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Non-steroidal anti inflammatory drugs (NSAIDs) because of their high efficacy as both anti-inflammatory and analgesic agents, are one of the most commonly prescribed drugs world-wide. They are used in treatment of many commonly occurring disorders such as chronic arthropathies, headache and low back pain. Their widespread and uncontrolled use is promoted by their over the counter availability. This acts as a double edge sword. One of the most common adverse effects that add largely to its morbidity and mortality
is the gastrointestinal tract damage.

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  2. 2. Review Article NON-STEROIDAL ANTI INFLAMMATORY DRUGS AND GASTROINTESTINAL TOXICITY Divij Mehta* and DK Bhargava** *Registrar, **Senior Consultant,Department of Gastroenterology and Hepatology, Indraprastha Apollo Hospitals, Sarita Vihar, New Delhi 110 076, India. Correspondence to: Dr DK Bhargava, Senior Consultant,Department of Gastroenterology and Hepatology, Indraprastha Apollo Hospitals, Sarita Vihar, New Delhi 110 076, India. Non-steroidal anti inflammatory drugs (NSAIDs) because of their high efficacy as both anti-inflammatory and analgesic agents, are one of the most commonly prescribed drugs world-wide. They are used in treatment of many commonly occurring disorders such as chronic arthropathies, headache and low back pain. Their widespread and uncontrolled use is promoted by their over the counter availability. This acts as a double edge sword. One of the most common adverse effects that add largely to its morbidity and mortality is the gastrointestinal tract damage. Key words: NSAIDS, Gastrointestinal disorders, Hodgkin’s disease. EPIDEMIOLOGY Because of the broad and nonspecific definitions of gastrointestinal disorders caused by the use of NSAIDs, as well as differences in patient populations, drugs, dosages, and periods of use, estimates of the prevalence of adverse effect vary greatly. In general, at least 10-20% of patients have dyspepsia while taking an NSAID, although the prevalence may range from 5-50% [1,2]. According to prospective data from the Arthritis, Rheumatism, and Aging Medical Information System (ARAMIS), 13 of every 1000 patients with rheumatoid arthritis (RA) who take NSAIDs for one year have a serious gastrointestinal complication. The risk in patients with osteoarthritis is somewhat lower (7.3 per 1000 patients per year) [3]. The mortality rate among patients who are hospitalized for NSAID-induced upper gastrointestinal bleeding is about 5-10% [4]. An analysis of data from ARAMIS has shown that the mortality rate attributed to NSAID-related gastrointestinal toxic effects is 0.22% per year, with an annual relative risk of 4.21 as compared with the risk for persons not using NSAIDs [3]. An estimated cost of $15,000 to $20,000 per hospitalization, the annual direct costs of gastrointestinal complications may exceed $2 billion [5]. It has been estimated conservatively that 16,500 NSAID-related deaths occur among patients with RA or OA every year in United States. This figure is similar to the number of deaths from the acquired immunodeficiency syndrome and considerably greater than the number of deaths from multiple myeloma, asthma, cervical cancer, or Hodgkin’s disease (Fig. 1) [3]. 251 To the worse these mortality statistics did not include deaths ascribed to the use of over-the-counter NSAIDs. Yet these toxic effects remain largely a silent epidemic with many physicians and most patients unaware of the magnitude of the problem. In UK, based on a widely quoted population study by Rockall TA, et al [6], it was estimated that there are 8528 hospitalisations for gastric and duodenal ulcer bleeding per annum in the UK. Three large cohort studies have found that the total risk of hospitalisation for gastrointestinal complications associated with NSAID use as between 1.3 – 2.2 events per 1000 patient years [7,8]. Risk factors for GI complications [3,9-21] Predisposing factors for NSAID induced GI ulceration Previous history or active peptic ulceration • • • • • • • • • • Advanced age (>65) - (linear increase in risk) Female gender Smoking, alcoholism Heavy coffee consumption Concomitant ingestion of GI toxic drugs (e.g., steroids) Prolonged use of heavy doses of NSAIDs Use of multiple NSAIDs; concomitant administration of anticoagulant Hepatic-renal dysfunction Serious systemic illness Concomitant infection with Helicobacter pylori Apollo Medicine, Vol. 7, No. 4, December 2010
