non-steroidal anti inflammatory drugs and gastrointestinal toxicity

NON-STEROIDAL ANTI INFLAMMATORY DRUGS AND GASTROINTESTINAL TOXICITY.

Review Article

EPIDEMIOLOGY

Because of the broad and nonspecific definitions ofgastrointestinal disorders caused by the use of NSAIDs, aswell as differences in patient populations, drugs, dosages,and periods of use, estimates of the prevalence of adverseeffect vary greatly. In general, at least 10-20% of patientshave dyspepsia while taking an NSAID, although theprevalence may range from 5-50% [1,2]. According toprospective data from the Arthritis, Rheumatism, and AgingMedical Information System (ARAMIS), 13 of every 1000patients with rheumatoid arthritis (RA) who take NSAIDs forone year have a serious gastrointestinal complication. Therisk in patients with osteoarthritis is somewhat lower (7.3 per1000 patients per year) [3].

The mortality rate among patients who are hospitalizedfor NSAID-induced upper gastrointestinal bleeding is about5-10% [4]. An analysis of data from ARAMIS has shownthat the mortality rate attributed to NSAID-relatedgastrointestinal toxic effects is 0.22% per year, with anannual relative risk of 4.21 as compared with the risk forpersons not using NSAIDs [3].

An estimated cost of $15,000 to $20,000 perhospitalization, the annual direct costs of gastrointestinalcomplications may exceed $2 billion [5]. It has beenestimated conservatively that 16,500 NSAID-related deathsoccur among patients with RA or OA every year in UnitedStates. This figure is similar to the number of deaths fromthe acquired immunodeficiency syndrome andconsiderably greater than the number of deaths frommultiple myeloma, asthma, cervical cancer, or Hodgkin’sdisease (Fig. 1) [3].

251 Apollo Medicine, Vol. 7, No. 4, December 2010

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-inflammatoryand analgesic agents, are one of the most commonly prescribed drugs world-wide. They are used intreatment of many commonly occurring disorders such as chronic arthropathies, headache and low backpain. Their widespread and uncontrolled use is promoted by their over the counter availability. This acts as adouble edge sword. One of the most common adverse effects that add largely to its morbidity and mortalityis the gastrointestinal tract damage.

Key words: NSAIDS, Gastrointestinal disorders, Hodgkin’s disease.

To the worse these mortality statistics did not includedeaths ascribed to the use of over-the-counter NSAIDs. Yetthese toxic effects remain largely a silent epidemic withmany physicians and most patients unaware of themagnitude of the problem.

In UK, based on a widely quoted population study byRockall TA, et al [6], it was estimated that there are 8528hospitalisations for gastric and duodenal ulcer bleeding perannum in the UK.

Three large cohort studies have found that the total riskof hospitalisation for gastrointestinal complicationsassociated with NSAID use as between 1.3 – 2.2 events per1000 patient years [7,8].

Risk factors for GI complications [3,9-21]

Predisposing factors for NSAID induced GIulceration

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 252

Review Article

Advanced age (>65 yrs) has been consistently found tobe a primary risk factor for adverse gastrointestinal events.The risk increases linearly with age [9-13]. Elderly patientsare particularly prone to develop GI toxicity andunfortunately they are the most frequent users of this groupof drugs [22]. These patients are deficient in cytoprotectivePGs (PGE2 and PGI2) that increase mucous production andimprove ulcer healing. Moreover, the vascular integrity of theulcer base is poor; therefore, ulcers bleed easily [23, 24].

Many studies have shown that use of multiple NSAIDs;non-use of anti-ulcer medication, and NSAID use in patientswith previous history of peptic ulcers raises the possibility ofdeveloping GI ulcers by 14-17 folds [23].

Other risk factors that have been identified are higherdoses of NSAIDs (including use of two or more NSAIDs), ahistory of gastroduodenal ulcer or gastrointestinal bleeding,concomitant use of corticosteroids, serious coexistingconditions, and concomitant use of anticoagulants.

