Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Systematic Review
  • Published:

Irritable bowel syndrome in children: the placebo response rate and influencing factors a meta-analysis

Pediatric Research (2024)Cite this article

Abstract

Background

Irritable bowel syndrome is common in children and exhibits a high placebo response. This study was to explore the placebo response rate and its influencing factors in children with irritable bowel syndrome.

Methods

A systematic search was performed on Pubmed, Embase, MEDLINE, Cochrane Library, CNKI, Wanfang, and CBM from database inception to March 2022. Randomized controlled trials of irritable bowel syndrome in children were included in the study. The primary outcome was the placebo response rate of improvement.

Results

Thirteen studies were included, with 445 patients in the placebo group. The rate of improvement and abdominal pain disappearance were 28.2% (95% CI, 16.6–39.9%) and 5% (95% CI, 0–18.4%). The placebo response based on the abdominal pain score was 0.675 (95% CI, 0.203–1.147). The mode of administration (P < 0.01), dosing schedule (P < 0.01), and clinical outcome assessor (P = 0.04) have a significant impact on the magnitude of placebo effect.

Conclusions

The placebo response rate for pediatric irritable bowel syndrome was 28.2%. In clinical trials, reducing dosing frequency, selecting appropriate dosage forms, and using patient-reported outcomes can help mitigate the placebo effect.

Impact

  • This is the first meta-analysis to assess the placebo response rates for improvement and disappearance in children with IBS.

  • The finding suggested that the mode of administration, dosing schedule, and clinical outcome assessor could potentially influence the magnitude of the placebo effect in children with IBS.

  • This study would provide a basis for estimating sample size in clinical trial design with a placebo control.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1
Fig. 2: The forest plot of the placebo response in pediatric irritable bowel syndrome (IBS).

Similar content being viewed by others

Data availability

The raw data and code can be obtained directly from the author.

References

  1. Drossman, D. A. ROME IV: Functional Gastrointestinal Disorders/Disorders of Gut-Brain Interaction (The Rome Foundation, Raleigh, 2016).

  2. Korterink, J. J., Diederen, K., Benninga, M. A. & Tabbers, M. M. Epidemiology of pediatric functional abdominal pain disorders: a meta-analysis. PLoS ONE 10, e0126982 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  3. Devanarayana, N. M. et al. Epidemiology of irritable bowel syndrome in children and adolescents in Asia. J. Pediatr. Gastroenterol. Nutr. 60, 792–798 (2015).

    Article  PubMed  Google Scholar 

  4. Thapar, N. et al. Paediatric functional abdominal pain disorders. Nat. Rev. Dis. Prim. 6, 89 (2020).

    Article  PubMed  Google Scholar 

  5. U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER). Guidance for industry irritable bowel syndrome-clinical evaluation of drugs for treatment. https://www.fda.gov/media/78622/download (2012).

  6. European Medicines Agency. Guideline on the evaluation of medicinal products for the treatment of irritable bowel syndrome. https://www.ema.europa.eu/en/evaluation-medicinal-products-treatment-irritable-bowel-syndrome (2014).

  7. China Food and Drug Administration. Clinical Research Guidance for New Drug of Chinese Medicine in Irritable Bowel Syndrome 2017. https://www.cde.org.cn/zdyz/domesticinfopage?zdyzIdCODE=c2b78e36b58535dfb0a1150be64d9470 (2017).

  8. Lacy, B. E. et al. ACG clinical guideline: management of irritable bowel syndrome. Am. J. Gastroenterol. 116, 17–44 (2021).

    Article  CAS  PubMed  Google Scholar 

  9. Saps, M. et al. Recommendations for pharmacological clinical trials in children with irritable bowel syndrome: the Rome foundation pediatric subcommittee on clinical trials. Neurogastroenterol. Motil. 28, 1619–1631 (2016).

    Article  CAS  PubMed  Google Scholar 

  10. Munnangi, S., Sundjaja, J. H., Singh, K., Dua, A. & Angus, L. D. Placebo effect. In StatPearls (StatPearls Publishing, Treasure Island, FL, 2022).

  11. Colloca, L. The placebo effect in pain therapies. Annu Rev. Pharmacol. Toxicol. 59, 191–211 (2019). Jan 6.

    Article  CAS  PubMed  Google Scholar 

  12. Pitz, M., Cheang, M. & Bernstein, C. N. Defining the predictors of the placebo response in irritable bowel syndrome. Clin. Gastroenterol. Hepatol. 3, 237–247 (2005).

