synthesis

Subgroup analysis and investigation of heterogeneity

Sensitivity analysis

Summary of findings and assessment of the certainty of the evidence

Results

Description of studies

Results of the search

1.

Included studies

Setting

Participants

Interventions

Outcomes

Primary outcomes

Treatment success as defined by the authors

Abdominal pain frequency or change in frequency of pain

Abdominal pain intensity or change in pain intensity using any validated scale

Withdrawal due to adverse events

Secondary outcomes

Anxiety/depression

Adverse events (total number of participants with any event)

Serious adverse events (as defined by the authors within the primary study )

Funding sources and conflicts of interest

Excluded studies

Risk of bias in included studies

2.

3.

Allocation

Blinding

Incomplete outcome data

Selective reporting

Other potential sources of bias

Effects of interventions

*Study characteristics*
Methods	RCT Setting: Spain, single centre, Inflammatory Intestinal Disease Unit of Asturias Central Hospital Study period: NS
Participants	Inclusion criteria: non‐active stage of the illness (HBI) and receiving pharmacological treatment with sulfasalazine (5‐ASA compounds), no dietary restrictions Exclusion criteria: dietary restrictions, as variability of these was considered to be a potential cause of error in the results Age (mean ± SD): IG: SM: 28.7 +/‐ 6.4 (19 to 52) IG: SDSM: 31 +/‐ 5.7 (22 to 40) CG: 35.3 +/‐ 9.1 (20 to 52) Sex (M/F): IG: SM: 5/10, SDSM: 5/10 CG: 6/9 Site of disease: NS Use of concurrent medication: NS Disease activity: non‐active. All participants had been diagnosed and treated in the Inflammatory Intestinal Disease Unit of Asturias Central Hospital (Spain). The evaluation was done by a physician on the basis of clinical history, physical examination, and radiological and laboratory tests. Disease duration: IG: SM: 5.6 +/‐ 6 (1 to 26 years) (text says 1 to 32 years range) CG: 8.2 +/‐ 5.7 (1 to 21 years) Number randomised: IG: SM: 15, SDSM: 15 CG: 15 Number reaching end of study: IG: SM: 13, SDSM: 14 CG: 13 Number analysed: IG: SM: 15, SDSM: 15 (2 groups) CG: 15 Postrandomisation exclusion: not clear 5 (2 SM, 1 SDSM, 2 CG)
Interventions	IG 1: SM: Stress management group. The aim of this treatment was to provide the participant with effective techniques to mitigate the physiological effects of stress and tension, and to modify or improve his/her coping skills. IG 2: SDSM: Self‐directed stress management group. This condition was similar to stress management, but the participant was his/her own therapist. Participants followed a self‐directed stress management programme according to a written guide on stress management procedures. Treatment of participants in the 2 experimental groups consisted of 8‐week individual sessions led by the same psychologist. The first 2 sessions were dedicated to the psychological evaluation of each participant in all 3 groups, establishment of the baseline symptomatology, and providing the participant basic information about gastrointestinal function. The remaining 6 sessions depended on the treatment group to which the participants had been allocated. It is unclear whether IG group 1 and 2 received conventional therapy as per the control group. There is no mention of any concurrent therapies or what the standard care protocol was. We wrote to the authors for clarity on this matter but received no response. CG: Participants in the control group received conventional medical treatment and did not receive any other special therapy. As mentioned above, participants attended the first and second visit to the therapist, at which they completed the semi‐structured interview and the symptoms self‐monitored in this period were recorded.
Outcomes	Length of intervention: 8 weeks of intervention and follow‐up again at 6 and 12 months Primary outcomes: Pain intensity: average intensity symptom (AIS) = sum of the daily symptom intensities/number of symptomatic days Secondary outcomes: None reported
Notes	Funding source: NS Conflict of interest: NS Author contact details: elenagv@correo.uniovi.es
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	The authors mention that sequence generation was random but do not explain how this was done. We contacted the author for this information but received no response.
Allocation concealment (selection bias)	Unclear risk	Not mentioned. We contacted the author but received no response.
Blinding of participants and personnel (performance bias) All outcomes	High risk	Not possible for this type of intervention
Blinding of outcome assessment (detection bias) All outcomes	Low risk	"All patients were assessed and treated by the same gastroenterologist and the same psychologist", "The 6 month check‐up was carried out by a gastroenterologist who did not know to which experimental group the patient belonged", "The 12 month check‐up was carried out by the gastroenterologist and the psychologist"
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	The data presented are not for all randomised participants; the number of dropouts can be inferred, but more details are needed. We contacted the author for this information but received no response.
Selective reporting (reporting bias)	Unclear risk	The statistical analysis methods are presented in the results section; indices are presented instead of raw data; and there are no pain intensity results, no protocol, and methods are unclear. We contacted the author for clarification but received no response.
Other bias	High risk	There is a considerable baseline difference between the SM and SDSM groups for abdominal pain frequency.

