Pharmacology of preventive and therapeutic drugs for NSAIDs ulcers in the gastrointestinal tract

NSAIDs have been associated with gastrointestinal (GI) toxicity. Proton pump inhibitors (PPIs) may be the first line in the treatment as well as in the prevention of NSAIDs-induced ulcers. Although there are no definite differences among three PPIs(omeprazole, lansoprazole, and rabeprazole) in the clinical field, it should be considered to inhibit gastric acid secretion rapidly and strongly in case of the treatment with acute gastric ulcer in patients who should be continued to be NSAIDs treatment. Recently, the serious problem of NSAID-induced small intestinal damage has become a topic of great interest to gastroenterologists, since capsule endoscopy and balloon enteroscopy are available for the detection of small intestinal lesions. Further understanding of the pathogenesis of NSAID-induced intestinal ulcers is important to enable the development of novel and effective preventive strategies.     

NSAID-induced gastric mucosal damage

Gastric mucosal damage is a common side effect of nonsteroidal anti-inflammatory drugs (NSAIDs). These drugs may cause gastrointestinal symptoms, gastric erosions, peptic ulcers or upper gastrointestinal bleeding. Therefore, NSAIDs should be used cautiously in patients with a history of gastrointestinal lesions. Drugs that may be useful in preventing or treating NSAID-induced gastric mucosal injury are under intensive clinical investigation.     

Comparison of Prevention of NSAID-Induced Gastrointestinal Complications by Rebamipide and Misoprostol: A Randomized, Multicenter, Controlled Trial-STORM STUDY

Nonsteroidal anti-inflammatory drugs (NSAIDs) have gastrointestinal side effects such as dyspepsia, peptic ulcer, hemorrhage, and perforation. Misoprostol and PPIs have been used to prevent NSAID-induced gastroduodenal injury. Rebamipide increases gastric mucus and stimulates the production of endogenous prostaglandins. The prophylactic effect of rebamipide on NSAID-induced gastrointestinal complications is unknown. The aim of this study was to compare NSAID-induced gastrointestinal complications in rebamipide- and misoprostol-treated groups. Patients were randomized to two groups and took a conventional NSAID plus rebamipide or misoprostol for 12 weeks. Gastric mucosal damage was evaluated by endoscopy at screening and the end of the study. The prevalences of active gastric ulcer were 7/176 (3.9%) in the rebamipide group and 3/156 (1.9%) in the misoprostol group. The prevalences of peptic ulcer were 8/176 (4.5%) in the rebamipide group and 7/156 (4.4%) in the misoprostol group. The cumulative incidences of peptic ulcer in the high-risk subgroup were 6/151 (4.0%) for rebamipide and 6/154 (3.9%) for misoprostol. In conclusion, rebamipide prevented NSAID-induced peptic ulcer as effectively as misoprostol in patients on long-term NSAID therapy. Rebamipide may be a useful therapeutic option for the prevention of NSAID-induced gastrointestinal ulcer because of its therapeutic effect and safety.     

Nonsteroidal anti-inflammatory drugs and peptic ulcer disease. An overview

Evidence is accumulating that use of nonsteroidal anti-inflammatory drugs (NSAIDs) is linked to ulceration of the stomach and duodenum and can cause significant, life-threatening ulcer complications. The mechanism of action seems to be both topical damage to the mucosal barrier and the systemic effect of a reduction in levels of mucosal prostaglandins. Patients especially at risk are the elderly, those with concomitant debilitating disease, those with a history of ulcers, and those taking corticosteroids. Histamine2 blockers are reported to significantly reduce the incidence of NSAID-induced duodenal ulcer, and misoprostol (Cytotec) has been shown to significantly reduce the incidence of NSAID-induced gastric ulcer. Prophylaxis with these agents should be considered for high-risk patients who need NSAID therapy to maintain a reasonable life-style.     

