310 Current Drug Safety, 2011, 6, 310-317

Adverse Drug Reactions and Safety Considerations of NSAIDs: Clinical

Analysis
Shiv Bahadur, Lav Keshri and Kamla Pathak*

Rajiv Academy for Pharmacy, Department of Pharmaceutics, National Highway#2, P.O. Chhattikara, Mathura, 281001,
Uttar Pradesh, India

Abstract: NSAIDs are the most frequently used drugs for treatment, in Europe and the United States, accounting for
approximately 5% of all prescriptions. Moreover, the use of NSAIDs is increasing because these constitute the first-line
drug therapy for a wide range of rheumatic conditions. This increase is in part the result of the increasing population of
elderly patients, who constitute the group of patients with greatest demand for these agents. There are many types of
NSAIDs that vary in potency, action and potential side effects. Thus various efforts have been made to determine the
safety considerations including adverse drug effects, duration of drug therapy, drug interactions, precautions and other
drugs applied to reduce side effects. Researchers have introduced some novel techniques to diagnose NSAIDs related
adverse effects on the gastrointestinal mucosa. The researchers dealing with the development of drug delivery system for
these drugs should aim at designing a therapeutically efficacious dosage form with reduced side/adverse effects. Thus an
effort has been made in this review to deal with the safety parameters of various NSAIDs with a special emphasis on
preclinical and clinical safety analysis and various attempts to minimize the side effects by structural modification or by
drug delivery system.
Keywords: Adverse effects, COX-2 inhibitors, COX- 3 inhibitors, drug safety, NSAIDs, non- selective NSAIDs.

INTRODUCTION
Non-steroidal anti-inflammatory drugs (NSAIDs) are
widely used medicines for treatment of arthritis and many
other painful conditions. Most NSAIDs are available only on
prescription; however, some can be bought over the counter
in shops and pharmacies. NSAIDs are the most commonly
used medications in the United States. It is reported that
seventy percent people of 65 years or older, use NSAID
(including aspirin) at least once in a week, and 34% at least
one pill per day. In a study it was found that approximately
111,400,000 prescriptions for NSAIDs are filled in the
United States annually at a cost of 4.8 billion dollars [1]. The
predominant factor that limits their use is gastrointestinal
(GI) toxicity.
NSAIDs act by blocking cyclo-oxygenases (COX-1 and
COX-2) that are responsible for the inflammation process.
NSAIDs vary in their ability for the selection of cyclo-
oxygenase enzymes. Selective inhibitors of COX-2 (Coxibs)
have a more targeted mechanism against COX-2 enzyme and
for this reason are thought to have fewer side-effects on the
gastrointestinal system. The risk of oral NSAIDs including
COX-2 inhibitors can cause gastrointestinal, renal, hepatic or
cardiovascular adverse effects that are related to the systemic
exposure, but may be reduced by local application.
Consequently there are very few reports on safety
considerations of local drug application of NSAIDs [2].
NSAIDs are generally well-tolerated and are associated
with common side-effects like gastrointestinal irritation (e.g.
abdominal pain, heartburn, nausea, and vomiting) on short
*Address correspondence to this author at the Department of Pharmaceutics,
National Highway#2, P.O Chhatikara, Mathura, 281001, Uttar Pradesh,
India; Tel: +919897612318; E-mail: kamla_rap@yahoo.co.in
term use. On prolonged use or ingesting high doses may lead
to adverse effects like gastrointestinal ulceration or bleeding.
NSAIDs can also cause allergic reactions, fluid retention and
various other side-effects. The cardiovascular risk with non-
selective NSAIDs was considered earlier by the UK and
European expert committees. Since then further evidence has
emerged which suggests that all the NSAIDs except aspirin
may be associated with an increased risk of thrombotic
events (e.g., heart attack or stroke) when used at high doses
and for a long time. Selection of an appropriate analgesic is
based on consideration of the risk-benefit factors of each
class of drugs, based on type of pain, severity of pain and
risk of adverse effects.
In acute pain, patients may be safely treated with
NSAIDs in limited doses, as high doses concern ulcerogenic
risks. For the NSAIDs, the risk of gastric ulcers may be dose
limiting. Therefore drugs and their doses should be adjusted
based on observation of therapeutic efficacy. Switching
patients from high to low doses and from narcotic analgesics
to non-narcotics is recommended when circumstances
permit. While the selective COX-2 inhibitors, celecoxib and
rofecoxib, represent advances in reduction of adverse effects,
are not fully suitable for long-term management of severe
pain. Generally, chronic pain management requires a
combination of drug therapy, life-style modification and
other treatment means. Presently, there is a $20 billion
market of analgesics and $4billion is needed to treat side-
effects [3]. Statistics from the Daily Telegraph suggest that
2000 deaths per annum happen due to aspirin alone. 20% of
the patients taking NSAIDs are associated with adverse
gastrointestinal and as per the annual estimation 107,000
hospitalizations and 16,500 deaths are attributed to NSAIDs
related GI complications. COX-2 inhibitors produce fewer
GI events than other NSAIDs but all NSAID’s even if they
are COX-2 inhibitors, have a portfolio of adverse effects [3].