*Study characteristics*
Methods	RCT, placebo controlled Setting: unstated (centres in the UK) Study period: November 1998 to November 2000
Participants	Inclusion criteria: Patients with a CDAI of > 150 and < 450 were identified after an initial interview and completion of a diary card for symptoms over 2 weeks. All participants were more than 16 years of age, with CD involving colon proximal to the rectosigmoid junction and/or distal small intestine (verified by colonoscopy, barium, or white cell scan studies). No participants were on maintenance doses of prednisolone greater than 20 mg, and all treatment, including 5‐ASA, azathioprine, and metronidazole, had remained unchanged for at least 6 weeks before entrance in the trial. Exclusion criteria: Previous surgical resection of ileum > 100 cm, the presence of an ileostomy, pouch, or colostomy, and a history of significant cardiac (especially hypertrophic obstructive cardiomyopathy, aortic or mitral valve stenosis, constrictive pericarditis or hypotensive episodes), respiratory, endocrine, renal, hepatic, neurological or psychiatric disease. Other exclusion criteria included significant coexisting gastrointestinal disease, anaemia, glaucoma, total parenteral nutrition, and patients already taking nitrates or calcium antagonists. Pregnancy, breastfeeding, participation in an interventional study within the past 3 months, or any factor likely to result in poor compliance with the study protocol were also reasons for exclusion. Age (mean ± SD): IG: 42.9 (15.1) CG: 35.8 (12.6) Sex (M/F): IG: 12/22 CG: 10/26 Site of disease: IG: small bowel only: 16, large bowel only: 3, both small and large bowel: 14, not known: 1 CG: small bowel only: 20, large bowel only: 2, both small and large bowel: 11, not known: 3 Use of concurrent medication: IG: Salicylates: 19 Prednisolone (or equivalent): (up to 5 mg) 6, (5 to 10 mg) 6, (10 to 20 mg) 7 Azathioprine: 7 CG: Salicylates: 22 Prednisolone (or equivalent): (up to 5 mg) 5, (5 to 10 mg) 3, (10 to 20 mg) 7 Azathioprine: 9 Disease activity: moderate‐severe CDAI of > 150 and < 450 verified by colonoscopy, barium, or white cell scan studies Disease duration IG: 10.9 (11.9) CG: 8 (7) Number randomised: IG: 34; CG: 36 Number reaching end of study: IG: 24; CG: 29 Number analysed: IG: 31; CG: 35 Postrandomisation exclusion: IG: 10 (headache 2, worsening clinical condition 4, generalised rash 1, mood change/irritability 1, loss of consciousness/memory 1, patient request 0, poor compliance 1) CG: 7 (headache 2, worsening clinical condition 1, generalised rash 0, mood change/irritability 0, loss of consciousness/memory 0, patient request 2, poor compliance 2)
Interventions	IG: GTN (enteric‐release glyceryl trinitrate) The study medication contained 3 mg of GTN dispersed in a polyglycolised triglyceride (Gelucire, Gattefosse) wax matrix, designed to produce both a delayed and sustained release of the drug. The matrix was contained in a size 1 hard gelatin capsule coated with Eudragit‐L (Rohm Pharma), an acrylic resin with an optimal dissolution at pH 6.8, which allowed the release of GTN to commence in the distal small bowel (pH 6.8) and continue through to the large bowel (pH 7.2). Those in the active treatment group were given GTN 6 mg twice daily for the first 6 weeks; if this was well tolerated, the dose was increased to 9 mg twice daily for the remaining 6 weeks. CG: placebo. "Identical placebo was used"
Outcomes	Length of intervention: 12 weeks Primary outcomes: Abdominal pain intensity: scores represent the sum of the previous 7‐day diary card score: for pain, on a scale of 0 = no pain to 3 = severe pain Withdrawal due to adverse events Secondary outcomes: Serious adverse events Total adverse events
Notes	Funding source: The trial capsules were produced by MW Encap Ltd, Livingston, UK. Drs Hawkes and Richardson were supported by the Gastrointestinal Foundation Trust. Conflict of interest: NS Author contact details: (email contact is out of date, we could not find any other contact details for authors) drjohnrhodes@cardiff40.freeserve.co.uk
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Participants were randomised according to a computer‐generated sequence.
Allocation concealment (selection bias)	Unclear risk	Not mentioned. Emails to the author went undelivered, and we could not identify any contact details for the other authors.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	The authors mention that an identical placebo was used to ensure that both the trial investigator and participant remained blind to the treatment allocation; no further details were provided.
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Not mentioned. Emails to the author went undelivered, and we could not identify any contact details for the other authors.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Data are presented for all participants included in ITT.
Selective reporting (reporting bias)	Low risk	All outcomes specified in methods were reported in results and were appropriate for the trial.
Other bias	Unclear risk	The authors mention baseline differences for smokers, which could have affected the results. Emails to the author went undelivered, and we could not identify any contact details for the other authors.