Identification of Helicobacter pylori infection as animportant factor in the development of peptic ulcer has raisedthe question of a possible synergistic relation between thepresence of H. Pylori infection and NSAID use. Althoughseveral studies have found these two factors to beindependent; two prospective studies have suggested asynergistic relation [25-28].

Bianchi Porro, et al. [29] used the combination ofamoxicillin and omeprazole to treat NSAID users infectedwith H. pylori. They found that the eradication of H. Pyloridid not affect the rate of ulcer healing. However, six months

after the end of combination therapy, the cumulative rate ofrecurrent ulcers was 31% among the patients in whomH. Pylori had been eradicated and 46% among those whowere still infected.

Chan, et al. [30] found that the use of a regimen thatincluded bismuth subcitrate to eradicate H. Pylorisignificantly decreased the rate of ulcer developmentassociated 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. pyloriwas eradicated.

In one study by Hawkey, et al. [31] randomly assigned285 patients with current ulcers or a history of ulcers whowere using NSAIDs to combined treatment withomeprazole, clarithromycin, and amoxicillin or to treatmentwith 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 weresuccessfully treated with antibiotics for H. Pylori infectionhence concluding that infection with H. Pylori increases therisk of gastroduodenal mucosal injury associated withNSAID use only minimally, if at all.

In another study by Hawkey CJ, et al. [32] did amultivariate regression analyses of three large trials{OPPULENT (Omeprazole versus Placebo as Prophylaxisagainst Ulcers or Erosions from NSAID Treatment) study,maintenance phases of the OMNIUM (Omeprazole versusMisoprostol for NSAID Induced Ulcer Management) andASTRONAUT (Acid Suppression Trial: Ranitidine orOmeprazole for NSAID Associated Ulcer Treatment)study} to find whether the increased risk of developing ulcerin a person with a past history of peptic ulceration duringNSAID use is due to H. pylori infection or to reactivation ofthe original lesion by comparing the efficacy of omeprazole20 mg daily, misoprostol 200 μg twice daily, and ranitidine150 mg twice daily in preventing ulcers and erosions atdifferent sites and in patients who were H pylori positive andnegative. They found that there was a highly significanttendency for the relapse lesion to replicate the site and type ofthe 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 withomeprazole than with placebo, misoprostol, or ranitidine.This advantage was especially evident in H. pylori positivepatients receiving acid suppression (5.7% v 16.6% forgastric ulcer with omeprazole).

In a prospective placebo-controlled, double blindrandomized trial by Feldman M, et al., 61 healthy men andwomen were recruited. Out of these, 46 received low doseaspirin therapy. Among them, 22 were H.pylori positive and

Fig.1. US Mortality data for seven selected disorders. A totalof 16,500 patients with rheumatoid arthritis or osteo-arthritis died from the gastrointestinal toxic effects ofNSAIDS. Data are from the National Center for HealthStatistics and the Arthritis, Rheumatism, and AgingMedical Information System.

Review Article


damage by diminishing the hydrophobicity of gastric mucus,thereby allowing endogenous gastric acid and pepsin toinjure the surface epithelium [37]. In addition, topicalmucosal injury may occur as a result of indirectmechanisms, mediated through the biliary excretion andsubsequent duodenogastric reflux of active NSAIDmetabolites [38,39].

The role of prostaglandins

Topical injury caused by NSAIDs contributes to thedevelopment of gastroduodenal mucosal injury. However,the systemic effects of these agents appear to have thepredominant role, [33,40,41] largely through the decreasedsynthesis of mucosal prostaglandins [42]. The use ofenteric-coated aspirin preparations [42], parenteral [43] orrectal [44] administration of NSAIDs in order to preventtopical mucosal injury has also failed to prevent thedevelopment of ulcers. Moreover, doses of aspirin as low as30 mg are sufficient to suppress prostaglandin synthesis inthe gastric mucosa [45]. Prostaglandins are derived fromarachidonic acid, which originates from cell-membranephospholipids through the action of phospholipase A2(Fig. 2).

