Small intestinal damage associated with the use of nonsteroidal anti-inflammatory drugs

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Abstract

The use of nonsteroidal anti-inflammatory drugs (NSAID), even if short-term, may be associated to small intestinal complications, such as erosions, ulcers and chronic mucosal inflammation. Video capsule endoscopy allows for identification of such lesions in 20 to 55% of the patients who have taken nonselective NSAID for 2 to 4  weeks. The pathophysiology of NSAID-induced enteropathy is related to a reduced reparative potential of the mucosa and abnormalities of the microbial balance in the small intestine. In real world practice, NSAID enteropathy is commonly asymptomatic, and its manifestations, such as bleeding, perforation and ileus, are quite rare (about 0.3 episodes per 100  patient-years). The main manifestation of NSAID enteropathy is chronic iron deficient anemia. The use of rebamipide, sulfasalazine, mesalazine, and rifaximin has been discussed in the treatment of NSAID enteropathy, whereas its prevention implies preferential administration of coxibs, the use of rebamipide and probiotics.

About the authors

A. E. Karateev

V.A. Nasonova Research Institute of Rheumatology, Russian Academy of Medical Sciences

Author for correspondence.
Email: aekarat@yandex.ru
ORCID iD: 0000-0002-1391-0711

Andrei E. Karateev – MD, PhD, Head of the Laboratory of the Pathophysiology of Pain and Polymorphism of Musculoskeletal Diseases

34A Kashirskoe shosse, Moscow, 115522

Russian Federation

E. V. Moroz

N.N. Burdenko Main Military Clinical Hospital

Email: fake@neicon.ru

Elena V. Moroz – MD, PhD, Head of the Gastroenterology Department2

3 Gospital'naya ploshchad', Moscow, 105094

Russian Federation

E. V. Kryukov

N.N. Burdenko Main Military Clinical Hospital

Email: fake@neicon.ru

Evgenii V. Kryukov – MD, PhD, Professor, Corresponding Member of Russian Academy of Sciences, Head of the Hospital2

