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.

1. NON-STEROIDAL ANTI INFLAMMATORY DRUGS AND
GASTROINTESTINAL TOXICITY.

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
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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.
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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.
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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.
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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
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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
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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
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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

10. Review Article
Experimental studies suggest that COX activity affords
protection against colonic ulceration and that 5-LO-derived
leukotrienes are not required for the development or
maintenance of spontaneous or NSAID-induced colonic
inflammation. By inhibiting COX-2 or other tumorigenic
linked targets, long-term treatment with NSAIDs, especially
ASA, or the new nitric oxide-NSAIDs derivates, may
prevent colon cancer in selected populations.
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