Prophylaxis and treatment of NSAID-induced gastroduodenal disorders.

A significant percentage of patients taking nonsteroidal anti-inflammatory drugs (NSAIDs) experience some type of adverse gastrointestinal symptoms, lesions of the gastroduodenal tract being clinically the most relevant. NSAIDs cause gastrointestinal damage by 2 independent mechanisms: a topical effect, which is pH and pKa related, and a systemic effect mediated by cyclooxygenase (COX) inhibition with a reduction in prostaglandin synthesis. Using endoscopy, gastroduodenal lesions identified include subepithelial haemorrhages, erosions and ulcers. The prevalence of ulceration in NSAID users has been reported as being between 14 and 31% with a 2-fold higher frequency of gastric ulcers compared with duodenal ulcers. Among the strategies used to decrease the risk of ulcer development are: (i) the use of analgesics other than NSAIDs; (ii) use of the lowest possible dosage of NSAID; (iii) the use of a COX-2 selective NSAID; (iv) the use of low doses of corticosteroids instead of NSAIDs; (v) avoidance of concomitant use of NSAIDs and corticosteroids; and (vi) use of preventive therapy. In an attempt to reduce the incidence of NSAID-induced gastrointestinal lesions, the following approaches have been proposed: (i) use of the prostaglandin analogue misoprostol, which is an antiulcer drug which has been proven to be as effective in the prevention of NSAID-induced gastric and duodenal ulcers as in the reduction of serious upper gastrointestinal complications; (ii) histamine H2 receptor antagonists (H2 antagonists), e.g. ranitidine, cimetidine and famotidine, which are useful in the prevention of NSAID-induced duodenal ulcers during long term treatment, but not in the prevention of NSAID-induced gastric ulcers; (iii) proton pump inhibitors, e.g omeprazole, and pantoprazole, whose efficacy in preventing NSAID-associated ulcers has been recently demonstrated; and (iv) barrier agents, e.g. sucralfate, which cannot be recommended as prophylactic agents to prevent NSAID-induced gastropathy. The first step in the treatment of NSAID-associated ulcers lies in a reduction in the dosage of the NSAID or discontinuation of the drug. If NSAID treatment cannot be withdrawn, a proton pump inhibitor appears to be the most effective treatment in healing ulcers, accelerating the slow healing observed with H2 antagonists.     

Novel therapeutic approaches to gastric and duodenal ulcers: an update

Over the last 25 years, a remarkable revolution in the pathophysiology and treatment of gastric and duodenal ulcers has occurred. Effective therapies were developed not only to heal ulcers, but also to cure most patients. The two principal causes for gastric and duodenal ulcers are either infection with Helicobacter pylori or the use of non-steroidal anti-inflammatory drugs (NSAIDs). With H. pylori eradication, gastric and duodenal ulcers are rapidly becoming historical diseases. This communication reviews the salient pharmacology of the novel anti-ulcer drugs currently in development, with particular emphasis on the treatment of gastric and duodenal ulcers. Intense research is currently focused on the development of proton pump inhibitors primarily for the treatment and prevention of gastroesophageal reflux disease. The older proton pump inhibitors, omeprazole and lansoprazole, are effective in healing gastric and duodenal ulcers. Furthermore, both drugs are effective in eradicating H. pylori when given with various antibiotics. Pantoprazole, rabeprazole and esomeprazole are new proton pump inhibitors, which appear to have comparable therapeutic profiles with omeprazole and lansoprazole. Rebamipide is a new mucosal protective drug, which is effective in healing gastric ulcers. Polaprezinc and nocloprost are also mucosal protective drugs, which are in clinical development. However, none of these three cytoprotective drugs have been evaluated for their efficacy in eradicating H. pylori when given in combination with antibiotics. Likewise, no published literature exists on the use of these drugs for preventing NSAID-induced ulcers. With the rapid eradication of H. pylori currently happening in the developed world, the therapeutic challenge is now directed toward preventing NSAID-associated ulcer. Significant reduction of NSAID-induced ulcers is achieved by using continuous prophylactic anti-ulcer therapy (misoprostol or omeprazole) or by using NSAIDs possessing selective COX-2 inhibitory activity. However, outcome clinical studies are needed to compare the adjuvant anti-ulcer therapies given with COX-1 inhibitors versus the selective COX-2 inhibitors given alone.     