24 were H.pylori negative. They were assessed after a periodof 45 days treatment with aspirin and it was found thaterosive disease from low dose aspirin occurred in 50% ofH.pylori infected volunteers and in 16% of their non-infectedcounter parts (p=0.02). Therefore, in light of the increasinguse of low dose aspirin for cardiovascular prophylaxis,screening and treating H.pylori might be a useful preventivestrategy for patients who are at risk of ulcer bleeding [33].

In a meta-analysis by Huang JQ, et al. to study the role ofH.pylori infection and NSAIDs in 1625 NSAIDs takers,uncomplicated peptic ulcer disease was significantly morecommon in patients positive than in those negative forH.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 ofPUD in NSAID users by 3.53 fold in addition to the riskassociated with NSAID use. Similarly NSAID increases riskof PUD in H.pylori infection by 3.55 fold [34].

But how much cost-effective this approach is, it is yet tobe found. The general practice today which is followed isthat when NSAIDs are to be used for short term then there isno need to screen for H. pylori, but if they are to be usedchronically (>3 months) then we may screen for and treat H.pylori .

Mechanism of GI toxicity

Gastroduodenal mucosal injury develops when thedeleterious effect of gastric acid overwhelms the normaldefensive properties of the mucosa. There are multiplemechanisms with both local and systemic effects in causingthis injury The systemic effects are largely the result of theinhibition of endogenous prostaglandin (PG) synthesis [35].PG inhibition, in turn, leads to decreases in epithelial mucus,secretion of bicarbonate, mucosal blood flow, epithelialproliferation, and mucosal resistance to injury [36,37]. Theimpairment in mucosal resistance permits injury byendogenous factors, including acid, pepsin, and bile salts, aswell as by exogenous factors such as NSAIDs and possiblyethanol and other noxious agents.

Topical injury

Mucosal injury is initiated topically by the acidicproperties of aspirin and many other NSAIDs. Most NSAIDsare weak organic acids and have low pKa, which variesaccording to the particular agent; these weak acids remain intheir non-ionized lipophilic form in the highly acidic gastriclumen. Such conditions favour migration through the gastricmucus across plasma membranes and into surface epithelialcells; they encounter a basic pH (e.g., 7.1). This causes socalled “trapping” of the drugs inside the cell, where NSAIDsare dissociated into the ionized form, resulting in trapping ofhydrogen ions [35]. NSAIDs can also cause topical mucosal

Fig.2. Biosynthesis of prostaglandins through thecyclooxygenase Pathways. The immediate precursorof prostaglandins, arachidonic acid, is derived frommembrane phospholipids and is catalyzed by the twocyclooxygenase isoenzymes (also designated asprostaglandin H synthase), cyclooxygenase-1 andcyclooxygenase-2. The gene for cyclooxygenase-1, thehousekeeping enzyme, is expressed constitutively andmaintains the homeostasis of organs, includinggastric mucosal integrity. In contrast, the gene forcyclooxygenase-2, the inflammatory enzyme, isinducible. Although both pathways can be variablyinhibited by different NSAIDS, only the gene forcycloozygenase-2 contains a corticosteroid-responsive repressor element in its promoter region.The broken arrows indicate the inhibitory effects ofpharmacologic agents.


Review Article

PGs protect GI mucosa by forming a cytoprotectivelayer and increasing the secretion of bicarbonate ions thatneutralise the gastric acidity. All therapeutically usefulNSAIDs act by inhibiting the synthesis of PGs [46].

The metabolism of arachidonic acid to prostaglandinsand leukotrienes is catalyzed by the cyclooxygenasepathway 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]. Despitetheir structural similarities, they are encoded by distinctgenes and differ with regard to their distribution andexpression in tissues [49,50]. The COX-1 gene contains apromoter region without a TATA sequence and is primarilyexpressed constitutively. In contrast, the COX-2 gene isthought to be the inducible form that is nearly undetectable inmost (but not all) tissues under normal physiologicconditions. COX-1 appears to function as a “housekeeping”enzyme in most tissues, including the gastric mucosa, thekidneys, and the platelets, whereas the expression of COX-2can be induced by inflammatory stimuli and mitogens inmany different types of tissue, including macrophages andsynovial cells [41]. It has thus been suggested that the anti-inflammatory properties of NSAIDs are mediated throughthe inhibition of COX-2, whereas adverse effects, such asgastroduodenal ulceration, occur as a result of effects on theconstitutively expressed COX-1 [41,48].