1574-8863/11 $58.00+.00 © 2011 Bentham Science Publishers

Adverse Drug Reactions and Safety Considerations of NSAIDs
Today, NSAIDs are widely used to treat inflammatory
conditions and acute pain by inhibiting cyclo-oxygenase
(COX)-2 mediated production of prostaglandins. Non-
selective NSAIDs are known to cause gastrointestinal
toxicity and a variety of nephrotoxic syndromes. An
alternative is selective COX-2 inhibitors available in the
form of older or newer agents. The newer COX-2 inhibitors
have been introduced into clinical practice and developed as
NSAIDs with an improved gastrointestinal side effect profile
[4]. The cardiovascular safety of all marketed newer COX-2
inhibitors requires thorough evaluation in view of the
increased cardiovascular and renal risk reported for several
of these drugs. Atrial fibrillation is the most common rhythm
disorder observed in clinical practice. It is associated with
increased mortality and morbidity mainly due to
haemodynamic impairments that exacerbate or even cause
heart failure and a threefold to fourfold increased risk of
thrombo-embolic stroke [5]. Use of NSAIDs may increase
the risk of atrial fibrillation through its adverse renal effects
for example fluid retention, electrolyte disturbances and
blood pressure destabilisation but the evidence for such
effects is limited. Although no original research has been
published on COX-2 inhibitors and atrial fibrillation, a meta-
analysis summarised data from 114 clinical trials found that
rofecoxib is associated with an increased risk of cardiac
arrhythmias [6]. As the meta-analysis included only 286
incident arrhythmias, precision was low and risk of
arrhythmia subtypes such as atrial fibrillation could not be
examined. Any confirmed association between use of
NSAIDs and atrial fibrillation would have major clinical and
public health implications. Older people are of special
concern because the prevalence of use of NSAIDs and the
incidence of atrial fibrillation increases with age. To address
the limitations of the existing literature a large population
based case-control study was conducted to examine to what
extent the use of NSAIDs increases the risk of atrial
fibrillation or flutter [6]. Currently there are approximately
50 different NSAIDs preparations available and as a class
they are the most commonly prescribed drugs. Guidelines for
usage have been suggested on the basis of research reports
and some meta-analysis worldwide [7]. This article is a
compilation of clinical reports and meta analytical data of
each class of NSAIDs.
CLASSIFICATION OF NSAIDs
NSAIDs have been classified on the basis of their
selectivity of COX isoforms as mentioned in Table 1. Non
selective cox inhibitors have similar selection ratio for cox-1
and cox-2. While preferential cox-2 inhibitors like
meloxicam have cox-2: cox-1 preference ratio of 13:1.
Table 1. Classification of NSAIDs with Examples
