Article Search
검색
검색 팝업 닫기

Metrics

Help

  • 1. Aims and Scope

    Gut and Liver is an international journal of gastroenterology, focusing on the gastrointestinal tract, liver, biliary tree, pancreas, motility, and neurogastroenterology. Gut atnd Liver delivers up-to-date, authoritative papers on both clinical and research-based topics in gastroenterology. The Journal publishes original articles, case reports, brief communications, letters to the editor and invited review articles in the field of gastroenterology. The Journal is operated by internationally renowned editorial boards and designed to provide a global opportunity to promote academic developments in the field of gastroenterology and hepatology. +MORE

  • 2. Editorial Board

    Editor-in-Chief + MORE

    Editor-in-Chief
    Yong Chan Lee Professor of Medicine
    Director, Gastrointestinal Research Laboratory
    Veterans Affairs Medical Center, Univ. California San Francisco
    San Francisco, USA

    Deputy Editor

    Deputy Editor
    Jong Pil Im Seoul National University College of Medicine, Seoul, Korea
    Robert S. Bresalier University of Texas M. D. Anderson Cancer Center, Houston, USA
    Steven H. Itzkowitz Mount Sinai Medical Center, NY, USA
  • 3. Editorial Office
  • 4. Articles
  • 5. Instructions for Authors
  • 6. File Download (PDF version)
  • 7. Ethical Standards
  • 8. Peer Review

    All papers submitted to Gut and Liver are reviewed by the editorial team before being sent out for an external peer review to rule out papers that have low priority, insufficient originality, scientific flaws, or the absence of a message of importance to the readers of the Journal. A decision about these papers will usually be made within two or three weeks.
    The remaining articles are usually sent to two reviewers. It would be very helpful if you could suggest a selection of reviewers and include their contact details. We may not always use the reviewers you recommend, but suggesting reviewers will make our reviewer database much richer; in the end, everyone will benefit. We reserve the right to return manuscripts in which no reviewers are suggested.

    The final responsibility for the decision to accept or reject lies with the editors. In many cases, papers may be rejected despite favorable reviews because of editorial policy or a lack of space. The editor retains the right to determine publication priorities, the style of the paper, and to request, if necessary, that the material submitted be shortened for publication.

Search

Search

Year

to

Article Type

Review

Split Viewer

Potential Strategies in the Prevention of Nonsteroidal Anti-inflammatory Drugs-Associated Adverse Effects in the Lower Gastrointestinal Tract

Chuan-Guo Guo , Wai K. Leung

Department of Medicine, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong

Correspondence to: Wai K. Leung
Department of Medicine, Queen Mary Hospital, Li Ka Shing Faculty of Medicine, University of Hong Kong, 4/F, Professorial Block, 102 Pokfulam Road, Hong Kong
Tel: +852-2255-3348, Fax: +852-2816-2863, E-mail: waikleung@hku.hk

Received: June 15, 2019; Accepted: July 9, 2019

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Gut Liver 2020;14(2):179-189. https://doi.org/10.5009/gnl19201

Published online September 25, 2019, Published date March 15, 2020

Copyright © Gut and Liver.

With the increasing use of nonsteroidal anti-inflammatory drugs (NSAIDs), the incidence of lower gastrointestinal (GI) complications is expected to increase. However, unlike upper GI complications, the burden, pathogenesis, prevention and treatment of NSAID-associated lower GI complications remain unclear. To date, no cost-effective and safe protective agent has been developed that can completely prevent or treat NSAID-related lower GI injuries. Selective COX-2 inhibitors, misoprostol, intestinal microbiota modulation, and some mucoprotective agents have been reported to show protective effects on NSAID-induced lower GI injuries. This review aims to provide an overview of the current evidence on the prevention of NSAID-related lower GI injuries.

Keywords: Anti-inflammatory agents, non-steroidal, Lower gastrointestinal bleeding, Protective agents

Nonsteroidal anti-inflammatory drugs (NSAIDs), which inhibit mucosal prostaglandin production, could induce both upper and lower gastrointestinal (GI) mucosal damages.1 In the Multinational Etoricoxib and Diclofenac Arthritis Long-term (MEDAL) trial, NSAIDs use was associated with a higher risk of upper GI bleeding (relative risk [RR], 2.6; 95% confidence intervals [CI], 2.0 to 3.5) than lower GI bleeding (RR, 1.4; 95% CI, 1.0 to 1.9).2 However, lower GI events still accounted for 40% of all NSAID-related serious GI events.3 With the increasing use of gastroprotective agents as well as the declining prevalence of Helicobacter pylori infection, the incidence of upper GI complications is generally decreasing but the incidence of lower GI complications is rising.4,5 Many of the lower GI complications are related to the use of NSAIDs and aspirin. Even with the concurrent use of gastroprotective agents, up to three-quarters of patients using NSAIDs could still suffer from small intestinal injuries.6 However, unlike upper GI complications, the burden, pathogenesis, prevention and treatment of NSAIDs-associated lower GI complications remain unclear.7 To date, there is no evidence-based effective and safe strategy that can completely prevent or treat NSAIDs-related lower GI injury.7,8 This review aims to give an overview of the current evidence of potential strategies in the prevention of NSAIDs-related lower GI injury. Details of all studies are presented in Table 1.9-45

Selective COX-2 inhibitors, with its selectivity on COX-2 inhibition, is one of the major candidates to replace nonselective NSAIDs in reducing the risk of GI injury. Although it has been widely studied in the prevention of upper GI complications,12,46-48 evidences supporting the benefits of selective COX2 inhibitors over nonselective NSAIDs in the lower GI tract were limited.

It was suggested that use of selective COX-2 inhibitors was associated with a reduced incidence of GI perforations, ulcers and bleeds, with less fecal blood loss and fewer endoscopically detectable lesions.49 Hawkey et al.10 compared the small-bowel injury of selective COX-2 inhibitor, lumiracoxib, with naproxen and placebo in a double-blind randomized controlled trial (RCT). They found that acute small-bowel injury induced by lumiracoxib is less frequent than with naproxen plus omeprazole and similar to placebo. However, this study included healthy volunteers with short follow up of 16 days only. Another study compared the incidence of small bowel injury, as assessed by video capsule endoscopy, in 408 healthy subjects receiving celecoxib with those receiving ibuprofen plus omeprazole. Celecoxib was also associated with significantly fewer small bowel mucosal breaks than ibuprofen and omeprazole.9 A larger RCT11 involving 8,076 rheumatoid arthritis patients reported that rofecoxib reduced the serious lower GI side effects (bleeding, perforation, obstruction, ulceration, or diverticulitis) by 54% when compared to naproxen with the rate of 0.41 and 0.89 per 100 patient-years (RR, 0.46; 95% Cl, 0.22 to 0.93), respectively. The CONDOR study12 is another RCT involving 4,484 patients which found that celecoxib was associated with a lower risk of adverse events throughout the GI tract when compared with diclofenac plus omeprazole. However, in the MEDAL study in which 34,701 patients were included, there was no statistically significant difference between etoricoxib3 and diclofenac in lower GI clinical events (perforation or obstruction requiring hospitalization or bleeding).

A systematic review of randomized trials, including nine trials with 7,616 participants, compared GI adverse effects between COX-2 inhibitors and NSAIDs plus proton pump inhibitor (PPI) and found that COX-2 inhibitors significantly reduced the risk of major GI complications, perforation, obstruction and bleeding (RR, 0.38; 95% CI, 0.25 to 0.56).13 However, after stratifying into upper, mid or lower GI tract, it was not significant for upper (RR, 0.83; 95% CI, 0.36 to 1.89) and lower GI complications (RR, 0.29; 95% CI, 0.01 to 4.18). In contrast, significant difference was detected in mid GI complications (RR, 0.38; 95% CI, 0.16 to 0.89) which favored COX-2 inhibitors. Based on current evidences, some selective COX-2 inhibitors, such as celecoxib and rofecoxib, could be an alternative to traditional NSAIDs to prevent lower GI damage.

It is generally considered that prostaglandins are important in the mediation of inflammation and maintenance of mucosal integrity of the GI tract.50 While inhibition of prostaglandin synthesis through COX is one of the major mechanisms of NSAIDs induced GI tract injury,51 supplementation with misoprostol, a prostaglandin analog, may be effective in protecting against NSAIDs induced enteropathy.50 Morris et al.16 reported that high dose (1,200 µg) misoprostol therapy was associated with an improvement in anemia with an increase of hemoglobin in patients with proven NSAID enteropathy in a retrospective study of 21 patients. Bjarnason et al.14,52 also found that co-administration of misoprostol with NSAIDs alleviated the indomethacin-induced increase in intestinal permeation. However, the study of Davies et al.15 showed that the protective effects of misoprostol (800 µg) on the intestinal permeability co-administration with indomethacin was limited. It was suggested that prostaglandin alleviation of NSAID-induced intestinal permeability may be dose-dependent or that intestinal permeability may only be partially mediated by reduced mucosal prostaglandins.53 This dose-response effect was also found in study comparing the efficacy of three misoprostol dosing regimens in the prevention of gastric and duodenal ulcers associated with long-term NSAIDs.17,18

The protective effects of misoprostol were further demonstrated in studies evaluating small intestine damage by capsule endoscopy. Watanabe et al.19 reported that misoprostol (200 µg given 4 times daily) improved the mucosal lesions found in the small intestine by capsule endoscopy in a case series of 11 patients who had developed gastric ulcers induced by low-dose enteric-coated aspirin. A pilot RCTs by Fujimori et al.,20 involving 34 healthy volunteers, showed that misoprostol (200 µg given 3 times daily) co-therapy reduced the incidence of small-intestinal mucosal breaks induced by a 2-week administration of diclofenac sodium. Recently, Kyaw et al.21 performed an RCT of 84 aspirin users with small bowel bleeding who required aspirin therapy and found that misoprostol (200 µg given 4 times daily) for 8 weeks was superior to placebo in healing of small bowel ulcers. Similar results were also reported in another randomized trial by Taha et al.22 Though the potential protective effects of misoprostol were observed in these studies, large clinical trials with long-term outcomes are lacking. Furthermore, significantly increased risk of drug-related adverse effects like abdominal pain, nausea or vomiting, diarrhea and high dropout rate related to the use of misoprostol were observed in clinical trials.18,22

It has been shown that nitric oxide (NO) plays a key role in the maintenance of the GI mucosa.54,55 NO and prostaglandin showed similar gastroprotective actions that they are both capable of modulating mucosal blood flow, mucus release, and repair of mucosal injury.56,57 Hence, cyclooxygenase inhibiting nitric oxide donators (CINODs) are a new class of anti-inflammatory and analgesic drugs, in which NO is coupled to an NSAID, could potentially minimize GI toxicity of traditional NSAIDs.57,58

In early animal studies, though prostaglandin was still suppressed, NO-releasing derivatives of a wide range of NSAIDs, including aspirin, flurbiprofen, naproxen, and diclofenac, have been shown to minimize the GI injury.58-62 Different from conventional NSAIDs or selective COX-2 inhibitors, which exacerbate experimental colitis in rats63 or inflammatory bowel disease in humans,64 NO-releasing diclofenac was found to be well tolerated by rats with colitis.65 Several clinical studies have also shown consistently that CINODs cause less upper GI damage.23-25 However, there is no clinical studies that evaluate the effects of CINODs in the lower GI tract.

Accumulating evidences suggest that intestinal bacteria may play a significant role in the pathogenesis of small-bowel damage induced by NSAIDs and that enterobacterial translocation into the mucosa represents the first step of a series of events leading to gross lesion formation.66,67 It has been reported that germ-free mice were resistant to NSAIDs related intestinal damage.68,69 However, when germ-free mice were colonized with jejunal bacteria from PPI-treated rats, the severity of NSAID-induced intestinal injury increased.70 Therefore, modulating intestinal microbiota could be a new strategy in the prevention of NSAID-induced intestinal damage.67,71

In keeping with this, several studies reported that antibiotics could attenuate NSAIDs induced enteropathy.66 A resent animal study showed that rifaximin treatment significantly prevents indomethacin-induced intestinal damage following with a decrease in tissue inflammation, oxidative stress and digestive bleeding as well as reversal of NSAID-induced alterations in bacterial population.72 Colucci et al.73 examined the pathophysiology of NSAID-associated intestinal lesions in a rat model and found that rifaximin prevents diclofenac-induced enteropathy through both anti-bacterial and anti-inflammatory activities. Other antibiotics like metronidazole, tetracycline, kanamycin, neomycin plus bacitracin and streptomycin were also reported to reduce the risk of NSAID induced enteropathy.26,74-76 In addition, rifaximin also demonstrated protective effect in patients receiving long-term PPIs treatment, which eradicated 87% to 91% of cases of small intestinal bacterial overgrowth.77 Nevertheless, current evidences supporting the effects of antibiotics in preventing NSAID-induced enteropathy are still weak and most of them were from animal models. Even though antibiotics showed protective effects on NSAIDs/PPIs induced enteropathy, the long-term efficacy and safety has not been confirmed and further large long-term clinical studies are necessary.

Probiotics is another approach in modulating the composition of intestinal flora and has been used in treating several GI disorders like inflammatory bowel diseases,78 irritable bowel syndrome,79 infectious diarrhea and antibiotic-induced diarrhea.80,81 It has been suggested that probiotics could also protect against NSAID-induced enteropathy by modulating the intestinal microbiota.82 Kinouchi et al.74 found that the metabolites of Lactobacillus acidophilus and Bifidobacterium adolescentis inhibited ileal ulcer formation by repressing unbalanced growth of the intestinal microflora and lipid peroxidation in rats. NSAID-induced small bowel injury in rats could be alleviated after restoring small intestinal Actinobacteria through administration of selected commensal bacteria during treatment with PPI and NSAIDs.70 It was also confirmed in a double-blind, cross-over study of 20 healthy volunteers taking the probiotic mixture (VSL#3) or placebo for 21 days, and found that treatment with VSL#3 before and during indomethacin therapy significantly reduces the intestinal inflammation.27 A pilot randomized trial of 35 patients who took low-dose enteric-coated aspirin for more than 3 months plus omeprazole, also found that co-administration of Lactobacillus casei could decrease the number of mucosal breaks under capsule endoscopy.28 However, the quality of evidence on protective effects of probiotics on NSAID-induced enteropathy are still low and further clinical trials are needed.

Gastroprotective agents, especially PPIs, are typically co-prescribed to protect the upper GI tract from NSAIDs induced mucosal injury, which was also recommended by guidelines.83 By suppressing gastric acid secretion, PPIs are effective in decreasing the risk of NSAIDs induced upper GI mucosal damage and bleeding, presumably by raising the pH of the stomach.84 However, lower GI bleeding could be not protected by PPIs,2 and emerging evidences further indicate that PPI may increase the risk of NSAIDs induced small bowel damage and bleeding.70,85,86 A similar exacerbation of NSAIDs induced small bowel damage was also observed in H2 receptor antagonists.85 It was suggested that long term use of PPIs may exacerbate NSAIDs induced small bowel injury by altering intestinal microbiota (dysbiosis) following acid suppression,7,70 which is supported by small intestinal bacterial overgrowth observed in patients with long-term use of PPIs.77,87 A recent multicenter case-control study found that the use of PPIs remained an independent risk factors for mid GI bleeding (adjusted OR, 1.94; p=0.034) even after adjusting for propensity score.88 Thus, the use of PPIs is considered to be an independent risk factor associated with NSAID-associated enteropathy and should be used cautiously.

