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Digestive Diseases and Sciences

, Volume 64, Issue 3, pp 838–845 | Cite as

Double-Blind Placebo-Controlled Study of Rifaximin and Lactulose Hydrogen Breath Test in Gulf War Veterans with Irritable Bowel Syndrome

  • Ashok K. TutejaEmail author
  • Nicholas J. Talley
  • Gregory J. Stoddard
  • G. Nicholas Verne
Original Article

Abstract

Background

Irritable bowel syndrome (IBS) occurs in up to 33% of Gulf War (GW) Veterans. Alterations in gut microflora including small intestinal bacterial overgrowth (SIBO) during deployment may play a role in development of IBS. Rifaximin is a minimally absorbed antibiotic speculated to improve IBS symptoms, in part, by restoring normal gut microflora. The aim of this study was to compare rifaximin to placebo on IBS symptoms and quality of life (QOL) in GW Veterans with IBS without constipation.

Methods

A double-blind, placebo-controlled study was performed. One hundred and twenty-two GW Veterans with IBS (Rome III) from our database and referral to gastroenterology and internal medicine clinics were screened. After a 2-week run-in period, 50 patients were randomized (1:1) to receive either rifaximin 550 gm or placebo twice daily for 2 weeks in a double-blind study. Patients were advised not to change their diet or medications during the study. The symptoms assessed were: (1) stool frequency, (2) stool consistency (Bristol stool scale, 1–7, very hard to watery), (3) urgency (1 = yes/0 = no daily for 7 days), (4) severity of abdominal pain (0–4, none to severe), (5) severity of bloating (1–4, none to severe), and (6) global improvement scale (1–7, substantially worse to substantially improved). These were recorded for 7 consecutive days and then averaged across the 7 days, to generate a continuous variable. The symptom data were compared after 2 weeks of treatment. QOL was assessed using IBS-QOL. The lactulose hydrogen breath test (LHBT) was performed at baseline and after 2 weeks of treatment.

Results

Fifty Veterans were randomized to receive treatment; 3 withdrew and 3 were lost to follow-up. Data were analyzed from 44 patients (38 men, 6 women, median age 52, range 33–77 years). Rifaximin was not associated with significant improvement in global symptoms, abdominal pain, bloating, stool urgency, frequency, or consistency (all P ≥ 0.25) or QOL (all P ≥ 0.26). Normalization of SIBO by LHBT was not different between rifaximin- and placebo-treated Veterans (7 vs. 22%, P = 0. 54).

Conclusion

Rifaximin was not effective in improving IBS symptoms and QOL in GW Veterans with non-constipated IBS.

Keywords

Gulf War illness Diarrhea Rifaximin Irritable bowel syndrome Veterans 

Notes

Acknowledgments

The authors thank Dr. Keith G. Tolman, M.D. for assistance in editing the initial proposal and periodic consultation. The study drug and placebo tablets were provided by Salix Pharmaceuticals.

Funding

AKT received grant support from the Department of Veterans Affairs and the Department of Defense (W81XWH-10-1-0593, W81XWH-15-1-0636). GNV received support from the Department of Veterans Affairs (1I01CX001477-01) and the National Institute of Diabetes and Digestive and Kidney Diseases (DK099052).

Compliance with ethical standards

Conflict of interest

AKT has received funding from Shire and Synergy Pharmaceuticals. NJT Grant/Research Support: Rome Foundation; Abbott Pharmaceuticals; Datapharm; Pfizer; Salix [Irritable bowel syndrome]; Prometheus Laboratories Inc [Irritable bowel syndrome (IBS Diagnostic)]; Janssen [Constipation]. Consultant/Advisory Boards: Adelphi Values [Functional dyspepsia (patient-reported outcome measures)]; (Budesonide)]; GI therapies [Chronic constipation (Rhythm IC)]; Sax Institute; Allergens PLC; Napo Pharmaceutical; Outpost Medicine; Samsung Bioepis; Yuhan [IBS]; Synergy [IBS]; Theravance [Gastroparesis]; Patent Holder: Biomarkers of irritable bowel syndrome [Irritable bowel syndrome] Licensing Questionnaires [Mayo Clinic Talley Bowel Disease Questionnaire—Mayo Dysphagia Questionnaire]; Nestec European Patent [Application No. 12735358.9]; Singapore “Provisional” Patent [NTU Ref: TD/129/17 “Microbiota Modulation Of BDNF Tissue Repair Pathway”].