Novel therapeutic approaches to gastric and duodenal ulcers: an update

Over the last 25 years, a remarkable revolution in the pathophysiology and treatment of gastric and duodenal ulcers has occurred. Effective therapies were developed not only to heal ulcers, but also to cure most patients. The two principal causes for gastric and duodenal ulcers are either infection with Helicobacter pylori or the use of non-steroidal anti-inflammatory drugs (NSAIDs). With H. pylori eradication, gastric and duodenal ulcers are rapidly becoming historical diseases. This communication reviews the salient pharmacology of the novel anti-ulcer drugs currently in development, with particular emphasis on the treatment of gastric and duodenal ulcers. Intense research is currently focused on the development of proton pump inhibitors primarily for the treatment and prevention of gastroesophageal reflux disease. The older proton pump inhibitors, omeprazole and lansoprazole, are effective in healing gastric and duodenal ulcers. Furthermore, both drugs are effective in eradicating H. pylori when given with various antibiotics. Pantoprazole, rabeprazole and esomeprazole are new proton pump inhibitors, which appear to have comparable therapeutic profiles with omeprazole and lansoprazole. Rebamipide is a new mucosal protective drug, which is effective in healing gastric ulcers. Polaprezinc and nocloprost are also mucosal protective drugs, which are in clinical development. However, none of these three cytoprotective drugs have been evaluated for their efficacy in eradicating H. pylori when given in combination with antibiotics. Likewise, no published literature exists on the use of these drugs for preventing NSAID-induced ulcers. With the rapid eradication of H. pylori currently happening in the developed world, the therapeutic challenge is now directed toward preventing NSAID-associated ulcer. Significant reduction of NSAID-induced ulcers is achieved by using continuous prophylactic anti-ulcer therapy (misoprostol or omeprazole) or by using NSAIDs possessing selective COX-2 inhibitory activity. However, outcome clinical studies are needed to compare the adjuvant anti-ulcer therapies given with COX-1 inhibitors versus the selective COX-2 inhibitors given alone.     

An overview of the key role of misoprostol in the prophylaxis of NSAID-associated ulcers and their complications

In 22 controlled endoscopic studies misoprostol has consistently been shown to prevent NSAID-associated gastric and duodenal ulcers. The clinical relevance of such studies has now been proven by the MUCOSA study. This study in 8843 arthritic patients has shown that misoprostol significantly reduces serious NSAID-induced upper GI complications by about half, compared with placebo. No other therapeutic agent has been shown to reduce serious complications of NSAIDs. In the majority of endoscopic studies H₂-receptor blockers and omeprazole prevent duodenal but not gastric ulcers caused by NSAIDs. Since the serious GI complications caused by NSAIDs arise from the stomach and duodenum in equal proportions, and since we cannot predict the site of occurrence, it is essential that any prophylactic agent should prevent ulcers at both sites. Misoprostol is the only agent consistently shown to do this, and allied with data showing that it reduces GI complications it can play a key role in modifying the natural history of this iatrogenic disease.     

Management of NSAID-related gastrointestinal mucosal injury

The three therapeutic goals in patients with NSAID-induced gastroduodenopathy are treatment of dyspeptic symptoms, management of NSAID-related ulcers and their complications, and prophylaxis against recurrent gastrointestinal toxicity. Both H₂-receptor antagonists and proton pump inhibitors (PPIs) appear to be helpful in relieving the symptoms associated with NSAID use, while treatment of NSAID-induced gastroduodenal ulcers, whether the NSAID is continued or not, is best achieved by the use of PPIs. However, because symptoms do not often predict the presence of gastroduodenal ulcers, the goal of prevention has become paramount in the treatment of patients with an increased likelihood of gastrointestinal toxicity. The best prophylaxis against NSAID-related toxicity is the use of an alternative agent such as salsalate or paracetamol (acetaminophen). However, if an NSAID is to be used, prophylaxis is best accomplished with a PPI or misoprostol, a prostaglandin E1 analogue. The use of misoprostol is limited by its frequent dosing, at least 200 μg three times a day, and its own gastrointestinal side effects. Future therapy will include NSAIDs that maintain their antiinflammatory effects, while possessing superior safety profiles, and include preferential and highly selective COX-2 inhibitors and nitric oxide releasing compounds.     

