Continued Nonsteroidal Anti-inflammatory Drugs Therapy Research Articles

Clinical experience with the interleukin-1β blocker canakinumab in patients with chronic tophaceous gout: abolishment of arthritis and prevention of exacerbations when allopurinol is used

The interleukin (IL)-1β inhibitor canakinumab may be effective in relieving an acute gout attack and in preventing an arthritis exacerbation. However, there are insufficient data on the use of this agent to abolish and prevent arthritis in patients who are resistant to another anti-inflammatory therapy. Objective : to evaluate the efficacy of the interleukin (IL)-1β inhibitor canakinumab in patients with chronic tophaceous gout, who are resistant to traditional anti-inflammatory therapy, in order to abolish arthritis and to prevent its exacerbations when adjusting the optimal dose of allopurinol. Subjects and methods. An open-labeled prospective study was conducted in 20 patients (mean age, 54.5±12.7 years) with chronic tophaceous gout. Serum uric acid (UA) levels were 486.3±135.2 μmol/l. The inclusion criteria were crystal-verified gout; arthritis affecting more than 5 joints; inefficacy of non-steroidal anti-inflammatory drugs (NSAIDs), glucocorticoids (GCs), or colchicine when used for over a month; more than 4 arthritis attacks during year. The exclusion criteria were Stage ≥3 chronic kidney disease, infectious diseases. All the patents received a single subcutaneous injection of canakinumab 150 mg. NSAIDs and/or colchicine was discontinued a day before the injection. The number of swollen and tender joints and visual analogue scale (VAS) pain intensity were estimated before and 14 and 120 days after the injection; SF-36v1 and HAQ changes were assessed before and 120 days after the injection. 14 days after the injection, all the patients were given allopurinol, the dosage of which was individually adjusted, by starting on 100 mg/day and subsequently increasing by 100 mg/day every 2 weeks (not more than 800 mg/day) until the goal UA level (<360 μmol/l) was reached. Results. 14 days after canakinumab injection, arthritis was abolished in 8 (40%) patients and 3 patients needed to continue NSAID therapy. Following 14 days of the injection, there was a decline in the number of swollen joints from 12 [5; 16] to 3 [0; 4] (р<0.001), that of tender joints from 10 [1; 25] to 4 [0; 15], VAS pain from 60 to 24 [10; 30] mm, and high-sensitivity serum C-reactive protein from 29 [1.8; 168] to 7.6 [0.2; 41] mg/l. After 120 days, the decline in the indicators remained in the majority of the patients; there were significant improvements in physical component summary (PCS) from 39±6.9 to 44.5±9.4 (р=0.04), mental component summary (MCS) from 52.6±7.6 to 55.6±8.2 (р=0.01); HAQ scores decreased from 1 [0.1; 1.5] to 0.7 [0; 0.9] (р=0.049). No attacks of arthritis were observed in 10 patients. Seven and 3 patients had 1 and 2 arthritis attacks, respectively. 17 (85%) patients achieved the goal serum UA level; the latter was <300 μmol/l in 12 (60%) patients. Median allopurinol dosage was 400 [300; 600] mg/day. By the completion of the study, 4 (20%) patients required continued NSAID therapy. Conclusion. The use of canakinumab in patients with severe gout, who are resistant to therapy with NSAIDs, colchicine, and GCs, is an effective method to treat arthritis and to prevent acute arthritis attacks during allopurinol therapy. The administration of high-dose allopurinol causes a target reduction in serum UA levels in most patents.

Should non-steroidal anti-inflammatory drugs be used continuously in ankylosing spondylitis?

ObjectiveThe 2010 update of ASAS/EULAR recommendations for managing ankylosing spondylitis (AS) specify that continuous non-steroidal anti-inflammatory drug (NSAID) treatment should be preferred in patients with persistently active, symptomatic disease. Here, our objective was to assess whether continuous NSAID therapy improves disease control and influences radiographic progression compared to on-demand therapy. We also assessed the safety profiles of both regimens. MethodsWe performed a review by searching the PubMed and Embase databases using two MeSH term combinations to compare continuous and on-demand NSAID therapy in terms of disease control, radiographic progression, and safety. ResultsThe only study evaluating the impact of continuous NSAID therapy on disease control showed no significant difference with on-demand therapy. In four studies, continuous treatment was associated with slower radiographic progression, as assessed in three studies using the modified Stoke Ankylosing Spondylitis Spinal Score (m-SASSS). Three studies compared the safety of continuous and on-demand celecoxib, two in osteoarthritis and one in AS, and found no significant differences regarding the usual side effects of Cox-2 inhibitors. ConclusionsSeveral studies showed slower radiographic progression with continuous NSAID therapy in AS. No studies demonstrated superiority of continuous NSAID therapy regarding symptom control. Continuous NSAID therapy (at least with Cox-2 inhibitors) does not modify safety compared to on-demand therapy.