*Study characteristics*
Methods	RCT, open‐label parallel‐group, phase 2a Setting: unstated (multicentre, USA) Study period: NS
Participants	Inclusion criteria: 18 to 80 years of age; diagnosed with CD for 3 months; quiescent to mild inflammation (simple endoscopic score CD < 10 or faecal calprotectin < 500 μg/g); average abdominal pain score 4 over 1 week; if taking concomitant biologic or anti‐inflammatory therapies for CD, must be on a stable dose Exclusion criteria: NS Age (mean ± SD): IG: 36.9 (15.2); 35 (10.8) Sex (M/F): IG: 4/4; CG: 2/4 Site of disease: IG: ileum: 7, colon: 5, rectum: 2, perianal: 2; CG: ileum: 3, colon: 4, rectum: 1, perianal: 1 Use of concurrent medication: IG: on active treatment: 7; CG: on active treatment: 5 Disease activity: quiescent (simple endoscopic score CD < 10 or faecal calprotectin < 500 μg/g) Disease duration (years ± SD): IG: 8.8 (8.9); CG: 15 (6.4) Number randomised: IG: 8; CG: 6 Number reaching end of study: IG: 8; CG: 6 Number analysed: IG: 8; CG: 6 Postrandomisation exclusion: IG: 3 (lost to follow‐up 1, withdrew consent 1, other 1); CG: 0
Interventions	IG: 100 mg olorinab 3 times/day CG: 25 mg olorinab 3 times/day
Outcomes	Length of intervention: 8 weeks and follow‐up visit at week 10 Primary outcomes: Treatment success as defined by the authors:Efficacy endpoints included change in AAPS (average abdominal pain score) from baseline week (BL) to weeks 4 and 8, change in AAPS from pre‐dose to 1.5 hours postdose, proportion of clinical responders (≥ 30% reduction in weekly AAPS from BL), pain‐free days, and CD Patient‐Reported Outcome (CD‐PRO) scores. Abdominal pain intensity: measured at 1.5 hours postdose and as change in AAPS from BL to the time of peak concentration during Week 8 Withdrawal due to adverse events Secondary outcomes: Serious adverse events Total adverse events
Notes	Funding source: Arena Pharmaceuticals, Inc Conflict of interest: 1 of the authors is an employee of Arena Pharma. Medical writing assistance was provided by ApotheCom. Author contact details: bruce.yacyshyn@louisville.edu
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	NS. Also, both groups using the same medication in different doses, which in a sense negates the control factor. We contacted the author but received no response.
Allocation concealment (selection bias)	Unclear risk	NS. We contacted the author for this information but received no response.
Blinding of participants and personnel (performance bias) All outcomes	High risk	Open‐label study
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	NS. We contacted the author for this information but received no response.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Data presented for all participants but in a confusing way.
Selective reporting (reporting bias)	Unclear risk	Data presented as 1 cohort at various points. The reporting of the results and adverse events is unclear and needs clarification. We contacted the author but received no response.
Other bias	High risk	An employee of Arena Pharmaceuticals is an author, also there are some differences between groups in disease duration at baseline.