  3. 3. Review Article after the end of combination therapy, the cumulative rate of recurrent ulcers was 31% among the patients in whom H. Pylori had been eradicated and 46% among those who were still infected. Chan, et al. [30] found that the use of a regimen that included bismuth subcitrate to eradicate H. Pylori significantly decreased the rate of ulcer development associated with the use of naproxen. In this study, gastroduodenal ulcers developed in 26% of H. Pylori – infected persons, but in only 7% of those in whom H. pylori was eradicated. Fig.1. US Mortality data for seven selected disorders. A total of 16,500 patients with rheumatoid arthritis or osteoarthritis died from the gastrointestinal toxic effects of NSAIDS. Data are from the National Center for Health Statistics and the Arthritis, Rheumatism, and Aging Medical Information System. Advanced age (>65 yrs) has been consistently found to be a primary risk factor for adverse gastrointestinal events. The risk increases linearly with age [9-13]. Elderly patients are particularly prone to develop GI toxicity and unfortunately they are the most frequent users of this group of drugs [22]. These patients are deficient in cytoprotective PGs (PGE2 and PGI2) that increase mucous production and improve ulcer healing. Moreover, the vascular integrity of the ulcer base is poor; therefore, ulcers bleed easily [23, 24]. In one study by Hawkey, et al. [31] randomly assigned 285 patients with current ulcers or a history of ulcers who were using NSAIDs to combined treatment with omeprazole, clarithromycin, and amoxicillin or to treatment with omeprazole alone. They found that the eradication of H. Pylori did not affect the rate of recurrent ulcer; in addition, ulcer healing was impaired even in the patients who were successfully treated with antibiotics for H. Pylori infection hence concluding that infection with H. Pylori increases the risk of gastroduodenal mucosal injury associated with NSAID use only minimally, if at all. Identification of Helicobacter pylori infection as an important factor in the development of peptic ulcer has raised the question of a possible synergistic relation between the presence of H. Pylori infection and NSAID use. Although several studies have found these two factors to be independent; two prospective studies have suggested a synergistic relation [25-28]. In another study by Hawkey CJ, et al. [32] did a multivariate regression analyses of three large trials {OPPULENT (Omeprazole versus Placebo as Prophylaxis against Ulcers or Erosions from NSAID Treatment) study, maintenance phases of the OMNIUM (Omeprazole versus Misoprostol for NSAID Induced Ulcer Management) and ASTRONAUT (Acid Suppression Trial: Ranitidine or Omeprazole for NSAID Associated Ulcer Treatment) study} to find whether the increased risk of developing ulcer in a person with a past history of peptic ulceration during NSAID use is due to H. pylori infection or to reactivation of the original lesion by comparing the efficacy of omeprazole 20 mg daily, misoprostol 200 μg twice daily, and ranitidine 150 mg twice daily in preventing ulcers and erosions at different sites and in patients who were H pylori positive and negative. They found that there was a highly significant tendency for the relapse lesion to replicate the site and type of the original lesion (mean odds ratios ranging from 3 to 14) and was not adversely affected by H. Pylori status. Treatment failure was significantly less likely with omeprazole than with placebo, misoprostol, or ranitidine. This advantage was especially evident in H. pylori positive patients receiving acid suppression (5.7% v 16.6% for gastric ulcer with omeprazole). Bianchi Porro, et al. [29] used the combination of amoxicillin and omeprazole to treat NSAID users infected with H. pylori. They found that the eradication of H. Pylori did not affect the rate of ulcer healing. However, six months In a prospective placebo-controlled, double blind randomized trial by Feldman M, et al., 61 healthy men and women were recruited. Out of these, 46 received low dose aspirin therapy. Among them, 22 were H.pylori positive and Many studies have shown that use of multiple NSAIDs; non-use of anti-ulcer medication, and NSAID use in patients with previous history of peptic ulcers raises the possibility of developing GI ulcers by 14-17 folds [23]. Other risk factors that have been identified are higher doses of NSAIDs (including use of two or more NSAIDs), a history of gastroduodenal ulcer or gastrointestinal bleeding, concomitant use of corticosteroids, serious coexisting conditions, and concomitant use of anticoagulants. Apollo Medicine, Vol. 7, No. 4, December 2010 252