Nonselective COX Inhibitors Preferential COX-2 Inhibitors
Asprin, Ibuprofen, Naproxen, Ketoprofen, Nimesulide, Meloxicam,
Flurbiprofen, Mephanemic acid Nabumetone
Diclofenac, Aceclofenac
Piroxicam, Tenoxicam,
Ketorolac, Indomethacin,
Phenylbutazone, Oxyphenbutazone
Current Drug Safety, 2011, Vol. 6, No. 5 311
Similarly selective COX-2 inhibitors have selectivity only to
the COX-2 isoform [8].
NON SELECTIVE NSAIDs
Most of the NSAIDs available are nonselective inhibitors
of cyclo-oxygenase enzymes, acting on both COX-1 and
COX-2 isoforms to decrease formation of prostaglandins and
thromboxanes. This is actually the primary mechanism by
which the NSAIDs act to show their actions including
analgesic, antipyretic, anti-inflammatory, and anti-platelet
effects [8].
Adverse effects of NSAIDs include a wide variety of
pharmacological and presumed immunologic reactions that are
characterized by their clinical presentation. Pharmacological
reactions induced by non selective NSAIDs are dependent on
inhibition of the COX-1 pathway and supposed immunologic-
mediated reactions are dependent on drug-specific IgE
production against NSAIDs. Patients taking NSAIDs may not
always produce one type of adverse reactions but mixed adverse
reactions may be caused such as a predominant urticarial
response with a less prominent respiratory tract reaction.
Similarly, the same NSAID can induce a pharmacological
reaction at one time and presumed IgE-mediated reaction at
another time in the same patient [9]. The tendency of NSAIDs
to cause adverse effect at various sites in the body is shown in
Table 2. Various adverse effects produced by non selective
NSAIDs are:
NSAIDs Induced Ulcer
There has been a deep relationship between the NSAIDs
and their tendency to cause gastro-dueodenal disorders.
Patients undergoing rheumatoid arthritis and osteoarthritis
treatment are 15 to 20% prone to ulcer incidence taking
NSAIDs [8, 10]. The overall risks of ulcer disease and
adverse gastrointestinal effect are more in patient taking
NSAIDs than compared to the control group. In the study
performed by Smalley and Griffin, observed that
approximately 20 million patients taking NSAIDs on a
regular basis showed 1–2% risk for hospitalization for
serious GI adverse effects resulting in approximately
200,000 to 400,000 hospitalizations per year at an average
cost of $4,000 per patient, or 0.8 –1.6 billion dollars annually
in United States [11]. Certain factors that have been found to
be responsible for placing patients at increased risk for
NSAID-related GI complications include- (1) prior history of
gastrointestinal event (ulcer, hemorrhage); (2) age >60 yr;
(3) high dosage; (4) concurrent use of corticosteroids and (5)
concurrent use of anticoagulants.
Selective COX-2 Inhibitors Preferential COX-3 Inhibitors
Celocoxib, Etoricoxib, Parecoxib, Acetaminophen, Phenacetin,
Valdecoxib Dipyrone
312 Current Drug Safety, 2011, Vol. 6, No. 5 Bahadur et al.