*Study characteristics*
Methods	RCT Setting: Hadassah Medical Center in Jerusalem Study period: NS The study presents results for the IBD cohort as a whole, does not separate between CD and UC. Where separate data do exist they are presented below.
Participants	Inclusion criteria: (1) confirmed diagnosis of IBD for at least 6 months prior to recruitment; (2) age over 18 years; (3) suffering from an "active" disease according to the "Disease Activity Questionnaire", by meeting 1 of the following criteria: more than 5 bowel movements a day, more than 1 hospitalisation a year over the previous 2 years, and had either suffered a fistula during the previous year or was using corticosteroids; (4) provided informed consent; (5) fluent in the Hebrew language Exclusion criteria: (1) expected surgery in the following 2 months; (2) diagnosed as suffering from an active psychosis or from active major depression (due to the hazard of psychotic‐symptom‐abreactions this would be contraindicative for relaxation); (3) undergoing psycho‐pharmacotherapy (anti‐anxiety, antidepression, or antipsychotic); (4) already participating in another research study; (5) acquainted with and already practicing relaxation techniques Age (mean ± SD): IG: 35.56 (14.45); CG: 35.57 (12.76) Sex (M/F): IG: 9/9: CG: 13/8 Site of disease: NS Use of concurrent medication: IG: without medication 2, corticosteroids 3, 5‐ASA 13, immunosuppressive drugs 5, alternative treatment 5 CG: without medication 4, corticosteroids 1, 5‐ASA 12, immunosuppressive drugs 8, alternative treatment 10 Disease duration: NS Disease activity: active Number randomised: IG: 28; CG: 28 Number reaching end of study: IG: 18 (CD: 10, UC: 8); CG: 21 (CD: 14, UC: 7) Number analysed: IG: 18; CG: 21 Postrandomisation exclusion: 17 IG: 10 (medical reasons, time constraints, failing to return questionnaires) CG: 7 (failing to return questionnaires)
Interventions	IG: Relaxation training. The intervention consisted of 3 individual relaxation‐training sessions at 2‐week intervals. Relaxation training with guided imagery served as the basis for the three 50‐minute treatment sessions. Each treatment session included: (1) a relaxation exercise with guided imagery, (2) a brief review of the relaxation monitoring forms, used to assess difficulties, and (3) a discussion of any problems the participant may have experienced whilst attempting to achieve relaxation. Each participant received an audio disc and was asked to continue to practice at home. Participants were advised to practice at least once a day during the 5‐week period of the study and to record the frequency of home practice in the provided log sheets. CG: Waitlist. The control participants on the waiting list were assessed at baseline and approximately 5 weeks later at the end of the waitlist period. Participants completed symptom‐monitoring diaries both at baseline and at the end of the trial. After completion of the diaries and following analysis of the collected data, the control participants were offered treatment in a group setting.
Outcomes	Length of intervention: 5 weeks Primary outcomes: Pain intensity was measured using 10‐centimetre VAS. The time scale referred to the 24 hours prior to assessment. VAS measurements evaluate changes in a person’s subjective perception. The overall scores for each measurement ranged from 0 to 10, with a higher score reflecting a worse state as perceived by the participant. Secondary outcomes: Anxiety/depression
Notes	Funding source: NS Conflict of interest: NS Author contact details: erang@szmc.org.il
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Not mentioned. We contacted the authors but received no response.
Allocation concealment (selection bias)	Unclear risk	Not mentioned. We contacted the authors but received no response.
Blinding of participants and personnel (performance bias) All outcomes	High risk	Not possible for this type of intervention
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Not mentioned. We contacted the authors but received no response.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Data were presented for all participants who completed the study; however, baseline characteristics do not include the participants who dropped out.
Selective reporting (reporting bias)	Low risk	All outcomes were presented in the results.
Other bias	High risk	"Statistically significant differences were found on the pain measurements between the groups at pre‐treatment, with the treatment group demonstrating higher levels of pain"