  4. 4. Review Article 24 were H.pylori negative. They were assessed after a period of 45 days treatment with aspirin and it was found that erosive disease from low dose aspirin occurred in 50% of H.pylori infected volunteers and in 16% of their non-infected counter parts (p=0.02). Therefore, in light of the increasing use of low dose aspirin for cardiovascular prophylaxis, screening and treating H.pylori might be a useful preventive strategy for patients who are at risk of ulcer bleeding [33]. In a meta-analysis by Huang JQ, et al. to study the role of H.pylori infection and NSAIDs in 1625 NSAIDs takers, uncomplicated peptic ulcer disease was significantly more common in patients positive than in those negative for H.pylori [341/817 (41.7%) vs 209/808 (25.9%)]; OR 2.12 (95% CI 1.68-2.67). H.pylori infection increases the risk of PUD in NSAID users by 3.53 fold in addition to the risk associated with NSAID use. Similarly NSAID increases risk of PUD in H.pylori infection by 3.55 fold [34]. But how much cost-effective this approach is, it is yet to be found. The general practice today which is followed is that when NSAIDs are to be used for short term then there is no need to screen for H. pylori, but if they are to be used chronically (>3 months) then we may screen for and treat H. pylori . damage by diminishing the hydrophobicity of gastric mucus, thereby allowing endogenous gastric acid and pepsin to injure the surface epithelium [37]. In addition, topical mucosal injury may occur as a result of indirect mechanisms, mediated through the biliary excretion and subsequent duodenogastric reflux of active NSAID metabolites [38,39]. The role of prostaglandins Topical injury caused by NSAIDs contributes to the development of gastroduodenal mucosal injury. However, the systemic effects of these agents appear to have the predominant role, [33,40,41] largely through the decreased synthesis of mucosal prostaglandins [42]. The use of enteric-coated aspirin preparations [42], parenteral [43] or rectal [44] administration of NSAIDs in order to prevent topical mucosal injury has also failed to prevent the development of ulcers. Moreover, doses of aspirin as low as 30 mg are sufficient to suppress prostaglandin synthesis in the gastric mucosa [45]. Prostaglandins are derived from arachidonic acid, which originates from cell-membrane phospholipids through the action of phospholipase A2 (Fig. 2). Mechanism of GI toxicity Gastroduodenal mucosal injury develops when the deleterious effect of gastric acid overwhelms the normal defensive properties of the mucosa. There are multiple mechanisms with both local and systemic effects in causing this injury The systemic effects are largely the result of the inhibition of endogenous prostaglandin (PG) synthesis [35]. PG inhibition, in turn, leads to decreases in epithelial mucus, secretion of bicarbonate, mucosal blood flow, epithelial proliferation, and mucosal resistance to injury [36,37]. The impairment in mucosal resistance permits injury by endogenous factors, including acid, pepsin, and bile salts, as well as by exogenous factors such as NSAIDs and possibly ethanol and other noxious agents. Topical injury Mucosal injury is initiated topically by the acidic properties of aspirin and many other NSAIDs. Most NSAIDs are weak organic acids and have low pKa, which varies according to the particular agent; these weak acids remain in their non-ionized lipophilic form in the highly acidic gastric lumen. Such conditions favour migration through the gastric mucus across plasma membranes and into surface epithelial cells; they encounter a basic pH (e.g., 7.1). This causes so called “trapping” of the drugs inside the cell, where NSAIDs are dissociated into the ionized form, resulting in trapping of hydrogen ions [35]. NSAIDs can also cause topical mucosal Fig.2. Biosynthesis of prostaglandins through the cyclooxygenase Pathways. The immediate precursor of prostaglandins, arachidonic acid, is derived from membrane phospholipids and is catalyzed by the two cyclooxygenase isoenzymes (also designated as prostaglandin H synthase), cyclooxygenase-1 and cyclooxygenase-2. The gene for cyclooxygenase-1, the housekeeping enzyme, is expressed constitutively and maintains the homeostasis of organs, including gastric mucosal integrity. In contrast, the gene for cyclooxygenase-2, the inflammatory enzyme, is inducible. Although both pathways can be variably inhibited by different NSAIDS, only the gene for cycloozygenase-2 contains a corticosteroidresponsive repressor element in its promoter region. The broken arrows indicate the inhibitory effects of pharmacologic agents. 253 Apollo Medicine, Vol. 7, No. 4, December 2010
