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.
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.
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.
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).
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.
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.
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.
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.