Clinical efficacy of esomeprazole in the prevention and healing of gastrointestinal toxicity associated with NSAIDs in elderly patients

NSAIDs are widely prescribed for the treatment of pain, inflammation and rheumatic disorders, but their use is associated with adverse gastrointestinal effects, ranging from dyspeptic symptoms and peptic ulcers to more serious complications. Elderly patients are at high risk of experiencing NSAID-induced gastrointestinal tract injury and should be considered candidates for prophylactic pharmacological therapy. In studies conducted in adult patients, proton pump inhibitors (PPIs) such as esomeprazole have been shown to prevent or reduce NSAID-induced gastrointestinal injury. The beneficial effects of esomeprazole can be ascribed largely to its ability to maintain sustained inhibition of gastric acid secretion, although there is evidence to suggest that pharmacodynamic properties unrelated to acid inhibition may also contribute to the gastroprotective effects of this agent. Although there are limited data on the use of esomeprazole specifically in elderly patient populations, studies of patients at high risk of NSAID-induced gastrointestinal toxicity because of advanced age indicate that this PPI is both effective and well tolerated when administered in conjunction with NSAIDs. Thus, esomeprazole can be regarded as a useful option for prophylactic therapy in elderly patients receiving long-term NSAID therapy.     

Nonsteroidal anti-inflammatory drugs: add an anti-ulcer drug for patients at high risk only. Always limit the dose and duration of treatment with NSAIDs

In addition to their cardiac, renal, hepatic, cutaneous and neuropsychological adverse effects, nonsteroidal anti-inflammatory drugs (NSAIDs) can have severe effects on the entire gastrointestinal tract, including bleeding, perforation and occlusion. Which anti-ulcer drugs reduce the risk of the severe gastrointestinal adverse effects of NSAIDs, and which patients should receive them? To answer these questions, we conducted a review of the literature, using the standard Prescrire methodology. The main risk factors for severe gastrointestinal adverse effects during NSAID therapy are: a high dose regimen; age over 65 years; a history of gastric or duodenal ulcer or gastrointestinal bleeding; heavy use of both alcohol and tobacco; and concomitant treatment with a corticosteroid, antiplatelet drug, anticoagulant, or selective serotonin reuptake inhibitor (SSRI) antidepressant. Gastrointestinal symptoms and ulceration (on endoscopy) are poor predictors of severe gastrointestinal reactions. A meta-analysis examined randomised placebo-controlled trials of misoprostol in more than 11 000 patients. The results were mainly based on a large trial including about 9000 rheumatoid arthritis patients with an average age of 68 years. Misoprostol (400 microg to 800 microg/day, in 4 doses) prevented about 4 severe gastroduodenal events when 1000 patients over 60 years of age were treated for 6 months. Diarrhoea and other mild gastrointestinal disorders were frequent. There are no randomised trials comparing proton pump inhibitors (PPIs) and histamine H2 receptor antagonists versus misoprostol or versus placebo therapy for the prevention of severe adverse effects associated with NSAIDs. PPIs and H2 antagonists both reduce the incidence of gastric or duodenal ulceration detected by routine endoscopy. A randomised trial compared an H2 antagonist (famotidine) versus a PPI (pantoprazole) in 128 patients with an average age of 69 years who had a very high risk of serious gastrointestinal adverse effects while taking low-dose aspirin. After 48 weeks of treatment, pantoprazole was more effective than famotidine for the prevention of overt gastrointestinal bleeding. The symptomatic effects of PPIs and H2 antagonists may create a false sense of security, leading some patients to increase their NSAID use and resulting in a paradoxical increase in severe gastrointestinal effects. In practice, anti-ulcer drugs are not sufficiently effective to warrant their use by NSAID-treated adults who are not at high risk of severe gastrointestinal events. Misoprostol has proven efficacy in patients with risk factors for NSAID-induced severe gastroduodenal adverse effects, especially patients over 65 years of age, but it also has frequent adverse effects and necessitates 4 daily doses. Omeprazole is an alternative when the adverse effects or dosing frequency of misoprostol are unacceptable, provided patients are warned not to increase their NSAID consumption.     