1. Rebamipide

Rebamipide, an amino acid derivative of 2-(1H)-quinolinone, is a mucosal protective drug that has been clinically used for treating gastritis and peptic ulcers.30,89 Studies have shown that rebamipide is effective to alleviate the NSAIDs induced injury of GI tract, and more recently, the small intestine.34,85 Rebamipide promotes the production of endogenous prostaglandins and modulates the composition of small intestinal microbiota, which supports its efficacy on NSAID-induced small intestinal damage.90-92

Small RCTs of healthy subjects supported that rebamipide had the potential to reduce NSAID-induced small intestinal injury.29,31-33,37 Kurokawa et al.35 performed a multicenter study involving 61 patients who had received more than 3 months of low dose aspirin and/or NSAID to take rebamipide (100 mg 3 times daily for 4 weeks) or placebo and found that rebamipide had the protective effect for NSAIDs-induced enteropathy by reducing the number of small intestinal ulcers and erosions as evaluated by capsule endoscopy. Another small multicenter study by Watanabe et al.36 also found that 8 weeks of high-dose rebamipide (300 mg 3 times daily) significantly decreased the number of mucosal breaks and improved intestinal damage severity. However, Ota et al.37 reported that standard-dose rebamipide (100 mg 3 times daily) was sufficient for preventing mucosal injury of the small intestine induced by low-dose aspirin, indicating that high-dose rebamipide (300 mg 3 times daily) may not be necessary. A systematic review and meta-analysis34 including 15 RCTs and 965 individuals, provided consistent results that rebamipide is effective and safe for defending against NSAID-induced lower GI injuries. However, most studies are with small sample size and short-term follow-up.

2. Irsogladine

Irsogladine, a phosphodiesterase inhibitor, is currently used as one of the anti-ulcer or gastroprotective agents for the treatment of gastric ulcer and gastritis.93 Irsogladine could also prevent NSAIDs or aspirin-induced peptic ulcer and gastritis.41 Furthermore, it has been reported that, in animal research, irsogladine also possessed protective effects against NSAID-induced small intestinal lesions.85,94 This protective effect was further confirmed in clinical studies. The study by Kuramoto et al.38 involving 32 healthy volunteers, found that co-administration of irsogladine for 14 days protected against NSAID-induced mucosal injuries throughout the GI tract, from esophagus to small intestine, which was significantly better than omeprazole. The result was consistent in the study of Isomura et al.39 that co-therapy of irsogladine for 4 weeks was effective for reducing NSAID-induced small-intestinal mucosal injury compared with control, in which 41 patients taking conventional NSAIDs for more than 4 weeks were enrolled. Irsogladine also presented treatment effects which significantly decreased the number of small intestinal lesions induced by NSAIDs.40

3. Other

Apart from the above agents, there are several other drugs such as sulphasalazine,42 ecabet sodium,43 egualen sodium,44 curcumin,95,96 and muscovite,45 which were reported to have a preventive effect on NSAIDs-induced small intestine injury. However, data is very limited for these agents.

So far, effective prevention and treatment of NSAID-associated lower GI injury are lacking. Though various agents including selective COX inhibitors, misoprostol, antibiotics and mucoprotective agents have been considered as candidates for NSAID-induced intestinal injury, they are not properly evaluated in clinical trials. High-quality well-designed randomized, placebo-controlled trials with long-term follow up are needed to verify the efficacy of potential agents in preventing NSAID-associated lower intestinal injury.

Summary of Studies on the Different Interventions to Prevent NSAID-Induced Lower GI Injuries

Author (year) Study design Intervention Study period Subject Main result
Selective COX-2 inhibitors
Goldstein et al. (2007)9 Multileft, double-blind RCT Celecoxib (200 mg bid), ibuprofen (800 mg tid) plus omeprazole (20 mg qd) or placebo 2 wk 408 Healthy subjects The mean number of small bowel mucosal breaks and the percentage of subjects with mucosal breaks were 0.7/25.9% for ibuprofen/omeprazole compared with 0.2/6.4% for celecoxib and 0.1/7.1% placebo (both comparisons p<0.001).
Hawkey et al. (2008)10 Double-blind RCT Lumiracoxib (100 mg qd), naproxen (500 mg bid) plus omeprazole (20 mg qd), or placebo 16 day 139 Healthy volunteers Acute small-bowel injury on lumiracoxib treatment is less frequent than with naproxen plus omeprazole and similar to placebo.
Laine et al. (2003)11 Post hoc analysis of a RCT Naproxen (500 mg bid) or rofecoxib (50 mg qd) 9 mo 8,076 Patients with RA The rate of serious lower GI events per 100 patient-years was 0.41 for rofecoxib and 0.89 for naproxen (RR, 0.46; 95% Cl, 0.22–0.93; p=0.032).
Laine et al. (2008)3 Pooled data from 3 RCTs Etoricoxib (60 or 90 mg qd) or diclofenac (150 mg qd) 18 mo 34,701 Patients with OA or RA Lower GI clinical events rates were 0.32 and 0.38 per 100 patient-years for etoricoxib and diclofenac (HR, 0.84; 95% CI, 0.63–1.13).
Chan et al. (2010)12 Multileft double-blind RCT Celecoxib (200 mg bid) or diclofenac slow release (75 mg bid) plus omeprazole (20 mg qd) 6 mo 4,484 Patients with OA or RA The rate primary endpoint during the 6-mo study period was 0.9% (95% CI, 0.5–1.3) in the celecoxib group and 3.8% (95% CI, 2.9–4.3) in the diclofenac plus omeprazole group (difference 2.9%, 95% CI, 2.0%–3.8%; p<0.0001).
Jarupongprapa et al. (2013)13 Meta-analysis of 9 RCTs COX-2 inhibitors or NSAIDs plus PPI 2–24 mo 7,616 Patients with OA or RA, or healthy COX-2 inhibitors were found to have significantly reduced the risk of major GI events, including perforation, obstruction, and bleeding (RR, 0.38; 95% CI, 0.25–0.56, p<0.001).
Misoprostol
Bjarnason et al. (1989)14 RCT Misoprostol (200 mg), indomethacin (75 mg), or coadministration - 12 Healthy male volunteers Indomethacin increased the permeation of 51Cr-EDTA selectively, and this increase was significantly reduced by the coadministration of misoprostol.
Davies et al. (1993)15 Double-blind RCT Metronidazole (400 mg bid) or misoprostol (200 μg qid), along with indomethacin (50 mg bid) 1 wk 16 Healthy volunteers Metronidazole prevented 51Cr-EDTA permeation increase (1.10 [0.39] before, 1.55 [0.54] after, p>0.05), whereas misoprostol did not (1.31 [0.51] before, 3.26 [1.10]) after, p=0.005).
Morris et al. (1994)16 Retrospective cohort study Misoprostol (1,200 μg/day) or no treatment - 21 Patients with NSAID-induced enteropathy Haemoglobin in the misoprostol-treated group rose significantly from median (range) 9.1 (6.2–10.6) g/dL to 10.6 (6.5–16.8) g/dL (p=0.004).
Raskin et al. (1995)17 Multicdnter double-blind RCT Placebo (qid); misoprostol (200 μg bid) and placebo (bid); misoprostol (200 μg tid) and placebo(qd); or micrograms (200 μg qid) 12 wk 1,197 Patients with upper GI symptoms during NSAID therapy The incidence of duodenal ulcers was significantly lower in the groups receiving misoprostol bid (2.6%; difference, 4.9% [95% CI, 1.5%–8.2%]; p=0.004), tid (3.3%; difference, 4.2% [95% CI, 0.6%–7.7%]; p=0.019), and qid (1.4%; difference, 6.1% [95% CI, 2.6%–9.6%]; p= 0.007) compared with placebo.
Rostom et al. (2002)18 Meta-analysis of 40 RCTs Misoprostol vs placebo, vs ranitidine, or vs PPI (23 RCTs on misoprostol) - - Misoprostol 800 μg/day was superior to 400 μg/day for the prevention of endoscopic gastric ulcers (RR=0.17, RR=0.39 respectively, p=0.0055). Misoprostol caused diarrhea at all doses, although significantly more at 800 μg/day than 400 μg/day (p=0.0012).
Watanabe et al. (2008)19 Single arm study Misoprostol (200 μg qid) 8 wk 11 Patients with aspirin-induced gastric ulcers Misoprostol significantly decreased the median number of red spots and mucosal breaks.
Fujimori et al. (2009)20 Single-blind RCT Diclofenac (25 mg tid) plus omeprazole (20 mg qd), or misoprostol (200 μg tid) plus diclofenac and omeprazole 2 wk 30 Healthy male volunteers NSAID treatment significantly increased the mean number of mucosal breaks in the NSAID-PPI group (p=0.012). In contrast, there was no significant change before and after misoprostol cotreatment (p=0.42).
Kyaw et al. (2018)21 Multicdnter double-blind RCT Misoprostol (200 μg qid) or placebo 8 wk 84 Aspirin users with small bowel bleeding Complete healing of small bowel ulcers was observed in 12 patients in the misoprostol group (28.6%) and 4 patients in the placebo group (9.5%), for a difference in proportion of 19.0% (95% CI, 2.8%–35.3%; p=0.026).
Taha et al. (2018)22 Double-blind RCT Misoprostol (200 μg qid) or placebo 8 wk 104 Aspirin or NSAIDs users with small bowel ulcers Complete healing of small bowel ulcers and erosions was noted at week 8 in 27 (54%) of 50 patients in the misoprostol group and 9 of 52 patients (17%) in the placebo group (percentage difference, 36.7%; 95% CI, 19.5–53.9; p=0.0002).
COX-inhibiting nitric oxide donors
Hawkey et al. (2003)23 Randomized crossover study AZD3582 (a nitroxybutyl derivative of naproxen, 750 mg bid), naproxen (500 mg bid), or placebo 12 day 31 Healthy volunteers The mean number of gastroduodenal erosions was 11.5 on naproxen vs 4.1 on AZD3582 (p<0.0001). Naproxen increased intestinal permeability whereas AZD3582 and placebo did not.
Fiorucci et al. (2004)24 RCT NCX-4016 (800 mg bid), NCX-4016 (800 mg bid) plus aspirin (325 mg qd), aspirin, or placebo 21 day 48 Healthy subjects NCX-4016 is equally effective as aspirin in inhibiting cyclooxygenase activity. However, NCX-4016 causes less gastric damage and prevents monocyte activation.
Lohmander et al. (2005)25 Double-blind RCT AZD3582 (750 mg bid), naproxen (500 mg bid), or placebo 6 wk 970 Patients with OA The incidence of ulcers with AZD3582 was 9.7% and with naproxen 13.7% (p=0.07, NS), vs 0% on placebo. Most secondary endoscopic GI end points favored AZD3582.
Intestinal microbiota modulation
Bjarnason et al. (1992)26 Single arm study Metronidazole 800 mg/day 2–12 wk 13 Patients using NSAIDs Intestinal inflammation and blood loss were significantly reduced after treatment. There were no significant changes in intestinal permeability, or endoscopic or microscopic appearances of the gastroduodenal mucosa.
Montalto et al. (2010)27 Randomized crossover study A daily dose of probiotic mixture (VSL#3) or placebo 21 day 20 Healthy volunteers Treatment with VSL#3 before and during indomethacin therapy significantly reduces FCCs in healthy subjects with respect to placebo.
Endo et al. (2011)28 RCT Probiotic with Lactobacillus casei for (L. casei group) or control group 3 mo 25 Aspirin users with unexplained iron deficiency anemia Significant decreases in the number of mucosal breaks and the capsule endoscopy score were observed at the 3-mo evaluation in the L. casei group as compared with the results in the control group (p=0.039).
Mucoprotective agents
Niwa et al. (2008)29 Randomized crossover study Rebamipide or placebo along with dicloenac 6 wk 10 Healthy subjects The number of subjects with small-intestinal mucosal injuries was higher in the placebo group (8/10) than in the rebamipide group (2/10) (p=0.023).
Thong-Ngam et al. (2009)30 Single arm study Rebamipide (100 mg tid) 8 wk 30 Patients with gastric ulcer Rebamipide is effective and well tolerated for treatment of gastric ulcers especially those caused by NSAIDs, as it promotes the improvement of gastric inflammation scores, clinical symptoms, and ulcer healing.
Fujimori et al. (2011)31 Double-blind RCT Rebamipide (300 mg/day), or placebo along with diclofenac (75 mg/day) and omeprazole (20 mg/day) 14 day 72 Healthy male volunteers NSAID therapy increased the mean number of mucosal injuries from 0.1 to 16 and 4.2 in the control and rebamipide groups, respectively, but not significant. For subjects with mucosal injuries, rebamipide tended to decrease mucosal injuries from 25 in the control to 8.9 in the rebamipide group (Mann-Whitney U test; p=0.038).
Mizukami et al. (2011)32 Randomized, crossover study Rebamipide (300 mg/day) or placebo, along with aspirin (100 mg qd) and omeprazole (20 mg qd) 12 wk 11 Healthy male subjects Rebamipide significantly prevented mucosal breaks on the ileum compared with the placebo group (p=0.017 at 1st wk and p=0.027 at 4th wk).
Mizukami et al. (2012)33 Randomized, crossover study Rebamipide (300 mg/day) or placebo, along with aspirin (100 mg qd) and omeprazole (20 mg qd) 12 wk 12 Healthy male subjects For the subjects receiving rebamipide, the total prevalence of lower GI symptoms was significantly different from the placebo group (p=0.0093) at wk 4.
Zhang et al. (2013)34 Meta-analysis of 15 RCTs Rebamipide vs placebo, or vs PPI, or vs misoprostol, or vs H2RA - 965 Subjects Rebamipide acted better than placebo against NSAID-induced GI injury, which was equal to or not superior to traditional strategies (PPIs, H2RA, or misoprostol). Rebamipide showed a beneficial effect against the small bowel damage (RR, 2.70; 95% CI, 1.02–7.16; p=0.045) vs placebo.
Kurokawa et al. (2014)35 Multileft, double-blind RCT Rebamipide (100 mg tid) or placebo 4 wk 61 Patients with NSAIDs-induced enteropathy Rebamipide has not only the healing effect for NSAIDs-induced enteropathy compared with placebo, but the improvement of nutritional condition.
Watanabe et al. (2015)36 Multileft, double-blind RCT Rebamipide (300 mg tid) or placebo 8 wk 38 Patients with aspirin-induced enteropathy High-dose rebamipide is effective for the treatment of LDA-induced moderate-to-severe enteropathy.
Ota et al. (2016)37 RCT Omeprazole 10 mg, rebamipide 300 mg, or rebamipide 900 mg, along with aspirin 2 wk 45 Healthy volunteers The fecal calprotectin levels only increased significantly in group A. The gastroscopic and capsule endoscopic findings and the fecal occult blood test findings did not differ significantly among three groups.
Kuramoto et al. (2013)38 RCT Group I: diclofenac (75 mg daily) and irsogladine (4 mg daily); or group O: diclofenac and omeprazole (10 mg daily) 14 day 32 Healthy volunteers No significant difference between group I and O in the upper GI lesion score change. NSAID significantly increased the mean number of small intestinal mucosal breaks in group O (p=0.0002), not in group I. The between-group difference was significant (p=0.004).
Isomura et al. (2014)39 Single-blind RCT Irsogladine (4 mg/day) or the control group 4 wk 41 Patients with NSAID-induced small intestinal injury The improvement rate was significantly higher in the irsogladine group (16/19 patients; 84.2%) than in the control group (9/20 patients; 45.0%; p=0.02).
Kojima et al. (2015)40 RCT Omeprazole (10 mg/day) for 6 wk, with irsogladine (4 mg/day) from 6 wk to 10, or irsogladine for 6 wk, or omeprazole for 10 wk, along with diclofenac (75 mg/day) 6 wk 37 Healthy volunteers Irsogladine was effective in both preventing and healing such lesions.
Shim et al. (2018)41 Multileft, double-blind RCT Irsogladine maleate (2 mg bid) or placebo 8 wk 76 Patients usingNSAIDs or aspirin There were no significant differences in gastric protective effects between test and placebo groups. However, 2 cases of peptic ulcer in the placebo group but none in the test group were observed.
Other
Hayllar et al. (1994)42 RCT Sulfasalazine (1.5–3.0 mg/day) or another antirheumatic drug 6–12 mo 46 Patients with RA Sulfasalazine reduced both intestinal inflammation and blood loss, whereas the other antirheumatic drugs did not.
Ota et al. (2019)43 Double-blind RCT Group A, low-dose aspirin; group B, low-dose aspirin and 4.0 g of ecabet sodium 2 wk 24 Healthy volunteers A significant difference was found in the median number of small intestinal lesions before or after treatment in group A (baseline: 1 [0–5], after: 5 [1–11]; p=0.0059) but not in group B (baseline: 0.5 [0–9], after: 3 [0–23]; p=0.0586).
Iguchi et al. (2018)44 RCT Aspirin 100 mg/kg daily or aspirin plus egualen sodium 30 mg daily. 2 wk 20 Healthy male volunteers Egualen sodium significantly suppressed the total number of small intestinal injuries detected by capsule endoscopy and the positive ratio for the fecal occult blood test.
Huang et al. (2014)45 RCT Diclofenac (75 mg bid) plus omeprazole (20 mg/day), or muscovite (3 g bid) plus diclofenac and omeprazole 14 day 30 Healthy volunteers A significant difference was observed in number of subjects with mucosal breaks comparing muscovite with the control. Co-administration of muscovite reduced the rate of mucosal break to 31.3% (5/16) (p=0.028).