3 Gospital'naya ploshchad', Moscow, 105094

Russian Federation

References

  1. Каратеев АЕ, Насонов ЕЛ, Ивашкин ВТ, Мартынов АИ, Яхно НН, Арутюнов ГП, Алексеева ЛИ, Абузарова ГР, Евсеев МА, Кукушкин МЛ, Копенкин СС, Лила АМ, Лапина ТЛ, Новикова ДС, Попкова ТВ, Ребров АП, Скоробогатых КВ, Чичасова НВ. Рациональное использование нестероидных противовоспалительных препаратов. Клинические рекомендации. Научно-практическая ревматология. 2018;56(Прилож):1–29. doi: 10.14412/1995-4484-2018-1-29.
  2. Zhou Y, Boudreau DM, Freedman AN. Trends in the use of aspirin and nonsteroidal anti-inflammatory drugs in the general U.S. population. Pharmacoepidemiol Drug Saf. 2014;23(1): 43–50. doi: 10.1002/pds.3463.
  3. Scarpignato C, Lanas A, Blandizzi C, Lems WF, Hermann M, Hunt RH; International NSAID Consensus Group. Safe prescribing of non-steroidal anti-inflammatory drugs in patients with osteoarthritis – an expert consensus addressing benefits as well as gastrointestinal and cardiovascular risks. BMC Med. 2015;13:55. doi: 10.1186/s12916-015-0285-8.
  4. Harirforoosh S, Asghar W, Jamali F. Adverse effects of nonsteroidal antiinflammatory drugs: an update of gastrointestinal, cardiovascular and renal complications. J Pharm Pharm Sci. 2013;16(5):821–47.
  5. Sung JJ, Kuipers EJ, El-Serag HB. Systematic review: the global incidence and prevalence of peptic ulcer disease. Aliment Pharmacol Ther. 2009;29(9):938–46. doi: 10.1111/j.1365-2036.2009.03960.x.
  6. Poudel DR, Acharya P, Ghimire S, Dhital R, Bharati R. Burden of hospitalizations related to adverse drug events in the USA: a retrospective analysis from large inpatient database. Pharmacoepidemiol Drug Saf. 2017;26(6): 635–41. doi: 10.1002/pds.4184.
  7. Thomsen RW, Riis A, Christensen S, McLaughlin JK, Sørensen HT. Outcome of peptic ulcer bleeding among users of traditional non-steroidal anti-inflammatory drugs and selective cyclo-oxygenase-2 inhibitors. Aliment Pharmacol Ther. 2006;24(10):1431–8. doi: 10.1111/j.1365-2036.2006.03139.x.
  8. Thomsen RW, Riis A, Munk EM, Nørgaard M, Christensen S, Sørensen HT. 30-day mortality after peptic ulcer perforation among users of newer selective COX-2 inhibitors and traditional NSAIDs: a population-based study. Am J Gastroenterol. 2006;101(12):2704–10. doi: 10.1111/j.1572-0241.2006.00825.x.
  9. Lanas A, Sopeña F. Nonsteroidal anti-inflammatory drugs and lower gastrointestinal complications. Gastroenterol Clin North Am. 2009;38(2):333–52. doi: 10.1016/j.gtc.2009.03.007.
  10. Tai FWD, McAlindon ME. NSAIDs and the small bowel. Curr Opin Gastroenterol. 2018;34(3):175–82. doi: 10.1097/MOG.0000000000000427.
  11. Moore A, Makinson G, Li C. Patient-level pooled analysis of adjudicated gastrointestinal outcomes in celecoxib clinical trials: meta-analysis of 51,000 patients enrolled in 52 randomized trials. Arthritis Res Ther. 2013;15(1):R6. doi: 10.1186/ar4134.
  12. Sands G, Shell B, Zhang R. Adverse events in patients with blood loss: a pooled analysis of 51 clinical studies from the celecoxib clinical trial database. Open Rheumatol J. 2012;6:44–9. doi: 10.2174/1874312901206010044.
  13. Flicek KT, Hara AK, De Petris G, Pasha SF, Yadav AD, Johnson CD. Diaphragm disease of the small bowel: a retrospective review of CT findings. AJR Am J Roentgenol. 2014;202(2):W140– 5. doi: 10.2214/AJR.13.10732.
  14. Wang ML, Miao F, Tang YH, Zhao XS, Zhong J, Yuan F. Special diaphragm-like strictures of small bowel unrelated to non-steroidal anti-inflammatory drugs. World J Gastroenterol. 2011;17(31):3596–604. doi: 10.3748/wjg.v17.i31.3596.
  15. Goldstein JL, Eisen GM, Lewis B, Gralnek IM, Zlotnick S, Fort JG; Investigators. Video capsule endoscopy to prospectively assess small bowel injury with celecoxib, naproxen plus omeprazole, and placebo. Clin Gastroenterol Hepatol. 2005;3(2):133–41. doi: 10.1016/S1542-3565(04)00619-6.
