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Prevention of Acute NSAID-Induced Gastroduodenal Damage Prevention of Acute NSAID-Induced Gastroduodenal Damage:
Which Strategy is the Best?
Shaden Salamae MDa, Meir Antopolsky MDa, Ruth Stalnikowicz MDa

* Department of Emergency Medicine, Hadassah University Hospital, Mount-Scopus, Jerusalem, ISRAEL

Abstract

Objectives: The aim of this review is to provide data on the efficacy of co-therapy of non selective NSAIDs
given for short periods of time with gastroprotective drugs in preventing severe gastroduodenal mucosal
damage, and data on the acute effect of Cyclooxygenase-2 inhibitors on the gastroduodenal mucosa.
Methods: Randomized trials on the use of gastroprotective drugs published after 1985 were identified through Medline and references of clinical reviews. Results: The combined data showed that co-therapy with misoprostol or proton pump inhibitors decreases non-selective NSAIDs-induced gastric and duodenal damage by 55% and 45% respectively, as compared to placebo. The prevalence of acute gastroduodenal injury caused by cyclooxygenase-2 inhibitors is similar to that caused by the combination of non selective NSAIDs and different gastroprotective drugs. Old age, use of multiple NSAIDs, H2-blockers, irrespective of H. pylori status raised as risk factors for acute NSAIDs induced gastroduodenal injury. Conclusions: The use of gastroprotective drugs in patients requiring NSAIDS for short periods of time, or alternatively the use of cyclooxygenase-2 inhibitors is recommended in certain clinical conditions.
MeSH Words: NSAIDS, gastritis, gastroprotection
Introduction
The Clinical Problem A 65 year old woman with rheumatoid arthritis is the disease has been quiescent. The patient has referred to the Emergency Department with ischemic heart disease and she is on low dose acute monoarthritis of the knee. She has been aspirin at a dose of 100 mg/day. She often treated with methotrexate for the last year and complains of upper abdominal pain relieved by Israeli Journal of Emergency Medicine – Vol. 6, No. 3 Sept. 2006 - הפוחד האופרל ילארשיה תעה בתכ 26 Prevention of Acute NSAID-Induced Gastroduodenal Damage food and antacids. After ruling- out septic Material and methods
arthritis what will be the best treatment modality for this patient? A review on the use of NSAIDs Randomized trials on the use of gastroprotective for short periods of time in patients with after 1985 were identified gastrointestinal risk factors is presented. through Medline and references of clinical reviews. Included were studies on the efficacy Co-administration of gastroprotective drugs, i.e. of misoprostol H-2 blockers and proton pump misoprostol, H2 blockers and proton pump inhibitors (PPIs) in the prevention of acute inhibitors, during chronic treatment with severe NSAIDs induced gastroduodenal mucosal NSAIDs has been demonstrated to be clinically injury. Only studies dealing with patients, but useful for the prevention of gastroduodenal not with healthy volunteers were included in the mucosal damage [1]. Administration of analysis. Patients took NSAIDs for a period of NSAIDsfor short periods of time, i.e. acute 4-30 days. The gastric and duodenal damage musculoskeletal injuries or acute inflammatory was evaluated by endoscopy. Only severe conditions is a very common practice in the damage defined as the presence of bleeding, Emergency Department. The purpose of the ulcers, or more than ten erosions, was included. present study is to review the need and efficacy We also searched the literature on randomized of different drugs in the prevention of acute studies looking for the effect of cyclooxygenase- NSAID-induced gastroduodenal mucosal 2 inhibitors (COX-2) on the gastroduodenal mucosa as compared to non-selective NSAIDs
Table 1. Prevalence of gastroduodenal mucosal damage in patients treated with non-selective NSAIDs
Patients
Severe Damage (%) Treatment
Gastric Damage
Misoprostol 3
759 15.6 3.6 [2-4] 856 19.7 12.8 [5-9] PPI 3 1 Not specified Mean 17.3 Duodenal Damage
Misoprostol 1