Ulcers and gastritis

This article reviews recently published literature regarding ulcers and gastritis. Although endoscopy is the most useful procedure for diagnosis in the upper gastrointestinal tract, complications do occur, and procedure-related costs are significant. The appropriate indication for endoscopy has recently been debated. Helicobacter pylori is known to be an important pathogen involved in gastric and duodenal inflammation. Peptic ulcer disease and severe gastric mucosal injury are caused by virulent strains, and many reports have focused on CagA. Follow-up studies on surveillance endoscopy in patients with peptic ulcer or gastritis report that patients with atrophic gastritis and intestinal metaplasia are at significantly higher risk for gastric cancer. H. pylori eradication sometimes causes gastroduodenal erosion and reflux esophagitis, and the mechanisms involved have been revealed. Proton-pump inhibitors are useful in the treatment of ulcers caused by nonsteroidal anti-inflammatory drugs (NSAIDs), reflux esophagitis, and for preventing rebleeding after endoscopic hemostasis, but the effect of long-term acid suppression on the gastric mucosa is still a matter of debate. H. pylori infection and NSAID intake are both risk factors for peptic ulcer disease, and are important aspects in this field.     

Cytotec (misoprostol)

NSAIDs have been associated with gastric ulcers and life-threatening complications, including hemorrhage and perforation. Cytotec (misoprostol) is the only drug approved for the prevention of NSAID-induced gastric ulcers. The administration of Cytotec represents benefits, particularly to an elderly population in which the usage trend of NSAIDs is increasing and the induced gastric injury is often silent. The nurse must have an adequate knowledge of this medication in order to provide patients receiving this drug with appropriate patient instruction.     

Prevention of anti-inflammatory drug-induced gastrointestinal damage: benefits and risks of therapeutic strategies

Patients who take non-steroidal anti-inflammatory drugs (NSAIDs) may develop serious gastrointestinal (GI) side effects in both the upper and lower GI tract. Those at risk should be considered for prevention with misoprostol, proton pump inhibitor (PPI) or COX-2 selective inhibitor (coxib) therapy. A coxib or an NSAID+PPI combination is considered to have comparable GI safety profiles, but evidence from direct comparison is limited. PPIs are effective in the prevention of upper GI events in endoscopy trials and in a few, small, outcome trials in patients at risk. Coxibs have been evaluated in endoscopic ulcer studies and clinical outcome trials, and shown to significantly reduce the risk of upper GI ulcer and complications. Moreover, unlike PPIs, coxibs significantly reduce toxicity in the lower GI tract compared with NSAIDs. Coxibs and possibly some NSAIDs also increase the risk of developing serious cardiovascular events, an effect which may depend on the drug, dose and duration of therapy. It is not known whether concomitant low-dose aspirin use, which occurs in more than 20% of patients, will reduce the incidence of cardiovascular events, although concomitant aspirin increases the risk of developing serious GI events in patients taking either an NSAID or a coxib. Such patients may require additional PPI co-therapy. Current prevention strategies with an NSAID+PPI, misoprostol or a coxib must be considered in the individual patient with GI and cardiovascular risk factors. A PPI+coxib is indicated in those at highest risk (e.g. previous ulcer bleeding). PPI therapy must be considered for the treatment and prevention of NSAID-induced dyspepsia.     

Strategy for peptic ulcer therapy in the era of H. pylori eradication therapy

The Japanese guideline for gastric ulcer therapy published 2003 has adopted a policy that eradication therapy for H. pylori as the first line therapy on ulcer patients with positive H. pylori status. For NSAID-induced gastric ulcer patients, cessation should be considered. In patients who cannot stop NSAIDs, proton-pump inhibitors or prostaglandin drugs is recommended. Similar strategy can be applied for duodenal ulcer patients. Implementation of this basic strategy in daily clinical practice, however, require further efforts to wider recognition of the new guideline for gastric ulcer therapy as well as to solve several barriers caused by discrepant health reimbursement policy.     