Table 2. Adverse Effect of NSAIDs and their Mechanism of Injury

Site of Damage Mechanism of Injury Adverse Effect

Gastrointestinal tract Prostaglandins protect the gastric mucosa by decreasing gastric acid secretion Peptic ulcer
and increasing mucus and bicarbonate secretion. NSAIDs inhibit PGs
synthesis and inhibit protection mechanism
Liver NSAIDs may cause hepatotoxicity and cholestatic damage which may result in Hepatitis, cirrhosis
increase aminotransferase and bilirubin levels
Kidney PGs regulate renal blood flow and maintains glomerular flow rate and sodium Renal stenosis, congestive heart failure
and water excretion. NSAIDs inhibit PGs synthesis preventing these effects.
Lungs NSAIDs block COX enzyme and may cause increase level of leukotrienes Aspirin sensitivity, asthma
resulting in bronchoconstriction
Hemovascular system NSAIDs may causes vasoconstriction and platelet aggregation by inhibiting Advanced age trauma
PGs synthesis

There are also some differences in the propensity of
individual agents to cause gastrointestinal ADRs. The
occurrence of gastrointestinal adverse side effect is more
prevalent with the use of non selective NSAIDs while the
use of preferential COX-2 inhibitors reduces the prevalence
of GI disorders. Similarly selective COX-2 inhibitors have
minimum GI related ADRs. Indomethacin, ketoprofen and
piroxicam appear to have the highest prevalence of gastric
ADRs, while ibuprofen (lower doses) and diclofenac appear
to have lower rates [12].
Various clinical trials had been performed on small scale,
on healthy volunteers, using a mucosal injury grading system
(e.g. grading sub-epithelial haemorrhage and erosions) as an
outcome measure. These studies suggested that low-dose
aspirin (75–100 mg) resulted in lower damage to GI mucosa
than higher doses, such as 300–325 mg. Furthermore, enteric
coating tablet is likely to decrease acute topical mucosal
injury when compared to plain or buffered aspirin [13-15].
The NSAIDs induced ulcers can be prevented by various
ways. Patients at high risk for hemorrhage and perforation
from NSAID-induced ulcers should be considered for
prophylaxis with misoprostol. However, several studies
showed that drop-out due to gastrointestinal intolerance
negate the potential benefit. Proton pump inhibitors also
constitute one of the most acceptable alternatives for
prevention of NSAIDs-related complications. H2 receptor
antagonists have been shown to prevent only duodenal ulcer,
and therefore cannot be recommended for prophylaxis [8].
Rhinitis and Asthma Induced by NSAIDs
Respiratory tract reactions (rhinorrhea, bronchospasm,
and layrngospasm) are the common side effects associated
with the use of NSAIDs that generally occurs in patients
with past history of asthma, nasal polyps or rhinosinusitis
[16]. Generally these reactions are caused by aspirin and are
referred as aspirin-induced asthma, aspirin sensitivity,
aspirin intolerance, or more appropriately aspirin-
exacerbated respiratory tract disease (AERD). The levels of
prostaglandin E2 are rapidly decreased during NSAID-
induced respiratory tract reactions due to COX-1 inhibition
[17]. The decrease in prostaglandin E2 level leads to absence
of the braking effect of prostaglandin E2 on 5-lipoxygenase
activating protein and 5-lipoxygenase enzyme, resulting in
uncontrolled synthesis of new leukotrienes and release of
histamine from mast cells. Patients with AERD are
particularly susceptible to the effects of leukotrienes that are
manifested by excessive naso-ocular and asthmatic reactions.
This airway hyper-reactivity may become severe enough to
require intubation. Patients taking more than one NSAIDs
have tendency to cross-react with each other [18].
Urticaria/Angioedema Induced by NSAIDs
Hypersensitivity to NSAIDs, resulting in urticaria and
angioedema, is being observed with increasing frequency.
Prevalence rate ranges from 0.1-0.3%, which is partly due to
the large size of the exposed population [19]. The patients
having a history of chronic idiopathic urticaria (CIU)
frequently experience an exacerbation of their
urticaria/angioedema when administered with any NSAIDs.
The occurrence of NSAID-induced urticaria in patients with
CIU is between 20% and 30% [20]. The pathogenesis of
NSAID-induced urticaria is generally unknown but may be
treated in similar way to AERD and it may be concluded that
patients with CIU are sensitive to COX-1 inhibition by
NSAIDs. Thus, these patients will have tendency to cross-
react with all NSAIDs that inhibit COX-1 resulting in this
adverse effect. It is believed that excessive leukotriene
production by 5-lipoxygenase enzyme causes increased
vasopermeability, resulting in urticaria. Patients with