  16. Goldstein JL, Eisen GM, Lewis B, Gralnek IM, Aisenberg J, Bhadra P, Berger MF. Small bowel mucosal injury is reduced in healthy subjects treated with celecoxib compared with ibuprofen plus omeprazole, as assessed by video capsule endoscopy. Aliment Pharmacol Ther. 2007;25(10):1211–22. doi: 10.1111/j.1365-2036.2007.03312.x.
  17. Allison MC, Howatson AG, Torrance CJ, Lee FD, Russell RI. Gastrointestinal damage associated with the use of nonsteroidal antiinflammatory drugs. N Engl J Med. 1992;327(11):749–54. doi: 10.1056/NEJM199209103271101.
  18. Laine L, Curtis SP, Langman M, Jensen DM, Cryer B, Kaur A, Cannon CP. Lower gastrointestinal events in a double-blind trial of the cyclo-oxygenase-2 selective inhibitor etoricoxib and the traditional nonsteroidal anti-inflammatory drug diclofenac. Gastroenterology. 2008;135(5):1517–25. doi: 10.1053/j.gastro.2008.07.067.
  19. Tachecí I, Bradna P, Douda T, Baštecká D, Kopáčová M, Rejchrt S, Bureš J. NSAID-induced enteropathy in rheumatoid arthritis patients with chronic occult gastrointestinal bleeding: A prospective capsule endoscopy study. Gastroenterol Res Pract. 2013;2013:268382. doi: 10.1155/2013/268382.
  20. Maiden L, Thjodleifsson B, Seigal A, Bjarnason II, Scott D, Birgisson S, Bjarnason I. Longterm effects of nonsteroidal anti-inflammatory drugs and cyclooxygenase-2 selective agents on the small bowel: a cross-sectional capsule enteroscopy study. Clin Gastroenterol Hepatol. 2007;5(9):1040–5. doi: 10.1016/j.cgh.2007.04.031.
  21. Chan FK, Lanas A, Scheiman J, Berger MF, Nguyen H, Goldstein JL. Celecoxib versus omeprazole and diclofenac in patients with osteoarthritis and rheumatoid arthritis (CONDOR): a randomised trial. Lancet. 2010;376(9736): 173–9. doi: 10.1016/S0140-6736(10)60673-3.
  22. Nissen SE, Yeomans ND, Solomon DH, Lüscher TF, Libby P, Husni ME, Graham DY, Borer JS, Wisniewski LM, Wolski KE, Wang Q, Menon V, Ruschitzka F, Gaffney M, Beckerman B, Berger MF, Bao W, Lincoff AM; PRECISION Trial Investigators. Cardiovascular safety of celecoxib, naproxen, or ibuprofen for arthritis. N Engl J Med. 2016;375(26):2519–29. doi: 10.1056/NEJMoa1611593.
  23. Bjarnason I, Scarpignato C, Holmgren E, Olszewski M, Rainsford KD, Lanas A. Mechanisms of damage to the gastrointestinal tract from nonsteroidal anti-inflammatory drugs. Gastroenterology. 2018;154(3):500–14. doi: 10.1053/j.gastro.2017.10.049.
  24. Srinivasan A, De Cruz P. Review article: a practical approach to the clinical management of NSAID enteropathy. Scand J Gastroenterol. 2017;52(9):941–7. doi: 10.1080/00365521.2017.1335769.
  25. Takeuchi K, Satoh H. NSAID-induced small intestinal damage – roles of various pathogenic factors. Digestion. 2015;91(3):218–32. doi: 10.1159/000374106.
  26. Marlicz W, Loniewski I, Grimes DS, Quigley EM. Nonsteroidal anti-inflammatory drugs, proton pump inhibitors, and gastrointestinal injury: contrasting interactions in the stomach and small intestine. Mayo Clin Proc. 2014;89(12): 1699–709. doi: 10.1016/j.mayocp.2014.07.015.
  27. Lué A, Lanas A. Protons pump inhibitor treatment and lower gastrointestinal bleeding: Balancing risks and benefits. World J Gastroenterol. 2016;22(48):10477–81. doi: 10.3748/wjg.v22.i48.10477.
  28. Otani K, Tanigawa T, Watanabe T, Shimada S, Nadatani Y, Nagami Y, Tanaka F, Kamata N, Yamagami H, Shiba M, Tominaga K, Fujiwara Y, Arakawa T. Microbiota plays a key role in non-steroidal anti-inflammatory drug-induced small intestinal damage. Digestion. 2017;95(1): 22–8. doi: 10.1159/000452356.