NSAIDs, nonsteroidal anti-inflammatory drugs; GI, gastrointestinal; RCT, randomized controlled trial; qd, one a day; bid, twice a day; tid, 3 times a day; qid, 4 times a day; RR, relative risk; CI, confidence interval; RA, rheumatoid arthritis; OA, osteoarthritis; HR, hazard ratio; PPI, proton pump inhibitor; EDTA, ethylenediamine tetraacetic acid; FCCs, faecal calprotectin concentrations; H2RA, histamine type-2 receptor antagonists; LDA, low-dose aspirin.


  1. Lanas A, Perez-Aisa MA, Feu F, et al. A nationwide study of mortality associated with hospital admission due to severe gastrointestinal events and those associated with nonsteroidal anti-inflammatory drug use. Am J Gastroenterol 2005;100:1685-1693.
    Pubmed CrossRef
  2. Lanas Á, Carrera-Lasfuentes P, Arguedas Y, et al. Risk of upper and lower gastrointestinal bleeding in patients taking nonsteroidal anti-inflammatory drugs, antiplatelet agents, or anticoagulants. Clin Gastroenterol Hepatol 2015;13:906-912.
    Pubmed CrossRef
  3. Laine L, Curtis SP, Langman M, et al. 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;135:1517-1525.
    Pubmed CrossRef
  4. Lanas A, García-Rodríguez LA, Polo-Tomás M, et al. Time trends and impact of upper and lower gastrointestinal bleeding and perforation in clinical practice. Am J Gastroenterol 2009;104:1633-1641.
    Pubmed CrossRef
  5. Lanas A, Sopeña F. Nonsteroidal anti-inflammatory drugs and lower gastrointestinal complications. Gastroenterol Clin North Am 2009;38:333-352.
    Pubmed CrossRef
  6. Wallace JL. NSAID gastropathy and enteropathy: distinct pathogenesis likely necessitates distinct prevention strategies. Br J Pharmacol 2012;165:67-74.
    Pubmed KoreaMed CrossRef
  7. Chan FK. NSAID-associated lower gastrointestinal bleeding: where do we stand?. Clin Gastroenterol Hepatol 2012;10:1060-1061.
    Pubmed CrossRef
  8. Lanza FL, Chan FK, Quigley EM; Practice Parameters Committee of the American College of Gastroenterology. Guidelines for prevention of NSAID-related ulcer complications. Am J Gastroenterol 2009;104:728-738.
    Pubmed CrossRef
  9. Goldstein JL, Eisen GM, Lewis B, et al. 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;25:1211-1222.
    Pubmed CrossRef
  10. Hawkey CJ, Ell C, Simon B, et al. Less small-bowel injury with lumiracoxib compared with naproxen plus omeprazole. Clin Gastroenterol Hepatol 2008;6:536-544.
    Pubmed CrossRef
  11. Laine L, Connors LG, Reicin A, et al. Serious lower gastrointestinal clinical events with nonselective NSAID or coxib use. Gastroenterology 2003;124:288-292.
    Pubmed CrossRef
  12. 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;376:173-179.
    Pubmed CrossRef
  13. Jarupongprapa S, Ussavasodhi P, Katchamart W. Comparison of gastrointestinal adverse effects between cyclooxygenase-2 inhibitors and non-selective, non-steroidal anti-inflammatory drugs plus proton pump inhibitors: a systematic review and meta-analysis. J Gastroenterol 2013;48:830-838.
    Pubmed CrossRef
  14. Bjarnason I, Smethurst P, Fenn CG, Lee CE, Menzies IS, Levi AJ. Misoprostol reduces indomethacin-induced changes in human small intestinal permeability. Dig Dis Sci 1989;34:407-411.
    Pubmed CrossRef
  15. Davies GR, Wilkie ME, Rampton DS. Effects of metronidazole and misoprostol on indomethacin-induced changes in intestinal permeability. Dig Dis Sci 1993;38:417-425.
    Pubmed CrossRef
  16. Morris AJ, Murray L, Sturrock RD, Madhok R, Capell HA, Mackenzie JF. Short report: the effect of misoprostol on the anaemia of NSAID enteropathy. Aliment Pharmacol Ther 1994;8:343-346.
    Pubmed CrossRef
  17. Raskin JB, White RH, Jackson JE, et al. Misoprostol dosage in the prevention of nonsteroidal anti-inflammatory drug-induced gastric and duodenal ulcers: a comparison of three regimens. Ann Intern Med 1995;123:344-350.
    Pubmed CrossRef
  18. Rostom A, Dube C, Wells G, et al. Prevention of NSAID-induced gastroduodenal ulcers. Cochrane Database Syst Rev 2002;4:CD002296.
    CrossRef
  19. Watanabe T, Sugimori S, Kameda N, et al. Small bowel injury by low-dose enteric-coated aspirin and treatment with misoprostol: a pilot study. Clin Gastroenterol Hepatol 2008;6:1279-1282.
    Pubmed CrossRef
  20. Fujimori S, Seo T, Gudis K, et al. Prevention of nonsteroidal anti-inflammatory drug-induced small-intestinal injury by prostaglandin: a pilot randomized controlled trial evaluated by capsule endoscopy. Gastrointest Endosc 2009;69:1339-1346.
    Pubmed CrossRef
  21. Kyaw MH, Otani K, Ching JYL, et al. Misoprostol heals small bowel ulcers in aspirin users with small bowel bleeding. Gastroenterology 2018;155:1090-1097.
    Pubmed CrossRef
  22. Taha AS, McCloskey C, McSkimming P, McConnachie A. Misoprostol for small bowel ulcers in patients with obscure bleeding taking aspirin and non-steroidal anti-inflammatory drugs (MASTERS): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Gastroenterol Hepatol 2018;3:469-476.
    Pubmed CrossRef
  23. Hawkey CJ, Jones JI, Atherton CT, et al. Gastrointestinal safety of AZD3582, a cyclooxygenase inhibiting nitric oxide donator: proof of concept study in humans. Gut 2003;52:1537-1542.
    Pubmed KoreaMed CrossRef
  24. Fiorucci S, Mencarelli A, Meneguzzi A, et al. Co-administration of nitric oxide-aspirin (NCX-4016) and aspirin prevents platelet and monocyte activation and protects against gastric damage induced by aspirin in humans. J Am Coll Cardiol 2004;44:635-641.
    Pubmed CrossRef
  25. Lohmander LS, McKeith D, Svensson O, et al. A randomised, placebo controlled, comparative trial of the gastrointestinal safety and efficacy of AZD3582 versus naproxen in osteoarthritis. Ann Rheum Dis 2005;64:449-456.
    Pubmed KoreaMed CrossRef
  26. 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;33:1204-1208.
    Pubmed KoreaMed CrossRef
  27. Montalto M, Gallo A, Curigliano V, et al. 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;32:209-214.
    Pubmed CrossRef
  28. Endo H, Higurashi T, Hosono K, et al. Efficacy of Lactobacillus casei treatment on small bowel injury in chronic low-dose aspirin users: a pilot randomized controlled study. J Gastroenterol 2011;46:894-905.
    Pubmed CrossRef
  29. Niwa Y, Nakamura M, Ohmiya N, et al. 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;43:270-276.
    Pubmed CrossRef
  30. Thong-Ngam D, Chayanupatkul M, Klaikeaw N, Rerknimitr R, Mahachai V. Effect of rebamipide on gastric ulcer healing caused by Helicobacter pylori and/or NSAIDs or non NSAIDs-non H. pylori. J Med Assoc Thai 2009;92:1207-1212.
  31. Fujimori S, Takahashi Y, Gudis K, et al. Rebamipide has the potential to reduce the intensity of NSAID-induced small intestinal injury: a double-blind, randomized, controlled trial evaluated by capsule endoscopy. J Gastroenterol 2011;46:57-64.
    Pubmed CrossRef
  32. Mizukami K, Murakami K, Abe T, et al. Aspirin-induced small bowel injuries and the preventive effect of rebamipide. World J Gastroenterol 2011;17:5117-5122.
    Pubmed KoreaMed CrossRef
  33. Mizukami K, Murakami K, Hirashita Y, et al. Efficacy of rebamipide for low-dose aspirin-related gastrointestinal symptoms. J Clin Biochem Nutr 2012;51:216-220.
    Pubmed KoreaMed CrossRef
  34. Zhang S, Qing Q, Bai Y, et al. Rebamipide helps defend against nonsteroidal anti-inflammatory drugs induced gastroenteropathy: a systematic review and meta-analysis. Dig Dis Sci 2013;58:1991-2000.
    Pubmed CrossRef
  35. Kurokawa S, Katsuki S, Fujita T, et al. 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;49:239-244.
    Pubmed CrossRef
  36. Watanabe T, Takeuchi T, Handa O, et al. 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:e0122330.
    Pubmed KoreaMed CrossRef
  37. Ota K, Takeuchi T, Nouda S, et al. Determination of the adequate dosage of rebamipide, a gastric mucoprotective drug, to prevent low-dose aspirin-induced gastrointestinal mucosal injury. J Clin Biochem Nutr 2016;59:231-237.
    Pubmed KoreaMed CrossRef
  38. Kuramoto T, Umegaki E, Nouda S, et al. Preventive effect of irsogladine or omeprazole on non-steroidal anti-inflammatory drug-induced esophagitis, peptic ulcers, and small intestinal lesions in humans, a prospective randomized controlled study. BMC Gastroenterol 2013;13:85.
    Pubmed KoreaMed CrossRef
  39. Isomura Y, Yamaji Y, Yamada A, et al. Irsogladine improves small-intestinal injuries in regular users of nonsteroidal anti-inflammatory drugs. Gastrointest Endosc 2014;80:118-125.
    Pubmed CrossRef
  40. Kojima Y, Takeuchi T, Ota K, et al. Effect of long-term proton pump inhibitor therapy and healing effect of irsogladine on nonsteroidal anti-inflammatory drug-induced small-intestinal lesions in healthy volunteers. J Clin Biochem Nutr 2015;57:60-65.
    Pubmed KoreaMed CrossRef
  41. Shim KN, Kim JI, Kim N, et al. The efficacy and safety of irsogladine maleate in nonsteroidal anti-inflammatory drug or aspirin-induced peptic ulcer and gastritis. Korean J Intern Med 2019;34:1008-1021.
    Pubmed KoreaMed CrossRef
  42. Hayllar J, Smith T, Macpherson A, Price AB, Gumpel M, Bjarnason I. Nonsteroidal antiinflammatory drug-induced small intestinal inflammation and blood loss: effects of sulfasalazine and other disease-modifying antirheumatic drugs. Arthritis Rheum 1994;37:1146-1150.
    Pubmed CrossRef
  43. Ota K, Takeuchi T, Kojima Y, et al. Preventive effect of ecabet sodium on low-dose aspirin-induced small intestinal mucosal injury: a randomized, double-blind, pilot study. BMC Gastroenterol 2019;19:4.
    Pubmed KoreaMed CrossRef
  44. Iguchi M, Kakimoto K, Kuramoto T, et al. Effect of egualen sodium hydrate on small-intestinal mucosal damage induced by low-dose aspirin: a prospective randomized clinical trial. J Clin Biochem Nutr 2018;62:174-178.
    Pubmed KoreaMed CrossRef
  45. Huang C, Lu B, Fan YH, et al. Muscovite is protective against non-steroidal anti-inflammatory drug-induced small bowel injury. World J Gastroenterol 2014;20:11012-11018.
    Pubmed KoreaMed CrossRef
  46. Latimer N, Lord J, Grant RL, et al. Cost effectiveness of COX 2 selective inhibitors and traditional NSAIDs alone or in combination with a proton pump inhibitor for people with osteoarthritis. BMJ 2009;339:b2538.
    Pubmed KoreaMed CrossRef
  47. Schnitzer TJ, Burmester GR, Mysler E, et al. Comparison of lumiracoxib with naproxen and ibuprofen in the Therapeutic Arthritis Research and Gastrointestinal Event Trial (TARGET), reduction in ulcer complications: randomised controlled trial. Lancet 2004;364:665-674.
    Pubmed CrossRef
  48. Dajani EZ, Agrawal NM. Selective COX-2 inhibitors and gastrointestinal mucosal injury: pharmacological and therapeutic considerations. J Assoc Acad Minor Phys 2000;11:28-31.
    Pubmed
  49. Hunt RH, Harper S, Callegari P, et al. Complementary studies of the gastrointestinal safety of the cyclo-oxygenase-2-selective inhibitor etoricoxib. Aliment Pharmacol Ther 2003;17:201-210.
    Pubmed CrossRef
  50. Wallace JL. Prostaglandins, NSAIDs, and gastric mucosal protection: why doesn’t the stomach digest itself?. Physiol Rev 2008;88:1547-1565.
    Pubmed CrossRef
  51. Whittle BJ. Temporal relationship between cyclooxygenase inhibition, as measured by prostacyclin biosynthesis, and the gastrointestinal damage induced by indomethacin in the rat. Gastroenterology 1981;80:94-98.
    Pubmed CrossRef
  52. Bjarnason I. Experimental evidence of the benefit of misoprostol beyond the stomach in humans. J Rheumatol Suppl 1990;20:38-41.
    Pubmed
  53. Davies NM, Saleh JY, Skjodt NM. Detection and prevention of NSAID-induced enteropathy. J Pharm Pharm Sci 2000;3:137-155.
    Pubmed
  54. MacNaughton WK, Cirino G, Wallace JL. Endothelium-derived relaxing factor (nitric oxide) has protective actions in the stomach. Life Sci 1989;45:1869-1876.
    Pubmed CrossRef
  55. Wallace JL, Miller MJ. Nitric oxide in mucosal defense: a little goes a long way. Gastroenterology 2000;119:512-520.
    Pubmed CrossRef
  56. Wallace JL, Del Soldato P. The therapeutic potential of NO-NSAIDs. Fundam Clin Pharmacol 2003;17:11-20.
    Pubmed CrossRef
  57. Lanas A. Role of nitric oxide in the gastrointestinal tract. Arthritis Res Ther 2008;10:S4.
    Pubmed KoreaMed CrossRef
  58. Wallace JL, Reuter B, Cicala C, McKnight W, Grisham MB, Cirino G. Novel nonsteroidal anti-inflammatory drug derivatives with markedly reduced ulcerogenic properties in the rat. Gastroenterology 1994;107:173-179.
    Pubmed CrossRef
  59. Wallace JL, Vergnolle N, Muscará MN, et al. Enhanced anti-inflammatory effects of a nitric oxide-releasing derivative of mesalamine in rats. Gastroenterology 1999;117:557-566.
    Pubmed CrossRef
  60. Tashima K, Fujita A, Umeda M, Takeuchi K. Lack of gastric toxicity of nitric oxide-releasing aspirin, NCX-4016, in the stomach of diabetic rats. Life Sci 2000;67:1639-1652.
    Pubmed CrossRef
  61. Wallace JL, Reuter B, Cicala C, McKnight W, Grisham M, Cirino G. A diclofenac derivative without ulcerogenic properties. Eur J Pharmacol 1994;257:249-255.
    Pubmed CrossRef
  62. Davies NM, Røseth AG, Appleyard CB, et al. NO-naproxen vs. naproxen: ulcerogenic, analgesic and anti-inflammatory effects. Aliment Pharmacol Ther 1997;11:69-79.
    Pubmed CrossRef
  63. Reuter BK, Asfaha S, Buret A, Sharkey KA, Wallace JL. Exacerbation of inflammation-associated colonic injury in rat through inhibition of cyclooxygenase-2. J Clin Invest 1996;98:2076-2085.
    Pubmed KoreaMed CrossRef
  64. Bonner GF. Exacerbation of inflammatory bowel disease associated with use of celecoxib. Am J Gastroenterol 2001;96:1306-1308.
    Pubmed CrossRef
  65. Reuter BK, Cirino G, Wallace JL. Markedly reduced intestinal toxicity of a diclofenac derivative. Life Sci 1994;55:PL1-PL8.
    Pubmed CrossRef
  66. Lanas A, Scarpignato C. Microbial flora in NSAID-induced intestinal damage: a role for antibiotics?. Digestion 2006;73:136-150.
    Pubmed CrossRef
  67. Otani K, Tanigawa T, Watanabe T, et al. Microbiota plays a key role in non-steroidal anti-inflammatory drug-induced small intestinal damage. Digestion 2017;95:22-28.
    Pubmed CrossRef
  68. Uejima M, Kinouchi T, Kataoka K, Hiraoka I, Ohnishi Y. Role of intestinal bacteria in ileal ulcer formation in rats treated with a nonsteroidal antiinflammatory drug. Microbiol Immunol 1996;40:553-560.
    Pubmed CrossRef
  69. Robert A, Asano T. Resistance of germfree rats to indomethacin-induced intestinal lesions. Prostaglandins 1977;14:333-341.
    Pubmed CrossRef
  70. Wallace JL, Syer S, Denou E, et al. Proton pump inhibitors exacerbate NSAID-induced small intestinal injury by inducing dysbiosis. Gastroenterology 2011;141:1314-1322.
    Pubmed CrossRef
  71. Scarpignato C. NSAID-induced intestinal damage: are luminal bacteria the therapeutic target?. Gut 2008;57:145-148.
    Pubmed CrossRef
  72. Fornai M, Antonioli L, Pellegrini C, et al. Small bowel protection against NSAID-injury in rats: effect of rifaximin, a poorly absorbed, GI targeted, antibiotic. Pharmacol Res 2016;104:186-196.
    Pubmed CrossRef
  73. Colucci R, Pellegrini C, Fornai M, et al. Pathophysiology of NSAID-associated intestinal lesions in the rat: luminal bacteria and mucosal inflammation as targets for prevention. Front Pharmacol 2018;9:1340.
    Pubmed KoreaMed CrossRef
  74. Kinouchi T, Kataoka K, Bing SR, et al. Culture supernatants of Lactobacillus acidophilus and Bifidobacterium adolescentis repress ileal ulcer formation in rats treated with a nonsteroidal antiinflammatory drug by suppressing unbalanced growth of aerobic bacteria and lipid peroxidation. Microbiol Immunol 1998;42:347-355.
    Pubmed CrossRef
  75. Koga H, Aoyagi K, Matsumoto T, Iida M, Fujishima M. Experimental enteropathy in athymic and euthymic rats: synergistic role of lipopolysaccharide and indomethacin. Am J Physiol 1999;276:G576-G582.
    Pubmed CrossRef
  76. Banerjee AK, Peters TJ. Experimental non-steroidal anti-inflammatory drug-induced enteropathy in the rat: similarities to inflammatory bowel disease and effect of thromboxane synthetase inhibitors. Gut 1990;31:1358-1364.
    Pubmed KoreaMed CrossRef
  77. Lombardo L, Foti M, Ruggia O, Chiecchio A. Increased incidence of small intestinal bacterial overgrowth during proton pump inhibitor therapy. Clin Gastroenterol Hepatol 2010;8:504-508.
    Pubmed CrossRef
  78. Shen J, Zuo ZX, Mao AP. Effect of probiotics on inducing remission and maintaining therapy in ulcerative colitis, Crohn’s disease, and pouchitis: meta-analysis of randomized controlled trials. Inflamm Bowel Dis 2014;20:21-35.
    Pubmed CrossRef
  79. Zhang Y, Li L, Guo C, et al. Effects of probiotic type, dose and treatment duration on irritable bowel syndrome diagnosed by Rome III criteria: a meta-analysis. BMC Gastroenterol 2016;16:62.
    Pubmed KoreaMed CrossRef
  80. Hempel S, Newberry SJ, Maher AR, et al. Probiotics for the prevention and treatment of antibiotic-associated diarrhea: a systematic review and meta-analysis. JAMA 2012;307:1959-1969.
    Pubmed CrossRef
  81. Szajewska H, Skórka A, Ruszczyński M, Gieruszczak-Białek D. Meta-analysis: Lactobacillus GG for treating acute gastroenteritis in children--updated analysis of randomised controlled trials. Aliment Pharmacol Ther 2013;38:467-476.
    Pubmed CrossRef
  82. Gallo A, Passaro G, Gasbarrini A, Landolfi R, Montalto M. Modulation of microbiota as treatment for intestinal inflammatory disorders: an uptodate. World J Gastroenterol 2016;22:7186-7202.
    Pubmed KoreaMed CrossRef
  83. Rostom A, Moayyedi P, Hunt R; Canadian Association of Gastroenterology Consensus Group. Canadian consensus guidelines on long-term nonsteroidal anti-inflammatory drug therapy and the need for gastroprotection: benefits versus risks. Aliment Pharmacol Ther 2009;29:481-496.
    Pubmed CrossRef
  84. Yeomans ND, Tulassay Z, Juhász L, et al. A comparison of omeprazole with ranitidine for ulcers associated with nonsteroidal antiinflammatory drugs. Acid Suppression Trial: Ranitidine versus Omeprazole for NSAID-associated Ulcer Treatment (ASTRONAUT) Study Group. N Engl J Med 1998;338:719-726.
    Pubmed CrossRef
  85. Satoh H, Amagase K, Takeuchi K. Mucosal protective agents prevent exacerbation of NSAID-induced small intestinal lesions caused by antisecretory drugs in rats. J Pharmacol Exp Ther 2014;348:227-235.
    Pubmed CrossRef
  86. Gwee KA, Goh V, Lima G, Setia S. Coprescribing proton-pump inhibitors with nonsteroidal anti-inflammatory drugs: risks versus benefits. J Pain Res 2018;11:361-374.
    Pubmed KoreaMed CrossRef
  87. Williams C, McColl KE. Review article: proton pump inhibitors and bacterial overgrowth. Aliment Pharmacol Ther 2006;23:3-10.
    Pubmed CrossRef
  88. Nagata N, Niikura R, Yamada A, et al. Acute middle gastrointestinal bleeding risk associated with NSAIDs, antithrombotic drugs, and PPIs: a multicenter case-control study. PLoS One 2016;11:e0151332.
    Pubmed KoreaMed CrossRef
  89. Kamada T, Sato M, Tokutomi T, et al. Rebamipide improves chronic inflammation in the lesser curvature of the corpus after Helicobacter pylori eradication: a multicenter study. Biomed Res Int 2015;2015:865146.
    Pubmed KoreaMed CrossRef
  90. Arakawa T, Watanabe T, Fukuda T, Yamasaki K, Kobayashi K. Rebamipide, novel prostaglandin-inducer accelerates healing and reduces relapse of acetic acid-induced rat gastric ulcer. Comparison with cimetidine. Dig Dis Sci 1995;40:2469-2472.
    Pubmed CrossRef
  91. Tanigawa T, Watanabe T, Otani K, et al. Rebamipide inhibits indomethacin-induced small intestinal injury: possible involvement of intestinal microbiota modulation by upregulation of α-defensin 5. Eur J Pharmacol 2013;704:64-69.
    Pubmed CrossRef
  92. Imaeda H, Fujimoto T, Takahashi K, Kasumi E, Fujiyama Y, Andoh A. Terminal-restriction fragment length polymorphism (T-RFLP) analysis for changes in the gut microbiota profiles of indomethacin- and rebamipide-treated mice. Digestion 2012;86:250-257.
    Pubmed CrossRef
  93. Hiraishi H, Haruma K, Miwa H, Goto H. Clinical trial: irsogladine maleate, a mucosal protective drug, accelerates gastric ulcer healing after treatment for eradication of Helicobacter pylori infection: the results of a multicentre, double-blind, randomized clinical trial (IMPACT study). Aliment Pharmacol Ther 2010;31:824-833.
    Pubmed CrossRef
  94. Kamei K, Kubo Y, Kato N, Hatazawa R, Amagase K, Takeuchi K. Prophylactic effect of irsogladine maleate against indomethacin-induced small intestinal lesions in rats. Dig Dis Sci 2008;53:2657-2666.
    Pubmed CrossRef
  95. Menozzi A, Pozzoli C, Poli E, et al. Effects of oral curcumin on indomethacin-induced small intestinal damage in the rat. Drug Discov Ther 2009;3:71-76.
    Pubmed
  96. Sivalingam N, Hanumantharaya R, Faith M, Basivireddy J, Balasubramanian KA, Jacob M. Curcumin reduces indomethacin-induced damage in the rat small intestine. J Appl Toxicol 2007;27:551-560.
    Pubmed CrossRef