*Study characteristics*
Methods	RCT Setting: single centre, gastroenterology unit in Turkey Study period: NS The study presents results for the IBD cohort as a whole, does not separate between CD and UC. Where separate data do exist they are presented below.
Participants	Inclusion criteria: diagnosed with IBD at least 6 months ago, able to use computer, Internet, and mobile phone, 18 years of age and over Exclusion criteria: patients with advanced comorbid diseases such as cancer, diabetes, chronic obstructive pulmonary disease, hypertension were excluded from the study since symptoms, disease activity, and quality of life would be affected at a different level. Age (mean ± SD): IG: 37.26 (12.99) CG: 41.63 (11.85) Sex (M/F): IG: 17/13 CG: 18/12 Site of disease: NS Use of concurrent medication: NS Disease activity: mix of active and inactive; the Mayo Score was used for UC and the HBI for CD Disease duration: IG: n = 7 (less than 36 months); n = 12 (less than 71 months); n = 11 (greater than 72 months) CG: n = 10 (less than 36 months); n = 6 (less than 71 months); n = 14 (greater than 72 months) Number randomised: IG: 30 (UC: 16, CD: 14); CG: 30 (UC: 16, CD: 14) Number reaching end of study: IG: 30; CG: 30 Number analysed: IG: 30; CG: 30 Postrandomisation exclusion: IG: 0; CG: 0
Interventions	IG: 8 weeks of web‐based education about UC and CD CG: 8 weeks of standard book‐based education about UC and CD The content and scope of the web‐based and standard education programmes carried out with IBD patients were prepared by the researcher to be exactly the same in line with the literature. Definitions, anatomy, and physiology, indications, diagnostic tests, treatment principles, the importance of drug use, nutritional principles, and specific descriptions for special cases such as pregnancy, sexuality, and puberty are included in the content of the education. A website was designed for the web‐based education group, and all information was presented to the user with different interfaces. The standard education group received education via easy‐to‐read, illustrated, colour‐printed books.
Outcomes	Length of intervention: 8 weeks Primary outcomes: Pain intensity was measured using VAS scoring system. Participants were asked to rate symptoms experienced in the last 3 months as "0 None" and "10 unendurable". Any reduction in scores was considered a success Withdrawal due to adverse events Secondary outcomes: Serious adverse events
Notes	Funding source: The authors declare no financial support. Conflicts of interest: The authors declare no conflicts of interest. Author contact details: bernanilgun@gmail.com
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	According to author correspondence, randomisation was done using a simple stratified randomisation method.
Allocation concealment (selection bias)	Unclear risk	Not mentioned. We contacted the authors but received no response.
Blinding of participants and personnel (performance bias) All outcomes	High risk	Not possible for this type of intervention
Blinding of outcome assessment (detection bias) All outcomes	Low risk	According to author correspondence, the analysis was done by a blinded biostatistics specialist.
Incomplete outcome data (attrition bias) All outcomes	Low risk	All outcomes are presented in the results.
Selective reporting (reporting bias)	Low risk	All outcomes are presented in the results.
Other bias	Low risk	No conflicts of interest, and baseline characteristics were balanced between groups

*Study characteristics*
Methods	RCT Setting: single centre, All India Institute of Medical Science (AIIMS), New Delhi, India Study period: 2004 to 2008
Participants	Inclusion criteria: Only patients between 16 and 60 years of age who were in the clinical remission phase of the disease were included in the study. UC and CD activity was assessed using the criteria of Truelove and Witts (1955) and the CDAI (Best and colleagues, 1976), respectively. The inclusion criteria for UC patients in the remission phase were (a) 1 or 2 stools a day without blood, (b) no fever, (c) no tachycardia, (d) haemoglobin normal or returning towards normal, and (e) ESR normal or returning towards normal. Patients with a CDAI score < 150 were considered to be in remission. Exclusion criteria: (a) IBD patients with other chronic diseases such as diabetes mellitus, hypertension, or cardiovascular disease, (b) any condition known to affect the cardiovascular autonomic functions such as chronic alcoholism or smoking, (c) patients who have undergone any surgical intervention for IBD, (d) pregnant women, (e) patients on any drug regimen affecting autonomic functions, (f) patients on psychiatric medication, and (g) patients who had practiced yoga within at least 1 year preceding the study Age (mean ± SD): NS Sex (M/F): NS Site of disease: NS Use of concurrent medication: NS "There were no significant differences between the medication used by the yoga and control groups" Disease activity: clinical remission phase The diagnosis of UC was established on the basis of clinical evidence of large bowel diarrhoea, haematochezia and tenesmus; endoscopic evidence of diffuse pattern of involvement of the gastrointestinal mucosa characterised by loss of vascular pattern, erythema, friability, or ulcerations; and histological evidence. The diagnosis of CD was established on the basis of the presence of characteristic clinical manifestations (chronic diarrhoea, haematochezia, abdominal pain, and intestinal obstructive manifestations), endoscopic features (skip lesion, asymmetrical involvement, deep ulcers, ileocaecal valve involvement, and terminal ileum involvement), together with histological evidence (acute or chronic colitis, presence of inflammation extending beyond muscularis mucosa, lymphoid follicles, and noncaseating granulomas). The involvement of the small intestine was assessed by barium meal follow‐through, small bowel enema, and/or retrograde ileoscopy. Disease duration: NS Number randomised: IG: 50 (UC: 30, CD: 20) CG: 50 (UC: 30, CD: 20) Number reaching end of study: IG: UC: 25, CD: 19 CG: UC: 26, CD: 17 Number analysed: IG: 44 (UC: 25, CD: 19) CG: 43 (UC: 26, CD: 17) Postrandomisation exclusion: IG: UC: 5 (relocation to another city 1, pregnancy 2, increased disease activity 1, lost contact 1) CD: 1 (bone fracture) CG: UC: 4 (increased disease activity 2, relocation to another city 1, started alternative therapy 1), CD: 3 (lost contact 1, busy schedule 1, increased disease activity 1)
Interventions	IG: yoga intervention. This was comprised of physical postures, pranayama (controlled breathing), and meditation. The supervised yoga intervention (1 week for 1 hour daily) was given under the guidance of a certified yoga trainer. Due to feasibility reasons, the supervised yoga training was provided for 1 week (each session for 1 hour) followed by a daily practice at home continuously over 2 months (1 hour daily). All participants continued standard medical treatment. A single yoga session was offered individually to participants during the follow‐up visits. During the home practice sessions, participants listened to the audio recording for relaxation; an instruction manual on different postures was also provided to all participants. CG: no treatment. The standard pharmacological treatment was used by all participants for maintenance of disease remission in both groups. All participants were treated with maintenance doses of mesalamines and azathioprine, along with multivitamins and calcium supplements. Telephone support was provided to both groups to motivate a high degree of compliance.
Outcomes	Length of intervention: 8 weeks (outcomes recorded at baseline, 1 month, 2 months) Primary outcomes: Treatment success as defined by the authors: change from presence to absence of pain Participants were given a symptom diary at the beginning of the study in which they were asked to record the presence or absence of clinical symptoms. In accordance with the wide range of proposals for indices of clinical activity of IBD, the following symptoms were considered: blood, tenesmus, intestinal colic, perianal pain, arthralgia, and anorexia. Participants were asked to fill the self‐report form once per day before going to bed. Withdrawal due to adverse events Secondary outcomes: Serious adverse events Total adverse events
Notes	Funding source: Central Council for Research in Yoga and Naturopathy (CCRYN), New Delhi, India Conflict of interest: The authors declare that they have no competing interests. Author contact details: purnimareceives@gmail.com
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Group assignment was determined by a randomisation scheme devised from computer‐generated random number tables. The tables were prepared by other researchers who were not involved in the study.
Allocation concealment (selection bias)	Low risk	The randomisation schedule was concealed in sequentially numbered, sealed, opaque envelopes. Participants were randomised by the research assistant.
Blinding of participants and personnel (performance bias) All outcomes	High risk	Not possible for this type of intervention
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Not mentioned. We contacted the author but received no response.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Data reported for all participants reaching end of study.
Selective reporting (reporting bias)	Unclear risk	No pain results for CD reported. All other outcomes mentioned in the methods were reported. We contacted the author but received no response.
Other bias	Low risk	No conflicts of interest, no differences at baseline