  5. 5. Review Article PGs protect GI mucosa by forming a cytoprotective layer and increasing the secretion of bicarbonate ions that neutralise the gastric acidity. All therapeutically useful NSAIDs act by inhibiting the synthesis of PGs [46]. The metabolism of arachidonic acid to prostaglandins and leukotrienes is catalyzed by the cyclooxygenase pathway and the 5-lipoxygenase pathway, respectively [1,35] (Fig. 3). There are two isoforms of cyclooxygenases: COX-1 (COX-1) and COX- 2 (COX-2) [47,48]. Despite their structural similarities, they are encoded by distinct genes and differ with regard to their distribution and expression in tissues [49,50]. The COX-1 gene contains a promoter region without a TATA sequence and is primarily expressed constitutively. In contrast, the COX-2 gene is thought to be the inducible form that is nearly undetectable in most (but not all) tissues under normal physiologic conditions. COX-1 appears to function as a “housekeeping” enzyme in most tissues, including the gastric mucosa, the kidneys, and the platelets, whereas the expression of COX-2 can be induced by inflammatory stimuli and mitogens in many different types of tissue, including macrophages and synovial cells [41]. It has thus been suggested that the antiinflammatory properties of NSAIDs are mediated through the inhibition of COX-2, whereas adverse effects, such as gastroduodenal ulceration, occur as a result of effects on the constitutively expressed COX-1 [41,48]. NSAID use is four times more than non-users [1,2]. Overthe-counter availability of PPIs and H2– receptor antagonists for short-term treatment of dyspepsia may lead a patient to delay optimal care for more severe gastrointestinal disease; if the drug is taken on a long- term basis, its use could delay a diagnosis of gastric cancer also [7]. Even aspirin use for prophylactic reasons in low dosages is not free of gastrointestinal complications. All formulations of aspirin like buffered, enteric coated and plain aspirin carry same amount of risk [24]. Besides this, there is evidence that other mechanisms are also involved. For example, ulcers do not develop spontaneously in mice with a disrupted COX-1 gene, [51] and Wallace, et al. [52,53] reported that NSAID-induced injury occurred in association with enhanced adherence of neutrophils to the gastric vascular endothelium, as the result of an increase in the expression of intercellular adhesion molecule 1 (ICAM 1) in the basal endothelium [54-57]. Neutrophil adherence, in turn, causes mucosal injury through the release of oxygen-derived free radicals and proteases [1]. The relative COX-1 inhibition of various NSAIDs is shown in Fig. 4. Arthritis, rheumatism, and ageing medical information system (ARAMIS) data suggested that risk of death from Many modifications of NSAIDs have been formulated to reduce their toxicity. Surveillance and various endoscopic studies have confirmed that the incidence of gastroduodenal mucosal injury is reduced with the use of nabumetone, etodolac, and meloxicam [58-60]. The improved safety of meloxicam appears to be due to its preferential inhibition of COX-2, with a minimal effect on COX-1. In contrast, nabumetone and etodolac appear to inhibit COX-2 preferentially at low doses, but the preferential inhibition of COX-2 is diminished at higher doses. These agents also have other properties that contribute to their safety. Etodolac has a low level of enterohepatic recirculation and a short half- life; nabumetone is a nonacidic prodrug formulation and has no enterohepatic recirculation [61]. Fig.3. Mechanism of action of NSAIDs Fig.4. Comparison between different NSAIDs including COX1 Vs COX-2. Conventional NSAIDs cause non-selective inhibition of COX, which leads to reduction in bicarbonate secretion and reduced mucous production. Coupled with it is vasoconstriction that occurs due to NSAIDs, which causes hypoxia and consequent formation of ulcer. Even short-term (<1 week) use of aspirin and other nonsteroidal antiinflammatory drugs (NSAIDs) can precipitate ulcer-related bleeding. Apollo Medicine, Vol. 7, No. 4, December 2010 254