Article

Review

Gut and Liver 2020; 14(2): 179-189

Published online March 15, 2020 https://doi.org/10.5009/gnl19201

Copyright © Gut and Liver.

Potential Strategies in the Prevention of Nonsteroidal Anti-inflammatory Drugs-Associated Adverse Effects in the Lower Gastrointestinal Tract

Chuan-Guo Guo , Wai K. Leung

Department of Medicine, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong

Correspondence to:Wai K. Leung
Department of Medicine, Queen Mary Hospital, Li Ka Shing Faculty of Medicine, University of Hong Kong, 4/F, Professorial Block, 102 Pokfulam Road, Hong Kong
Tel: +852-2255-3348, Fax: +852-2816-2863, E-mail: waikleung@hku.hk

Received: June 15, 2019; Accepted: July 9, 2019

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

With the increasing use of nonsteroidal anti-inflammatory drugs (NSAIDs), the incidence of lower gastrointestinal (GI) complications is expected to increase. However, unlike upper GI complications, the burden, pathogenesis, prevention and treatment of NSAID-associated lower GI complications remain unclear. To date, no cost-effective and safe protective agent has been developed that can completely prevent or treat NSAID-related lower GI injuries. Selective COX-2 inhibitors, misoprostol, intestinal microbiota modulation, and some mucoprotective agents have been reported to show protective effects on NSAID-induced lower GI injuries. This review aims to provide an overview of the current evidence on the prevention of NSAID-related lower GI injuries.

Keywords: Anti-inflammatory agents, non-steroidal, Lower gastrointestinal bleeding, Protective agents

INTRODUCTION

Nonsteroidal anti-inflammatory drugs (NSAIDs), which inhibit mucosal prostaglandin production, could induce both upper and lower gastrointestinal (GI) mucosal damages.1 In the Multinational Etoricoxib and Diclofenac Arthritis Long-term (MEDAL) trial, NSAIDs use was associated with a higher risk of upper GI bleeding (relative risk [RR], 2.6; 95% confidence intervals [CI], 2.0 to 3.5) than lower GI bleeding (RR, 1.4; 95% CI, 1.0 to 1.9).2 However, lower GI events still accounted for 40% of all NSAID-related serious GI events.3 With the increasing use of gastroprotective agents as well as the declining prevalence of Helicobacter pylori infection, the incidence of upper GI complications is generally decreasing but the incidence of lower GI complications is rising.4,5 Many of the lower GI complications are related to the use of NSAIDs and aspirin. Even with the concurrent use of gastroprotective agents, up to three-quarters of patients using NSAIDs could still suffer from small intestinal injuries.6 However, unlike upper GI complications, the burden, pathogenesis, prevention and treatment of NSAIDs-associated lower GI complications remain unclear.7 To date, there is no evidence-based effective and safe strategy that can completely prevent or treat NSAIDs-related lower GI injury.7,8 This review aims to give an overview of the current evidence of potential strategies in the prevention of NSAIDs-related lower GI injury. Details of all studies are presented in Table 1.9-45

SELECTIVE COX-2 INHIBITORS

Selective COX-2 inhibitors, with its selectivity on COX-2 inhibition, is one of the major candidates to replace nonselective NSAIDs in reducing the risk of GI injury. Although it has been widely studied in the prevention of upper GI complications,12,46-48 evidences supporting the benefits of selective COX2 inhibitors over nonselective NSAIDs in the lower GI tract were limited.

It was suggested that use of selective COX-2 inhibitors was associated with a reduced incidence of GI perforations, ulcers and bleeds, with less fecal blood loss and fewer endoscopically detectable lesions.49 Hawkey et al.10 compared the small-bowel injury of selective COX-2 inhibitor, lumiracoxib, with naproxen and placebo in a double-blind randomized controlled trial (RCT). They found that acute small-bowel injury induced by lumiracoxib is less frequent than with naproxen plus omeprazole and similar to placebo. However, this study included healthy volunteers with short follow up of 16 days only. Another study compared the incidence of small bowel injury, as assessed by video capsule endoscopy, in 408 healthy subjects receiving celecoxib with those receiving ibuprofen plus omeprazole. Celecoxib was also associated with significantly fewer small bowel mucosal breaks than ibuprofen and omeprazole.9 A larger RCT11 involving 8,076 rheumatoid arthritis patients reported that rofecoxib reduced the serious lower GI side effects (bleeding, perforation, obstruction, ulceration, or diverticulitis) by 54% when compared to naproxen with the rate of 0.41 and 0.89 per 100 patient-years (RR, 0.46; 95% Cl, 0.22 to 0.93), respectively. The CONDOR study12 is another RCT involving 4,484 patients which found that celecoxib was associated with a lower risk of adverse events throughout the GI tract when compared with diclofenac plus omeprazole. However, in the MEDAL study in which 34,701 patients were included, there was no statistically significant difference between etoricoxib3 and diclofenac in lower GI clinical events (perforation or obstruction requiring hospitalization or bleeding).

A systematic review of randomized trials, including nine trials with 7,616 participants, compared GI adverse effects between COX-2 inhibitors and NSAIDs plus proton pump inhibitor (PPI) and found that COX-2 inhibitors significantly reduced the risk of major GI complications, perforation, obstruction and bleeding (RR, 0.38; 95% CI, 0.25 to 0.56).13 However, after stratifying into upper, mid or lower GI tract, it was not significant for upper (RR, 0.83; 95% CI, 0.36 to 1.89) and lower GI complications (RR, 0.29; 95% CI, 0.01 to 4.18). In contrast, significant difference was detected in mid GI complications (RR, 0.38; 95% CI, 0.16 to 0.89) which favored COX-2 inhibitors. Based on current evidences, some selective COX-2 inhibitors, such as celecoxib and rofecoxib, could be an alternative to traditional NSAIDs to prevent lower GI damage.