Therapeutic evaluation of omeprazole

The pharmacology, pharmacokinetics, clinical efficacy, adverse effects, and dosage and administration of omeprazole are reviewed. Omeprazole, a substituted benzimidazole, has a unique site and mechanism of action because it inhibits the proton pump--i.e., hydrogen, potassium adenosine triphosphatase (H+,K+-ATPase)--and consequently blocks the final common step in the gastric acid secretory pathway. Omeprazole inhibits basal and histamine-, gastrin- and pentagastrin-stimulated gastric hydrochloric acid secretion. It produces a dose-dependent reduction in gastric acidity, gastric acid output, and gastric juice volume and has variable effects on pepsin secretion. Omeprazole has no documented effect on esophageal motility or lower esophageal sphincter pressure. Omeprazole is variably absorbed from the gastrointestinal tract, and food appears to decrease the rate, but not the extent, of drug absorption. The drug is approximately 95% bound to plasma proteins and is metabolized to inactive components that are enterohepatically or renally eliminated. Omeprazole is more effective (in most studies) than H2-receptor antagonists in treating duodenal ulcer, at least as effective in treating benign gastric ulcer, and more effective in treating reflux esophagitis. Omeprazole has been used successfully in patients with Zollinger-Ellison syndrome refractory to treatment with H2-receptor antagonists. Gastrointestinal complaints (nausea and diarrhea) are the most commonly reported adverse effects associated with omeprazole therapy. The most frequently reported laboratory abnormality occurring with omeprazole use is elevation of serum aspartate aminotransferase and alanine aminotransferase concentrations. Omeprazole will serve a valuable role in the management of gastrointestinal tract ulcers and hypersecretory conditions.     

Gastroprotection and nonsteroidal anti-inflammatory drugs (NSAIDS). Rationale and clinical implications.

There is no doubt that nonsteroidal anti-inflammatory drugs (NSAIDs) cause gastrointestinal injury. The most serious consequences are gastric and duodenal ulcers which can cause bleeding and perforation, and which may lead to the premature death of 3000 to 4000 patients in the UK annually. The immediate actions of NSAIDs operate at a subcellular level; in particular altering of mitochondrial function which causes depletion of ATP and renders the cell vulnerable to oxidant stress. Secondary consequences follow, such as the inhibition of prostaglandin synthesis which delays cellular repair. While adaptation can be shown in volunteers despite continued NSAID ingestion, studies in patients suggest mucosal damage develops continuously and cumulatively even with low doses of aspirin. Histamine H2-receptor antagonists and proton pump inhibitors heal NSAID-related ulcers, though healing rates with H2-antagonists are slower in patients who continue NSAID treatment. They have little role in preventing damage. In addition to acid suppression, prostaglandin analogues cause bicarbonate secretion and enhance mucosal blood flow. They have a specific role in both prevention and treatment of NSAID-related damage. The use of misoprostol offers a rational approach to reduce the high prevalence of unwanted gastroduodenal damage from NSAIDs. On a purely financial basis more information is needed before routine coprescribing can be recommended. However, for any patient on NSAIDs with a previous ulcer or for patients aged over 60 years (where the risks and seriousness of complications are markedly increased), the use of misoprostol should be considered. Further developments in prostaglandin analogues may reduce their adverse effects and perhaps thereby improve their efficacy at symptom control.     

Diclofenac/misoprostol. Pharmacoeconomic implications of therapy.

The combined formulation of diclofenac/misoprostol provides effective relief of pain and inflammation, with a 2- to 3-fold lower incidence of NSAID-associated gastroduodenal ulcers than diclofenac monotherapy. Both components of the combined formulation have been widely used and have well documented efficacy and tolerability profiles. Compared with other agents used as prophylaxis for NSAID-induced gastropathies, misoprostol is generally considered to have the most extensive outcomes data establishing its efficacy in preventing both gastric and duodenal ulcers associated with long term NSAID use. Economic analyses conducted to date have shown that diclofenac/misoprostol is associated with similar or lower total direct medical treatment costs compared with other NSAIDs (with or without coprescribed misoprostol or an alternate prophylactic agent). As with pharmacoeconomic studies of coprescribed misoprostol with NSAIDs, the most favourable results with the combined formulation of diclofenac/misoprostol appear to be in patients at high risk of developing NSAID-associated gastroduodenal ulcers (e.g. the elderly). Although economic analyses with diclofenac/misoprostol were conducted in several different countries using a variety of methodologies and employing a wide range of clinical and economic assumptions, results have been generally favourable for the combined formulation. However, as is the case with pharmacoeconomic analyses in general, results of individual studies with diclofenac/misoprostol may not be generalisable between countries and are subject to change over time. Overall, clinical and economic data suggest that the optimal and most cost-effective use of the combined formulation of diclofenac/misoprostol is in patients requiring long term NSAID therapy who are at increased risk of developing NSAID-induced gastropathy, such as elderly patients with rheumatoid arthritis or osteoarthritis.     