  6. 6. Review Article Highly selective cyclooxygenase-2 inhibitors Many new highly selective COX-2 inhibitors have recently been developed that, in studies to date, have had a markedly reduced capacity to cause injury to the gastroduodenal mucosa. Celecoxib and rofecoxib, are now not new to us and they have been studied extensively for their selective COX-2 inhibitory action. But there are still few important questions to be answered regarding these selective COX-2 inhibitor. For example, COX-2 might generate endogenous prostanoids that are biologically important. Mice in which the gene for COX-2 has been disrupted have defects in renal function and regulation of bone resorption, and female mice have impaired reproductive physiology [61]. Mizuno, et al. [62] have suggested that an increase in mucosal COX-2 expression may be necessary for the normal healing of gastroduodenal ulcers. However, nonselective NSAIDs also inhibit cyclooxygenase-2 to varying degrees, and the critical factor may be the ratio of isoenzyme inhibition. McAdam, et al. [63] recently reported that celecoxib, but not ibuprofen, suppressed the urinary excretion of prostacyclin in healthy subjects, whereas thromboxane activity related to COX-1 was suppressed only by ibuprofen. It is speculated that long-term therapy with these agents might increase the rate of thrombotic events in patients who were at increased risk for cardiovascular disease [63]. However, it is seen that the expression of cyclooxygenase-2 messenger RNA is enhanced in human colorectal adenomas and adenocarcinomas, and selective COX-2 inhibition may thereby reduce the risk of colorectal cancer [64]. NSAIDs containing nitric oxide Nitric oxide and PGs act synergistically to mediate mucosal protective effects [1] and Salvemini, et al. [65] demonstrated that nitric oxide stimulates COX enzymes. A formulation which releases nitric oxide was thought that it may compensate for the suppression of mucosal PGs. Under these conditions, the desired effects of NSAIDs are maintained, including the inhibition of both COX isoenzymes, while toxicity is minimized (Fig. 5) [66-68]. Nitric oxide–containing compounds have anti-inflammatory and antipyretic activities that are similar to those of the parent compound and may have analgesic effects that are greater than those of the parent compound [67]. Effect on upper GIT On esophagus Because of the above explained mechanism, NSAIDs Fig.5. Postulated mechanism by which nitric oxide-releasing NSAIDs maintain the ability to protect the gastroduodenal mucosa while suppressing the level of endogenous mucosal prostaglandins. Nitric oxide appears to stimulate some of the defensive properties of the mucosa that are affected by inhibition of the cyclooxygenase-1 isoenzyme. In addition, nitric oxide inhibits intercellular adhesion molecule 1, thereby decreasing neutrophil adherence, resulting in the prevention of NSAID-induced gastroduodenal mucosal injury. causes various injuries to the GIT. It may lead to the formation of esophageal ulcers; the common mechanism is prolonged mucosal contact with a medicine having caustic physical activity. The diagnosis of NSAID induced esophageal ulcer is made by excluding other probable causes (Like GERD, cancer, infection). Simple measures like avoiding taking NSAID’s empty stomach or taking with atleast 6 oz water or before recumbency can prevent them. Also strictures which are less widely appreciated (more commonly due to GERD) may be formed. Important differentiating feature between the two is that unlike in NSAID induced stricture, in GERD induced strictures mucosa between GE junction and stricture will be inflammed. NSAIDs are also found to exacerbate esophagitis caused by GERD. On stomach and duodenum Stomach is most common organ affected by NSAIDs. In an endoscipic study by Graham DY, et al, he has shown incidence of gastric ulcer as 10-40% and that of duodenal ulcer as 4-15% during the first 3 months of NSAID use [69]. Features of NSAID induced problem ulcers More than 3 mm in size Deep lesions Prone to complications like bleeding, perforation, and obstruction Gastric duodenal in location Multiple erosions (more than 10) Antral in location 255 Apollo Medicine, Vol. 7, No. 4, December 2010
  7. 7. Review Article NSAID ingestion and GI injury Injury type Gastro-duodenal lesion Frequency Acute (1-2 weeks) mucosal erythema, superficial erosions, submucosal haemorrhage, increased faecal blood loss 60-100% Chronic (>4 weeks) gastric antral erosions and ulcers, duodenal ulcers and erosions 5-30% Management of UGI toxicity Management of upper GI complications is based on two strategies – either prevention or treatment. Prevention can be done by two ways – either by using some protective agent or by using a safer NSAID. Concurrent use of protective agent- it is seen that majority of NSAID uses do not develop PUD clinically. So protective agents should be better used in high risk groups like short comings of these studies endoscopic rather than clinical assessment was used as the criteria and it did not compare with high dose of H2R blockers. Safe NSAIDs COX-2 specific inhibitors: found 3-5% incidence of