THU0261 Continuous nsaid use reverts the effects of inflammation on radiographic progression in patients with ankylosing spondylitis

BackgroundIn a recent clinical trial it was shown that continued treatment with nonsteroidal anti-inflammatory drugs (NSAIDs), in comparison to on-demand use of NSAIDs, reduced radiological progression in the spine in...

FRI0437 How to identify patients at high risk for rapid radiographic spinal progression early in the course of axial spondyloarthritis?

BackgroundIdentification of patients with axial spondyloarthritis (axSpA) who are at high risk for rapid radiographic progression is of high relevance, because these patients might require an active treatment and they...

TREATMENT IN PATIENTS WITH ANKYLOSING SPONDYLITIS IN THE REAL CLINICAL PRACTICE OF A RHEUMATOLOGIST IN RUSSIA

Objective: to analyze the treatment of ankylosing spondylitis (AS) in the real practice of a rheumatologist in Russia. Subjects and methods. The cross-sectional study included 330 AS patients who had been actively seeking medical advice from rheumatologists during 4 months in 24 cities and towns of the Russian Federation. The therapy performed was studied using the medical history data recorded by physicians in the specially designed clinical chart. Drug intake, its regularity, reasons for discontinuation of medications, and their clinical effect were elucidated in all the patients. The need to intensify the therapy and to use genetically engineered biological agents was determined by disease activity at the time of examination. Results. The medical histories indicated that 62% of the patients received nonsteroidal anti-inflammatory drugs (NSAIDs) regularly, 34% had them periodically, and 4% were not treated; two thirds of the patients took diclofenac, nimesulide, or meloxicam. 33, 14, and 9% of the patients used sulfasalazine, methotrexate, and oral glucocorticosteroids, respectively. Sixty (18%) patients received tumor necrosis factor-α (TNF-α) inhibitors. Different physiotherapeutic methods were used in 30% of cases; only 46% did exercises regularly; as high as 4% of the patients had sanatorium-and-spa treatment. In the physicians' opinion, 81% of the patients needed intensified therapy and 62% did therapy with TNF-α inhibitors. At the same time TNF-α inhibitors were indicated in 38% of the patients according to the ASAS recommendations. Conclusion. In real clinical practice, AS treatment does not always meet the current recommendations: only 62% of the patients received continuous NSAID therapy; disease-modifying antirheumatic drugs were frequently used without any indications. 18% of the patients took TNF-α inhibitors and 38% really needed them.

Efficacy and safety of TNFα antagonist therapy in patients with juvenile spondyloarthropathies

Objectives To evaluate the efficacy and safety of TNFα antagonist therapy in patients with juvenile spondyloarthropathies refractory to nonsteroidal anti-inflammatory drugs (NSAIDs). Methods Retrospective review of the medical charts of 20 patients (16 males and 4 females) with a mean age of 11.6 years at diagnosis. Median time from diagnosis to initiation of TNFα antagonist therapy was 41 months. Escape phenomenon developed in 3 patients, who were switched to another TNFα antagonist. Etanercept was used for 19/23 treatments, infliximab for 3/23 treatments, and adalimumab for 1 treatment. The efficacy criteria were morning stiffness duration; nocturnal awakenings; tender and swollen joint counts; entheseal count; back, buttock, and hip pain; percentage of patients on NSAIDs and/or glucocorticoid therapy; and mean and median values of the erythrocyte sedimentation rate, C-reactive protein level, and hemoglobin level. A remission was defined as resolution of the axial and peripheral pain, joint swelling, and laboratory evidence of inflammation, with or without continued NSAID therapy. Results TNFα antagonist therapy was associated with clinical and laboratory improvements after 3 months, and the benefits were sustained after 1 year. Axial pain required 6 months to improve. A remission was achieved in 59% of patients after 3 months and 70% after 6 and 12 months. Median time to remission under treatment was 3 months. The interval between the TNFα antagonist injections was increased for 12/18 treatments and the treatment was stopped in 7 cases. However, treatment discontinuation was consistently followed by a relapse, after a median time of 2.5 months. Two serious adverse events occurred, namely, acute bacterial pneumonia and recurrent impetigo; in both cases the outcome was promptly favorable after a brief interruption of the TNFα antagonist. Conclusion TNFα antagonist therapy seems safe and rapidly effective in patients with juvenile spondyloarthropathies refractory to NSAIDs, in keeping with data from adults. However, prospective studies in larger patient populations are needed.