856 9.8 6.0 [5-9] PPI 3 1 Not specified 355 6.8 2.1 [10-12] * Pantoprazole versus one-week H. pylori eradication. Israeli Journal of Emergency Medicine – Vol. 6, No. 3 Sept. 2006 - הפוחד האופרל ילארשיה תעה בתכ 27 Prevention of Acute NSAID-Induced Gastroduodenal Damage specific NSAIDs (i.e celecoxib, and others) The pooled data shows that non-selective NSAIDs induced acute damage is more frequent in the stomach as compared to the duodenum Most of the data on NSAID-induced (mean 17.3% vs. 7.9%, respectively). Co- gastroduodenal damage as well as on the efficacy therapy of NSAIDs and misoprostol or PPIs but of gastroprotection comes from studies on not H2-blockers significantly decreases NSAIDs patients who took NSAIDs regularly for more induced gastric and duodenal damage by 55% than one month [1]. Short-term studies comprise and 45% respectively, as compared to placebo a minority, and a great number of these studies (Table 1). The prevalence of acute were performed in healthy volunteers. A meta- gastroduodenal injury caused by analysis of controlled clinical trials on cyclooxygenase-2 inhibitors is similar to that prevention of acute NSAID-related caused by the combination of non-selective gastroduodenal damage showed that co- NSAIDs and different gastroprotective drugs treatment with gastroprotective drugs was more effective in healthy subjects than in patients with
Discussion
As Emergency Medicine physicians, our main concern is the short-term administration of Nonsteroidal anti-inflammatory drugs (NSAIDs) NSAIDs for conditions such as acute are widely prescribed all over the world. inflammation or acute pain. The present analysis Gastroduodenal damage due to NSAID use is shows that co-treatment with gastroprotective probably the most frequent drug-induced adverse drugs is effective in the short-term prevention of event [16]. NSAIDs cause gastrointestinal side severe non-selective NSAID-related damage. effects, ranging in severity from mild dyspepsia The mean reduction of severe gastric and to gastric hemorrhage and perforation resulting duodenal damage was 55 percent and 45 percent in admission to hospital, surgery and death. Risk respectively. Misoprostol was the most effective factors for NSAIDs induced gastroduodenal drug in reducing NSAIDs induced gastric injury damage include: old age, use of high dose or while PPIs and misoprostol reduced duodenal multiple NSAIDs, concomitant use of low-dose damage by the same extent. The role of age, aspirin and other antiplatelet drugs, steroids and concomitant use of two NSAIDs, the presence of H. pylori and the use of gastroprotection are further discussed in the following studies. It is known that NSAID-related peptic ulcer and Age over 60 years is a risk factor for NSAIDs its complications occur both in chronic and in induced gastroduodenal damage and its recent NSAID users, especially in elderly complications. Pilotto et al. (2000) conducted a subjects [17,18]. It has been reported that over study in patients over 60 years old who needed 50% of NSAID-induced gastroduodenal lesions NSAIDs and who tested positive for H. pylori. occurred in patients who had taken NSAIDs in the seven-day period before endoscopy [18]. Patients on NSAIDs were randomized to Moreover, it has been reported that recent concomitant therapy with pantoprazole 40 mg NSAID use, for 30 or fewer days, was daily for one month or to one week eradication significantly associated with a bleeding therapy for H. pylori. In the pantoprazole group, complication in elderly peptic ulcer patients [19]. none of the patients developed severe gastroduodenal damage as compared to 28.5% in Standard protection against gastrointestinal the eradication group [12]. In another, toxicity induced by NSAIDs has entailed co- observational study, peptic ulcer disease was prescription of gastroprotective agents such as found in 48% of 289 patients older than 65 years H2 receptor antagonists, proton pump inhibitors of age undergoing upper endoscopy. All of them (PPIs) or prostaglandin analogues. Another had taken NSAIDs regularly for a period not protective strategy includes the use of COX-2 shorter than 7 days and not longer than 30 days selective NSAIDs (i.e. etodolac) or COX-2 previous to endoscopy. Ulcers were found in 50.9% of those subjects not treated with PPIs or Israeli Journal of Emergency Medicine – Vol. 6, No. 3 Sept. 2006 - הפוחד האופרל ילארשיה תעה בתכ 28 Prevention of Acute NSAID-Induced Gastroduodenal Damage Table 2: Acute gastroduodenal damage from COX2-inhibitors as compared to non-
selective NSAIDs
Severe damage