endoscopically seen gastroduodenal ulcers with COX-2 inhibitors as compared with 10-40% by traditional NSAID’s. Various COX2 selective inhibitors available are: • First generation • Age > 65 years • H/o PUD or presently having PUD • Using other anticoagulants - Rofecoxib - drugs like Celecoxib • Second generation - Valdicoxib corticosteroids, - A. H2 receptor antagonists B. Prostaglandin analogues C. PPI’s The MUCOSA (Misoprostol Ulcer Complications Outcome Safety Assessment) trial was a 6 months randomized, double-blind, placebo controlled multi-centric trial in 8843 subjects receiving continuous therapy with NSAID for RA were studied. Patients were randomly assigned to receive 200μg of misoprostol or placebo QID. Serious upper GI complications were found to be reduced by 40% among patients receiving misoprostol compared with those receiving placebo. Also the rate of withdrawal from study was more in misoprostol group (because of diarrhea and related problems) (20% vs. 15%). [70]. In another study done by Andreas Maetzel, et al. showed that for averting 1 serious GI complication by prescribing misoprostol would cost around $ 94, 766 [71]. Two endoscopic studies demonstrated omeprazole (20mg OD) to be more effective than ranitidine (150mg BD) or misoprostol (200μg BD) in prevention of NSAID induced gastric and duodenal ulcer [72,73]. However, there were 2 Apollo Medicine, Vol. 7, No. 4, December 2010 Etoricoxib - Various options which are available are: Paracoxib Lumicoxib In the CLASS study (Celecoxib Long-term Arthritis Safety Study) [8] – a double blind randomized controlled trial conducted from Sept 1998 to March 2000 in which 7968 patients with osteoarthritis (72%) or rheumatoid arthritis (28%) were enrolled. In this about half received celecoxib and others received non-specific NSAID’s. 21% of these were also taking low dose aspirin (≤325 mg OD). It was seen that in patients not taking aspirin, the annualized incidence rates of UGI ulcer complications alone and combined with symptomatic ulcers for celecoxib vs NSAID were 0.44% vs 1.27% (p=0.04) and 1.40% vs 2.91% (p=0.002). But in those who were also receiving aspirin, this difference was not statistically significant. In the VIGOR study (Vioxx Gastrointestinal Outcomes Research) [7] – a multi-centric, double blind, randomized controlled trial involving 8076 patients of rheumatoid arthritis and none was receiving aspirin, comparison of rofecoxib (50mg OD) with naproxen (500mg BD) was done with a follow up of 9 months. 2.1 confirmed gastrointestinal events per 100 patients years with rofecoxib as compared with 4.5 per 100 patientsyears with naproxen (p<0.001). Rates of complicated confirmed events were 0.6 per 100 patients-years and 1.4 256
  8. 8. Review Article per 100 patient years respectively (p=0.005). Incidence of MI was lower among patients in naproxen group than among those in rofecoxib group. blood stained stools, blood in vamitus, and malena, etc. Two importa2nt studies have shown the superior efficacy of PPI’s over H2R blockers and PG analogues. Adverse events in the lower GI tract due to NSAIDs have been increasingly reported and include increased mucosal permeability and inflammation, anemia, malabsorption, protein loss, diarrhea, mucosal ulceration, bleeding, perforation, symptomatic diverticular disease, and strictures due to fibrous diaphragms [76]. The frequency of these events has not been well studied, but estimates from randomized clinical trials suggest that GI complications beyond the duodenum may represent no less than 40% of all gastrointestinal complications associated with NSAIDs. However, one recent study from Canada by Rahme E, et al. evaluating the rates of hospitalization due to ulceration, perforation, or bleeding in the upper or lower gastrointestinal tract among elderly patients (65 years of age or older) taking NSAIDs and/or acetaminophen with and without a proton-pump inhibitor (PPI) reported lower figures for GI events in the distal tract than in the upper tract [77]. They conducted a population-based retrospective cohort study that included 644183 elderly patients who received 1778541 prescriptions for NSAIDs (315222, 17.7% with a PPI). Among users of NSAIDs without PPIs, the crude rates of hospitalization were 0.7 cases/1000 patient-years for complications in the lower GI tract compared with 4.4/1000 patient-years for complications in the upper GI tract. Among users of NSAIDs and PPIs, the rates were of 1.4/1000 patientyears for the lower GI tract compared with 2.0/1000 patient-years for the upper GI, suggesting that PPIs reduced hospitalizations for upper but not lower GI complications