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
Yong Chan Lee |
Professor of Medicine Director, Gastrointestinal Research Laboratory Veterans Affairs Medical Center, Univ. California San Francisco San Francisco, USA |
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 |
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.
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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
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
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
The protective effects of misoprostol were further demonstrated in studies evaluating small intestine damage by capsule endoscopy. Watanabe
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
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
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.
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
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
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.
No potential conflict of interest relevant to this article was reported.
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 |
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 |
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 |
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 |
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 |
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 |
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 |
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 |
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 |
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 |
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 |
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 |
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 |
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 |
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 |
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 |
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 |
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 |
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 |
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 |
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 |
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 |
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 |
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 |
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 |
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 |
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 |
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 |
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 |
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 |
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 |
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 |
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 |
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 |
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 |
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 |
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 |
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 |
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.
Gut and Liver 2020; 14(2): 179-189
Published online March 15, 2020 https://doi.org/10.5009/gnl19201
Copyright © Gut and Liver.
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
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.
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
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
The protective effects of misoprostol were further demonstrated in studies evaluating small intestine damage by capsule endoscopy. Watanabe
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
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
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.
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
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
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.
No potential conflict of interest relevant to this article was reported.
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 |
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 |
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 |
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 |
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 |
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 |
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 |
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 |
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 |
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 |
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 |
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 |
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 |
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 |
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 |
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 |
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 |
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 |
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 |
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 |
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 |
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 |
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 |
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 |
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 |
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 |
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 |
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 |
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 |
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 |
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 |
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 |
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 |
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 |
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 |
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 |
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 |
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 |
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 design | Intervention | Study period | Subject | Main result |
---|---|---|---|---|---|
Selective COX-2 inhibitors | |||||
Goldstein | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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.