treated with H2 blockers as compared to 14.28% the gastric mucosa within the first month of of subjects treated with PPIs. In this study the treatment with NSAIDs are known to be risk of peptic ulcer was higher in acute than in significantly less functional in older subjects chronic NSAIDs users [21]. As compared to than in adults [23]. The increased risk of peptic data shown in Table 1, the prevalence of peptic ulceration and bleeding in this older population ulcer in these two studies was higher than the co-treated with H2-blockers, could be attributed mean gastric and duodenal NSAIDs related to masking of warning symptoms [22]. damage in the placebo group. The effects of COX-2 specific NSAIDs In another study, the risk of upper inhibitors on the gastroduodenal mucosa have gastrointestinal bleeding in elderly users of been analyzed principally in patients treated for aspirin and other NSAIDs was 7.87 (CI 4.90- periods longer than six weeks [24,25]. 12.60) in acute users and 3.97 (CI 2.27-6.96) in Celecoxib in a dose of 400mg/day caused chronic users. In acute users, concomitant gastroduodenal damage in 4% of 270 treated therapy with PPIs reduced the risk of bleeding patients as compared to 19% of 267 patients compared with non-users, whereas co-treatment treated with naproxen 1g/day, during one month. with H2 blockers was associated with a Celecoxib-induced gastroduodenal damage was significantly higher risk of bleeding than in non similar to that caused during co-treatment of users. This study confirms also previous data non-selective NSAIDS and PPIs or Misoprostol. that concomitant use of two NSAIDs or NSAID The results with valdecoxib are even better plus aspirin increases the risk of bleeding. The (Table 2), but the drug has been withdrawn last presence of H. pylori was not significantly year because elevated risk of cardiovascular associated with an increased risk of bleeding events and other side effects. In a recent [22]. This finding is in agreement with the systematic review it was concluded that COX-2 previous report that H. pylori eradication is not specific NSAIDs inhibitors significantly reduce sufficient to reduce the risk of gastroduodenal the risk of symptomatic ulcers and probably damage which is better prevented by continuous reduce the risk of serious gastrointestinal pantoprazole treatment. The pathophysiological complications, but data quality is low [26]. It characteristics of the ageing stomach may seems logical that this finding will be similar for account for the increased risk of bleeding during acute NSAID use, since adaptive processes of In summary, all the strategies except H2 blockers are apparently protective of symptomatic ulcers Israeli Journal of Emergency Medicine – Vol. 6, No. 3 Sept. 2006 - הפוחד האופרל ילארשיה תעה בתכ 29 Prevention of Acute NSAID-Induced Gastroduodenal Damage and against endoscopic ulcers. In the present 2. Saggioro A, Alvisi V, Blasi A, Dobrilla G, review based on one study PPIs significantly Fioravanti A, Marcolongo R. Misoprostol reduced serious gastrointestinal complications. prevents NSAID-induced gastroduodenal lesions Still, should all individuals receiving NSAIDs in patients with osteoarthritis and rheumatoid for short periods of time be cotreated with arthritis. Italian J Gastroenterol, 1991; 23:119- gastroprotective drugs or specific COX-2 inhibitors? The answer is probably no. Suitable guidelines as recommended by several 3. Piette F, Teillet L, Naudin R, Boichut D, investigators include the following strategies Capron MH. Efficacy of misoprostol in the prophylaxis of gastroduodenal lesions induced by short-term nonsteroidal antiiflammatory drug therapy in elderly patients. Rev Rhum (Engl Ed), 1. In patients without risk factors the least 1997; 64:259-264. ulcerogenic conventional NSAID is recommended 4. Graham DY, Agrawal NM, Roth SH. 2. In patients with moderate risk (one to two risk Prevention of NSAID-induced gastric ulcer with factors), the combination of a non-selective misoprostol: Multicentre, double-blind, placebo- NSAID and misoprostol or a PPI. The other controlled trial. Lancet, 1988; 2:1277-1280. alternative is the substitution for a COX-2 inhibitor alone. There are no sufficient data 5. 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Roberts C, Symons D. The effectiveness of five strategies for the prevention of gastrointestinal Funding: None
toxicity induced by non-steroidal anti- inflammatory drugs: systematic review. BMJ, This manuscript has been peer reviewed. 2004; 329:948-956. 27. Chan FKL, Graham DY. Review article: prevention of non-steroidal anti-inflammatory Ruth Stalnikowicz M drug gastrointestinal complications-review and Department of Emergency Medicine recommendations based on risk assessment Hadassah University Hospital Aliment Pharmacol Ther, 2004; 19:1051-1061. POB 24035Jerusalem 91240 ISRAEL e-mail: darvasi@md.huji.ac.il Israeli Journal of Emergency Medicine – Vol. 6, No. 3 Sept. 2006 - הפוחד האופרל ילארשיה תעה בתכ 32

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