References

  1. 1.
    Chronic Multisymptom Illness in Gulf War Veterans. Case Definitions Reexamined. Institute of Medicine: National Academy of Sciences, National Academies Press; 2014.Google Scholar
  2. 2.
    Gulf War and Health. Update of health effects of serving in the Gulf War. Institute of Medicine: National Academy of Sciences, National Academies Press; 2016.Google Scholar
  3. 3.
    Steele L. Prevalence and patterns of Gulf War illness in Kansas veterans: association of symptoms with characteristics of person, place, and time of military service. Am J Epidemiol. 2000;152:992–1002.CrossRefGoogle Scholar
  4. 4.
    Longstreth GF, Thompson WG, Chey WD, Houghton LA, Mearin F, Spiller RC. Functional bowel disorders. Gastroenterology. 2006;130:1480–1491.CrossRefGoogle Scholar
  5. 5.
    Chey WD, Kurlander J, Eswaran S. Irritable bowel syndrome: a clinical review. JAMA. 2015;313:949–958.CrossRefGoogle Scholar
  6. 6.
    Halvorson HA, Schlett CD, Riddle MS. Postinfectious irritable bowel syndrome–a meta-analysis. Am J Gastroenterol. 2006;101:1894–1899. quiz 942.CrossRefGoogle Scholar
  7. 7.
    Pimentel M, Chow EJ, Lin HC. Eradication of small intestinal bacterial overgrowth reduces symptoms of irritable bowel syndrome. Am J Gastroenterol. 2000;95:3503–3506.CrossRefGoogle Scholar
  8. 8.
    Hyams KC, Bourgeois AL, Merrell BR, et al. Diarrheal disease during Operation Desert Shield. N Engl J Med. 1991;325:1423–1428.CrossRefGoogle Scholar
  9. 9.
    Porter CK, Choi D, Cash B, et al. Pathogen-specific risk of chronic gastrointestinal disorders following bacterial causes of foodborne illness. BMC Gastroenterol. 2013;13:46.CrossRefGoogle Scholar
  10. 10.
    Khoshini R, Dai SC, Lezcano S, Pimentel M. A systematic review of diagnostic tests for small intestinal bacterial overgrowth. Dig Dis Sci. 2008;53:1443–1454.CrossRefGoogle Scholar
  11. 11.
    Ford AC, Spiegel BM, Talley NJ, Moayyedi P. Small intestinal bacterial overgrowth in irritable bowel syndrome: systematic review and meta-analysis. Clin Gastroenterol Hepatol. 2009;7:1279–1286.CrossRefGoogle Scholar
  12. 12.
    Huang DB, DuPont HL. Rifaximin–a novel antimicrobial for enteric infections. J Infect. 2005;50:97–106.CrossRefGoogle Scholar
  13. 13.
    Meyrat P, Safroneeva E, Schoepfer AM. Rifaximin treatment for the irritable bowel syndrome with a positive lactulose hydrogen breath test improves symptoms for at least 3 months. Aliment Pharmacol Ther. 2012;36:1084–1093.CrossRefGoogle Scholar
  14. 14.
    Pimentel M, Lembo A, Chey WD, et al. Rifaximin therapy for patients with irritable bowel syndrome without constipation. N Engl J Med. 2011;364:22–32.CrossRefGoogle Scholar
  15. 15.
    Sharara AI, Aoun E, Abdul-Baki H, Mounzer R, Sidani S, Elhajj I. A randomized double-blind placebo-controlled trial of rifaximin in patients with abdominal bloating and flatulence. Am J Gastroenterol. 2006;101:326–333.CrossRefGoogle Scholar
  16. 16.
    Talley NJ, Phillips SF, Melton J 3rd, Wiltgen C, Zinsmeister AR. A patient questionnaire to identify bowel disease. Ann Intern Med. 1989;111:671–674.CrossRefGoogle Scholar
  17. 17.
    Patrick DL, Drossman DA, Frederick IO, DiCesare J, Puder KL. Quality of life in persons with irritable bowel syndrome: development and validation of a new measure. Dig Dis Sci. 1998;43:400–411.CrossRefGoogle Scholar
  18. 18.
    Derogatis L. Brief Symptom Inventory-18 (BSI-18): Administration, Scoring, and Procedure Manual. Ed 3 ed. Minneapolis, MN: National Computer Systems; 2000.Google Scholar
  19. 19.
    Bratten JR, Spanier J, Jones MP. Lactulose breath testing does not discriminate patients with irritable bowel syndrome from healthy controls. Am J Gastroenterol. 2008;103:958–963.CrossRefGoogle Scholar
  20. 20.