The safety of celecoxib in ankylosing spondylitis treatment

Background: Nonsteroidal anti-inflammatory drugs (NSAIDs) play a crucial role in the treatment of ankylosing spondylitis (AS). Most of the AS patients require a continuous and long-term NSAIDs therapy; therefore the question of NSAIDs safety in this population becomes very important. Objective: to review the safety of celecoxib in ankylosing spondylitis treatment. Methods: The PubMed database was searched using the keywords ‘ankylosing spondylitis’ and ‘celecoxib’, with the following extraction of clinical trials investigating efficacy and safety of celecoxib in AS. Results/conclusions: Four clinical trials were found: three randomized controlled trials (RCTs) and one open-label extension of a previous RCT. All RCTs showed a good safety profile for celecoxib treatment in AS, similar to that of nonselective NSAIDs. However, long-term (≥ 1 year) celecoxib safety in AS was not investigated in RCTs. Based on the results of long-term non-AS celecoxib studies, most of the AS patients (because of young age and fewer comorbidities) are probably at low risk for cardiovascular and gastrointestinal complications. Celecoxib showed a good efficacy and safety profile in AS, but further investigations are needed to clarify the long-term safety of celecoxib in this group of patients.

Clinical trial: healing of NSAID‐associated gastric ulcers in patients continuing NSAID therapy – a randomized study comparing ranitidine with esomeprazole

The use of non-steroidal anti-inflammatory drugs (NSAID) is associated with an increased risk of gastric ulcer (GU) development. This multicentre, randomized, double-blind, parallel-group trial compared endoscopic healing rates at 4 and 8 weeks after treatment with oral esomeprazole 40 or 20 mg once daily, or ranitidine 150 mg twice daily, in patients with 1 baseline GU > or = 5 mm but no GUs or duodenal ulcers >25 mm in diameter who received continued cyclooxygenase-2-selective or non-selective NSAID therapies. The primary outcome was the percentage of patients in each treatment group who had no GUs at week 8. Four hundred and forty patients were randomized to treatment. At week 8, GU healing rates (95% CI) with esomeprazole 40 mg, esomeprazole 20 mg and ranitidine were 85.7 (79.8-91.7)%, 84.8 (78.8-90.8)% and 76.3 (69.2-83.3)%, respectively; between-group differences were not statistically significant. Week-4 GU healing rates were 70.7 (62.9-78.4)% and 72.5 (65.0-79.9)% with esomeprazole 40 and 20 mg, respectively, and were significantly higher (P < 0.01 for both doses) than those with ranitidine [55.4 (47.1-63.7)%]. In patients who require continued NSAID therapy, GU healing rates at 8 weeks numerically favoured esomeprazole but were not significantly different from ranitidine.

NSAID-induced urticaria and angioedema: a reappraisal of its clinical management.