MISOPROSTOL

It is generally considered that prostaglandins are important in the mediation of inflammation and maintenance of mucosal integrity of the GI tract.50 While inhibition of prostaglandin synthesis through COX is one of the major mechanisms of NSAIDs induced GI tract injury,51 supplementation with misoprostol, a prostaglandin analog, may be effective in protecting against NSAIDs induced enteropathy.50 Morris et al.16 reported that high dose (1,200 µg) misoprostol therapy was associated with an improvement in anemia with an increase of hemoglobin in patients with proven NSAID enteropathy in a retrospective study of 21 patients. Bjarnason et al.14,52 also found that co-administration of misoprostol with NSAIDs alleviated the indomethacin-induced increase in intestinal permeation. However, the study of Davies et al.15 showed that the protective effects of misoprostol (800 µg) on the intestinal permeability co-administration with indomethacin was limited. It was suggested that prostaglandin alleviation of NSAID-induced intestinal permeability may be dose-dependent or that intestinal permeability may only be partially mediated by reduced mucosal prostaglandins.53 This dose-response effect was also found in study comparing the efficacy of three misoprostol dosing regimens in the prevention of gastric and duodenal ulcers associated with long-term NSAIDs.17,18

The protective effects of misoprostol were further demonstrated in studies evaluating small intestine damage by capsule endoscopy. Watanabe et al.19 reported that misoprostol (200 µg given 4 times daily) improved the mucosal lesions found in the small intestine by capsule endoscopy in a case series of 11 patients who had developed gastric ulcers induced by low-dose enteric-coated aspirin. A pilot RCTs by Fujimori et al.,20 involving 34 healthy volunteers, showed that misoprostol (200 µg given 3 times daily) co-therapy reduced the incidence of small-intestinal mucosal breaks induced by a 2-week administration of diclofenac sodium. Recently, Kyaw et al.21 performed an RCT of 84 aspirin users with small bowel bleeding who required aspirin therapy and found that misoprostol (200 µg given 4 times daily) for 8 weeks was superior to placebo in healing of small bowel ulcers. Similar results were also reported in another randomized trial by Taha et al.22 Though the potential protective effects of misoprostol were observed in these studies, large clinical trials with long-term outcomes are lacking. Furthermore, significantly increased risk of drug-related adverse effects like abdominal pain, nausea or vomiting, diarrhea and high dropout rate related to the use of misoprostol were observed in clinical trials.18,22

COX-INHIBITING NITRIC OXIDE DONORS (CINODS)

It has been shown that nitric oxide (NO) plays a key role in the maintenance of the GI mucosa.54,55 NO and prostaglandin showed similar gastroprotective actions that they are both capable of modulating mucosal blood flow, mucus release, and repair of mucosal injury.56,57 Hence, cyclooxygenase inhibiting nitric oxide donators (CINODs) are a new class of anti-inflammatory and analgesic drugs, in which NO is coupled to an NSAID, could potentially minimize GI toxicity of traditional NSAIDs.57,58

In early animal studies, though prostaglandin was still suppressed, NO-releasing derivatives of a wide range of NSAIDs, including aspirin, flurbiprofen, naproxen, and diclofenac, have been shown to minimize the GI injury.58-62 Different from conventional NSAIDs or selective COX-2 inhibitors, which exacerbate experimental colitis in rats63 or inflammatory bowel disease in humans,64 NO-releasing diclofenac was found to be well tolerated by rats with colitis.65 Several clinical studies have also shown consistently that CINODs cause less upper GI damage.23-25 However, there is no clinical studies that evaluate the effects of CINODs in the lower GI tract.

INTESTINAL MICROBIOTA MODULATION

Accumulating evidences suggest that intestinal bacteria may play a significant role in the pathogenesis of small-bowel damage induced by NSAIDs and that enterobacterial translocation into the mucosa represents the first step of a series of events leading to gross lesion formation.66,67 It has been reported that germ-free mice were resistant to NSAIDs related intestinal damage.68,69 However, when germ-free mice were colonized with jejunal bacteria from PPI-treated rats, the severity of NSAID-induced intestinal injury increased.70 Therefore, modulating intestinal microbiota could be a new strategy in the prevention of NSAID-induced intestinal damage.67,71

In keeping with this, several studies reported that antibiotics could attenuate NSAIDs induced enteropathy.66 A resent animal study showed that rifaximin treatment significantly prevents indomethacin-induced intestinal damage following with a decrease in tissue inflammation, oxidative stress and digestive bleeding as well as reversal of NSAID-induced alterations in bacterial population.72 Colucci et al.73 examined the pathophysiology of NSAID-associated intestinal lesions in a rat model and found that rifaximin prevents diclofenac-induced enteropathy through both anti-bacterial and anti-inflammatory activities. Other antibiotics like metronidazole, tetracycline, kanamycin, neomycin plus bacitracin and streptomycin were also reported to reduce the risk of NSAID induced enteropathy.26,74-76 In addition, rifaximin also demonstrated protective effect in patients receiving long-term PPIs treatment, which eradicated 87% to 91% of cases of small intestinal bacterial overgrowth.77 Nevertheless, current evidences supporting the effects of antibiotics in preventing NSAID-induced enteropathy are still weak and most of them were from animal models. Even though antibiotics showed protective effects on NSAIDs/PPIs induced enteropathy, the long-term efficacy and safety has not been confirmed and further large long-term clinical studies are necessary.

Probiotics is another approach in modulating the composition of intestinal flora and has been used in treating several GI disorders like inflammatory bowel diseases,78 irritable bowel syndrome,79 infectious diarrhea and antibiotic-induced diarrhea.80,81 It has been suggested that probiotics could also protect against NSAID-induced enteropathy by modulating the intestinal microbiota.82 Kinouchi et al.74 found that the metabolites of Lactobacillus acidophilus and Bifidobacterium adolescentis inhibited ileal ulcer formation by repressing unbalanced growth of the intestinal microflora and lipid peroxidation in rats. NSAID-induced small bowel injury in rats could be alleviated after restoring small intestinal Actinobacteria through administration of selected commensal bacteria during treatment with PPI and NSAIDs.70 It was also confirmed in a double-blind, cross-over study of 20 healthy volunteers taking the probiotic mixture (VSL#3) or placebo for 21 days, and found that treatment with VSL#3 before and during indomethacin therapy significantly reduces the intestinal inflammation.27 A pilot randomized trial of 35 patients who took low-dose enteric-coated aspirin for more than 3 months plus omeprazole, also found that co-administration of Lactobacillus casei could decrease the number of mucosal breaks under capsule endoscopy.28 However, the quality of evidence on protective effects of probiotics on NSAID-induced enteropathy are still low and further clinical trials are needed.

ROLE OF PPIs

Gastroprotective agents, especially PPIs, are typically co-prescribed to protect the upper GI tract from NSAIDs induced mucosal injury, which was also recommended by guidelines.83 By suppressing gastric acid secretion, PPIs are effective in decreasing the risk of NSAIDs induced upper GI mucosal damage and bleeding, presumably by raising the pH of the stomach.84 However, lower GI bleeding could be not protected by PPIs,2 and emerging evidences further indicate that PPI may increase the risk of NSAIDs induced small bowel damage and bleeding.70,85,86 A similar exacerbation of NSAIDs induced small bowel damage was also observed in H2 receptor antagonists.85 It was suggested that long term use of PPIs may exacerbate NSAIDs induced small bowel injury by altering intestinal microbiota (dysbiosis) following acid suppression,7,70 which is supported by small intestinal bacterial overgrowth observed in patients with long-term use of PPIs.77,87 A recent multicenter case-control study found that the use of PPIs remained an independent risk factors for mid GI bleeding (adjusted OR, 1.94; p=0.034) even after adjusting for propensity score.88 Thus, the use of PPIs is considered to be an independent risk factor associated with NSAID-associated enteropathy and should be used cautiously.

MUCOPROTECTIVE AGENTS

1. Rebamipide

Rebamipide, an amino acid derivative of 2-(1H)-quinolinone, is a mucosal protective drug that has been clinically used for treating gastritis and peptic ulcers.30,89 Studies have shown that rebamipide is effective to alleviate the NSAIDs induced injury of GI tract, and more recently, the small intestine.34,85 Rebamipide promotes the production of endogenous prostaglandins and modulates the composition of small intestinal microbiota, which supports its efficacy on NSAID-induced small intestinal damage.90-92

Small RCTs of healthy subjects supported that rebamipide had the potential to reduce NSAID-induced small intestinal injury.29,31-33,37 Kurokawa et al.35 performed a multicenter study involving 61 patients who had received more than 3 months of low dose aspirin and/or NSAID to take rebamipide (100 mg 3 times daily for 4 weeks) or placebo and found that rebamipide had the protective effect for NSAIDs-induced enteropathy by reducing the number of small intestinal ulcers and erosions as evaluated by capsule endoscopy. Another small multicenter study by Watanabe et al.36 also found that 8 weeks of high-dose rebamipide (300 mg 3 times daily) significantly decreased the number of mucosal breaks and improved intestinal damage severity. However, Ota et al.37 reported that standard-dose rebamipide (100 mg 3 times daily) was sufficient for preventing mucosal injury of the small intestine induced by low-dose aspirin, indicating that high-dose rebamipide (300 mg 3 times daily) may not be necessary. A systematic review and meta-analysis34 including 15 RCTs and 965 individuals, provided consistent results that rebamipide is effective and safe for defending against NSAID-induced lower GI injuries. However, most studies are with small sample size and short-term follow-up.

2. Irsogladine

Irsogladine, a phosphodiesterase inhibitor, is currently used as one of the anti-ulcer or gastroprotective agents for the treatment of gastric ulcer and gastritis.93 Irsogladine could also prevent NSAIDs or aspirin-induced peptic ulcer and gastritis.41 Furthermore, it has been reported that, in animal research, irsogladine also possessed protective effects against NSAID-induced small intestinal lesions.85,94 This protective effect was further confirmed in clinical studies. The study by Kuramoto et al.38 involving 32 healthy volunteers, found that co-administration of irsogladine for 14 days protected against NSAID-induced mucosal injuries throughout the GI tract, from esophagus to small intestine, which was significantly better than omeprazole. The result was consistent in the study of Isomura et al.39 that co-therapy of irsogladine for 4 weeks was effective for reducing NSAID-induced small-intestinal mucosal injury compared with control, in which 41 patients taking conventional NSAIDs for more than 4 weeks were enrolled. Irsogladine also presented treatment effects which significantly decreased the number of small intestinal lesions induced by NSAIDs.40

3. Other

Apart from the above agents, there are several other drugs such as sulphasalazine,42 ecabet sodium,43 egualen sodium,44 curcumin,95,96 and muscovite,45 which were reported to have a preventive effect on NSAIDs-induced small intestine injury. However, data is very limited for these agents.

SUMMARY

So far, effective prevention and treatment of NSAID-associated lower GI injury are lacking. Though various agents including selective COX inhibitors, misoprostol, antibiotics and mucoprotective agents have been considered as candidates for NSAID-induced intestinal injury, they are not properly evaluated in clinical trials. High-quality well-designed randomized, placebo-controlled trials with long-term follow up are needed to verify the efficacy of potential agents in preventing NSAID-associated lower intestinal injury.

CONFLICTS OF INTEREST

No potential conflict of interest relevant to this article was reported.

Tables

Summary of Studies on the Different Interventions to Prevent NSAID-Induced Lower GI Injuries