The choice of selective COX-2 inhibitors

Non-steroidal anti-inflammatory drug (NSAID) has been widely prescribed as a useful antifebrile or painkiller. But, gastrointestinal injury as a side effect of NSAIDs has been a big social probrem. NSAID-induced gastric damage has been shown to be induced by the inhibition of both cyclooxygenase (COX)-1 and 2. Thus, selective COX-2 inhibitors are expected to induce less gastric injury and to be safe as compared to traditional NSAIDs. But in certain situations such as gastric ulcer or H. pylori-induced gastritis, selective COX-2 inhibitors may delay ulcer healing or repair processes. Previous reports have shown that COX-2 inhibitors increase cardiovascular (CV) events as compared with placebo and recent studies further suggest that all NSAIDs might also be involved in increases in CV events. Therefore, any NSAIDs must be carefully used when they are prescribed for patients with CV risks.     

Proton pump inhibitor H2 receptor antagonist

Recently, Japanese guidelines for the treatment and prevention of peptic ulcers were established by the Japanese Society of Gastroenterology. Herein, we focus on proton pump inhibitor(PPI) and H2 receptor antagonist (H2RA) for prophylaxis and treatment of peptic ulcer associated with NSAIDs including low dose of aspirin. Double dose of H2RAs are effective at preventing chronic NSAID related ulcers, however, the effect is not superior to PPI. Full-dose misoprostol and PPI are clinically equivalent, although the potential adverse effects of misoprostol are a major cause of poor compliance. Overall, PPIs have the best profile of efficacy and side-effects for the healing and prevention of NSAID-associated ulcers, especially in the patients with high risk, such as history of peptic ulcer.     

Medical treatment of peptic ulcer disease.

Our understanding of PUD and its treatment has improved dramatically during the past 15 years. During this time, many new effective drugs have been approved by the FDA, and possibly even more potent and effective therapies are now being evaluated. The H2-blockers, sucralfate, and antacids heal over 90% of duodenal ulcers in 6 to 8 weeks, and H2-blockers heal about 80% of gastric ulcers by 8 weeks and over 90% by 12 weeks. The new, more potent pump blockers (omeprazole) promise to be even more effective drugs, even for the healing of patients who are taking NSAIDS. However, the potential hazards of marked, long-term acid suppression must still be evaluated. Maintenance therapy with H2-blockers or sucralfate, ideally used for patients who would otherwise have frequent symptomatic recurrences of duodenal ulcer disease or who have had complications, reduces the relapses, especially symptomatic relapses. Maintenance therapy with H2-blockers also seems to reduce the recurrences of GUD, but this use has not yet received FDA approval. Elimination of H. pylori infection with antibiotics may prove to reduce recurrent ulcer disease and negate the need for maintenance therapy. Colloidal bismuth subcitrate alone, which suppresses but does not eradicate H. pylori infection, seems to be an effective ulcer drug and may even reduce the rate of early recurrences. Effective ulcer therapy, especially if it prevents recurrent disease, may reduce the complications of PUD, but this expectation has yet to be established. The use of prophylactic cytoprotective prostaglandins (misoprostol) reduces the incidence of NSAID-induced GUD.     

Prevention and treatment of nonsteroidal anti-inflammatory drugs induced ulcers

There are many randomized controlled trials (RCTs) about prevention and treatment for nonsteroidal anti-inflammatory drugs (NSAIDs) induced ulcers in the world. Prevention and treatment about NSAIDs induced ulcers by proton pump inhibitors (PPIs) and misoprostol are well established. Cyclooxygenase (COX)-2 inhibitors reduce ulcers but some reports revealed that these drugs increased cardiovascular adverse events than conventional NSAIDs. In Japan, there are few RCTs about NSAIDs induced ulcers. The approved dosages of NSAIDs are much fewer in Japan than in the United States and Western countries. So it is necessary to study about efficacy and safety of PPIs and misoprostol for Japanese patients and clear the most appropriate dosages of these drugs and distinguish the high risk patients.     