Hypersensitivity to nonsteroidal anti-inflammatory drugs (NSAIDs), resulting in urticaria and angioedema, is being observed with increasing frequency. Prevalence rates range from 0.1-0.3%, which is partly due to the large size of the exposed (at risk) population. Some predisposing factors for these cutaneous reactions have been identified, among them atopic diathesis, female sex, young adulthood, a history of chronic urticaria and the use of the NSAID for the relief of acute pain. The description of two different arachidonic acid cyclo-oxygenases (COX) about a decade ago, designated COX-1 and COX-2, and the incorporation into the therapeutic armamentarium of more selective enzyme inhibitors for the control of inflammation and pain, has led to an improved understanding of the pathogenesis of adverse reactions to NSAIDs. This has allowed investigators to study 'sensitive' individuals to see if they can safely receive these new pharmaceutical compounds. The reasons why some people react to NSAIDs are not completely clarified. The prevalent theory about the pathogenesis of urticaria and angioedema due to NSAIDs in cross-reactive patients assumes that the inhibition of COX-1 leads to a shunting of arachidonic acid metabolism towards the 5-lipoxygenase pathway, which results in an increased synthesis and release of cysteinyl leukotrienes. Although COX-2 inhibitors are well tolerated by the majority of classic NSAID-sensitive patients, cutaneous reactions to highly selective inhibitors of COX-2 have been described in some of these individuals, casting some doubts about the relevance of such hypotheses. On the other hand, in patients who react to a single NSAID and chemically similar products (single-reactors), specific immunoglobulin E antibodies to haptenated NSAID metabolites have been suspected, although these metabolites are not easily demonstrated by means of routine in vivo or in vitro techniques. Facial (periorbital) angioedema constitutes the most common form of clinical presentation, and one-third of the patients show a mixed clinical pattern of cutaneous (urticaria and/or angioedema) and respiratory symptoms which include upper respiratory tract edema, rhinorrhea, cough, breathlessness and tearing. When necessary, diagnosis is confirmed by means of controlled peroral drug challenges done by experienced physicians in the hospital setting and test results are helpful for clinical management, which will be based on strict avoidance, and the use of alternative tolerated medications. This approach is specially indicated in hypersensitive patients with chronic medical conditions who require continuous NSAID therapy, such as those with arthritis and coronary heart disease.

Gastro-duodenal protection in an era of cyclo-oxygenase-2-selective nonsteroidal anti-inflammatory drugs.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are effective and necessary for the relief of pain and inflammation in patients with arthritis. NSAIDs are however also associated with an increased risk for ulceration in the stomach and in the duodenum, and many NSAID users experience bothersome dyspeptic symptoms during continued NSAID therapy. PPIs like omeprazole, have been shown to heal and to prevent ulcers and dyspeptic symptoms during continued NSAID therapy, and during continued NSAID therapy the prostaglandin analogue, misoprostol, has been shown to reduce the risk for ulcer complications. The COX-2 selective NSAID, rofecoxib, is in comparison with naproxen, a non-selective NSAID, associated with fewer clinically important upper gastrointestinal events. The incidence of myocardial infarctions seems, however, to be lower with naproxen than with rofecoxib, and this is expected to lead to low-dose aspirin use in rofecoxib users at risk for cardiovascular events. Co-administration of the COX-2 selective NSAID, celecoxib, and low-dose aspirin, is associated with the same risk for upper gastrointestinal ulcer complications alone and combined with symptomatic ulcers, as the non-selective NSAIDs, ibuprofen and diclofenac. A proton pump inhibitor (PPI) should be used for healing of NSAID-associated ulcers, and a PPI or misoprostol should be considered for prevention of ulceration in non-selective NSAID users at risk for ulceration. The experience with COX-2 selective NSAIDs is still limited, and it remains to be studied whether subpopulations of COX-2 selective NSAID users will benefit from gastro-duodenal protection.

The cost effectiveness of misoprostol prophylaxis alongside long-term nonsteroidal anti-inflammatory drugs. Implications of the MUCOSA trial.

This study considered the cost effectiveness of misoprostol prophylaxis for nonsteroidal anti-inflammatory drug (NSAID)-induced gastrointestinal damage, using data from the Misoprostol Ulcer Complications Outcomes Safety Assessment (MUCOSA) trial. The initial aim was to gain listing of misoprostol on the Australian National Formulary. The economic evaluation followed a 2-stage approach in considering the cost effectiveness of misoprostol, a 'within-trial' analysis followed by a simple modelled analysis which explored the implications of the trial results for life-years saved beyond the trial setting. The perspective of the evaluation is that of the healthcare system. Three different populations were considered: the total trial population; patients with a history of peptic ulcer disease; and patients over 65 years of age. Patient data were taken from the MUCOSA trial, which involved 8843 patients receiving continuous NSAID therapy for the control of rheumatoid arthritis. Misoprostol plus any NSAID therapy was compared with placebo (no misoprostol) plus any NSAID therapy. The study found the incremental cost per definite serious gastrointestinal complication avoided with misoprostol was 39,603 Australian dollars ($A) for the total trial population, $A5599 for patients with a history of peptic ulcer disease and $A35,405 for patients over 65 years of age. The incremental cost per life-year saved with misoprostol was $A41,866 for the whole group, $A6244 for patients with a history of peptic ulcer disease and $A40,322 for patients over 65 years of age. The study found misoprostol to be cost effective in this setting.

Use of proton-pump inhibitors in complicated ulcer disease and upper gastrointestinal tract bleeding.