Author (year) Study design Intervention Study period Subject Main result
Selective COX-2 inhibitors
Goldstein et al. (2007)9 Multileft, double-blind RCT Celecoxib (200 mg bid), ibuprofen (800 mg tid) plus omeprazole (20 mg qd) or placebo 2 wk 408 Healthy subjects The mean number of small bowel mucosal breaks and the percentage of subjects with mucosal breaks were 0.7/25.9% for ibuprofen/omeprazole compared with 0.2/6.4% for celecoxib and 0.1/7.1% placebo (both comparisons p<0.001).
Hawkey et al. (2008)10 Double-blind RCT Lumiracoxib (100 mg qd), naproxen (500 mg bid) plus omeprazole (20 mg qd), or placebo 16 day 139 Healthy volunteers Acute small-bowel injury on lumiracoxib treatment is less frequent than with naproxen plus omeprazole and similar to placebo.
Laine et al. (2003)11 Post hoc analysis of a RCT Naproxen (500 mg bid) or rofecoxib (50 mg qd) 9 mo 8,076 Patients with RA The rate of serious lower GI events per 100 patient-years was 0.41 for rofecoxib and 0.89 for naproxen (RR, 0.46; 95% Cl, 0.22–0.93; p=0.032).
Laine et al. (2008)3 Pooled data from 3 RCTs Etoricoxib (60 or 90 mg qd) or diclofenac (150 mg qd) 18 mo 34,701 Patients with OA or RA Lower GI clinical events rates were 0.32 and 0.38 per 100 patient-years for etoricoxib and diclofenac (HR, 0.84; 95% CI, 0.63–1.13).
Chan et al. (2010)12 Multileft double-blind RCT Celecoxib (200 mg bid) or diclofenac slow release (75 mg bid) plus omeprazole (20 mg qd) 6 mo 4,484 Patients with OA or RA The rate primary endpoint during the 6-mo study period was 0.9% (95% CI, 0.5–1.3) in the celecoxib group and 3.8% (95% CI, 2.9–4.3) in the diclofenac plus omeprazole group (difference 2.9%, 95% CI, 2.0%–3.8%; p<0.0001).
Jarupongprapa et al. (2013)13 Meta-analysis of 9 RCTs COX-2 inhibitors or NSAIDs plus PPI 2–24 mo 7,616 Patients with OA or RA, or healthy COX-2 inhibitors were found to have significantly reduced the risk of major GI events, including perforation, obstruction, and bleeding (RR, 0.38; 95% CI, 0.25–0.56, p<0.001).
Misoprostol
Bjarnason et al. (1989)14 RCT Misoprostol (200 mg), indomethacin (75 mg), or coadministration - 12 Healthy male volunteers Indomethacin increased the permeation of 51Cr-EDTA selectively, and this increase was significantly reduced by the coadministration of misoprostol.
Davies et al. (1993)15 Double-blind RCT Metronidazole (400 mg bid) or misoprostol (200 μg qid), along with indomethacin (50 mg bid) 1 wk 16 Healthy volunteers Metronidazole prevented 51Cr-EDTA permeation increase (1.10 [0.39] before, 1.55 [0.54] after, p>0.05), whereas misoprostol did not (1.31 [0.51] before, 3.26 [1.10]) after, p=0.005).
Morris et al. (1994)16 Retrospective cohort study Misoprostol (1,200 μg/day) or no treatment - 21 Patients with NSAID-induced enteropathy Haemoglobin in the misoprostol-treated group rose significantly from median (range) 9.1 (6.2–10.6) g/dL to 10.6 (6.5–16.8) g/dL (p=0.004).
Raskin et al. (1995)17 Multicdnter double-blind RCT Placebo (qid); misoprostol (200 μg bid) and placebo (bid); misoprostol (200 μg tid) and placebo(qd); or micrograms (200 μg qid) 12 wk 1,197 Patients with upper GI symptoms during NSAID therapy The incidence of duodenal ulcers was significantly lower in the groups receiving misoprostol bid (2.6%; difference, 4.9% [95% CI, 1.5%–8.2%]; p=0.004), tid (3.3%; difference, 4.2% [95% CI, 0.6%–7.7%]; p=0.019), and qid (1.4%; difference, 6.1% [95% CI, 2.6%–9.6%]; p= 0.007) compared with placebo.
Rostom et al. (2002)18 Meta-analysis of 40 RCTs Misoprostol vs placebo, vs ranitidine, or vs PPI (23 RCTs on misoprostol) - - Misoprostol 800 μg/day was superior to 400 μg/day for the prevention of endoscopic gastric ulcers (RR=0.17, RR=0.39 respectively, p=0.0055). Misoprostol caused diarrhea at all doses, although significantly more at 800 μg/day than 400 μg/day (p=0.0012).
Watanabe et al. (2008)19 Single arm study Misoprostol (200 μg qid) 8 wk 11 Patients with aspirin-induced gastric ulcers Misoprostol significantly decreased the median number of red spots and mucosal breaks.
Fujimori et al. (2009)20 Single-blind RCT Diclofenac (25 mg tid) plus omeprazole (20 mg qd), or misoprostol (200 μg tid) plus diclofenac and omeprazole 2 wk 30 Healthy male volunteers NSAID treatment significantly increased the mean number of mucosal breaks in the NSAID-PPI group (p=0.012). In contrast, there was no significant change before and after misoprostol cotreatment (p=0.42).
Kyaw et al. (2018)21 Multicdnter double-blind RCT Misoprostol (200 μg qid) or placebo 8 wk 84 Aspirin users with small bowel bleeding Complete healing of small bowel ulcers was observed in 12 patients in the misoprostol group (28.6%) and 4 patients in the placebo group (9.5%), for a difference in proportion of 19.0% (95% CI, 2.8%–35.3%; p=0.026).
Taha et al. (2018)22 Double-blind RCT Misoprostol (200 μg qid) or placebo 8 wk 104 Aspirin or NSAIDs users with small bowel ulcers Complete healing of small bowel ulcers and erosions was noted at week 8 in 27 (54%) of 50 patients in the misoprostol group and 9 of 52 patients (17%) in the placebo group (percentage difference, 36.7%; 95% CI, 19.5–53.9; p=0.0002).
COX-inhibiting nitric oxide donors
Hawkey et al. (2003)23 Randomized crossover study AZD3582 (a nitroxybutyl derivative of naproxen, 750 mg bid), naproxen (500 mg bid), or placebo 12 day 31 Healthy volunteers The mean number of gastroduodenal erosions was 11.5 on naproxen vs 4.1 on AZD3582 (p<0.0001). Naproxen increased intestinal permeability whereas AZD3582 and placebo did not.
Fiorucci et al. (2004)24 RCT NCX-4016 (800 mg bid), NCX-4016 (800 mg bid) plus aspirin (325 mg qd), aspirin, or placebo 21 day 48 Healthy subjects NCX-4016 is equally effective as aspirin in inhibiting cyclooxygenase activity. However, NCX-4016 causes less gastric damage and prevents monocyte activation.
Lohmander et al. (2005)25 Double-blind RCT AZD3582 (750 mg bid), naproxen (500 mg bid), or placebo 6 wk 970 Patients with OA The incidence of ulcers with AZD3582 was 9.7% and with naproxen 13.7% (p=0.07, NS), vs 0% on placebo. Most secondary endoscopic GI end points favored AZD3582.
Intestinal microbiota modulation
Bjarnason et al. (1992)26 Single arm study Metronidazole 800 mg/day 2–12 wk 13 Patients using NSAIDs Intestinal inflammation and blood loss were significantly reduced after treatment. There were no significant changes in intestinal permeability, or endoscopic or microscopic appearances of the gastroduodenal mucosa.
Montalto et al. (2010)27 Randomized crossover study A daily dose of probiotic mixture (VSL#3) or placebo 21 day 20 Healthy volunteers Treatment with VSL#3 before and during indomethacin therapy significantly reduces FCCs in healthy subjects with respect to placebo.
Endo et al. (2011)28 RCT Probiotic with Lactobacillus casei for (L. casei group) or control group 3 mo 25 Aspirin users with unexplained iron deficiency anemia Significant decreases in the number of mucosal breaks and the capsule endoscopy score were observed at the 3-mo evaluation in the L. casei group as compared with the results in the control group (p=0.039).
Mucoprotective agents
Niwa et al. (2008)29 Randomized crossover study Rebamipide or placebo along with dicloenac 6 wk 10 Healthy subjects The number of subjects with small-intestinal mucosal injuries was higher in the placebo group (8/10) than in the rebamipide group (2/10) (p=0.023).
Thong-Ngam et al. (2009)30 Single arm study Rebamipide (100 mg tid) 8 wk 30 Patients with gastric ulcer Rebamipide is effective and well tolerated for treatment of gastric ulcers especially those caused by NSAIDs, as it promotes the improvement of gastric inflammation scores, clinical symptoms, and ulcer healing.
Fujimori et al. (2011)31 Double-blind RCT Rebamipide (300 mg/day), or placebo along with diclofenac (75 mg/day) and omeprazole (20 mg/day) 14 day 72 Healthy male volunteers NSAID therapy increased the mean number of mucosal injuries from 0.1 to 16 and 4.2 in the control and rebamipide groups, respectively, but not significant. For subjects with mucosal injuries, rebamipide tended to decrease mucosal injuries from 25 in the control to 8.9 in the rebamipide group (Mann-Whitney U test; p=0.038).
Mizukami et al. (2011)32 Randomized, crossover study Rebamipide (300 mg/day) or placebo, along with aspirin (100 mg qd) and omeprazole (20 mg qd) 12 wk 11 Healthy male subjects Rebamipide significantly prevented mucosal breaks on the ileum compared with the placebo group (p=0.017 at 1st wk and p=0.027 at 4th wk).
Mizukami et al. (2012)33 Randomized, crossover study Rebamipide (300 mg/day) or placebo, along with aspirin (100 mg qd) and omeprazole (20 mg qd) 12 wk 12 Healthy male subjects For the subjects receiving rebamipide, the total prevalence of lower GI symptoms was significantly different from the placebo group (p=0.0093) at wk 4.
Zhang et al. (2013)34 Meta-analysis of 15 RCTs Rebamipide vs placebo, or vs PPI, or vs misoprostol, or vs H2RA - 965 Subjects Rebamipide acted better than placebo against NSAID-induced GI injury, which was equal to or not superior to traditional strategies (PPIs, H2RA, or misoprostol). Rebamipide showed a beneficial effect against the small bowel damage (RR, 2.70; 95% CI, 1.02–7.16; p=0.045) vs placebo.
Kurokawa et al. (2014)35 Multileft, double-blind RCT Rebamipide (100 mg tid) or placebo 4 wk 61 Patients with NSAIDs-induced enteropathy Rebamipide has not only the healing effect for NSAIDs-induced enteropathy compared with placebo, but the improvement of nutritional condition.
Watanabe et al. (2015)36 Multileft, double-blind RCT Rebamipide (300 mg tid) or placebo 8 wk 38 Patients with aspirin-induced enteropathy High-dose rebamipide is effective for the treatment of LDA-induced moderate-to-severe enteropathy.
Ota et al. (2016)37 RCT Omeprazole 10 mg, rebamipide 300 mg, or rebamipide 900 mg, along with aspirin 2 wk 45 Healthy volunteers The fecal calprotectin levels only increased significantly in group A. The gastroscopic and capsule endoscopic findings and the fecal occult blood test findings did not differ significantly among three groups.
Kuramoto et al. (2013)38 RCT Group I: diclofenac (75 mg daily) and irsogladine (4 mg daily); or group O: diclofenac and omeprazole (10 mg daily) 14 day 32 Healthy volunteers No significant difference between group I and O in the upper GI lesion score change. NSAID significantly increased the mean number of small intestinal mucosal breaks in group O (p=0.0002), not in group I. The between-group difference was significant (p=0.004).
Isomura et al. (2014)39 Single-blind RCT Irsogladine (4 mg/day) or the control group 4 wk 41 Patients with NSAID-induced small intestinal injury The improvement rate was significantly higher in the irsogladine group (16/19 patients; 84.2%) than in the control group (9/20 patients; 45.0%; p=0.02).
Kojima et al. (2015)40 RCT Omeprazole (10 mg/day) for 6 wk, with irsogladine (4 mg/day) from 6 wk to 10, or irsogladine for 6 wk, or omeprazole for 10 wk, along with diclofenac (75 mg/day) 6 wk 37 Healthy volunteers Irsogladine was effective in both preventing and healing such lesions.
Shim et al. (2018)41 Multileft, double-blind RCT Irsogladine maleate (2 mg bid) or placebo 8 wk 76 Patients usingNSAIDs or aspirin There were no significant differences in gastric protective effects between test and placebo groups. However, 2 cases of peptic ulcer in the placebo group but none in the test group were observed.
Other
Hayllar et al. (1994)42 RCT Sulfasalazine (1.5–3.0 mg/day) or another antirheumatic drug 6–12 mo 46 Patients with RA Sulfasalazine reduced both intestinal inflammation and blood loss, whereas the other antirheumatic drugs did not.
Ota et al. (2019)43 Double-blind RCT Group A, low-dose aspirin; group B, low-dose aspirin and 4.0 g of ecabet sodium 2 wk 24 Healthy volunteers A significant difference was found in the median number of small intestinal lesions before or after treatment in group A (baseline: 1 [0–5], after: 5 [1–11]; p=0.0059) but not in group B (baseline: 0.5 [0–9], after: 3 [0–23]; p=0.0586).
Iguchi et al. (2018)44 RCT Aspirin 100 mg/kg daily or aspirin plus egualen sodium 30 mg daily. 2 wk 20 Healthy male volunteers Egualen sodium significantly suppressed the total number of small intestinal injuries detected by capsule endoscopy and the positive ratio for the fecal occult blood test.
Huang et al. (2014)45 RCT Diclofenac (75 mg bid) plus omeprazole (20 mg/day), or muscovite (3 g bid) plus diclofenac and omeprazole 14 day 30 Healthy volunteers A significant difference was observed in number of subjects with mucosal breaks comparing muscovite with the control. Co-administration of muscovite reduced the rate of mucosal break to 31.3% (5/16) (p=0.028).

NSAIDs, nonsteroidal anti-inflammatory drugs; GI, gastrointestinal; RCT, randomized controlled trial; qd, one a day; bid, twice a day; tid, 3 times a day; qid, 4 times a day; RR, relative risk; CI, confidence interval; RA, rheumatoid arthritis; OA, osteoarthritis; HR, hazard ratio; PPI, proton pump inhibitor; EDTA, ethylenediamine tetraacetic acid; FCCs, faecal calprotectin concentrations; H2RA, histamine type-2 receptor antagonists; LDA, low-dose aspirin.

Table 1 Summary of Studies on the Different Interventions to Prevent NSAID-Induced Lower GI Injuries

