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Irritable Bowel Syndrome

Efficacy of interventions for the treatment of irritable bowel syndrome, functional abdominal pain-not otherwise specified, and abdominal migraine in children: a systematic review and network meta-analysis

Author/s: 
Vasiliki Sinopoulou, Jip Groen, Morris Gordon, Ed Mougey, James P Franciosi, Tim G J de Meij, Merit M Tabbers, Marc A Benninga

Background: Many treatments for abdominal pain-related disorders of gut-brain interaction (AP-DGBI) in children have been studied. We aimed to assess the efficacy and safety of all known treatment options for paediatric AP-DGBI.

Methods: For this systematic review and network meta-analysis, we searched Embase, MEDLINE, and CENTRAL databases from inception to Jan 16, 2025, for published randomised controlled trials. We included trials of any treatment for AP-DGBIs (irritable bowel syndrome, functional abdominal pain-not otherwise specified, and abdominal migraine, excluding functional dyspepsia) in children aged 4-18 years. We excluded randomised controlled trials that solely included children with functional dyspepsia, but we included studies in which children with functional dyspepsia were included alongside children with the other AP-DGBI diagnoses and outcome data could not be separated. Data extraction and quality appraisal were performed in duplicate. The primary outcome for this network meta-analysis was author-defined treatment success. Network meta-analysis methodology was used within a frequentist framework using multivariate meta-analysis and outcomes were assessed using the Grading of Recommendations, Assessment, Development and Evaluation methodology. Clinical relevance of effect sizes was interpreted according to consensus definitions.

Findings: Of 19 337 records identified through the database search, 155 records representing 91 original randomised controlled trials were included in the network meta-analysis: these 91 trials comprised 7226 participants (4119 females and 2673 males). 12 studies assessed dietary treatments (n=730), 25 assessed pharmacological treatments (n=2140), 23 assessed probiotic treatments (n=1762), and 35 assessed psychosocial treatments (n=2952). Two treatments were probably more effective for treatment success than control treatments (moderate certainty): hypnotherapy (risk ratio [RR] 4·99 [95% CI 2·15 to 11·57]; large effect size) and cognitive behavioural therapy (CBT; RR 1·99 [95% CI 1·33 to 2·98]; moderate effect size). All other treatments evaluated for treatment success were either not effective or the data were of very low certainty and thus no conclusions could be made.

Interpretation: Hypnotherapy and CBT show moderate certainty for treatment efficacy with clinically relevant effect sizes. No conclusions can be made about the other therapies and treatment success due to very low evidence certainty. Future randomised controlled trials should focus on improving the evidence certainty for those other therapies with regard to core AP-DGBI outcomes.

Funding: None.

Keywords 
abdominal pain Irritable Bowel Syndrome Migraine Disorders gut-brain interaction

Amitriptyline at Low-Dose and Titrated for Irritable Bowel Syndrome as Second-Line Treatment in primary care (ATLANTIS): a randomised, double-blind, placebo-controlled, phase 3 trial

Author/s: 
Alexander C Ford, Alexandra Wright-Hughes, Sarah L Alderson, Pei-Loo Ow, Matthew J Ridd, Robbie Foy, Gina Bianco, Felicity L Bishop, Matthew Chaddock, Heather Cook, Deborah Cooper, Catherine Fernandez, Elspeth A Guthrie, Suzanne Hartley, Amy Herbert, Daniel Howdon, Delia P Muir, Taposhi Nath, Sonia Newman, Thomas Smith, Christopher A Taylor, Emma J Teasdale, Ruth Thornton, Amanda J Farrin, Hazel A Everitt, ATLANTIS trialists

Background: Most patients with irritable bowel syndrome (IBS) are managed in primary care. When first-line therapies for IBS are ineffective, the UK National Institute for Health and Care Excellence guideline suggests considering low- dose tricyclic antidepressants as second-line treatment, but their effectiveness in primary care is unknown, and they are infrequently prescribed in this setting.

Methods: This randomised, double-blind, placebo-controlled trial (Amitriptyline at Low-Dose and Titrated for Irritable Bowel Syndrome as Second-Line Treatment [ATLANTIS]) was conducted at 55 general practices in England. Eligible participants were aged 18 years or older, with Rome IV IBS of any subtype, and ongoing symptoms (IBS Severity Scoring System [IBS-SSS] score ≥75 points) despite dietary changes and first-line therapies, a normal full blood count and C-reactive protein, negative coeliac serology, and no evidence of suicidal ideation. Participants were randomly assigned (1:1) to low-dose oral amitriptyline (10 mg once daily) or placebo for 6 months, with dose titration over 3 weeks (up to 30 mg once daily), according to symptoms and tolerability. Participants, their general practitioners, investigators, and the analysis team were all masked to allocation throughout the trial. The primary outcome was the IBS-SSS score at 6 months. Effectiveness analyses were according to intention-to-treat; safety analyses were on all participants who took at least one dose of the trial medication. This trial is registered with the ISRCTN Registry (ISRCTN48075063) and is closed to new participants.

Findings: Between Oct 18, 2019, and April 11, 2022, 463 participants (mean age 48·5 years [SD 16·1], 315 [68%] female to 148 [32%] male) were randomly allocated to receive low-dose amitriptyline (232) or placebo (231). Intention-to-treat analysis of the primary outcome showed a significant difference in favour of low-dose amitriptyline in IBS-SSS score between groups at 6 months (-27·0, 95% CI -46·9 to -7·10; p=0·0079). 46 (20%) participants discontinued low-dose amitriptyline (30 [13%] due to adverse events), and 59 (26%) discontinued placebo (20 [9%] due to adverse events) before 6 months. There were five serious adverse reactions (two in the amitriptyline group and three in the placebo group), and five serious adverse events unrelated to trial medication.

Interpretation: To our knowledge, this is the largest trial of a tricyclic antidepressant in IBS ever conducted. Titrated low-dose amitriptyline was superior to placebo as a second-line treatment for IBS in primary care across multiple outcomes, and was safe and well tolerated. General practitioners should offer low-dose amitriptyline to patients with IBS whose symptoms do not improve with first-line therapies, with appropriate support to guide patient-led dose titration, such as the self-titration document developed for this trial.

Funding: National Institute for Health and Care Research Health Technology Assessment Programme (grant reference 16/162/01).

Keywords 
amitriptyline Irritable Bowel Syndrome primary health care antidepressive agents
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