*Study characteristics*
Methods	RCT Setting: NS, Italy Study period: 2017 The study presents results for the IBD cohort as a whole, does not separate between CD and UC. Where separate data do exist they are presented below.
Participants	Inclusion criteria: clinical remission (CDAI < 150 for CD and full Mayo < 3 for UC) with normal values of ESR, CRP, white blood cells and neutrophil count, but with residual intestinal symptoms (abdominal pain, bloating, and abnormal stool consistency ‐ Bristol stool classification > 5) Exclusion criteria: NS Age (mean ± SD): NS Sex (M/F): NS Site of disease: NS Use of concurrent medication: NS Disease activity: inactive Disease duration: NS Number randomised: IG: 10; CG: 20 Number reaching end of study: NS Number analysed: NS Postrandomisation exclusion: NS
Interventions	IG: low FODMAP diet CG: sham control diet
Outcomes	Length of intervention: 6 to 8 weeks Primary outcomes: Abdominal pain intensity measured on a 0‐to‐10‐centimetre VAS. Secondary outcomes: None reported
Notes	Funding source: NS Conflict of interest: NS Author contact details: g.tapete@studenti.unipi.it
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	NS. We contacted the author but received no response.
Allocation concealment (selection bias)	Unclear risk	NS. We contacted the author but received no response.
Blinding of participants and personnel (performance bias) All outcomes	High risk	Not possible for this type of intervention
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	NS. We contacted the author but received no response.
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	More information is needed. We contacted the author but received no response.
Selective reporting (reporting bias)	Low risk	The outcomes mentioned in the methods are reported in the results.
Other bias	Low risk	No apparent sources of bias; conflicts of interest are not clear, but not downgraded