Conventional NSAIDs cause non-selective inhibition ofCOX, which leads to reduction in bicarbonate secretion andreduced mucous production. Coupled with it isvasoconstriction that occurs due to NSAIDs, which causeshypoxia and consequent formation of ulcer. Even short-term(<1 week) use of aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) can precipitate ulcer-relatedbleeding.

Arthritis, rheumatism, and ageing medical informationsystem (ARAMIS) data suggested that risk of death from

NSAID use is four times more than non-users [1,2]. Over-the-counter availability of PPIs and H2– receptorantagonists for short-term treatment of dyspepsia may leada patient to delay optimal care for more severegastrointestinal disease; if the drug is taken on a long- termbasis, its use could delay a diagnosis of gastric cancer also[7]. Even aspirin use for prophylactic reasons in lowdosages is not free of gastrointestinal complications. Allformulations of aspirin like buffered, enteric coated andplain aspirin carry same amount of risk [24].

Besides this, there is evidence that other mechanismsare also involved. For example, ulcers do not developspontaneously in mice with a disrupted COX-1 gene, [51]and Wallace, et al. [52,53] reported that NSAID-inducedinjury occurred in association with enhanced adherence ofneutrophils to the gastric vascular endothelium, as theresult of an increase in the expression of intercellularadhesion molecule 1 (ICAM 1) in the basal endothelium[54-57]. Neutrophil adherence, in turn, causes mucosalinjury through the release of oxygen-derived free radicalsand proteases [1]. The relative COX-1 inhibition of variousNSAIDs is shown in Fig. 4.

Many modifications of NSAIDs have been formulatedto reduce their toxicity. Surveillance and variousendoscopic studies have confirmed that the incidence ofgastroduodenal mucosal injury is reduced with the use ofnabumetone, etodolac, and meloxicam [58-60]. Theimproved safety of meloxicam appears to be due to itspreferential inhibition of COX-2, with a minimal effect onCOX-1. In contrast, nabumetone and etodolac appear toinhibit COX-2 preferentially at low doses, but thepreferential inhibition of COX-2 is diminished at higherdoses. These agents also have other properties thatcontribute to their safety. Etodolac has a low level ofenterohepatic recirculation and a short half- life;nabumetone is a nonacidic prodrug formulation and has noenterohepatic recirculation [61].

Fig.3. Mechanism of action of NSAIDsFig.4. Comparison between different NSAIDs including COX-

1 Vs COX-2.

Review Article


Highly selective cyclooxygenase-2 inhibitors

Many new highly selective COX-2 inhibitors haverecently been developed that, in studies to date, have had amarkedly reduced capacity to cause injury to thegastroduodenal mucosa. Celecoxib and rofecoxib, are nownot new to us and they have been studied extensively fortheir selective COX-2 inhibitory action.

But there are still few important questions to beanswered regarding these selective COX-2 inhibitor. Forexample, COX-2 might generate endogenous prostanoidsthat are biologically important. Mice in which the gene forCOX-2 has been disrupted have defects in renal functionand regulation of bone resorption, and female mice haveimpaired reproductive physiology [61].

Mizuno, et al. [62] have suggested that an increase inmucosal COX-2 expression may be necessary for thenormal healing of gastroduodenal ulcers. However, non-selective NSAIDs also inhibit cyclooxygenase-2 to varyingdegrees, and the critical factor may be the ratio ofisoenzyme inhibition.

McAdam, et al. [63] recently reported that celecoxib,but not ibuprofen, suppressed the urinary excretion ofprostacyclin in healthy subjects, whereas thromboxaneactivity related to COX-1 was suppressed only byibuprofen. It is speculated that long-term therapy withthese agents might increase the rate of thrombotic events inpatients who were at increased risk for cardiovasculardisease [63]. However, it is seen that the expression ofcyclooxygenase-2 messenger RNA is enhanced in humancolorectal adenomas and adenocarcinomas, and selectiveCOX-2 inhibition may thereby reduce the risk of colorectalcancer [64].