associated with NSAIDs. Of interest, they confirmed that NSAIDs increased the risk of hospitalization from lesions of either the upper or the lower GI tract when compared with acetaminophen at less than 3 g/day. Also they found that among elderly patients requiring analgesic/ antiinflammatory treatment, use of the combination of a NSAID and acetaminophen may increase the risk of gastrointestinal bleeding compared with either of the agents alone. In ASTRONAUT study, a randomized double blind trial in which 541 patients who were on NSAID and has peptic ulcers were randomly assigned to Omeprazole 20mg OD and Ranitidine 150mg BD. At eight weeks, treatment was successful in 80% of patients in group receiving 20mg of omeprazole and 63% in ramitidine group (p<0.001). During maintenance therapy, the proportion of patients in remission at end of six months was 72% in omeprazole group and 59% in ranitidine group [72]. In OMNIUM study, a randomized double blind trial in which 935 patients of RA were taken - at eight weeks, treatment was successful in 76% of patients receiving omeprazole and 71% of those given misoprostol. During maintenance phase, the proportion of patients in remission was 61% in omeprazole group and 48% in misoprostol group (p=0.001). The percentage of adverse events was more with misoprostol as compared to omeprazole. Thus omeprazole is more effective and better tolerated [74]. In a double blind randomized trial by Singh G, et al. [75], efficacy of pantoprazole was compared to omeprazole and misoprostol in NSAID associated gastric ulcer. 120 patients were randomly divided into three groups (pantoprazole 40 mg qd, omeprazole 20 mg qd and misoprostol 200μg BD). They found that rate of ulcer healing in first 4 weeks was 87% vs 75% vs 72%, but all ulcers healed within 8 weeks. The rate of maintaining remission was 66% vs 55% vs 44% on duration of follow up for 3 months. Prevention of NSAIDs induced ulcers Use single NSAIDs Use the lowest possible doses Use for short durations Use less gastrotoxic drugs like paracetamol, ibuprofen, and diclofenac Use selective COX-2 inhibitors wherever possible and especially in high risk cases Review drug use in elderly Avoid concomitant gastrotoxic drugs like steroids Consider prophylaxis with omepraxole in high risk cases Have a high index of suspicion on GI symptoms in NSAID users Educate patients against non-prescription use; counsel them about the warning symptoms of GI damage such as Adverse effects on the GI tract Several studies have shown that coxibs perform better than NSAIDs and PPIs in the small bowel in healthy volunteers. Hawkey, et al. have recently showed that lumiracoxib 100 mg once daily induces less damage to the lower gastrointestinal tract (small bowel) than naproxen 500 mg twice daily and omeprazole 20 mg once daily. This study provides evidence from a multifactorial perspective, including videocapsule endoscopy and biochemical test of inflammation and permeability that the COX-2 selective inhibitor, lumiracoixb, induces less damage to the small bowel than a traditional NSAID and a PPI [78]. 257 Apollo Medicine, Vol. 7, No. 4, December 2010
  9. 9. Review Article However, Maiden L, et al. found no differences in the proportion and type of small bowel lesions in patients taking NSAIDs in comparison with coxibs [79]. Therefore, to test this hypothesis, we will need new studies, ideally focused on clinically relevant events. To avoid direct contact of NSAIDs with the upper GI tract, several enteric-coated formulations have been introduced in the market. In most cases, these formulations have reduced the incidence of acute mucosal damage to the stomach, but have not decreased the risk of major upper gastrointestinal bleeding. A new formulation releasing naproxen in the distal small bowel and the upper colon was recently proposed and preliminary work suggests that it induces little or no direct damage to the distal GI tract mucosa [80]. However, this new formulation may well have the same problems associated with the enteric-coated compounds. Inflammatory bowel diseases and NSAIDs There is clear evidence that prostaglandin (PG) production is increased in active inflammatory bowel disease (IBD). PG levels correlate with disease activity and decrease with successful medical intervention. Disease activity has also been correlated with COX expression, especially COX-2. Prostaglandins derived from COX-1 and COX-2 seems to play a protective role. Evidence from inhibition of prostaglandin synthesis with NSAIDs or COX-2 selective inhibitors has also shown conflicting data in both clinical studies and animal models. On