Effect of omeprazole on delayed healing of acetic acid-induced gastric ulcers in rats

Omeprazole, a gastric mucosal proton pump inhibitor, significantly and dose-dependently prevented the delayed healing of acetic acid-induced gastric ulcers in response to repeatedly administered indomethacin to rats. Both basal and histamine-stimulated gastric acid secretions in rats with acetic acid-induced ulcers that were given indomethacin were markedly and persistently (greater than 24 hr) inhibited after 4 weeks treatment with omeprazole. The prevention of delayed ulcer healing by omeprazole appears to be due to its long-lasting antisecretory activity.     

Omeprazole promotes gastric epithelial cell migration

Proton pump inhibitors (PPIs) are effective at preventing non-steroidal anti-inflammatory drug (NSAID)-induced gastric ulcers. They are also superior to histamine H(2)-receptor antagonists and misoprostol in treating NSAID-induced gastric ulcer healing. This study explored whether omeprazole, a PPI, can modulate ulcer healing through epithelial cell proliferation and/or cell migration using a rat normal gastric epithelial cell line (RGM-1). Flow cytometry was used to determine cell proliferation and an artificial wound model was used to measure cell migration. Western blot analysis was performed to evaluate the possible mechanisms of action. Omeprazole treatment (10(-8), 10(-6) and 10(-4)M) for 12 and 24 h did not promote cell proliferation. However, similar doses of the drug (10(-6) and 10(-4)M) incubated for 24-48 h significantly promoted the basal cell migration of gastric epithelial cells. Further, the higher concentration of omeprazole (10(-4)M) reversed the inhibitory action of indometacin (10(-5)) on cell migration. Western blot results showed that omeprazole did not increase cyclooxygenase-2 expression and did not activate signal transduction pathways, including extracellular signal-regulated kinase (ERK1/ERK2), P38 mitogenic-activated protein kinase, and phosphatidyl inositol 3-kinase. The results suggest that omeprazole is beneficial in basal ulcer healing and it reversed the adverse action of indometacin on ulcer repair under acid-independent conditions. These actions are likely to be mediated through the promotion of gastric epithelial cell migration but not cell proliferation.     

Omeprazole. A preliminary review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in peptic ulcer disease and Zollinger-Ellison syndrome

Omeprazole is a substituted benzimidazole derivative which markedly inhibits basal and stimulated gastric acid secretion. It has a unique mode of action, irreversibly blocking the so-called proton pump of the parietal cell which is supposedly the terminal step in the acid secretory pathway. In animals, on a weight basis, omeprazole is 2 to 10 times more potent than cimetidine in inhibiting gastric acid secretion. Toxicological studies in rats have shown that very high doses of omeprazole administered for 2 years produce hyperplasia of gastric enterochromaffin-like cells and carcinoids, a few with proliferations into the submucosa. The significance of such findings to the clinical situation is wholly speculative and requires further research. Preliminary studies in patients with duodenal ulcers or Zollinger-Ellison syndrome have found no mucosal changes which would suggest that the drug represents a risk for development of carcinoid tumours at therapeutic dosages. In patients with duodenal ulcers omeprazole, at dosages of at least 20mg once daily, produced ulcer healing rates of between 60 and 100% after 2 weeks and between 90 and 100% after 4 weeks, even in patients resistant to treatment with H2-receptor antagonists. Comparative trials clearly demonstrated that omeprazole 20 to 40 mg administered once daily was significantly more effective than usual dosage regimens of cimetidine and ranitidine in healing duodenal ulcers during 2 to 4 weeks of treatment. At present no data are available evaluating omeprazole as maintenance therapy once ulcers have healed. Other clinical trials have also shown that omeprazole is effective for treating gastric ulcers, ulcerative peptic oesophagitis, and Zollinger-Ellison syndrome. In patients with Zollinger-Ellison syndrome the profound and long lasting antisecretory activity of omeprazole may make it the drug of choice for treating the massive acid hypersecretion associated with the disease, especially when H2-receptor antagonists are ineffective. During clinical trials reported to date omeprazole has been very well tolerated but further clinical experience is essential to fully evaluate its safety profile. Thus, omeprazole represents a pharmacologically unique antisecretory drug which is very effective for rapidly healing peptic ulcers and peptic oesophagitis, and for reducing gastric acid hypersecretion in patients with Zollinger-Ellison syndrome. If the apparent absence of undesirable mucosal morphological changes during treatment with usual doses in patients with peptic ulcer disease is confirmed, it may be a major advance in the treatment of these diseases.     