*Study characteristics*
Methods	RCT, cross‐over Setting: NS, Italy Study period: NR The study presents results for the IBD cohort as a whole, does not separate between CD and UC. Where separate data do exist they are presented below.
Participants	Inclusion criteria: UC or CD with normal inflammatory parameters (CRP, white blood cells) and no clinical activity (CDAI < 150 for CD and a full Mayo < 2 for UC) but with residual abdominal symptoms (abdominal pain, diarrhoea, bloating) Exclusion criteria: patients with abdominal abscess, fistula, intestinal active bleeding, or extra‐intestinal manifestations Age (mean ± SD): total cohort: 43.9 (17) years total Sex (M/F): total cohort: 28/22 total Site of disease: NS Use of concurrent medication: All participants were being treated with intravenous biologic therapy (infliximab or vedolizumab). Disease activity: inactive Disease duration: NS Number randomised: NS per IG/CG, 50 in total (CD: 25, UC: 25) Number reaching end of study: NS per IG/CG, 47 in total Number analysed: NS per IG/CG, 47 total Postrandomisation exclusion: 3
Interventions	IG: low FODMAP diet CG: high FODMAP/normal diet
Outcomes	Length of intervention: 8 weeks cross‐over (4 weeks per arm) Primary outcomes: Abdominal pain intensity was measured on a 0‐to‐10‐centimetre VAS at the beginning, at 4 weeks (end of first cross‐over arm), and at 8 weeks (end of second cross‐over arm); it was unclear if this measured pain frequency or intensity or what range was used. Secondary outcomes: None reported
Notes	Funding source: NS Conflict of interest: NS Author contact details: g.tapete@studenti.unipi.it
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	NS. We contacted the author but received no response.
Allocation concealment (selection bias)	Unclear risk	NS. We contacted the author but received no response.
Blinding of participants and personnel (performance bias) All outcomes	High risk	Not possible for this type of intervention
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	NS. We contacted the author but received no response.
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Cohort presented as a whole, more information is needed. We contacted the author but received no response.
Selective reporting (reporting bias)	Unclear risk	The outcomes mentioned in methods are reported in the results, but there are no pre‐cross‐over data. We contacted the author for this information but received no response.
Other bias	Unclear risk	There is a difference in baseline pain levels, and conflicts of interest are not clear. We contacted the author but received no response.

*Study characteristics*
Methods	RCT, sham‐controlled Setting: single centre, Medical Department I (Gastroenterology, Infectious Diseases, Rheumatology) of the Charite‐Campus Benjamin Franklin, Germany Study period: January 2014 to December 2016 The study presents results for the IBD cohort as a whole, does not separate between CD and UC. Where separate data do exist they are presented below.
Participants	Inclusion criteria: (1) age between 18 and 80 years; (2) patients with a diagnosis of IBD (verified by medical report, discharge letter, and outpatient centre records); (3) patients with chronic abdominal pain, defined as duration of 3 months in the past 6 months; (4) patients with a pain intensity of 3/10 on the VAS Exclusion criteria: (1) had additional severe or untreated internal, neurological, or psychiatric disorders; (2) had ongoing drug/substance abuse; (3) or were pregnant and/or breastfeeding. Due to ethical considerations, participants were allowed to stay on anti‐inflammatory drugs and acute pain medication. Age (mean ± SD): IG: 40.6 (12.5) CG: 34.4 (13.2) Sex (M/F): IG: 3/7 CG: 4/6 Site of disease: NS Use of concurrent medication: IG: other anti‐inflammatory drugs 8, pain medication ‐ regular intake 7 CG: other anti‐inflammatory drugs 8, pain medication ‐ regular intake 7 Disease activity: active SCCAI or HBI (not clear which applies to which group): 7.3 (3.3) for IG and 9 (3.6) for CG Disease duration: IG: 10 (8.9) CG: 7 (4.7) Number randomised: IG: 10 (CD: 7, UC: 3); CG: 10 (CD: 7, UC: 3) Number reaching end of study: IG: 10; CG: 10 Number analysed: IG: 10; CG: 10 Postrandomisation exclusion: IG: 0; CG: 0
Interventions	IG: Transcranial direct current stimulation was applied over 5 consecutive days. It was administered through saline‐soaked surface sponge electrodes (35 cm²) and delivered by a battery‐driven constant‐current stimulator (TCT Research Limited, Hong Kong, China). Participants received anodal stimulation for 20 minutes. CG: Sham stimulation. In sham stimulation, the current flow was ramped down after 30 seconds. A constant current of 2 mA in intensity was applied.
Outcomes	Length of intervention: 5 days of intervention plus follow‐up after 1 week Primary outcomes: Pain intensity was measured with VAS pain scores. IG average pain in the last 6 months, mean VAS (0 to 10) (SD): 5.8 (1.43) IG average pain in the last 6 months, mean VAS (0 to 10) (SD): 6.3 (1.3) IG baseline: VAS, (0 to 10) (SD): 4.85 (1.7) CG baseline: VAS, (0 to 10) (SD): 4.55 (1.6) IG end of study: VAS, (0 to 10) (SD): 2.8 (2.3) IG VAS 1‐week follow‐up: difference of −1.44 (2.7) from baseline CG end of study: VAS, (0 to 10) (SD): 4.45 (1.3) CG VAS 1‐week follow‐up: difference of +0.28 (2.2) from baseline Withdrawal due to adverse events: IG: 0; CG: 0 Secondary outcomes: Total adverse events
Notes	Funding source: This study has been supported by the grant “Patienten orientier te Forschung bei CED 2014” of the “Deutsche Morbus Crohn/Colitis ulcerosa Vereinigung e.V.” (DCCV e.V.) commissioned to Magdalena Sarah Pruss geb. Volz. Conflict of interest: The authors have no conflicts of interest to declare. Author contact details: magdalena.pruess@charite.de
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Randomisation was performed by the unblinded researcher (AF) in blocks of 4 generated from a computer‐based random allocation.
Allocation concealment (selection bias)	Unclear risk	Not mentioned. We contacted the author but received no response.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Both the participant and the researcher were blinded to the intervention.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Both the participant and the assessor (who was the researcher) were blinded to the intervention.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Full data are provided for every participant.
Selective reporting (reporting bias)	Low risk	All outcomes are reported clearly.
Other bias	Low risk	No conflicts of interest, and no significant differences at baseline