NSAIDs containing nitric oxide

Nitric oxide and PGs act synergistically to mediatemucosal protective effects [1] and Salvemini, et al. [65]demonstrated that nitric oxide stimulates COX enzymes. Aformulation which releases nitric oxide was thought that itmay compensate for the suppression of mucosal PGs.Under these conditions, the desired effects of NSAIDs aremaintained, including the inhibition of both COXisoenzymes, while toxicity is minimized (Fig. 5) [66-68].Nitric oxide–containing compounds have anti-inflammatoryand antipyretic activities that are similar to those of theparent compound and may have analgesic effects that aregreater than those of the parent compound [67].

Effect on upper GIT

On esophagus

Because of the above explained mechanism, NSAIDs

causes various injuries to the GIT. It may lead to theformation of esophageal ulcers; the common mechanism isprolonged mucosal contact with a medicine having causticphysical activity. The diagnosis of NSAID inducedesophageal ulcer is made by excluding other probable causes(Like GERD, cancer, infection). Simple measures likeavoiding taking NSAID’s empty stomach or taking withatleast 6 oz water or before recumbency can prevent them.Also strictures which are less widely appreciated (morecommonly due to GERD) may be formed. Importantdifferentiating feature between the two is that unlike inNSAID induced stricture, in GERD induced strictures -mucosa between GE junction and stricture will beinflammed. NSAIDs are also found to exacerbate esophagitiscaused 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 shownincidence of gastric ulcer as 10-40% and that of duodenalulcer as 4-15% during the first 3 months of NSAID use [69].

Features of NSAID induced problem ulcers

More than 3 mm in sizeDeep lesionsProne to complications like bleeding, perforation, and

obstructionGastric duodenal in locationMultiple erosions (more than 10)Antral in location

Fig.5. Postulated mechanism by which nitric oxide-releasingNSAIDs maintain the ability to protect thegastroduodenal mucosa while suppressing the levelof endogenous mucosal prostaglandins. Nitric oxideappears to stimulate some of the defensive propertiesof the mucosa that are affected by inhibition of thecyclooxygenase-1 isoenzyme. In addition, nitric oxideinhibits intercellular adhesion molecule 1, therebydecreasing neutrophil adherence, resulting in theprevention of NSAID-induced gastroduodenal mucosalinjury.


Review Article

Management of UGI toxicity

Management of upper GI complications is based on twostrategies – either prevention or treatment.

Prevention can be done by two ways – either by usingsome protective agent or by using a safer NSAID.

Concurrent use of protective agent- it is seen thatmajority of NSAID uses do not develop PUD clinically. Soprotective agents should be better used in high risk groupslike

• Age > 65 years

• H/o PUD or presently having PUD

• Using other drugs like corticosteroids,anticoagulants

Various options which are available are:

A. H2 receptor antagonists

B. Prostaglandin analogues

C. PPI’s

The MUCOSA (Misoprostol Ulcer ComplicationsOutcome Safety Assessment) trial was a 6 monthsrandomized, double-blind, placebo controlled multi-centrictrial in 8843 subjects receiving continuous therapy withNSAID for RA were studied. Patients were randomlyassigned to receive 200μg of misoprostol or placebo QID.Serious upper GI complications were found to be reduced by40% among patients receiving misoprostol compared withthose receiving placebo. Also the rate of withdrawal fromstudy was more in misoprostol group (because of diarrheaand related problems) (20% vs. 15%). [70]. In another studydone by Andreas Maetzel, et al. showed that for averting 1serious GI complication by prescribing misoprostol wouldcost 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 inducedgastric and duodenal ulcer [72,73]. However, there were 2

short comings of these studies endoscopic rather thanclinical assessment was used as the criteria and it did notcompare with high dose of H2R blockers.