Author (year)Study designInterventionStudy periodSubjectMain result
Selective COX-2 inhibitors
Goldstein et al. (2007)9Multileft, double-blind RCTCelecoxib (200 mg bid), ibuprofen (800 mg tid) plus omeprazole (20 mg qd) or placebo2 wk408 Healthy subjectsThe mean number of small bowel mucosal breaks and the percentage of subjects with mucosal breaks were 0.7/25.9% for ibuprofen/omeprazole compared with 0.2/6.4% for celecoxib and 0.1/7.1% placebo (both comparisons p<0.001).
Hawkey et al. (2008)10Double-blind RCTLumiracoxib (100 mg qd), naproxen (500 mg bid) plus omeprazole (20 mg qd), or placebo16 day139 Healthy volunteersAcute small-bowel injury on lumiracoxib treatment is less frequent than with naproxen plus omeprazole and similar to placebo.
Laine et al. (2003)11Post hoc analysis of a RCTNaproxen (500 mg bid) or rofecoxib (50 mg qd)9 mo8,076 Patients with RAThe rate of serious lower GI events per 100 patient-years was 0.41 for rofecoxib and 0.89 for naproxen (RR, 0.46; 95% Cl, 0.22–0.93; p=0.032).
Laine et al. (2008)3Pooled data from 3 RCTsEtoricoxib (60 or 90 mg qd) or diclofenac (150 mg qd)18 mo34,701 Patients with OA or RALower GI clinical events rates were 0.32 and 0.38 per 100 patient-years for etoricoxib and diclofenac (HR, 0.84; 95% CI, 0.63–1.13).
Chan et al. (2010)12Multileft double-blind RCTCelecoxib (200 mg bid) or diclofenac slow release (75 mg bid) plus omeprazole (20 mg qd)6 mo4,484 Patients with OA or RAThe rate primary endpoint during the 6-mo study period was 0.9% (95% CI, 0.5–1.3) in the celecoxib group and 3.8% (95% CI, 2.9–4.3) in the diclofenac plus omeprazole group (difference 2.9%, 95% CI, 2.0%–3.8%; p<0.0001).
Jarupongprapa et al. (2013)13Meta-analysis of 9 RCTsCOX-2 inhibitors or NSAIDs plus PPI2–24 mo7,616 Patients with OA or RA, or healthyCOX-2 inhibitors were found to have significantly reduced the risk of major GI events, including perforation, obstruction, and bleeding (RR, 0.38; 95% CI, 0.25–0.56, p<0.001).
Misoprostol
Bjarnason et al. (1989)14RCTMisoprostol (200 mg), indomethacin (75 mg), or coadministration-12 Healthy male volunteersIndomethacin increased the permeation of 51Cr-EDTA selectively, and this increase was significantly reduced by the coadministration of misoprostol.
Davies et al. (1993)15Double-blind RCTMetronidazole (400 mg bid) or misoprostol (200 μg qid), along with indomethacin (50 mg bid)1 wk16 Healthy volunteersMetronidazole prevented 51Cr-EDTA permeation increase (1.10 [0.39] before, 1.55 [0.54] after, p>0.05), whereas misoprostol did not (1.31 [0.51] before, 3.26 [1.10]) after, p=0.005).
Morris et al. (1994)16Retrospective cohort studyMisoprostol (1,200 μg/day) or no treatment-21 Patients with NSAID-induced enteropathyHaemoglobin in the misoprostol-treated group rose significantly from median (range) 9.1 (6.2–10.6) g/dL to 10.6 (6.5–16.8) g/dL (p=0.004).
Raskin et al. (1995)17Multicdnter double-blind RCTPlacebo (qid); misoprostol (200 μg bid) and placebo (bid); misoprostol (200 μg tid) and placebo(qd); or micrograms (200 μg qid)12 wk1,197 Patients with upper GI symptoms during NSAID therapyThe incidence of duodenal ulcers was significantly lower in the groups receiving misoprostol bid (2.6%; difference, 4.9% [95% CI, 1.5%–8.2%]; p=0.004), tid (3.3%; difference, 4.2% [95% CI, 0.6%–7.7%]; p=0.019), and qid (1.4%; difference, 6.1% [95% CI, 2.6%–9.6%]; p= 0.007) compared with placebo.
Rostom et al. (2002)18Meta-analysis of 40 RCTsMisoprostol vs placebo, vs ranitidine, or vs PPI (23 RCTs on misoprostol)--Misoprostol 800 μg/day was superior to 400 μg/day for the prevention of endoscopic gastric ulcers (RR=0.17, RR=0.39 respectively, p=0.0055). Misoprostol caused diarrhea at all doses, although significantly more at 800 μg/day than 400 μg/day (p=0.0012).
Watanabe et al. (2008)19Single arm studyMisoprostol (200 μg qid)8 wk11 Patients with aspirin-induced gastric ulcersMisoprostol significantly decreased the median number of red spots and mucosal breaks.
Fujimori et al. (2009)20Single-blind RCTDiclofenac (25 mg tid) plus omeprazole (20 mg qd), or misoprostol (200 μg tid) plus diclofenac and omeprazole2 wk30 Healthy male volunteersNSAID treatment significantly increased the mean number of mucosal breaks in the NSAID-PPI group (p=0.012). In contrast, there was no significant change before and after misoprostol cotreatment (p=0.42).
Kyaw et al. (2018)21Multicdnter double-blind RCTMisoprostol (200 μg qid) or placebo8 wk84 Aspirin users with small bowel bleedingComplete healing of small bowel ulcers was observed in 12 patients in the misoprostol group (28.6%) and 4 patients in the placebo group (9.5%), for a difference in proportion of 19.0% (95% CI, 2.8%–35.3%; p=0.026).
Taha et al. (2018)22Double-blind RCTMisoprostol (200 μg qid) or placebo8 wk104 Aspirin or NSAIDs users with small bowel ulcersComplete healing of small bowel ulcers and erosions was noted at week 8 in 27 (54%) of 50 patients in the misoprostol group and 9 of 52 patients (17%) in the placebo group (percentage difference, 36.7%; 95% CI, 19.5–53.9; p=0.0002).
COX-inhibiting nitric oxide donors
Hawkey et al. (2003)23Randomized crossover studyAZD3582 (a nitroxybutyl derivative of naproxen, 750 mg bid), naproxen (500 mg bid), or placebo12 day31 Healthy volunteersThe mean number of gastroduodenal erosions was 11.5 on naproxen vs 4.1 on AZD3582 (p<0.0001). Naproxen increased intestinal permeability whereas AZD3582 and placebo did not.
Fiorucci et al. (2004)24RCTNCX-4016 (800 mg bid), NCX-4016 (800 mg bid) plus aspirin (325 mg qd), aspirin, or placebo21 day48 Healthy subjectsNCX-4016 is equally effective as aspirin in inhibiting cyclooxygenase activity. However, NCX-4016 causes less gastric damage and prevents monocyte activation.
Lohmander et al. (2005)25Double-blind RCTAZD3582 (750 mg bid), naproxen (500 mg bid), or placebo6 wk970 Patients with OAThe incidence of ulcers with AZD3582 was 9.7% and with naproxen 13.7% (p=0.07, NS), vs 0% on placebo. Most secondary endoscopic GI end points favored AZD3582.
Intestinal microbiota modulation
Bjarnason et al. (1992)26Single arm studyMetronidazole 800 mg/day2–12 wk13 Patients using NSAIDsIntestinal inflammation and blood loss were significantly reduced after treatment. There were no significant changes in intestinal permeability, or endoscopic or microscopic appearances of the gastroduodenal mucosa.
Montalto et al. (2010)27Randomized crossover studyA daily dose of probiotic mixture (VSL#3) or placebo21 day20 Healthy volunteersTreatment with VSL#3 before and during indomethacin therapy significantly reduces FCCs in healthy subjects with respect to placebo.
Endo et al. (2011)28RCTProbiotic with Lactobacillus casei for (L. casei group) or control group3 mo25 Aspirin users with unexplained iron deficiency anemiaSignificant decreases in the number of mucosal breaks and the capsule endoscopy score were observed at the 3-mo evaluation in the L. casei group as compared with the results in the control group (p=0.039).
Mucoprotective agents
Niwa et al. (2008)29Randomized crossover studyRebamipide or placebo along with dicloenac6 wk10 Healthy subjectsThe number of subjects with small-intestinal mucosal injuries was higher in the placebo group (8/10) than in the rebamipide group (2/10) (p=0.023).
Thong-Ngam et al. (2009)30Single arm studyRebamipide (100 mg tid)8 wk30 Patients with gastric ulcerRebamipide is effective and well tolerated for treatment of gastric ulcers especially those caused by NSAIDs, as it promotes the improvement of gastric inflammation scores, clinical symptoms, and ulcer healing.
Fujimori et al. (2011)31Double-blind RCTRebamipide (300 mg/day), or placebo along with diclofenac (75 mg/day) and omeprazole (20 mg/day)14 day72 Healthy male volunteersNSAID therapy increased the mean number of mucosal injuries from 0.1 to 16 and 4.2 in the control and rebamipide groups, respectively, but not significant. For subjects with mucosal injuries, rebamipide tended to decrease mucosal injuries from 25 in the control to 8.9 in the rebamipide group (Mann-Whitney U test; p=0.038).
Mizukami et al. (2011)32Randomized, crossover studyRebamipide (300 mg/day) or placebo, along with aspirin (100 mg qd) and omeprazole (20 mg qd)12 wk11 Healthy male subjectsRebamipide significantly prevented mucosal breaks on the ileum compared with the placebo group (p=0.017 at 1st wk and p=0.027 at 4th wk).
Mizukami et al. (2012)33Randomized, crossover studyRebamipide (300 mg/day) or placebo, along with aspirin (100 mg qd) and omeprazole (20 mg qd)12 wk12 Healthy male subjectsFor the subjects receiving rebamipide, the total prevalence of lower GI symptoms was significantly different from the placebo group (p=0.0093) at wk 4.
Zhang et al. (2013)34Meta-analysis of 15 RCTsRebamipide vs placebo, or vs PPI, or vs misoprostol, or vs H2RA-965 SubjectsRebamipide acted better than placebo against NSAID-induced GI injury, which was equal to or not superior to traditional strategies (PPIs, H2RA, or misoprostol). Rebamipide showed a beneficial effect against the small bowel damage (RR, 2.70; 95% CI, 1.02–7.16; p=0.045) vs placebo.
Kurokawa et al. (2014)35Multileft, double-blind RCTRebamipide (100 mg tid) or placebo4 wk61 Patients with NSAIDs-induced enteropathyRebamipide has not only the healing effect for NSAIDs-induced enteropathy compared with placebo, but the improvement of nutritional condition.
Watanabe et al. (2015)36Multileft, double-blind RCTRebamipide (300 mg tid) or placebo8 wk38 Patients with aspirin-induced enteropathyHigh-dose rebamipide is effective for the treatment of LDA-induced moderate-to-severe enteropathy.
Ota et al. (2016)37RCTOmeprazole 10 mg, rebamipide 300 mg, or rebamipide 900 mg, along with aspirin2 wk45 Healthy volunteersThe fecal calprotectin levels only increased significantly in group A. The gastroscopic and capsule endoscopic findings and the fecal occult blood test findings did not differ significantly among three groups.
Kuramoto et al. (2013)38RCTGroup I: diclofenac (75 mg daily) and irsogladine (4 mg daily); or group O: diclofenac and omeprazole (10 mg daily)14 day32 Healthy volunteersNo significant difference between group I and O in the upper GI lesion score change. NSAID significantly increased the mean number of small intestinal mucosal breaks in group O (p=0.0002), not in group I. The between-group difference was significant (p=0.004).
Isomura et al. (2014)39Single-blind RCTIrsogladine (4 mg/day) or the control group4 wk41 Patients with NSAID-induced small intestinal injuryThe improvement rate was significantly higher in the irsogladine group (16/19 patients; 84.2%) than in the control group (9/20 patients; 45.0%; p=0.02).
Kojima et al. (2015)40RCTOmeprazole (10 mg/day) for 6 wk, with irsogladine (4 mg/day) from 6 wk to 10, or irsogladine for 6 wk, or omeprazole for 10 wk, along with diclofenac (75 mg/day)6 wk37 Healthy volunteersIrsogladine was effective in both preventing and healing such lesions.
Shim et al. (2018)41Multileft, double-blind RCTIrsogladine maleate (2 mg bid) or placebo8 wk76 Patients usingNSAIDs or aspirinThere were no significant differences in gastric protective effects between test and placebo groups. However, 2 cases of peptic ulcer in the placebo group but none in the test group were observed.
Other
Hayllar et al. (1994)42RCTSulfasalazine (1.5–3.0 mg/day) or another antirheumatic drug6–12 mo46 Patients with RASulfasalazine reduced both intestinal inflammation and blood loss, whereas the other antirheumatic drugs did not.
Ota et al. (2019)43Double-blind RCTGroup A, low-dose aspirin; group B, low-dose aspirin and 4.0 g of ecabet sodium2 wk24 Healthy volunteersA significant difference was found in the median number of small intestinal lesions before or after treatment in group A (baseline: 1 [0–5], after: 5 [1–11]; p=0.0059) but not in group B (baseline: 0.5 [0–9], after: 3 [0–23]; p=0.0586).
Iguchi et al. (2018)44RCTAspirin 100 mg/kg daily or aspirin plus egualen sodium 30 mg daily.2 wk20 Healthy male volunteersEgualen sodium significantly suppressed the total number of small intestinal injuries detected by capsule endoscopy and the positive ratio for the fecal occult blood test.
Huang et al. (2014)45RCTDiclofenac (75 mg bid) plus omeprazole (20 mg/day), or muscovite (3 g bid) plus diclofenac and omeprazole14 day30 Healthy volunteersA significant difference was observed in number of subjects with mucosal breaks comparing muscovite with the control. Co-administration of muscovite reduced the rate of mucosal break to 31.3% (5/16) (p=0.028).

NSAIDs, nonsteroidal anti-inflammatory drugs; GI, gastrointestinal; RCT, randomized controlled trial; qd, one a day; bid, twice a day; tid, 3 times a day; qid, 4 times a day; RR, relative risk; CI, confidence interval; RA, rheumatoid arthritis; OA, osteoarthritis; HR, hazard ratio; PPI, proton pump inhibitor; EDTA, ethylenediamine tetraacetic acid; FCCs, faecal calprotectin concentrations; H2RA, histamine type-2 receptor antagonists; LDA, low-dose aspirin.