*Study characteristics*
Methods	RCT Setting: unstated (single centre, Turkey) Study period: May 2015 to December 2016
Participants	Inclusion criteria: Patients with IBD participated in the study. CDAI was used for CD, and Truelove‐Witts scoring systems were used for UC for disease assessment scores (10‐11). Patients with CD whose CDAI score was < 450 were admitted to the study. Patients with UC whose Truelove‐Witts score was severe were not admitted to the study. Participants also had to be > 18 years old. Exclusion criteria: Patients with alcohol consumption > 20 g/day, allergies or intolerance to milk, antibiotic treatment within the last 1 month, column or bowel operation history up to 3 months before the start of the study, and the presence of active infection within 1 month prior to the start of the study or during the study were excluded. In addition, if a participant requested to leave on his/her own will, or if kefir was not consumed continuously for 2 weeks, the trial protocol was assessed and was not approved. Age (mean (range)): IG CD: 33 (24 to 65) CG CD: 42 (21 to 66) IG UC: 33 (19 to 68) CG UC: 43.5 (29 to 76) Sex (M/F): IG CD: 4/6 CG CD: 6/4 IG UC: 9/6 CG UC: 4/6 Site of disease: IG CD: colon: 1; ileum: 6; colon + ileum: 3 CG CD: colon: 0; ileum: 10; colon + ileum: 0 IG UC: colon: 15; ileum: 0; colon + ileum: 0 CG UC: colon: 10; ileum: 0; colon + ileum: 0 Use of concurrent medication: NS Disease activity: inactive to moderate Disease duration: IG CD: 2 (1 to 9) years CG CD: 2 (1 to 10) years IG UC: 4 (1 to 12) years CG UC: NS Number randomised: IG: 28 CG: 20 Number reaching end of study: IG CD: 10 CG CD: 10 IG UC: 15 CG UC: 10 Number analysed: IG CD: 10 CG CD: 10 IG UC: 15 CG UC: 10 Postrandomisation exclusion: IG: 3 (did not want to drink kefir); CG: 0
Interventions	IG: 400 mL/day kefir was administered twice a day to participants for 4 weeks, which contains a total of 2.0 × 10¹⁰ colony‐forming units/mL viable Lactobacillus bacteria. CG: no placebo or other intervention
Outcomes	Length of intervention: 4 weeks Primary outcomes: Pain intensity: Participants were asked to fill out the symptoms diary, which included questionnaires about bowel habits. Abdominal pain was rated on a 4‐point scale: 0 = none, 1 = mild, 2 = moderate, 3 = severe. The results were received after contact with the author Secondary outcomes: None reported
Notes	Funding source: The authors declared that this study received no financial support. Conflict of interest: The authors have no conflicts of interest to declare. Author contact details: ilkayilmaz001@hotmail.com
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	We contacted the author, who responded that randomisation was determined via a computer.
Allocation concealment (selection bias)	Unclear risk	Not mentioned. We requested further information from the author but did not receive a response.
Blinding of participants and personnel (performance bias) All outcomes	High risk	Not possible for this type of intervention
Blinding of outcome assessment (detection bias) All outcomes	Low risk	We contacted the author, who responded that the outcome assessor was blinded.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Data are presented for all completers.
Selective reporting (reporting bias)	Low risk	All outcomes are reported in the results, and scores were provided to us by the author.
Other bias	Low risk	The authors report no conflicts of interest, and the baseline characteristics appear to be reasonably balanced, although this is not mentioned in the text.