  29. Jackson MA, Goodrich JK, Maxan ME, Freedberg DE, Abrams JA, Poole AC, Sutter JL, Welter D, Ley RE, Bell JT, Spector TD, Steves CJ. Proton pump inhibitors alter the composition of the gut microbiota. Gut. 2016;65(5):749–56. doi: 10.1136/gutjnl-2015-310861.
  30. Ishihara M, Ohmiya N, Nakamura M, Funasaka K, Miyahara R, Ohno E, Kawashima H, Itoh A, Hirooka Y, Watanabe O, Ando T, Goto H. Risk factors of symptomatic NSAID-induced small intestinal injury and diaphragm disease. Aliment Pharmacol Ther. 2014;40(5):538–47. doi: 10.1111/apt.12858.
  31. Lim YJ, Chun HJ. Recent advances in NSAIDs-induced enteropathy therapeutics: new options, new challenges. Gastroenterol Res Pract. 2013;2013:761060. doi: 10.1155/2013/761060.
  32. Rostom A, Muir K, Dube C, Lanas A, Jolicoeur E, Tugwell P. Prevention of NSAID-related upper gastrointestinal toxicity: a meta-analysis of traditional NSAIDs with gastroprotection and COX-2 inhibitors. Drug Healthc Patient Saf. 2009;1:47–71.
  33. Silverstein FE, Graham DY, Senior JR, Davies HW, Struthers BJ, Bittman RM, Geis GS. Misoprostol reduces serious gastrointestinal complications in patients with rheumatoid arthritis receiving nonsteroidal anti-inflammatory drugs. A randomized, double-blind, placebo-controlled trial. Ann Intern Med. 1995;123(4):241–9. doi: 10.7326/0003-4819-123-4-199508150-00001.
  34. Fujimori S, Seo T, Gudis K, Ehara A, Kobayashi T, Mitsui K, Yonezawa M, Tanaka S, Tatsuguchi A, Sakamoto C. Prevention of nonsteroidal anti-inflammatory drug-induced small-intestinal injury by prostaglandin: a pilot randomized controlled trial evaluated by capsule endoscopy. Gastrointest Endosc. 2009;69(7):1339–46. doi: 10.1016/j.gie.2008.08.017.
  35. Watanabe T, Sugimori S, Kameda N, Machida H, Okazaki H, Tanigawa T, Watanabe K, Tominaga K, Fujiwara Y, Oshitani N, Higuchi K, Arakawa T. Small bowel injury by low-dose enteric-coated aspirin and treatment with misoprostol: a pilot study. Clin Gastroenterol Hepatol. 2008;6(11):1279–82. doi: 10.1016/j.cgh.2008.06.021.
  36. Raskin JB, White RH, Jackson JE, Weaver AL, Tindall EA, Lies RB, Stanton DS. Misoprostol dosage in the prevention of nonsteroidal anti-inflammatory drug-induced gastric and duodenal ulcers: a comparison of three regimens. Ann Intern Med. 1995;123(5):344–50. doi: 10.7326/0003-4819-123-5-199509010-00004.
  37. Naito Y, Yoshikawa T. Rebamipide: a gastrointestinal protective drug with pleiotropic activities. Expert Rev Gastroenterol Hepatol. 2010;4(3):261–70. doi: 10.1586/egh.10.25.
  38. Niwa Y, Nakamura M, Ohmiya N, Maeda O, Ando T, Itoh A, Hirooka Y, Goto H. Efficacy of rebamipide for diclofenac-induced small-intestinal mucosal injuries in healthy subjects: a prospective, randomized, double-blinded, placebo-controlled, cross-over study. J Gastroenterol. 2008;43(4):270–6. doi: 10.1007/s00535-007-2155-4.
  39. Naito Y, Yoshikawa T, Iinuma S, Yagi N, Matsuyama K, Boku Y, Fujii T, Yoshida N, Kondo M, Sasaki E. Rebamipide protects against indomethacin-induced gastric mucosal injury in healthy volunteers in a double-blind, placebo-controlled study. Dig Dis Sci. 1998;43(9 Suppl):83S–89S.
  40. Mizukami K, Murakami K, Abe T, Inoue K, Uchida M, Okimoto T, Kodama M, Fujioka T. Aspirin-induced small bowel injuries and the preventive effect of rebamipide. World J Gastroenterol. 2011;17(46):5117–22. doi: 10.3748/wjg.v17.i46.5117.
  41. Tozawa K, Oshima T, Okugawa T, Ogawa T, Ohda Y, Tomita T, Hida N, Fukui H, Hori K, Watari J, Nakamura S, Miwa H. A randomized, double-blind, placebo-controlled study of rebamipide for gastric mucosal injury taking aspirin with or without clopidogrel. Dig Dis Sci. 2014;59(8):1885–90. doi: 10.1007/s10620-014-3108-4.