Safe NSAIDs

COX-2 specific inhibitors: found 3-5% incidence ofendoscopically seen gastroduodenal ulcers with COX-2inhibitors as compared with 10-40% by traditional NSAID’s.

Various COX2 selective inhibitors available are:

• First generation - Rofecoxib- Celecoxib

• Second generation - Valdicoxib- Paracoxib- Etoricoxib- Lumicoxib

In the CLASS study (Celecoxib Long-term ArthritisSafety Study) [8] – a double blind randomized controlled trialconducted from Sept 1998 to March 2000 in which 7968patients with osteoarthritis (72%) or rheumatoid arthritis(28%) were enrolled. In this about half received celecoxiband others received non-specific NSAID’s. 21% of thesewere also taking low dose aspirin (≤325 mg OD). It wasseen that in patients not taking aspirin, the annualizedincidence rates of UGI ulcer complications alone andcombined with symptomatic ulcers for celecoxib vs NSAIDwere 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, thisdifference was not statistically significant.

In the VIGOR study (Vioxx GastrointestinalOutcomes Research) [7] – a multi-centric, double blind,randomized controlled trial involving 8076 patients ofrheumatoid arthritis and none was receiving aspirin,comparison of rofecoxib (50mg OD) with naproxen(500mg BD) was done with a follow up of 9 months. 2.1confirmed gastrointestinal events per 100 patients yearswith rofecoxib as compared with 4.5 per 100 patients-years with naproxen (p<0.001). Rates of complicatedconfirmed events were 0.6 per 100 patients-years and 1.4

NSAID ingestion and GI injury

Injury type Gastro-duodenal lesion Frequency

Acute (1-2 weeks) mucosal erythema, superficial erosions, 60-100%submucosal haemorrhage, increased faecal blood loss

Chronic (>4 weeks) gastric antral erosions and ulcers, duodenal 5-30%ulcers and erosions

Review Article


per 100 patient years respectively (p=0.005). Incidence ofMI was lower among patients in naproxen group thanamong those in rofecoxib group.

Two importa2nt studies have shown the superiorefficacy of PPI’s over H2R blockers and PG analogues.

In ASTRONAUT study, a randomized double blindtrial in which 541 patients who were on NSAID and haspeptic ulcers were randomly assigned to Omeprazole20mg OD and Ranitidine 150mg BD. At eight weeks,treatment was successful in 80% of patients in groupreceiving 20mg of omeprazole and 63% in ramitidinegroup (p<0.001). During maintenance therapy, theproportion of patients in remission at end of six monthswas 72% in omeprazole group and 59% in ranitidinegroup [72].

In OMNIUM study, a randomized double blind trial inwhich 935 patients of RA were taken - at eight weeks,treatment was successful in 76% of patients receivingomeprazole and 71% of those given misoprostol. Duringmaintenance phase, the proportion of patients in remissionwas 61% in omeprazole group and 48% in misoprostolgroup (p=0.001). The percentage of adverse events wasmore with misoprostol as compared to omeprazole. Thusomeprazole is more effective and better tolerated [74].

In a double blind randomized trial by Singh G, et al.[75], efficacy of pantoprazole was compared toomeprazole and misoprostol in NSAID associated gastriculcer. 120 patients were randomly divided into threegroups (pantoprazole 40 mg qd, omeprazole 20 mg qd andmisoprostol 200μg BD). They found that rate of ulcerhealing in first 4 weeks was 87% vs 75% vs 72%, but allulcers healed within 8 weeks. The rate of maintainingremission was 66% vs 55% vs 44% on duration of followup for 3 months.

Prevention of NSAIDs induced ulcers

Use single NSAIDsUse the lowest possible dosesUse for short durationsUse less gastrotoxic drugs like paracetamol, ibuprofen,

and diclofenacUse selective COX-2 inhibitors wherever possible and

especially in high risk casesReview drug use in elderlyAvoid concomitant gastrotoxic drugs like steroidsConsider prophylaxis with omepraxole in high risk casesHave a high index of suspicion on GI symptoms in

NSAID usersEducate patients against non-prescription use; counselthem about the warning symptoms of GI damage such as

blood stained stools, blood in vamitus, and malena, etc.