Non-steroidal antiinflammatory drug--management of gastrointestinal complications and inhibition of COX-2

Non-steroidal antiinflammatory drugs (NSAID) are widely used for the treatment of rheumatoid arthritis and other collagen vascular diseases, and now more than 30 drugs are available. However, caution should be paid in using NSAIDs because of their serious side effects, especially gastrointestinal toxicity. Misoprostol has been shown to prevent NSAID-induced gastrointestinal damage, and proton-pump inhibitor omeprazole and misoprostol have been shown to be effective in the treatment of ulcers and erosions induced by NSAIDs. After the discovery of cyclooxygenase-2 (COX-2), investigators have raised a hypothesis that specific inhibitor of COX-2 should have anti-inflammatory activity with least gastrointestinal toxicity. According to this, efforts have been paid to produce COX-2 selective inhibitors. Although several COX-2 inhibitors have been reported to show reduced toxicity, further investigations are needed to establish their usefulness.     

Prevention of anti‐inflammatory drug‐induced gastrointestinal damage: Benefits and risks of therapeutic strategies

Patients who take non‐steroidal anti‐inflammatory drugs (NSAIDs) may develop serious gastrointestinal (GI) side effects in both the upper and lower GI tract. Those at risk should be considered for prevention with misoprostol, proton pump inhibitor (PPI) or COX‐2 selective inhibitor (coxib) therapy. A coxib or an NSAID+PPI combination is considered to have comparable GI safety profiles, but evidence from direct comparison is limited. PPIs are effective in the prevention of upper GI events in endoscopy trials and in a few, small, outcome trials in patients at risk. Coxibs have been evaluated in endoscopic ulcer studies and clinical outcome trials, and shown to significantly reduce the risk of upper GI ulcer and complications. Moreover, unlike PPIs, coxibs significantly reduce toxicity in the lower GI tract compared with NSAIDs. Coxibs and possibly some NSAIDs also increase the risk of developing serious cardiovascular events, an effect which may depend on the drug, dose and duration of therapy. It is not known whether concomitant low‐dose aspirin use, which occurs in more than 20% of patients, will reduce the incidence of cardiovascular events, although concomitant aspirin increases the risk of developing serious GI events in patients taking either an NSAID or a coxib. Such patients may require additional PPI co‐therapy. Current prevention strategies with an NSAID+PPI, misoprostol or a coxib must be considered in the individual patient with GI and cardiovascular risk factors. A PPI+coxib is indicated in those at highest risk (e.g. previous ulcer bleeding). PPI therapy must be considered for the treatment and prevention of NSAID‐induced dyspepsia.     

Prevention and treatment of NSAIDs-induced gastrointestinal complications by prostaglandin derivatives

Non-steroidal anti-inflammatory drugs(NSAIDs) are widely used for the treatment of many rheumatic diseases. Gastrointestinal ulcers are the most important complication during long-term NSAIDs therapy and sometimes, serious complications, such as perforation, stenosis, and bleeding occurs. Recently, use of COX-2 selective NSAIDs reduced such complications, however the increase of cardiovascular risks has been reported. Administration of misoprostol, one of the prostaglandin derivatives has been proven to be effective for both prevention and treatment of gastrointestinal ulcers associated with NSAIDs therapy and is recommended by the Japanese guidelines. In addition, the reduction of NSAIDs-related serious complications, such as perforation, stenosis, and bleeding have been reported with misoprostol therapy. The important side effects include abdominal pain, flatulence, and diarrhea.     

Management of NSAID-induced ulcer disease.

The use of nonsteroidal anti-inflammatory drugs (NSAIDs) is associated with an increased risk of gastric and duodenal ulcers, especially in patients with previous ulcer disease, heavy smokers, patients who are taking steroids and those with other illnesses. In patients at risk for gastroduodenal complications, prophylactic therapy with misoprostol or an H2-receptor antagonist should be considered. If ulcers occur during NSAID therapy, the anti-inflammatory drug should be discontinued and standard ulcer-healing therapy instituted. If NSAID therapy must be continued, ulcer healing may be prolonged.     

Celecoxib versus a non-selective NSAID plus proton-pump inhibitor: what are the considerations?