    Levitt MD, Furne JK, Kuskowski M, Ruddy J. Stability of human methanogenic flora over 35 years and a review of insights obtained from breath methane measurements. Clin Gastroenterol Hepatol. 2006;4:123–129.CrossRefGoogle Scholar
  21. 21.
    Kassinen A, Krogius-Kurikka L, Makivuokko H, et al. The fecal microbiota of irritable bowel syndrome patients differs significantly from that of healthy subjects. Gastroenterology. 2007;133:24–33.CrossRefGoogle Scholar
  22. 22.
    Pimentel M, Park S, Mirocha J, Kane SV, Kong Y. The effect of a nonabsorbed oral antibiotic (rifaximin) on the symptoms of the irritable bowel syndrome: a randomized trial. Ann Intern Med. 2006;145:557–563.CrossRefGoogle Scholar
  23. 23.
    Acosta A, Camilleri M, Shin A, et al. Effects of Rifaximin on Transit, Permeability, Fecal Microbiome, and Organic Acid Excretion in Irritable Bowel Syndrome. Clin Transl Gastroenterol. 2016;7:e173.CrossRefGoogle Scholar
  24. 24.
    Menees SB, Maneerattannaporn M, Kim HM, Chey WD. The efficacy and safety of rifaximin for the irritable bowel syndrome: a systematic review and meta-analysis. Am J Gastroenterol. 2012;107:28–35. quiz 6.CrossRefGoogle Scholar
  25. 25.
    Rezaie A, Buresi M, Lembo A, et al. Hydrogen and methane-based breath testing in gastrointestinal disorders: The North American consensus. Am J Gastroenterol. 2017;112:775–784.CrossRefGoogle Scholar
  26. 26.
    Pimentel M, Chow EJ, Lin HC. Normalization of lactulose breath testing correlates with symptom improvement in irritable bowel syndrome A double-blind, randomized, placebo-controlled study. Am J Gastroenterol. 2003;98:412–419.Google Scholar
  27. 27.
    Shah ED, Basseri RJ, Chong K, Pimentel M. Abnormal breath testing in IBS: a meta-analysis. Dig Dis Sci. 2010;55:2441–2449.CrossRefGoogle Scholar
  28. 28.
    Gasbarrini A, Corazza GR, Gasbarrini G, et al. Methodology and indications of H2-breath testing in gastrointestinal diseases: the Rome Consensus Conference. Aliment Pharmacol Ther. 2009;29:1–49.Google Scholar
  29. 29.
    Yu D, Cheeseman F, Vanner S. Combined oro-caecal scintigraphy and lactulose hydrogen breath testing demonstrate that breath testing detects oro-caecal transit, not small intestinal bacterial overgrowth in patients with IBS. Gut. 2011;60:334–340.CrossRefGoogle Scholar
  30. 30.
    Rezaie A, Pimentel M, Rao SS. How to test and treat small intestinal bacterial overgrowth: an evidence-based approach. Curr Gastroenterol Rep. 2016;18:8.CrossRefGoogle Scholar
  31. 31.
    Saad RJ, Chey WD. Breath testing for small intestinal bacterial overgrowth: maximizing test accuracy. Clin Gastroenterol Hepatol. 2014;12:1964–1972. quiz e119-20.CrossRefGoogle Scholar
  32. 32.
    Bhattarai Y, Muniz Pedrogo DA, Kashyap PC. Irritable bowel syndrome: a gut microbiota-related disorder? Am J Physiol Gastrointest Liver Physiol. 2017;312:G52–G62.CrossRefGoogle Scholar
  33. 33.
    Tuteja AK. Deployment-associated functional gastrointestinal disorders: do we know the etiology? Dig Dis Sci. 2011;56:3109–3111.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Ashok K. Tuteja
    • 1
    • 2
    Email author
  • Nicholas J. Talley
    • 3
  • Gregory J. Stoddard
    • 4
  • G. Nicholas Verne
    • 5
    • 6
  1. 1.George E. Whalen Veterans Affairs Medical CenterSalt Lake CityUSA
  2. 2.Division of Gastroenterology, Department of Medicine, School of MedicineUniversity of UtahSalt Lake CityUSA
  3. 3.University of NewcastleCallaghanAustralia
  4. 4.Division of EpidemiologyUniversity of UtahSalt Lake CityUSA
  5. 5.Department of MedicineTulane University School of MedicineNew OrleansUSA
  6. 6.North Florida/South Georgia Veterans Affairs Medical CenterGainesvilleUSA

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