acetylsalicylic acid desensitization protocols have recurrent
flare-ups of urticaria until the NSAID is withdrawn [21].
The patient having suspected NSAID sensitivity should
be determined by the mechanism of an adverse reaction of
NSAID. Sometimes the differentiation between the two
mechanisms is sometimes difficult due to occurrence of
double blended reactions. However, historical data indicated
that COX inhibition mechanism include reactions occurring
with the exposure to the medication and cross-reactivity to
other COX-1-inhibiting NSAIDs. Similarly, clues to indicate
an IgE-mediated mechanism occurs due to lack of cross-
reactivity with other NSAIDs and need for prior exposure to
initiate an immune-mediated reaction [18, 22]. If COX-1
inhibition is suspected as the mechanism, then aspirin
desensitization should be strongly considered, as the patient
will cross-react with acetylsalicylic acid given the similar
COX-1 inhibition mechanism.
Management of patients to these side effects can be
affected in following ways – avoidance of cylooxygenase-1
Adverse Drug Reactions and Safety Considerations of NSAIDs
inhibiting NSAIDs; use of alternative NSAIDs (weak COX-
1 inhibitors) such as salycilate, sodium salycilate,
salicylamide, choline-magnesium trisalicylate, floctafenine
or COX-2 inhibitors (coxibs) for relief of pain, fever or
inflammation; high-dose topical (nasal, inhaled)
corticosteroids; use of systemic corticosteroids; CysLT1-
receptor antagonists along with or without 5- lipooxygenase
inhibitors; surgery; sinus drainage, polypectomy; use of
antihistamines and desensitization.
NSAIDs-Induced Hypertension
The patients suffering from hypertension may have
increased activation of renin-angiotensin and sympathetic
nervous system, with subsequent release of vasodilator
prostaglandins from kidney, that act locally to diminish the
degree of renal ischemia. When this response is inhibited by
NSAIDs then increase in renal and systemic vascular
resistance can cause high blood pressure averaging 3 to 6
mm Hg. This effect may be most pronounced in salt
sensitive patients and those ingesting a relatively high salt
diet. In a prospective study of over 80,000 women of 31 to
50 years age, without any history of hypertension, the
relative risk for development of hypertension after 2 years of
follow up was 1.86 with NSAIDs compared to non-NSAIDs
except with aspirin [23]
NSAIDs Caused Parkinsonism
The use of NSAID’s and its tendency to cause
Parkinsonism disease was observed by Etminan and Suissa.
They selected a group of people undergoing antihypertension
therapy and used nest- case control design to access the
association between the NSAIDs usage and development of
parkinsonism disease. The study performed using 1259 cases
and 12590 controls, resulted that, in comparison to non-
NSAIDs user, the NSAIDs users had increased risk of
developing parkinsonism disease. This may be due to the
early identification of the Parkinsonian like symptoms in
those taking NSAIDs and putting them on parkinsonism
disease therapy. It may be also possible that the NSAIDs
may inhibit the action of antihypertensives which may cause
increase in the risk of parkinsonism [24].
Hepatic Adverse Events with NSAIDs
Although hepatic adverse effects associated with the use
of the NSAIDs are uncommon but the wide spread use of
these drugs may impact public health. Epidemiological
studies have reported incidence of acute liver injury to be 1
to 9 cases among the 100,000 users of NSAIDs. This effect
may increase with concurrent use of the other hepatotoxic
medications. Practically, different hepatic disorders have
been reported with the use of all NSAIDs [8]. Although,
most of the cases are mild and asymptomatic with liver
returning to the normal, on cessation of the treatment.
However, hepatic toxicity is the one of the leading causes of
withdrawal of NSAID from the US market even after one
year on the market. In recent years nimeuslide was
withdrawn in various countries (e.g. Finland, Israel, Portugal
and Spain) after post-marketing surveillance, due to risk of
liver toxicity. In post-marketing period, both celecoxib and
rofecoxib have also been associated with liver disorders [25].
Current Drug Safety, 2011, Vol. 6, No. 5 313
In a case study analysis data of WHO/UMC and FDA/FOI it
was found that bromfenac, nimesulide, sulindac and
diclofenac exhibit higher hepatic disorders compared to other
NSAID. The data did not give the safety concern for
celecoxib or rofecoxib vs NSAIDs for overall hepatic
disorders and hepatic failure [25]
PREFERENTIAL COX-2 INHIBITORS
The preferential COX-2 inhibitors are the drugs which
effectively inhibit both isoforms COX-1 and COX-2