Adverse effects on the GI tract

Adverse events in the lower GI tract due to NSAIDshave been increasingly reported and include increasedmucosal permeability and inflammation, anemia,malabsorption, protein loss, diarrhea, mucosal ulceration,bleeding, perforation, symptomatic diverticular disease,and strictures due to fibrous diaphragms [76]. Thefrequency of these events has not been well studied, butestimates from randomized clinical trials suggest that GIcomplications beyond the duodenum may represent no lessthan 40% of all gastrointestinal complications associatedwith NSAIDs. However, one recent study from Canada byRahme E, et al. evaluating the rates of hospitalization dueto ulceration, perforation, or bleeding in the upper or lowergastrointestinal tract among elderly patients (65 years ofage or older) taking NSAIDs and/or acetaminophen withand without a proton-pump inhibitor (PPI) reported lowerfigures for GI events in the distal tract than in the uppertract [77]. They conducted a population-basedretrospective cohort study that included 644183 elderlypatients who received 1778541 prescriptions for NSAIDs(315222, 17.7% with a PPI). Among users of NSAIDswithout PPIs, the crude rates of hospitalization were 0.7cases/1000 patient-years for complications in the lower GItract compared with 4.4/1000 patient-years forcomplications in the upper GI tract. Among users ofNSAIDs and PPIs, the rates were of 1.4/1000 patient-years for the lower GI tract compared with 2.0/1000patient-years for the upper GI, suggesting that PPIsreduced hospitalizations for upper but not lower GIcomplications associated with NSAIDs. Of interest, theyconfirmed that NSAIDs increased the risk of hospitalizationfrom lesions of either the upper or the lower GI tract whencompared with acetaminophen at less than 3 g/day. Alsothey found that among elderly patients requiring analgesic/antiinflammatory treatment, use of the combination of aNSAID and acetaminophen may increase the risk ofgastrointestinal bleeding compared with either of the agentsalone.

Several studies have shown that coxibs perform betterthan NSAIDs and PPIs in the small bowel in healthyvolunteers. Hawkey, et al. have recently showed thatlumiracoxib 100 mg once daily induces less damage to thelower gastrointestinal tract (small bowel) than naproxen500 mg twice daily and omeprazole 20 mg once daily. Thisstudy provides evidence from a multifactorial perspective,including videocapsule endoscopy and biochemical test ofinflammation and permeability that the COX-2 selectiveinhibitor, lumiracoixb, induces less damage to the smallbowel than a traditional NSAID and a PPI [78].


Review Article

However, Maiden L, et al. found no differences in theproportion and type of small bowel lesions in patientstaking NSAIDs in comparison with coxibs [79]. Therefore,to test this hypothesis, we will need new studies, ideallyfocused on clinically relevant events.

To avoid direct contact of NSAIDs with the upper GItract, several enteric-coated formulations have beenintroduced in the market. In most cases, these formulationshave reduced the incidence of acute mucosal damage tothe stomach, but have not decreased the risk of majorupper gastrointestinal bleeding. A new formulation releasingnaproxen in the distal small bowel and the upper colon wasrecently proposed and preliminary work suggests that itinduces little or no direct damage to the distal GI tractmucosa [80]. However, this new formulation may wellhave the same problems associated with the enteric-coatedcompounds.

Inflammatory bowel diseases and NSAIDs

There is clear evidence that prostaglandin (PG)production is increased in active inflammatory boweldisease (IBD). PG levels correlate with disease activity anddecrease with successful medical intervention. Diseaseactivity has also been correlated with COX expression,especially COX-2. Prostaglandins derived from COX-1and COX-2 seems to play a protective role. Evidence frominhibition of prostaglandin synthesis with NSAIDs orCOX-2 selective inhibitors has also shown conflicting datain both clinical studies and animal models. On theoreticalgrounds, both NSAIDs and COX-2 inhibitors appear to becapable of triggering a flare-up of IBD by inhibiting theintestinal production of prostaglandins involved in the tissuereparative processes. One experimental study byDudhgaonkar SP, et al. found that the selective inhibition ofinducible nitric oxide synthase (iNOS) and COX-2, asoccurs with the potent anti-inflammatory glucocorticoids,afforded maximal protection from colonic injury inducedby a trinitrobenzenesulphonic acid (TNBS) enema. Thisstudy supports the idea that simultaneous inhibition of iNOSand COX-2 has a promising potential in the treatment ofcolitis [81].