Recent advances in gastric ulcer therapeutics

In developed countries at least, ulcers related to Helicobacter pylori infection are becoming rarer. However, ulcers associated with the use of non-steroidal anti-inflammatory drugs (NSAIDs) remain a major clinical problem, which has not been solved through the introduction of selective inhibitors of cyclooxygenase (COX)-2. Recent studies suggest that NSAID-induced ulcers can be prevented largely through co-administration of a proton pump inhibitor to block acid secretion in the stomach. In patients requiring aspirin therapy to prevent cardiovascular diseases, co-administration of aspirin plus a proton pump inhibitor was found to be safer than using another anti-platelet therapy that does not block gastric prostaglandin production (e.g. clopidogrel). Several recent papers have clarified further the contribution of COX-2 to gastric mucosal defence and to the healing of ulcers. In some circumstances, COX-2 produces a highly potent gastroprotective substance (15-R-lipoxin A(4)), and analogues of this substance could have therapeutic value for preventing gastric ulceration. Nitric oxide-releasing NSAIDs continue to show promise in terms of limiting damage to the gastrointestinal tract, even when given in combination with aspirin. Recent studies support the notion that platelets make a major contribution to ulcer healing, and the release of several key growth factors from platelets appears to be regulated by proteinase-activated receptors.     

Management of NSAID/aspirin-induced small intestinal damage by GI-sparing NSAIDs, anti-ulcer drugs and food constituents

Recent advances in endoscopic techniques such as capsule endoscopy have revealed that aspirin and other nonsteroidal antiinflammatory drugs (NSAIDs) often cause mucosal lesions not only in the upper gastrointestinal tract, but also in the small intestine in humans. Gastric and duodenal lesions caused by NSAIDs can be treated with anti-secretory agents such as proton pump inhibitors or histamine H2-receptor antagonists; however, these drugs are ineffective in treating NSAID-induced lesions in the small intestine. Furthermore, there are few effective agents for the treatment of small intestinal lesions. Therefore, identification of effective therapies for the treatment of NSAID/aspirin-induced small intestinal lesions remains an urgent priority. In the present review, we focus on novel pharmacological treatments to prevent or reduce NSAID-induced intestinal lesions, i.e., 1) GI-sparing NSAIDs (NO- or H2S-NSAIDs, NSAIDs mixed with phosphatidylcholine); 2) anti-ulcer drugs such as mucosal protective agents (misoprostol, rebamipide, teprenone, etc.) and anti-secretory agents (lansoprazole, etc.); 3) antibiotics (metronidazole) and probiotics (Lactobacillus sp.); and 4) food constituents (lactoferrin and soluble dietary fibers). We surveyed data from clinical trials evaluating these novel treatments. Also reviewed herein were the pros and cons of the novel protective methods from the standpoint of safety, efficacy, convenience, and cost.     

A review of treatment of duodenal and gastric ulcers--pantoprazole vs. omeprazole.

The efficacy and safety of pantoprazole in the treatment of duodenal and gastric ulcers has been compared with that of the first proton pump inhibitor omeprazole in two (previously reported) clinical studies. Pantoprazole (40 mg/day) administered orally was an effective and well- tolerated treatment for both indications. Pantoprazole was as effective as omeprazole (20 mg/day) and had a similar safety profile. For gastric ulcers, the healing rate with pantoprazole was superior to that with omeprazole at 4 weeks.