enzymes but have more affinity for COX-2 enzymes and
therefore undesirable side effects tend to occur despite
preferential inhibition of COX-2 isoenzymes [26].
Meloxicam is a new NSAID which has greater inhibitory
action against the inducible isoform of cyclo-oxygenase
(COX-2) than the constitutive form of this enzyme (COX-1),
responsible for the anti-inflammatory response. These
inhibitions are responsible for various adverse effects like
gastric and renal adverse effects. Clinical trials on
meloxicam revealed the drug related gastrointestinal side-
effect, is due to its more selective inhibition of COX-2
relative to COX-1 enzyme [27, 28].
Martin et al. studied the incidence of adverse events and
risk factors for the upper gastrointestinal disorders associated
with meloxicam. 19087 patients were selected for the study
and it was concluded that during the exposure of drug, in the
first month the rate of dyspepsia was 28.3 per 1000 patient.
Thirty three cases of upper gastrointestinal haemorrhage
were reported during the treatment. A history of
gastrointestinal disorder in the previous report was
associated with an increased rate of dyspepsia, abdominal
pain and peptic ulcer. Prior NSAID use was associated with
a 20±30% decrease in the rate of dyspepsia and abdominal
pain in patients starting meloxicam, while patients prescribed
with concomitant gastro-protective agents had a two to three-
fold increased rate of dyspepsia, abdominal pain and peptic
ulceration. Apart from these there were other events reported
as thrombocytopenia, interstitial nephritis and idiosyncratic
liver abnormalities [29].
Chopra et al. performed a randomized clinical trial of
meloxicam on rheumatoid arthritis and osteoarthritis and
compared its efficacy with piroxicam and diclofenac. The
study included 121 patients with rheumatoid arthritis (RA)
and 133 patients with osteoarthritis (OA) knees were
selected which were randomized into two different multi-
centric, double-blind, drug trials of four- weeks duration
each. 7.5 mg and 15mg meloxicam was administered for OA
and RA study and was compared to diclofenac 100 mg and
piroxicam 20 mg in daily dosages. No significant differences
were reported between meloxicam and piroxicam in the RA
study as the joint count for the pain and tenderness improved
(P < 0.05) with both meloxicam and piroxicam. On the other
hand meloxicam showed significant improvement (P < 0.05)
in swollen joints. Osteoarthritis study revealed that although
diclofenac showed marginally better pain VAS (visual
analogue scale) reduction but meloxicam and diclofenac
showed equal effect in improving WOMAC (Western
Ontario and McMaster Universities osteoarthritis index)
physical function. Finally it was stated that meloxicam
showed superior safety and gut tolerability compared to both
the drugs. The drug toxicity in the trials was found to be
314 Current Drug Safety, 2011, Vol. 6, No. 5
mild as only 1 patient reported haemoturia with diclofenac
[30].
In the early 1990s nimesulide was introduced in the
Indian market for the management of pain, fever and
inflammatory conditions. Recently, nimesulide has been
found to cause hepatotoxicity. Moreover the efficacy and
safety of nimesulide in pediatric as well as adult population
in different clinical situations have been demonstrated by its
extensive prescription of drug in more than 50 countries past
17 years. Recently, controversial and ambiguous reports
were available which showed cases of hepatotoxicity. In
India, the sales of nimesulide have reached upto 1200 lac
unit with a steady growth of 18% in the last few years while
an international survey on 300 doctors in Europe recognized
it as the most effective and one of the safest NSAID
available in the market [31].
Nabumetone had been evidenced to have lower risk of
gastrointestinal side effects than most of the NSAIDs since it
is a non-acidic prodrug which is then metabolized to its
active 6MNA (6-methoxy-2-naphthylacetic acid) form after
systemic exposure. However, like the other NSAID
medications, it still can cause abdominal pain, cramping,
nausea, gastritis, and liver toxicity. Nabumetone should be
avoided by patients with a history of exacerbation of asthma,
hives, or other allergic reactions to aspirin or other NSAIDs.
Rare but severe allergic reactions have been reported in such
individuals [32].
SELECTIVE COX-2 INHIBITORS
Selective COX-2 inhibitors are the class of NSAIDs
which act by inhibiting the COX-2 enzyme. The potential
side effect related to this class of drugs is the ability to cause
cardiotoxicity and cardiac disorders. Atrial fibrillation is the
most common rhythm disorder observed in clinical practice
with COX-2 inhibitors. The prevalence of the NSAIDs