In a different experimental model of colitis, induced bytreatment with 2.5% dextran sulfate sodium (DSS) indrinking water for 6 days, indomethacin (a nonselectiveCOX inhibitor), SC-560 (a selective COX-1 inhibitor), andcelecoxib (a selective COX-2 inhibitor) given for 6 dayssignificantly worsened the severity of DSS-induced colonicdamage. However, each agent had a different effect on thetime of colonic damage. The aggravation was observed inthe first 3 days of SC-560 administration and in the last 3days of celecoxib administration. The expression of COX-

2 mRNA in the colon was upregulated on day 3 during DSStreatment, with a significant increase in prostaglandin E2(PGE2) production, suggesting that endogenousprostaglandins derived from the COX activity affordprotection against colonic ulceration; COX-1 in the earlystage and COX-2 in the late stage [82]. Elevated levels ofthe proinflammatory leukotriene B4 (LTB4) have beenfound in preclinical models of IBD, as well as in colonictissue from individuals with IBD. The role of 5-lipoxigenase (5-LO) derivates like LTB4 has beeninvestigated in another model of colitis in IL-10 (-/-) mice.In these animals, 5-LO-derived leukotrienes were notrequired for the development or maintenance ofspontaneous or NSAID-induced colonic inflammation[83]. The relevance of these animal models to humans isunclear; although all of the tested agents induced ulcerationand inflammation in the animals, different and complexmechanisms were involved in these reactions, and thesemechanisms may differ significantly from those in humans.Good clinical studies are required before we can reachappropriate conclusions.

In a study by Sidhu R, et al. [84] on 76 patients (52female; mean age 50 years) undergoing routine capsuleendoscopy (CE) for some small bowel pathology likeanaemia, bleeding or symptoms suggestive of Crohn’sdisease he found that urinalysis (a salicylate spot test and gaschromatography mass spectrometry for NSAIDmetabolites urine samples) was positive in 13.6% of patients(n=10/76), although only one of these patients declared therelevant drug (aspirin) in their drug history. The presence ofsalicylates was detected in 3.9% of patients (n=3) whileNSAID metabolites were detected in 9.2% (n=7: 6 patientsibuprofen alone and both ibuprofen and diclofenac in 1patient). While CE was normal in 2 patients, positive findingswere seen in 80% of patients (n=8) which included thepresence of erosions ± red patches in 5 patients, small bowelulceration in 2 patients and ulceration with early stricturing inone patient. Follow-up in these patients revealed that thepatient with small bowel stricturing was subsequentlydiagnosed as Crohn’s disease while a patient with smallbowel ulceration underwent small bowel resection at afurther presentation which confirmed NSAID enteropathyhistologically.

CONCLUSION

Inhibition of COX-1 and COX-2 by NSAIDs in thegastrointestinal tract has been associated with both adverseand beneficial effects. NSAIDs increase the risk ofhospitalizations due to complications from both the upperand the lower in the lower gastrointestinal tract, including thecolon. The effects of NSAIDs and COX-2 inhibitors inpatients with inflammatory bowel disease are still unclear.

Review Article


Experimental studies suggest that COX activity affordsprotection against colonic ulceration and that 5-LO-derivedleukotrienes are not required for the development ormaintenance of spontaneous or NSAID-induced colonicinflammation. By inhibiting COX-2 or other tumorigeniclinked targets, long-term treatment with NSAIDs, especiallyASA, or the new nitric oxide-NSAIDs derivates, mayprevent colon cancer in selected populations.

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non-steroidal anti inflammatory drugs and gastrointestinal toxicity

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