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. 2021 Nov 29;11(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
Affiliations

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

Vassiliki Sinopoulou et al. Cochrane Database Syst Rev. .

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Selection criteria: All published, unpublished, and ongoing randomised trials that compared interventions for the management of abdominal pain in the setting of Crohn's disease and IBD, with other active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.

PubMed Disclaimer

Conflict of interest statement

VS: None.

M Gordon: Since August 2016, I have received travel fees to attend international scientific and training meetings from pharma companies. These grants included no honoraria, inducement, advisory role, or any other relationship and were restricted to the travel‐ and meeting‐related costs of attending such meetings. These include: DDW May 2017, World Congress of Gastroenterology October 2017, DDW May 2018, Advances in IBD December 2018, and DDW May 2019. The companies include: Biogaia (2017‐19), Ferring (2018), Allergan (2017), Synergy (bankrupt ‐ 2018), and Tillots (2017‐19). None of these companies has had any involvement in any works completed by me, and I have never received payment for any other activities from them. From August 2019 onwards, I have made a personal undertaking to receive no further funds from any pharmaceutical or formula company in any form for travel or other related activities. This is to lift the limitations such funding has on my ability to act as a first and corresponding author on reviews, in line with Cochrane policies on such matters, and is reported in line with these policies. These current declarations will expire over the next three years, and this statement will be updated regularly to reflect this.

AKA: None.

M Gasparetto: Since 2015, I have received travel fees to attend international scientific and training meetings from pharma companies. These grants included no honoraria, inducement, advisory role, or any other relationship and were restricted to the travel‐ and meeting‐related costs of attending such meetings. These include ESPGHAN 2017 and ESPGHAN 2019, when I was sponsored by Nutricia. None of these companies has had any involvement in any works completed by me, and I have never received payment for any other activities from them.

MS: None.

JV: None.

TD: None

Figures

1
1
Study flow diagram.
2
2
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
3
3
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
1.1
1.1. Analysis
Comparison 1: Low FODMAP diet versus sham diet, Outcome 1: Pain frequency defined by days of pain by IBS‐SSS scores (0 to 100) for IBD
1.2
1.2. Analysis
Comparison 1: Low FODMAP diet versus sham diet, Outcome 2: Days with moderate or severe pain by GSRS scores for IBD (0 to 3) for IBD
1.3
1.3. Analysis
Comparison 1: Low FODMAP diet versus sham diet, Outcome 3: Pain frequency defined by days of pain by IBS‐SSS scores (0 to 100) for CD
1.4
1.4. Analysis
Comparison 1: Low FODMAP diet versus sham diet, Outcome 4: Pain intensity IBD (0 to 100)
1.5
1.5. Analysis
Comparison 1: Low FODMAP diet versus sham diet, Outcome 5: Pain intensity IBD (0 to 3)
1.6
1.6. Analysis
Comparison 1: Low FODMAP diet versus sham diet, Outcome 6: Pain intensity CD (0 to 100)
1.7
1.7. Analysis
Comparison 1: Low FODMAP diet versus sham diet, Outcome 7: Withdrawals due to adverse events
2.1
2.1. Analysis
Comparison 2: Medicine‐separated moxibustion combined with acupuncture versus wheat bran‐separated moxibustion combined with shallow acupuncture, Outcome 1: Withdrawals due to adverse events
3.1
3.1. Analysis
Comparison 3: Mindfulness with cognitive behavioural therapy (CBT) versus no treatment (both groups received standard medical therapy), Outcome 1: Pain frequency and severity of abdominal discomfort, severity of abdominal bloating, satisfaction with bowel habit, and impact of symptoms on life in general
3.2
3.2. Analysis
Comparison 3: Mindfulness with cognitive behavioural therapy (CBT) versus no treatment (both groups received standard medical therapy), Outcome 2: Withdrawals due to adverse events
4.1
4.1. Analysis
Comparison 4: soft non‐manipulative osteopathic treatment versus no intervention, Outcome 1: Pain intensity
4.2
4.2. Analysis
Comparison 4: soft non‐manipulative osteopathic treatment versus no intervention, Outcome 2: Withdrawals due to adverse events
5.1
5.1. Analysis
Comparison 5: Directed stress management versus standard treatment, Outcome 1: Pain intensity
6.1
6.1. Analysis
Comparison 6: Self‐directed stress management vs conventional therapy, Outcome 1: Pain intensity
7.1
7.1. Analysis
Comparison 7: Enteric‐release glyceryl trinitrate versus placebo, Outcome 1: Withdrawals due to adverse events
8.1
8.1. Analysis
Comparison 8: 100 mg olorinab 3 times/day versus 25 mg olorinab 3 times/day, Outcome 1: Pain intensity
8.2
8.2. Analysis
Comparison 8: 100 mg olorinab 3 times/day versus 25 mg olorinab 3 times/day, Outcome 2: Withdrawals due to adverse events
9.1
9.1. Analysis
Comparison 9: Relaxation training versus waitlist, Outcome 1: Pain intensity
10.1
10.1. Analysis
Comparison 10: Web‐based education versus standard book‐based education, Outcome 1: Pain intensity
10.2
10.2. Analysis
Comparison 10: Web‐based education versus standard book‐based education, Outcome 2: Withdrawals due to adverse events
11.1
11.1. Analysis
Comparison 11: Yoga intervention versus no treatment (both groups received standard medical therapy), Outcome 1: Withdrawals due to adverse events
12.1
12.1. Analysis
Comparison 12: Transcranial direct current stimulation versus sham stimulation, Outcome 1: Pain intensity (0 to 100)
12.2
12.2. Analysis
Comparison 12: Transcranial direct current stimulation versus sham stimulation, Outcome 2: Withdrawals due to adverse events
13.1
13.1. Analysis
Comparison 13: Kefir versus no intervention, Outcome 1: CD pain intensity (0 to 3)
13.2
13.2. Analysis
Comparison 13: Kefir versus no intervention, Outcome 2: IBD pain intensity (0 to 3)
13.3
13.3. Analysis
Comparison 13: Kefir versus no intervention, Outcome 3: Withdrawals due to adverse events
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References

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    1. NCT03667586. Group cognitive behavioral therapy for IBD patients. clinicaltrials.gov/ct2/show/NCT03667586 (first received 12 September 2018).
NCT03798405 {published data only}
    1. NCT03798405. Reactive vs. proactive pain control in IBD (PAIN-Sparing). clinicaltrials.gov/ct2/show/NCT03798405 (first received 10 January 2019).
NCT03809195 {published data only}
    1. NCT03809195. Clinical hypnosis in pediatric Crohn's disease (HypnoCrohns). clinicaltrials.gov/ct2/show/NCT03809195 (first received 18 January 2019).
NCT03825900 {published data only}
    1. NCT03825900. Transcranial direct current stimulation and the interaction between chronic pain and the intestinal epithelial barrier in patients with chronic inflammatory bowel diseases (IBD). clinicaltrials.gov/ct2/show/NCT03825900 (first received 1 February 2019).
NCT04173273 {published data only}
    1. NCT04173273. A study evaluating the efficacy and safety of etrasimod in the treatment of patients with moderately to severely active Crohn's disease (CULTIVATE). clinicaltrials.gov/ct2/show/NCT04173273 (first received 21 November 2019).

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