induced atrial fibrillation increases as the life advances, from
0.5% chance of occurrence at the age of 50-59 years to more
than 10% at the 80- 89 years [5]. It is mainly associated with
increased morbidity and mortality due to hemodynamic
impairments that may finally lead to heart failure and 3 to 4
fold increase in thromboembolic stroke risk. Clinical trials
on 114 patients for rofecoxib showed that it has increased
risk of cardiac arrhythmias (relative risk 2.90, 95%
confidence interval 1.07 to 7.88). Some reports are available
indicating that the non selective NSAIDs and selective COX-
2 inhibitors have been associated with increased risk of
chronic atrial fibrillation [5].
The meta-analysis, involving 1,16,094 patients using
newer COX-2 inhibitors, had 6394 composite renal outcome
events compared to 286 composite arrhythmia outcome
events, of which ventricular fibrillation, cardiac arrest, and
sudden cardiac death accounted for the most. Rofecoxib was
associated with an increased relative risk for the composite
renal outcome of 1.53 (95% confidence interval 1.33 to 1.76)
and the composite arrhythmia outcome (2.90, 1.07 to 7.88).
Small number and types of arrhythmias available for analysis
did not allow for examination of atrial fibrillation as an
outcome. It was found that the risk of atrial fibrillation or
flutter was increased while using older and newer COX-2
inhibitors [33].
Bahadur et al.
The selective COX-2 NSAIDs have shown better GI
tolerability and less GI toxicity when compared to non-
selective NSAIDs [34]. Various clinical reports are available
on comparison of selective COX-2 inhibitors with the non
selective NSAIDs and are illustrated in Table 3.
COX-2 inhibitors have also been found to cause renal
toxicity. In normal subjects basal rate of renal prostaglandin
synthesis is relatively low and does not play a major role in
the regulation of renal hemodynamics. Release of renal PGI 2
and PGE2 increased by glomerular disease, renal
insufficiency, hypercalmia and in case of effective volume
depletion like heart failure, cirrhosis and true volume
depletion. In these situations renal vasodialator prostaglandin
maintain glomerular filtration rates and renal blood flow by
relaxing preglomerular resistance and antagonizing
vasoconstrictor effects of angiotensin II and norepinephrine.
Under this situation NSAID inhibition of prostaglandin
synthesis can cause reversible renal ischemia resulting in
decline in globular hydraulic pressure, glomerular filtration
rate and acute renal failure. COX-2 selective or non-selective
NSAID may cause acute renal failure. In a case controlled
study in 121,722 patients of older than 65 years of age higher
the risk of renal failure was observed within 30 days of
treatment. Use of NSAID is also associated with acute
interstitial nephritis, membranous nephropathy and nephritic
syndrome. The underlying pathophysiological mechanisms
are not known due to minimal change in disease [7].
COX 3 INHIBITORS
COX-3 is an enzyme that is encoded by the PTGS1
(COX1) gene, but is not functional in humans. COX-3 is the
third and most recently discovered cycloxygenase(COX)
isozyme, the others being COX-1 and COX-2. The COX-3
isozyme is encoded by the same gene as COX-1, with the
difference that COX-3 retains an intron that is not retained in
COX-1 [44,45].
Phenacetin, analgesic/antipyretic drug that has been
withdrawn from the market because of the occurrence of
methemoglobinemia, renal toxicity, and suspected renal and
bladder carcinogenesis is COX-3 inhibitor. Phenacetin, in
body gets converted to acetaminophen by O-deethylation,
that is further metabolized to other minor but toxic
compounds. Thus, only small levels of phenacetin circulate
in the blood. Chandrashekaran et al. reported that phenacetin
was more potent in inhibiting COX-3 than acetaminophen as
phenacitin at30 μM inhibited COX-3 at an IC50 value of 102
μM, while 460 μM of acetaminophen was required to
produce same effect under similar conditions. As with
acetaminophen, phenacetin preferentially inhibits COX-3.
Another analgesic/antipyretic drug, dipyrone, was also
significantly more potent at inhibiting COX-3 than either
COX-1 or -2. Dipyrone inhibited COX-3 with an IC50 value
of 52 μM and COX-1 at a 6.6-fold higher concentration [46].
The safety aspects of COX-3 are a matter of concern that
needs extensive clinical investigations.
TREATMENT GUIDELINES FOR NSAIDs
Guidelines for NSAIDs treatment have been put forward
by American College of Gastroenterology (ACG), European
League against Rheumatism (EULAR) and International
Adverse Drug Reactions and Safety Considerations of NSAIDs Current Drug Safety, 2011, Vol. 6, No. 5 315