    Article  PubMed  Google Scholar 

  13. Patel, S. M. et al. The placebo effect in irritable bowel syndrome trials: a meta-analysis. Neurogastroenterol. Motil. 17, 332–340 (2005).

    Article  CAS  PubMed  Google Scholar 

  14. Dorn, S. D. et al. A meta-analysis of the placebo response in complementary and alternative medicine trials of irritable bowel syndrome. Neurogastroenterol. Motil. 19, 630–637 (2007).

    Article  CAS  PubMed  Google Scholar 

  15. Ford, A. C. & Moayyedi, P. Meta-analysis: factors affecting placebo response rate in the irritable bowel syndrome. Aliment Pharmacol Ther. 32, 144–158 (2010).

    Article  CAS  PubMed  Google Scholar 

  16. Barberio, B., Savarino, E. V., Black, C. J. & Ford, A. C. Placebo response rates in trials of licensed drugs for irritable bowel syndrome with constipation or diarrhea: meta-analysis. Clin. Gastroenterol. Hepatol. S1542-3565, 00905–00908 (2021).

    Google Scholar 

  17. Bosman, M. et al. The placebo response rate in pharmacological trials in patients with irritable bowel syndrome: a systematic review and meta-analysis[J]. Lancet Gastroenterol. Hepatol. 6, 459–473 (2021).

    Article  PubMed  Google Scholar 

  18. Hoekman, D. R. et al. The placebo response in pediatric abdominal pain-related functional gastrointestinal disorders: a systematic review and meta-analysis. J. Pediatr. 182, 155–163.e7 (2017).

    Article  PubMed  Google Scholar 

  19. Hyams, J. S. et al. Functional disorders: children and adolescents. Gastroenterology S0016-5085, 00181–00185 (2016).

    Google Scholar 

  20. Rajindrajith, S., Zeevenhooven, J., Devanarayana, N. M., Perera, B. J. C. & Benninga, M. A. Functional abdominal pain disorders in children. Expert Rev. Gastroenterol. Hepatol. 12, 369–390 (2018).

    Article  CAS  PubMed  Google Scholar 

  21. Enck, P. & Klosterhalfen, S. Placebos and the placebo effect in drug trials. Handb. Exp. Pharmacol. 260, 399–431 (2019).

    Article  CAS  PubMed  Google Scholar 

  22. Sterne, J. A. C. et al. RoB 2: a revised tool for assessing risk of bias in randomised trials. BMJ 366, l4898 (2019).

    Article  PubMed  Google Scholar 

  23. Luo, M. et al. Meta analysis of single rate in R software. J. Evid. Based Med. 13, 181–184 (2013).

    Google Scholar 

  24. Kline, R. M., Kline, J. J., Di Palma, J. & Barbero, G. J. Enteric-coated, pH-dependent peppermint oil capsules for the treatment of irritable bowel syndrome in children. J. Pediatr. 138, 125–128 (2001).

    Article  CAS  PubMed  Google Scholar 

  25. Bauserman, M. & Michail, S. The use of Lactobacillus GG in irritable bowel syndrome in children: a double-blind randomized control trial. J. Pediatr. 147, 197–201 (2005).

    Article  PubMed  Google Scholar 

  26. Gawrońska, A., Dziechciarz, P., Horvath, A. & Szajewska, H. A randomized double-blind placebo-controlled trial of Lactobacillus GG for abdominal pain disorders in children. Aliment Pharmacol. Ther. 25, 177–184 (2007).

    Article  PubMed  Google Scholar 

  27. Bahar, R. J., Collins, B. S., Steinmetz, B. & Ament, M. E. Double-blind placebo-controlled trial of amitriptyline for the treatment of irritable bowel syndrome in adolescents. J. Pediatr. 152, 685–689 (2008).

    Article  CAS  PubMed  Google Scholar 

  28. Handen, B. L. et al. A double-blind, placebo-controlled trial of oral human immunoglobulin for gastrointestinal dysfunction in children with autistic disorder. J. Autism Dev. Disord. 39, 796–805 (2009).

    Article  PubMed  Google Scholar 

  29. Francavilla, R. et al. A randomized controlled trial of Lactobacillus GG in children with functional abdominal pain. Pediatrics 126, e1445–e1452 (2010).

    Article  PubMed  Google Scholar 

  30. Guandalini, S. et al. VSL#3 improves symptoms in children with irritable bowel syndrome: a multicenter, randomized, placebo-controlled, double-blind, crossover study. J. Pediatr. Gastroenterol. Nutr. 51, 24–30 (2010).