Nonsteroidal anti-inflammatory drugs (NSAIDs) are extensively used worldwide. However, associated adverse gastrointestinal effects (NSAID gastropathy) such as bleeding, perforation and obstruction result in considerable morbidity, mortality, and expense. Although it is essential to employ gastroprotective strategies to minimize these complications in patients at risk, controversy remains on whether celecoxib alone or a non-selective NSAID in conjunction with a proton-pump inhibitor (PPI) is a superior choice. Recent concerns regarding potential cardiovascular toxicities associated with cox-2 selective inhibitors may favor non-selective NSAID/PPI co-therapy as the preferred choice. Concomitant use of low-dose aspirin with any NSAID increases the risk of gastrointestinal complications and diminishes the improved gastrointestinal safety profile of celecoxib; whereas use of ibuprofen plus PPI regimens may negate aspirin's antiplatelet benefits. Evidence shows that concurrent use of a non-selective NSAID (such as naproxen) plus a PPI is as effective in preventing NSAID gastropathy as celecoxib, and may be more cost-effective. Patients failing or intolerant to this therapy would be candidates for celecoxib at the lowest effective dose for the shortest duration of time. Potential benefits from using low-dose celecoxib with a PPI in patients previously experiencing bleeding ulcers while taking NSAIDs remains to be proven. An evidence-based debate is presented to assist clinicians with the difficult decision-making process of preventing NSAID gastropathy while minimizing other complications.     

Proton pump inhibitors: update on their role in acid-related gastrointestinal diseases

Gastric acid is pathogenic in many gastrointestinal disorders, such as gastroesophageal reflux disease and peptic ulcer disease. Proton pump inhibitors (PPIs) are the antisecretory drugs of choice for serious acid-related conditions. Ample recent data exist to explicate virtually every aspect of the clinical management of acid-peptic disorders with PPIs. Although all PPIs are effective, there are some differences in their clinical performance, particularly in terms of the degree and speed of gastric acid suppression. Rapid onset of acid suppression may be particularly relevant to newer approaches, such as 'on-demand' or intermittent therapy for non-erosive reflux disease and shorter regimens for Helicobacter pylori eradication. New data, in addition, highlight differences in PPI metabolism that may both affect efficacy and predispose patients to drug-drug interactions. PPI selection should involve the awareness of these issues.     

The gastroduodenal toxicity of nonsteroidal anti-inflammatory drugs: a review of the literature

Nonsteroidal anti-inflammatory drugs (NSAIDs) are popular and important for the treatment of inflammation and pain. However, conventional NSAIDs are intrinsically toxic to the gastroduodenal (GD) mucosa. The literature can, and should, guide us towards safer prescribing of NSAIDs. Factors known to increase the risk of GD toxicity include: history of peptic ulcer disease; advanced age; high doses; and coadministration of aspirin, anticoagulants or corticosteroids. Patients with any one of these risk factors, with the possible exception of age alone, should receive gastroprotective prophylaxis with proton pump inhibitors or misoprostol. Standard dose H2 antagonists do not protect against NSAID-induced gastric ulcers and are unsuitable for prophylaxis. Awareness of risk factors and appropriate prophylactic agents will minimize the risk to patients. Whether the new generation of highly selective COX-2 inhibitors and nitric oxide-donating NSAIDs are safer drugs in long-term use be remains to be proven, though initial clinical trial data are positive.     

Clinical features of NSAID-induced small intestinal damage

Various factors have been shown to be involved in the pathophysiology of NSAID-induced small intestinal damage. Recent advances in diagnostic methods including video capsule endoscopy and double-balloon endoscopy have enabled us to examine the entire small intestine, and we now recognize that prevalence of small intestinal damage in patients taking NSAIDs is high. NSAIDs cause intestinal damage including redness, erosions, and ulcers in both jejunum and ileum. Most of patients with intestinal pathology are asymptomatic, although a few patients present with iron deficiency anemia and/or hypoalbuminaemia. The risk factors for NSAID-induced enteropathy are unknown. Experimental and clinical studies would unravel the mechanism by which NSAIDs injure intestinal mucosa.