  42. Kurokawa S, Katsuki S, Fujita T, Saitoh Y, Ohta H, Nishikawa K, Sato Y, Sato Y, Ohira K, Yamada M, Kato M. A randomized, double-blinded, placebo-controlled, multicenter trial, healing effect of rebamipide in patients with low-dose aspirin and/or non-steroidal anti-inflammatory drug induced small bowel injury. J Gastroenterol. 2014;49(2):239–44. doi: 10.1007/s00535-013-0805-2.
  43. Watanabe T, Takeuchi T, Handa O, Sakata Y, Tanigawa T, Shiba M, Naito Y, Higuchi K, Fujimoto K, Yoshikawa T, Arakawa T. A multicenter, randomized, double-blind, placebo-controlled trial of high-dose rebamipide treatment for low-dose aspirin-induced moderate-to-severe small intestinal damage. PLoS One. 2015;10(4):e0122330. doi: 10.1371/journal.pone.0122330.
  44. Bjarnason I, Hopkinson N, Zanelli G, Prouse P, Smethurst P, Gumpel JM, Levi AJ. Treatment of non-steroidal anti-inflammatory drug induced enteropathy. Gut. 1990;31(7): 777–80. doi: 10.1136/gut.31.7.777.
  45. Rácz I, Szalai M, Kovács V, Regőczi H, Kiss G, Horváth Z. Mucosal healing effect of mesalazine granules in naproxen-induced small bowel enteropathy. World J Gastroenterol. 2013;19(6): 889–96. doi: 10.3748/wjg.v19.i6.889.
  46. Lanas A, Scarpignato C. Microbial flora in NSAID-induced intestinal damage: a role for antibiotics? Digestion. 2006;73 Suppl 1:136– 50. doi: 10.1159/000089789.
  47. Leite AZ, Sipahi AM, Damião AO, Coelho AM, Garcez AT, Machado MC, Buchpiguel CA, Lopasso FP, Lordello ML, Agostinho CL, Laudanna AA. Protective effect of metronidazole on uncoupling mitochondrial oxidative phosphorylation induced by NSAID: a new mechanism. Gut. 2001;48(2):163–7. doi: 10.1136/gut.48.2.163.
  48. Bjarnason I, Hayllar J, Smethurst P, Price A, Gumpel MJ. Metronidazole reduces intestinal inflammation and blood loss in non-steroidal anti-inflammatory drug induced enteropathy. Gut. 1992;33(9):1204–8. doi: 10.1136/gut.33.9.1204.
  49. Maconi G, Barbara G, Bosetti C, Cuomo R, Annibale B. Treatment of diverticular disease of the colon and prevention of acute diverticulitis: a systematic review. Dis Colon Rectum. 2011;54(10):1326–38. doi: 10.1097/DCR.0b013e318223cb2b.
  50. Fornai M, Antonioli L, Pellegrini C, Colucci R, Sacco D, Tirotta E, Natale G, Bartalucci A, Flaibani M, Renzulli C, Ghelardi E, Blandizzi C, Scarpignato C. Small bowel protection against NSAID-injury in rats: Effect of rifaximin, a poorly absorbed, GI targeted, antibiotic. Pharmacol Res. 2016;104:186–96. doi: 10.1016/j.phrs.2015.12.031.
  51. Scarpignato C, Dolak W, Lanas A, Matzneller P, Renzulli C, Grimaldi M, Zeitlinger M, Bjarnason I. Rifaximin reduces the number and severity of intestinal lesions associated with use of nonsteroidal anti-inflammatory drugs in humans. Gastroenterology. 2017;152(5):980–2.e3. doi: 10.1053/j.gastro.2016.12.007.
  52. Montalto M, Gallo A, Curigliano V, D'Onofrio F, Santoro L, Covino M, Dalvai S, Gasbarrini A, Gasbarrini G. Clinical trial: the effects of a probiotic mixture on non-steroidal anti-inflammatory drug enteropathy – a randomized, double-blind, cross-over, placebo-controlled study. Aliment Pharmacol Ther. 2010;32(2):209–14. doi: 10.1111/j.1365-2036.2010.04324.x.
  53. Endo H, Higurashi T, Hosono K, Sakai E, Sekino Y, Iida H, Sakamoto Y, Koide T, Takahashi H, Yoneda M, Tokoro C, Inamori M, Abe Y, Nakajima A. Efficacy of Lactobacillus casei treatment on small bowel injury in chronic low-dose aspirin users: a pilot randomized controlled study. J Gastroenterol. 2011;46(7):894–905. doi: 10.1007/s00535-011-0410-1.
  54. Suzuki T, Masui A, Nakamura J, Shiozawa H, Aoki J, Nakae H, Tsuda S, Imai J, Hideki O, Matsushima M, Mine T, Tamura A, Ohtsu T, Asami Y, Takagi A. Yogurt containing Lactobacillus gasseri mitigates aspirin-induced small bowel injuries: a prospective, randomized, double-blind, placebo-controlled trial. Digestion. 2017;95(1):49–54. doi: 10.1159/000452361.

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