    Article  PubMed  Google Scholar 

  31. Romano, C., Comito, D., Famiani, A., Calamarà, S. & Loddo, I. Partially hydrolyzed guar gum in pediatric functional abdominal pain. World J. Gastroenterol. 19, 235–240 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  32. Kianifar, H. et al. Probiotic for irritable bowel syndrome in pediatric patients: a randomized controlled clinical trial. Electron Physician 7, 1255–1260 (2015).

    PubMed  PubMed Central  Google Scholar 

  33. Shulman, R. J. et al. Psyllium fiber reduces abdominal pain in children with irritable bowel syndrome in a randomized, double-blind trial. Clin. Gastroenterol. Hepatol. 15, 712–719.e4 (2017).

    Article  CAS  PubMed  Google Scholar 

  34. Shulman, R. J. et al. Randomized, double blind trial of psyllium fiber in children with irritable bowel syndrome (IBS). Gastroenterology 148, S120 (2015).

    Article  Google Scholar 

  35. Giannetti, E. et al. A mixture of 3 bifidobacteria decreases abdominal pain and improves the quality of life in children with irritable bowel syndrome: a multicenter, randomized, double-blind, placebo-controlled, crossover trial. J. Clin. Gastroenterol. 51, e5–e10 (2017).

    Article  PubMed  Google Scholar 

  36. Sudha, M. R., Jayanthi, N., Aasin, M., Dhanashri, R. D. & Anirudh, T. Efficacy of Bacillus coagulans unique IS2 in treatment of irritable bowel syndrome in children: a double blind, randomised placebo controlled study. Benef. Microbes 9, 563–572 (2018).

    Article  CAS  PubMed  Google Scholar 

  37. Rahmani, P., Ghouran-Orimi, A., Motamed, F. & Moradzadeh, A. Evaluating the effects of probiotics in pediatrics with recurrent abdominal pain. Clin. Exp. Pediatr. 63, 485–490 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Schober, P., Mascha, E. J. & Vetter, T. R. Statistics from A (Agreement) to Z (z Score): a guide to interpreting common measures of association, agreement, diagnostic accuracy, effect size, heterogeneity, and reliability in medical research. Anesth. Analg. 133, 1633–1641 (2021).

    Article  PubMed  Google Scholar 

  39. Weimer, K. et al. Placebo effects in children: a review. Pediatr. Res. 74, 96–102 (2013).

    Article  PubMed  Google Scholar 

  40. Janiaud, P. et al. Is the perceived placebo effect comparable between adults and children? A meta-regression analysis. Pediatr. Res. 81, 11–17 (2017).

    Article  PubMed  Google Scholar 

  41. Gniß, S., Kappesser, J. & Hermann, C. Placebo effect in children: the role of expectation and learning. Pain 161, 1191–1201 (2020).

    Article  PubMed  Google Scholar 

  42. Mohammad, S., Pusatcioglu, C. & Saps, M. Comparison of primary efficacy endpoints recommended by regulatory agencies in children with functional gastrointestinal disorders. Gastroenterology 148, S–586 (2015)..

  43. Nurko, S. et al. Effect of open-label placebo on children and adolescents with functional abdominal pain or irritable bowel syndrome: a randomized clinical trial. JAMA Pediatr. 176, 349–356 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Clinical Trial Center, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China

    Li-Li Cai, Xuan Li, Qiu-Han Cai, Sheng-Xuan Guo, Yi Zhang, Wen-Cong Sun, Ze-Hui Zhao & Si-Yuan Hu

  2. Department of Pediatrics, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China

    Si-Yuan Hu

Authors
  1. Li-Li Cai
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xuan Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Qiu-Han Cai
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Sheng-Xuan Guo
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yi Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Wen-Cong Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Ze-Hui Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Si-Yuan Hu
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

L.L.C. and X.L. contributed equally to this manuscript and should be considered joint first author. L.L.C. and X.L. carried out the concept, design and drafting of the manuscript, performed the acquisition, analysis, and interpretation of data, and critically revised the manuscript for important intellectual content. Q.H.C. and S.Y.H. carried out the concept, design and drafting of the manuscript. G.S.X. and Y.Z. performed the Statistical analysis. WCS and Z.H.Z. searched databases, screened articles, and extracted data. All authors approved the final version of the manuscript.

Corresponding author

Correspondence to Si-Yuan Hu.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Cai, LL., Li, X., Cai, QH. et al. Irritable bowel syndrome in children: the placebo response rate and influencing factors a meta-analysis. Pediatr Res (2024). https://doi.org/10.1038/s41390-023-02996-2

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1038/s41390-023-02996-2

Search

Advanced search

Quick links