The use of proton-pump inhibitors in the management of complicated peptic ulcer disease and upper gastrointestinal bleeding is described. Treatment of peptic ulcers in patients who are Helicobacter pylori positive should include antimicrobial therapy to eradicate the infection; based on considerations of primary antimicrobial resistance and safety, one recommended regimen is the combination of a proton-pump inhibitor (lansoprazole 30 mg or omeprazole 20 mg), clarithromycin 500 mg, and amoxicillin 1 g, each twice daily for 14 days. The proportion of H. pylori-negative ulcers has increased in the United States, now accounting for 39% of patients with ulcers who report no intake of nonsteroidal anti-inflammatory drugs (NSAIDs). Compared with H. pylori-positive ulcers, H. pylori-negative ulcers are more aggressive, characterized by high recurrence rates and increased risk of bleeding and perforation. Long-term therapy with a proton-pump inhibitor may be useful in these patients. Acid suppressants may also have a role in the initial treatment of patients who have a bleeding ulcer, including those associated with NSAID use. For patients who require continuous NSAID therapy, proton-pump inhibitors have been shown to heal a significantly higher percentage of peptic ulcers in eight weeks than histamine H2-receptor antagonists, and maintenance therapy with either lansoprazole or omeprazole reduces ulcer recurrence. Preliminary data suggest a role for proton-pump inhibitors in the prevention of stress ulcers among critically ill patients. Proton-pump inhibitors play an important role in the treatment of both H. pylori-negative and H. pylori-positive peptic ulcers, as well as in upper gastrointestinal tract bleeding. Further study is needed regarding their role in preventing stress ulcers in critically ill patients.

Omeprazole Compared with Misoprostol for Ulcers Associated with Nonsteroidal Antiinflammatory Drugs

Background Misoprostol is effective for ulcers associated with the use of nonsteroidal antiinflammatory drugs (NSAIDs) but is often poorly tolerated because of diarrhea and abdominal pain. We compared the efficacy of omeprazole and misoprostol in healing and preventing ulcers associated with NSAIDs. Methods In a double-blind study, we randomly assigned 935 patients who required continuous NSAID therapy and who had ulcers or more than 10 erosions in the stomach or duodenum (or both) to receive 20 mg or 40 mg of omeprazole orally in the morning or 200 μg of misoprostol orally four times daily. Patients were treated for four weeks or, in the absence of healing, eight weeks. Treatment success was defined as the absence of ulcers and the presence of fewer than five erosions at each site and not more than mild dyspepsia. We then randomly reassigned 732 patients in whom treatment was successful to maintenance therapy with 20 mg of omeprazole daily, 200 μg of misoprostol twice daily, or placebo for six months. Re...

Management of nonsteroidal anti-inflammatory drug-induced gastroduodenal disease by acid suppression.

One major cause of peptic ulceration is the use of nonsteroidal anti-inflammatory drugs (NSAIDs). The precise mechanisms through which NSAIDs cause peptic ulceration are unknown, but the discovery that they reduce the production of 'cytoprotective' prostaglandins led to the hypothesis that coadministration of exogenous prostaglandins heals and prevents NSAID-induced gastroduodenal ulcers and other mucosal lesions. Studies using high doses of misoprostol have shown that it does have a protective effect; however, gastrointestinal intolerance of this prostaglandin E2 analogue is common. Early indications that acid suppression was effective in the management of NSAID-related peptic ulcers came from studies showing that gastric ulcers could be healed by omeprazole in patients who continued to take NSAIDs. Other studies suggested that acid suppression reduces the incidence of mucosal lesions but that standard dose ranitidine protects only against duodenal lesions. Subsequent studies reported that higher dose H2 receptor antagonist therapy can protect against both gastric and duodenal ulcers during continued NSAID therapy. An ideal therapeutic strategy would heal NSAID-related ulcers and prevent the development of new NSAID-related lesions and complications in patients who are unable to discontinue NSAID therapy. A number of recent studies indicate that effective acid-suppressive treatment with the proton pump inhibitor omeprazole can achieve these aims. Overall, data from recent studies show that acid suppression with the proton pump inhibitor omeprazole at a dose of 20 mg daily is the most effective means of healing NSAID-associated gastroduodenal lesions and that it is the most effective prophylactic therapy. In the long run, the role of omeprazole will have to be evaluated with respect to its cost effectiveness compared with other strategies and with respect to the development of less damaging NSAIDs.