theoretical grounds, both NSAIDs and COX-2 inhibitors appear to be capable of triggering a flare-up of IBD by inhibiting the intestinal production of prostaglandins involved in the tissue reparative processes. One experimental study by Dudhgaonkar SP, et al. found that the selective inhibition of inducible nitric oxide synthase (iNOS) and COX-2, as occurs with the potent anti-inflammatory glucocorticoids, afforded maximal protection from colonic injury induced by a trinitrobenzenesulphonic acid (TNBS) enema. This study supports the idea that simultaneous inhibition of iNOS and COX-2 has a promising potential in the treatment of colitis [81]. In a different experimental model of colitis, induced by treatment with 2.5% dextran sulfate sodium (DSS) in drinking water for 6 days, indomethacin (a nonselective COX inhibitor), SC-560 (a selective COX-1 inhibitor), and celecoxib (a selective COX-2 inhibitor) given for 6 days significantly worsened the severity of DSS-induced colonic damage. However, each agent had a different effect on the time of colonic damage. The aggravation was observed in the first 3 days of SC-560 administration and in the last 3 days of celecoxib administration. The expression of COXApollo Medicine, Vol. 7, No. 4, December 2010 2 mRNA in the colon was upregulated on day 3 during DSS treatment, with a significant increase in prostaglandin E2 (PGE2) production, suggesting that endogenous prostaglandins derived from the COX activity afford protection against colonic ulceration; COX-1 in the early stage and COX-2 in the late stage [82]. Elevated levels of the proinflammatory leukotriene B4 (LTB4) have been found in preclinical models of IBD, as well as in colonic tissue from individuals with IBD. The role of 5lipoxigenase (5-LO) derivates like LTB4 has been investigated in another model of colitis in IL-10 (-/-) mice. In these animals, 5-LO-derived leukotrienes were not required for the development or maintenance of spontaneous or NSAID-induced colonic inflammation [83]. The relevance of these animal models to humans is unclear; although all of the tested agents induced ulceration and inflammation in the animals, different and complex mechanisms were involved in these reactions, and these mechanisms may differ significantly from those in humans. Good clinical studies are required before we can reach appropriate conclusions. In a study by Sidhu R, et al. [84] on 76 patients (52 female; mean age 50 years) undergoing routine capsule endoscopy (CE) for some small bowel pathology like anaemia, bleeding or symptoms suggestive of Crohn’s disease he found that urinalysis (a salicylate spot test and gas chromatography mass spectrometry for NSAID metabolites urine samples) was positive in 13.6% of patients (n=10/76), although only one of these patients declared the relevant drug (aspirin) in their drug history. The presence of salicylates was detected in 3.9% of patients (n=3) while NSAID metabolites were detected in 9.2% (n=7: 6 patients ibuprofen alone and both ibuprofen and diclofenac in 1 patient). While CE was normal in 2 patients, positive findings were seen in 80% of patients (n=8) which included the presence of erosions ± red patches in 5 patients, small bowel ulceration in 2 patients and ulceration with early stricturing in one patient. Follow-up in these patients revealed that the patient with small bowel stricturing was subsequently diagnosed as Crohn’s disease while a patient with small bowel ulceration underwent small bowel resection at a further presentation which confirmed NSAID enteropathy histologically. CONCLUSION Inhibition of COX-1 and COX-2 by NSAIDs in the gastrointestinal tract has been associated with both adverse and beneficial effects. NSAIDs increase the risk of hospitalizations due to complications from both the upper and the lower in the lower gastrointestinal tract, including the colon. The effects of NSAIDs and COX-2 inhibitors in patients with inflammatory bowel disease are still unclear. 258
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  14. 14. A o oh s i l ht:w wa o o o p a . m/ p l o p a : t / w .p l h s i lc l ts p / l ts o T ie: t s / ie. m/o p a A o o wt rht :t t r o H s i l p l t p /w t c ts l Y uu e ht:w wy uu ec m/p l h s i ln i o tb : t / w . tb . a o o o p a i a p/ o o l ts d F c b o : t :w wfc b o . m/h A o o o p a a e o k ht / w . e o k o T e p l H s i l p/ a c l ts Si s ae ht:w wsd s aen t p l _ o p a l e h r: t / w .i h r.e/ o o H s i l d p/ le A l ts L k d : t :w wl k d . m/ mp n /p l -o p a i e i ht / w . e i c c a y o oh s i l n n p/ i n no o a l ts Bo : t :w wl s l e l . / l ht / w . t a h a hi g p/ e tk t n