References

  1. Lanas A, Perez-Aisa MA, Feu F, et al. A nationwide study of mortality associated with hospital admission due to severe gastrointestinal events and those associated with nonsteroidal anti-inflammatory drug use. Am J Gastroenterol 2005;100:1685-1693.
    Pubmed CrossRef
  2. Lanas Á, Carrera-Lasfuentes P, Arguedas Y, et al. Risk of upper and lower gastrointestinal bleeding in patients taking nonsteroidal anti-inflammatory drugs, antiplatelet agents, or anticoagulants. Clin Gastroenterol Hepatol 2015;13:906-912.
    Pubmed CrossRef
  3. Laine L, Curtis SP, Langman M, et al. 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;135:1517-1525.
    Pubmed CrossRef
  4. Lanas A, García-Rodríguez LA, Polo-Tomás M, et al. Time trends and impact of upper and lower gastrointestinal bleeding and perforation in clinical practice. Am J Gastroenterol 2009;104:1633-1641.
    Pubmed CrossRef
  5. Lanas A, Sopeña F. Nonsteroidal anti-inflammatory drugs and lower gastrointestinal complications. Gastroenterol Clin North Am 2009;38:333-352.
    Pubmed CrossRef
  6. Wallace JL. NSAID gastropathy and enteropathy: distinct pathogenesis likely necessitates distinct prevention strategies. Br J Pharmacol 2012;165:67-74.
    Pubmed KoreaMed CrossRef
  7. Chan FK. NSAID-associated lower gastrointestinal bleeding: where do we stand?. Clin Gastroenterol Hepatol 2012;10:1060-1061.
    Pubmed CrossRef
  8. Lanza FL, Chan FK, Quigley EM; Practice Parameters Committee of the American College of Gastroenterology. Guidelines for prevention of NSAID-related ulcer complications. Am J Gastroenterol 2009;104:728-738.
    Pubmed CrossRef
  9. Goldstein JL, Eisen GM, Lewis B, et al. 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;25:1211-1222.
    Pubmed CrossRef
  10. Hawkey CJ, Ell C, Simon B, et al. Less small-bowel injury with lumiracoxib compared with naproxen plus omeprazole. Clin Gastroenterol Hepatol 2008;6:536-544.
    Pubmed CrossRef
  11. Laine L, Connors LG, Reicin A, et al. Serious lower gastrointestinal clinical events with nonselective NSAID or coxib use. Gastroenterology 2003;124:288-292.
    Pubmed CrossRef
  12. 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;376:173-179.
    Pubmed CrossRef
  13. Jarupongprapa S, Ussavasodhi P, Katchamart W. Comparison of gastrointestinal adverse effects between cyclooxygenase-2 inhibitors and non-selective, non-steroidal anti-inflammatory drugs plus proton pump inhibitors: a systematic review and meta-analysis. J Gastroenterol 2013;48:830-838.
    Pubmed CrossRef
  14. Bjarnason I, Smethurst P, Fenn CG, Lee CE, Menzies IS, Levi AJ. Misoprostol reduces indomethacin-induced changes in human small intestinal permeability. Dig Dis Sci 1989;34:407-411.
    Pubmed CrossRef
  15. Davies GR, Wilkie ME, Rampton DS. Effects of metronidazole and misoprostol on indomethacin-induced changes in intestinal permeability. Dig Dis Sci 1993;38:417-425.
    Pubmed CrossRef
  16. Morris AJ, Murray L, Sturrock RD, Madhok R, Capell HA, Mackenzie JF. Short report: the effect of misoprostol on the anaemia of NSAID enteropathy. Aliment Pharmacol Ther 1994;8:343-346.
    Pubmed CrossRef
  17. Raskin JB, White RH, Jackson JE, et al. Misoprostol dosage in the prevention of nonsteroidal anti-inflammatory drug-induced gastric and duodenal ulcers: a comparison of three regimens. Ann Intern Med 1995;123:344-350.
    Pubmed CrossRef
  18. Rostom A, Dube C, Wells G, et al. Prevention of NSAID-induced gastroduodenal ulcers. Cochrane Database Syst Rev 2002;4:CD002296.
    CrossRef
  19. Watanabe T, Sugimori S, Kameda N, et al. Small bowel injury by low-dose enteric-coated aspirin and treatment with misoprostol: a pilot study. Clin Gastroenterol Hepatol 2008;6:1279-1282.
    Pubmed CrossRef
  20. Fujimori S, Seo T, Gudis K, et al. Prevention of nonsteroidal anti-inflammatory drug-induced small-intestinal injury by prostaglandin: a pilot randomized controlled trial evaluated by capsule endoscopy. Gastrointest Endosc 2009;69:1339-1346.
    Pubmed CrossRef
  21. Kyaw MH, Otani K, Ching JYL, et al. Misoprostol heals small bowel ulcers in aspirin users with small bowel bleeding. Gastroenterology 2018;155:1090-1097.
    Pubmed CrossRef
  22. Taha AS, McCloskey C, McSkimming P, McConnachie A. Misoprostol for small bowel ulcers in patients with obscure bleeding taking aspirin and non-steroidal anti-inflammatory drugs (MASTERS): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Gastroenterol Hepatol 2018;3:469-476.
    Pubmed CrossRef
  23. Hawkey CJ, Jones JI, Atherton CT, et al. Gastrointestinal safety of AZD3582, a cyclooxygenase inhibiting nitric oxide donator: proof of concept study in humans. Gut 2003;52:1537-1542.
    Pubmed KoreaMed CrossRef
  24. Fiorucci S, Mencarelli A, Meneguzzi A, et al. Co-administration of nitric oxide-aspirin (NCX-4016) and aspirin prevents platelet and monocyte activation and protects against gastric damage induced by aspirin in humans. J Am Coll Cardiol 2004;44:635-641.
    Pubmed CrossRef
  25. Lohmander LS, McKeith D, Svensson O, et al. A randomised, placebo controlled, comparative trial of the gastrointestinal safety and efficacy of AZD3582 versus naproxen in osteoarthritis. Ann Rheum Dis 2005;64:449-456.
    Pubmed KoreaMed CrossRef
  26. 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;33:1204-1208.
    Pubmed KoreaMed CrossRef
  27. Montalto M, Gallo A, Curigliano V, et al. 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;32:209-214.
    Pubmed CrossRef
  28. Endo H, Higurashi T, Hosono K, et al. Efficacy of Lactobacillus casei treatment on small bowel injury in chronic low-dose aspirin users: a pilot randomized controlled study. J Gastroenterol 2011;46:894-905.
    Pubmed CrossRef
  29. Niwa Y, Nakamura M, Ohmiya N, et al. 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;43:270-276.
    Pubmed CrossRef
  30. Thong-Ngam D, Chayanupatkul M, Klaikeaw N, Rerknimitr R, Mahachai V. Effect of rebamipide on gastric ulcer healing caused by Helicobacter pylori and/or NSAIDs or non NSAIDs-non H. pylori. J Med Assoc Thai 2009;92:1207-1212.
  31. Fujimori S, Takahashi Y, Gudis K, et al. Rebamipide has the potential to reduce the intensity of NSAID-induced small intestinal injury: a double-blind, randomized, controlled trial evaluated by capsule endoscopy. J Gastroenterol 2011;46:57-64.
    Pubmed CrossRef
  32. Mizukami K, Murakami K, Abe T, et al. Aspirin-induced small bowel injuries and the preventive effect of rebamipide. World J Gastroenterol 2011;17:5117-5122.
    Pubmed KoreaMed CrossRef
  33. Mizukami K, Murakami K, Hirashita Y, et al. Efficacy of rebamipide for low-dose aspirin-related gastrointestinal symptoms. J Clin Biochem Nutr 2012;51:216-220.
    Pubmed KoreaMed CrossRef
  34. Zhang S, Qing Q, Bai Y, et al. Rebamipide helps defend against nonsteroidal anti-inflammatory drugs induced gastroenteropathy: a systematic review and meta-analysis. Dig Dis Sci 2013;58:1991-2000.
    Pubmed CrossRef
  35. Kurokawa S, Katsuki S, Fujita T, et al. 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;49:239-244.
    Pubmed CrossRef
  36. Watanabe T, Takeuchi T, Handa O, et al. 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:e0122330.
    Pubmed KoreaMed CrossRef
  37. Ota K, Takeuchi T, Nouda S, et al. Determination of the adequate dosage of rebamipide, a gastric mucoprotective drug, to prevent low-dose aspirin-induced gastrointestinal mucosal injury. J Clin Biochem Nutr 2016;59:231-237.
    Pubmed KoreaMed CrossRef
  38. Kuramoto T, Umegaki E, Nouda S, et al. Preventive effect of irsogladine or omeprazole on non-steroidal anti-inflammatory drug-induced esophagitis, peptic ulcers, and small intestinal lesions in humans, a prospective randomized controlled study. BMC Gastroenterol 2013;13:85.
    Pubmed KoreaMed CrossRef
  39. Isomura Y, Yamaji Y, Yamada A, et al. Irsogladine improves small-intestinal injuries in regular users of nonsteroidal anti-inflammatory drugs. Gastrointest Endosc 2014;80:118-125.
    Pubmed CrossRef
  40. Kojima Y, Takeuchi T, Ota K, et al. Effect of long-term proton pump inhibitor therapy and healing effect of irsogladine on nonsteroidal anti-inflammatory drug-induced small-intestinal lesions in healthy volunteers. J Clin Biochem Nutr 2015;57:60-65.
    Pubmed KoreaMed CrossRef
  41. Shim KN, Kim JI, Kim N, et al. The efficacy and safety of irsogladine maleate in nonsteroidal anti-inflammatory drug or aspirin-induced peptic ulcer and gastritis. Korean J Intern Med 2019;34:1008-1021.
    Pubmed KoreaMed CrossRef
  42. Hayllar J, Smith T, Macpherson A, Price AB, Gumpel M, Bjarnason I. Nonsteroidal antiinflammatory drug-induced small intestinal inflammation and blood loss: effects of sulfasalazine and other disease-modifying antirheumatic drugs. Arthritis Rheum 1994;37:1146-1150.
    Pubmed CrossRef
  43. Ota K, Takeuchi T, Kojima Y, et al. Preventive effect of ecabet sodium on low-dose aspirin-induced small intestinal mucosal injury: a randomized, double-blind, pilot study. BMC Gastroenterol 2019;19:4.
    Pubmed KoreaMed CrossRef
  44. Iguchi M, Kakimoto K, Kuramoto T, et al. Effect of egualen sodium hydrate on small-intestinal mucosal damage induced by low-dose aspirin: a prospective randomized clinical trial. J Clin Biochem Nutr 2018;62:174-178.
    Pubmed KoreaMed CrossRef
  45. Huang C, Lu B, Fan YH, et al. Muscovite is protective against non-steroidal anti-inflammatory drug-induced small bowel injury. World J Gastroenterol 2014;20:11012-11018.
    Pubmed KoreaMed CrossRef
  46. Latimer N, Lord J, Grant RL, et al. Cost effectiveness of COX 2 selective inhibitors and traditional NSAIDs alone or in combination with a proton pump inhibitor for people with osteoarthritis. BMJ 2009;339:b2538.
    Pubmed KoreaMed CrossRef
  47. Schnitzer TJ, Burmester GR, Mysler E, et al. Comparison of lumiracoxib with naproxen and ibuprofen in the Therapeutic Arthritis Research and Gastrointestinal Event Trial (TARGET), reduction in ulcer complications: randomised controlled trial. Lancet 2004;364:665-674.
    Pubmed CrossRef
  48. Dajani EZ, Agrawal NM. Selective COX-2 inhibitors and gastrointestinal mucosal injury: pharmacological and therapeutic considerations. J Assoc Acad Minor Phys 2000;11:28-31.
    Pubmed
  49. Hunt RH, Harper S, Callegari P, et al. Complementary studies of the gastrointestinal safety of the cyclo-oxygenase-2-selective inhibitor etoricoxib. Aliment Pharmacol Ther 2003;17:201-210.
    Pubmed CrossRef
  50. Wallace JL. Prostaglandins, NSAIDs, and gastric mucosal protection: why doesn’t the stomach digest itself?. Physiol Rev 2008;88:1547-1565.
    Pubmed CrossRef
  51. Whittle BJ. Temporal relationship between cyclooxygenase inhibition, as measured by prostacyclin biosynthesis, and the gastrointestinal damage induced by indomethacin in the rat. Gastroenterology 1981;80:94-98.
    Pubmed CrossRef
  52. Bjarnason I. Experimental evidence of the benefit of misoprostol beyond the stomach in humans. J Rheumatol Suppl 1990;20:38-41.
    Pubmed
  53. Davies NM, Saleh JY, Skjodt NM. Detection and prevention of NSAID-induced enteropathy. J Pharm Pharm Sci 2000;3:137-155.
    Pubmed
  54. MacNaughton WK, Cirino G, Wallace JL. Endothelium-derived relaxing factor (nitric oxide) has protective actions in the stomach. Life Sci 1989;45:1869-1876.
    Pubmed CrossRef
  55. Wallace JL, Miller MJ. Nitric oxide in mucosal defense: a little goes a long way. Gastroenterology 2000;119:512-520.
    Pubmed CrossRef
  56. Wallace JL, Del Soldato P. The therapeutic potential of NO-NSAIDs. Fundam Clin Pharmacol 2003;17:11-20.
    Pubmed CrossRef
  57. Lanas A. Role of nitric oxide in the gastrointestinal tract. Arthritis Res Ther 2008;10:S4.
    Pubmed KoreaMed CrossRef
  58. Wallace JL, Reuter B, Cicala C, McKnight W, Grisham MB, Cirino G. Novel nonsteroidal anti-inflammatory drug derivatives with markedly reduced ulcerogenic properties in the rat. Gastroenterology 1994;107:173-179.
    Pubmed CrossRef
  59. Wallace JL, Vergnolle N, Muscará MN, et al. Enhanced anti-inflammatory effects of a nitric oxide-releasing derivative of mesalamine in rats. Gastroenterology 1999;117:557-566.
    Pubmed CrossRef
  60. Tashima K, Fujita A, Umeda M, Takeuchi K. Lack of gastric toxicity of nitric oxide-releasing aspirin, NCX-4016, in the stomach of diabetic rats. Life Sci 2000;67:1639-1652.
    Pubmed CrossRef
  61. Wallace JL, Reuter B, Cicala C, McKnight W, Grisham M, Cirino G. A diclofenac derivative without ulcerogenic properties. Eur J Pharmacol 1994;257:249-255.
    Pubmed CrossRef
  62. Davies NM, Røseth AG, Appleyard CB, et al. NO-naproxen vs. naproxen: ulcerogenic, analgesic and anti-inflammatory effects. Aliment Pharmacol Ther 1997;11:69-79.
    Pubmed CrossRef
  63. Reuter BK, Asfaha S, Buret A, Sharkey KA, Wallace JL. Exacerbation of inflammation-associated colonic injury in rat through inhibition of cyclooxygenase-2. J Clin Invest 1996;98:2076-2085.
    Pubmed KoreaMed CrossRef
  64. Bonner GF. Exacerbation of inflammatory bowel disease associated with use of celecoxib. Am J Gastroenterol 2001;96:1306-1308.
    Pubmed CrossRef
  65. Reuter BK, Cirino G, Wallace JL. Markedly reduced intestinal toxicity of a diclofenac derivative. Life Sci 1994;55:PL1-PL8.
    Pubmed CrossRef
  66. Lanas A, Scarpignato C. Microbial flora in NSAID-induced intestinal damage: a role for antibiotics?. Digestion 2006;73:136-150.
    Pubmed CrossRef
  67. Otani K, Tanigawa T, Watanabe T, et al. Microbiota plays a key role in non-steroidal anti-inflammatory drug-induced small intestinal damage. Digestion 2017;95:22-28.
    Pubmed CrossRef
  68. Uejima M, Kinouchi T, Kataoka K, Hiraoka I, Ohnishi Y. Role of intestinal bacteria in ileal ulcer formation in rats treated with a nonsteroidal antiinflammatory drug. Microbiol Immunol 1996;40:553-560.
    Pubmed CrossRef
  69. Robert A, Asano T. Resistance of germfree rats to indomethacin-induced intestinal lesions. Prostaglandins 1977;14:333-341.
    Pubmed CrossRef
  70. Wallace JL, Syer S, Denou E, et al. Proton pump inhibitors exacerbate NSAID-induced small intestinal injury by inducing dysbiosis. Gastroenterology 2011;141:1314-1322.
    Pubmed CrossRef
  71. Scarpignato C. NSAID-induced intestinal damage: are luminal bacteria the therapeutic target?. Gut 2008;57:145-148.
    Pubmed CrossRef
  72. Fornai M, Antonioli L, Pellegrini C, et al. Small bowel protection against NSAID-injury in rats: effect of rifaximin, a poorly absorbed, GI targeted, antibiotic. Pharmacol Res 2016;104:186-196.
    Pubmed CrossRef
  73. Colucci R, Pellegrini C, Fornai M, et al. Pathophysiology of NSAID-associated intestinal lesions in the rat: luminal bacteria and mucosal inflammation as targets for prevention. Front Pharmacol 2018;9:1340.
    Pubmed KoreaMed CrossRef
  74. Kinouchi T, Kataoka K, Bing SR, et al. Culture supernatants of Lactobacillus acidophilus and Bifidobacterium adolescentis repress ileal ulcer formation in rats treated with a nonsteroidal antiinflammatory drug by suppressing unbalanced growth of aerobic bacteria and lipid peroxidation. Microbiol Immunol 1998;42:347-355.
    Pubmed CrossRef
  75. Koga H, Aoyagi K, Matsumoto T, Iida M, Fujishima M. Experimental enteropathy in athymic and euthymic rats: synergistic role of lipopolysaccharide and indomethacin. Am J Physiol 1999;276:G576-G582.
    Pubmed CrossRef
  76. Banerjee AK, Peters TJ. Experimental non-steroidal anti-inflammatory drug-induced enteropathy in the rat: similarities to inflammatory bowel disease and effect of thromboxane synthetase inhibitors. Gut 1990;31:1358-1364.
    Pubmed KoreaMed CrossRef
  77. Lombardo L, Foti M, Ruggia O, Chiecchio A. Increased incidence of small intestinal bacterial overgrowth during proton pump inhibitor therapy. Clin Gastroenterol Hepatol 2010;8:504-508.
    Pubmed CrossRef
  78. Shen J, Zuo ZX, Mao AP. Effect of probiotics on inducing remission and maintaining therapy in ulcerative colitis, Crohn’s disease, and pouchitis: meta-analysis of randomized controlled trials. Inflamm Bowel Dis 2014;20:21-35.
    Pubmed CrossRef
  79. Zhang Y, Li L, Guo C, et al. Effects of probiotic type, dose and treatment duration on irritable bowel syndrome diagnosed by Rome III criteria: a meta-analysis. BMC Gastroenterol 2016;16:62.
    Pubmed KoreaMed CrossRef
  80. Hempel S, Newberry SJ, Maher AR, et al. Probiotics for the prevention and treatment of antibiotic-associated diarrhea: a systematic review and meta-analysis. JAMA 2012;307:1959-1969.
    Pubmed CrossRef
  81. Szajewska H, Skórka A, Ruszczyński M, Gieruszczak-Białek D. Meta-analysis: Lactobacillus GG for treating acute gastroenteritis in children--updated analysis of randomised controlled trials. Aliment Pharmacol Ther 2013;38:467-476.
    Pubmed CrossRef
  82. Gallo A, Passaro G, Gasbarrini A, Landolfi R, Montalto M. Modulation of microbiota as treatment for intestinal inflammatory disorders: an uptodate. World J Gastroenterol 2016;22:7186-7202.
    Pubmed KoreaMed CrossRef
  83. Rostom A, Moayyedi P, Hunt R; Canadian Association of Gastroenterology Consensus Group. Canadian consensus guidelines on long-term nonsteroidal anti-inflammatory drug therapy and the need for gastroprotection: benefits versus risks. Aliment Pharmacol Ther 2009;29:481-496.
    Pubmed CrossRef
  84. Yeomans ND, Tulassay Z, Juhász L, et al. A comparison of omeprazole with ranitidine for ulcers associated with nonsteroidal antiinflammatory drugs. Acid Suppression Trial: Ranitidine versus Omeprazole for NSAID-associated Ulcer Treatment (ASTRONAUT) Study Group. N Engl J Med 1998;338:719-726.
    Pubmed CrossRef
  85. Satoh H, Amagase K, Takeuchi K. Mucosal protective agents prevent exacerbation of NSAID-induced small intestinal lesions caused by antisecretory drugs in rats. J Pharmacol Exp Ther 2014;348:227-235.
    Pubmed CrossRef
  86. Gwee KA, Goh V, Lima G, Setia S. Coprescribing proton-pump inhibitors with nonsteroidal anti-inflammatory drugs: risks versus benefits. J Pain Res 2018;11:361-374.
    Pubmed KoreaMed CrossRef
  87. Williams C, McColl KE. Review article: proton pump inhibitors and bacterial overgrowth. Aliment Pharmacol Ther 2006;23:3-10.
    Pubmed CrossRef
  88. Nagata N, Niikura R, Yamada A, et al. Acute middle gastrointestinal bleeding risk associated with NSAIDs, antithrombotic drugs, and PPIs: a multicenter case-control study. PLoS One 2016;11:e0151332.
    Pubmed KoreaMed CrossRef
  89. Kamada T, Sato M, Tokutomi T, et al. Rebamipide improves chronic inflammation in the lesser curvature of the corpus after Helicobacter pylori eradication: a multicenter study. Biomed Res Int 2015;2015:865146.
    Pubmed KoreaMed CrossRef
  90. Arakawa T, Watanabe T, Fukuda T, Yamasaki K, Kobayashi K. Rebamipide, novel prostaglandin-inducer accelerates healing and reduces relapse of acetic acid-induced rat gastric ulcer. Comparison with cimetidine. Dig Dis Sci 1995;40:2469-2472.
    Pubmed CrossRef
  91. Tanigawa T, Watanabe T, Otani K, et al. Rebamipide inhibits indomethacin-induced small intestinal injury: possible involvement of intestinal microbiota modulation by upregulation of α-defensin 5. Eur J Pharmacol 2013;704:64-69.
    Pubmed CrossRef
  92. Imaeda H, Fujimoto T, Takahashi K, Kasumi E, Fujiyama Y, Andoh A. Terminal-restriction fragment length polymorphism (T-RFLP) analysis for changes in the gut microbiota profiles of indomethacin- and rebamipide-treated mice. Digestion 2012;86:250-257.
    Pubmed CrossRef
  93. Hiraishi H, Haruma K, Miwa H, Goto H. Clinical trial: irsogladine maleate, a mucosal protective drug, accelerates gastric ulcer healing after treatment for eradication of Helicobacter pylori infection: the results of a multicentre, double-blind, randomized clinical trial (IMPACT study). Aliment Pharmacol Ther 2010;31:824-833.
    Pubmed CrossRef
  94. Kamei K, Kubo Y, Kato N, Hatazawa R, Amagase K, Takeuchi K. Prophylactic effect of irsogladine maleate against indomethacin-induced small intestinal lesions in rats. Dig Dis Sci 2008;53:2657-2666.
    Pubmed CrossRef
  95. Menozzi A, Pozzoli C, Poli E, et al. Effects of oral curcumin on indomethacin-induced small intestinal damage in the rat. Drug Discov Ther 2009;3:71-76.
    Pubmed
  96. Sivalingam N, Hanumantharaya R, Faith M, Basivireddy J, Balasubramanian KA, Jacob M. Curcumin reduces indomethacin-induced damage in the rat small intestine. J Appl Toxicol 2007;27:551-560.
    Pubmed CrossRef
Gut and Liver

Vol.17 No.1
January, 2023

pISSN 1976-2283
eISSN 2005-1212

qrcode
qrcode

Share this article on :

  • line

Popular Keywords

Gut and LiverQR code Download
qr-code

Editorial Office