The role of viscosupplementation with hylan G-F 20 (Synvisc®) in the treatment of osteoarthritis of the knee: a Canadian multicenter trial comparing hylan G-F 20 alone, hylan G-F 20 with non-steroidal anti-inflammatory drugs (NSAIDs) and NSAIDs alone

To determine the safety and efficacy of viscosupplementation with hylan G-F 20, a cross-linked hyaluronan preparation, used either alone or in combination with continuous non-steroidal anti-inflammatory drug (NSAID) therapy, a randomized, controlled, multicenter clinical trial, assessed by a blinded assessor, was conducted in 102 patients with osteoarthritis (OA) of the knee. All patients were on continuous NSAID therapy for at least 30 days prior to entering the study. Patients were randomized into three parallel groups: (1) NSAID continuation plus three control arthrocenteses at weekly intervals; (2) NSAID discontinuation but with three weekly intra-articular injections of hylan G-F 20; and (3) NSAID continuation plus three injections, one every week, intra-articular injections of hylan G-F 20. Outcome measures of pain and joint function were evaluated by both the patients and an evaluator at baseline and weeks 1, 2, 3, 7 and 12, with a follow-up telephone evaluation at 26 weeks. At 12 weeks all groups showed statistically significant improvements from baseline, but did not differ from each other. A statistical test for the equivalence, the q-statistic, demonstrated that viscosupplementation with hylan G-F 20 was at least as good or better than continuous NSAID therapy for all outcome measurements except activity restriction. At 26 weeks both groups receiving hylan G-F 20 were significantly better than the group receiving NSAIDs alone. A transient local reaction was observed in three patients after hylan G-F 20 injection; only one patient withdrew from the study as a result and all recovered without any sequela. Hylan G-F 20 is a safe and effective treatment for OA of the knee and can be used either as a replacement for or an adjunct to NSAID therapy.

NSAID-induced peptic ulcer disease: a critical review of pathogenesis and management.

Nonsteroidal anti-inflammatory drugs (NSAIDs) initiate gastroduodenal ulceration and promote complications such as bleeding and perforation. Age greater than 60 years, a prior history of ulcer disease, and concomitant corticosteroid use are important risk factors for ulcer development. NSAIDs interfere with mucosal defense via direct toxic effects in addition to cyclooxygenase inhibition and subsequent depletion of endogenous prostaglandins. While all NSAIDs are ulcerogenic, drugs which avoid topical injury and do not inhibit mucosal prostaglandins appear to have lesser risk of toxicity. Although NSAID injury requires luminal acid, prophylactic use of H2 receptor antagonists has been disappointing, preventing duodenal injury only. Greater acid suppression with proton pump inhibition appears promising. Prostaglandins are effective for prevention of NSAID-induced gastroduodenal injury, but are not well tolerated. Recent evidence suggests NSAID ulcers heal rapidly with proton pump inhibitors compared to H2 receptor antagonists in those patients who require continued NSAID therapy.

NSAID-Induced Gastrointestinal Damage

Nonsteroidal anti-inflammatory drugs (NSAIDs) cause acute diffuse injury to the gastroduodenal mucosa, and also cause chronic focal ulcers that may bleed or perforate without warning symptoms. Acute and chronic lesions are distinct, are pathogenetically different, respond differently to drugs, and require different management strategies. The principal rationale for antiulcer therapy in NSAID users is to prevent or reduce potentially fatal outcomes; to date no evaluated drug meets this criterion for efficacy. Antacids and H2-receptor antagonists, based on open uncontrolled studies, appear to heal both gastric and duodenal ulcers, and maintain them healed during continued NSAID use; larger gastric ulcers show delayed healing with conventional doses of H2-receptor antagonists during NSAID therapy. No such delay occurs with omeprazole therapy. The suggests that if NSAID-associated gastric ulcers are treated with H2-receptor antagonists, larger doses should be given for longer periods. In patients with no pre-existing ulcer disease, H2-receptor antagonists given prophylactically prevent duodenal but not gastric ulcers; sucralfate does the same. In individuals without peptic ulcer disease taking NSAIDs, misoprostol, given as prophylaxis, reduces the development of gastric ulcers; its beneficial effects on ulcer healing or symptoms during continued NSAID therapy, or its ability to prevent duodenal ulcers or ulcer complications, are not established. Because of diarrhea, the 400 micrograms/day dosage is recommended, especially in the elderly.