Table 3. Comparison of Selective COX-2 Inhibitors vs NSAID with Respect to Gastrointestinal Tolerability

Selective COX-2 Control Non Selective Number of Duration of

Conclusion References
NSAID NSAID Patients Treatment

Celecoxib100, 200 or Naproxen 500mg bid 1149 RA 12 weeks There was no difference in the occurrence of [34]
400mg bid patients gastrointestinal ulcer between the placebo and
any dose of Cel while naproxen showed higher
rate of incidence of gastrointestinal ulcer
compared to placebo and celecoxib
Celecoxib 400mg Ibuprofen 800 mg tid or 8059 OA or 6 months The combined incidence of symptomatic ulcers [35]
diclofenac 400mg bid RA patients and ulcer complication was lower with Cel
compared to control NSAIDs
Celecoxib 200mg or Naproxen 1000mg/day or 13274 OA 12weeks Comparatively less complication of [36-38]
400mg/ day diclofenac 100mg/day patients symptomatic ulcers in upper GI tract with Cel
compared with Control NSAIDs
Celecoxib 200mg bid Diclofenac SR 75mg bid 655 RA 24 weeks The incidence of Ulcers and the withdrawal rates [39]
patients due to GI toxicity was higher for diclofenac
compared to celecoxib
Rofecoxib 250mg/day Ibuprofen 800mg tid or 170 healthy 1 week Rofecoxib caused significantly less [40]
aspirin 650 mg qds volunteers gastrointestinal mucosal damage compared with
ibuprofen and aspirin
Rofecoxib 50 mg/day Naproxen 500mg bid 8076RA 1 year Rofecoxib showed significantly fewer upper GI [41, 42]
patients events compared to naproxen
Etoricoxib 90/120 Ibuprofen 2400mg/day and 588 6 months Etoricoxib showed mild nausea in few volunteer [43]
mg/day paracetamol 2400mg/day volunteers but ibuprofen and paracetamol reported GI
bleeding in some volunteers.

Working Party (IWP). The current treatment guideline states
that NSAIDs should be used in lowest effective dose so that
prolonged use can be avoided. The patients with increased
gastrointestinal risk should be recommended NSAIDs with a
gastro protective agent (proton pump inhibitors (PPI) or
misoprostol) or COX-2 selective inhibitors. The ACG and
IWP recommend PPI or misoprostol to be prescribed with
COX-2 inhibitors when high risk for GI events is anticipated.
The guideline from National Institute for Health and Clinical
Excellence (NICE) recommends that PPI to be prescribed
with all the NSAIDs including COX-2 inhibitors. The 2008
American College of Cardiology Foundation/ACG/American
Heart Association (AHA) reported that for reducing the risk
of antiplatelet treatment and NSAID the PPI must be
preferred gastroprotective agents for the treatment and
prevention of GI toxicity related to use of NSAIDs including
aspirin [6].
In patients receiving long term NSAIDs, treatment to
reduce GI risk and eradication of H. pylori infection is
recommended. The guidelines from AHA and Osteoarthritis
Research Society International (OARSI) give that the
patients with cardiovascular risk, COX-2 inhibitors should
be prescribed in lowest dose in circumstances when no
alternative of COX-2 inhibitors is available and shortest
duration of therapy is mandatory. The ACG and IWP advise
most of the COX-2 inhibitors are not suitable in patients with
high cardiovascular risk and only naproxen can be the choice
of NSAID. The ACG and IWP also states that the in patients
with history of GI event and high cardiovascular risk (having
CV disease or requiring aspirin for prevention of CV events),
COX-2 inhibitors and NSAIDs are not suitable and in this
condition other treatments should be preferred. WIP also
suggests that these patients can be given naproxen with a PPI
or misoprostol. In certain patients having high risk for both
GI and CV events, an appropriate treatment strategy is yet to
be identified [47].
Physicians must consider both gastrointestinal and
cardiovascular risks of individual patients before prescribing
NSAIDs. As a central dictum in NSAID treatment, physician
should always prescribe the lowest effective dose for shortest
possible time. In case of ulcers and in symptomatic patients
with no ulcer history, the physician should first consider H.
pylori before long term therapy of the NSAID therapy.
Patients with low gastrointestinal risk can be treated with
non-selective NSAID and patients with moderate
gastrointestinal risk may be treated with either non-selective
NSAID with PPI or misoprostol or with COX-2 selective
NSAID. In patients having high gastrointestinal risk
alternative treatment option like prophylactic low dose of
aspirin and additional NSAID may be explored. Naproxen is
the most preferred NSAID in combination with PPI or
misoprostol. Naproxen is advised to be taken 2 hours after
aspirin.
CONCLUSION
In summary the NSAIDs are the oldest and most
successful drugs known to modern medicine used for
alleviating pain, fever and inflammation by inhibiting
prostaglandin synthesis. Additionally NSAIDs may also
inhibit colorectal carcinogenesis. The efficacy of NSAIDs
varies by patients and by indication. NSAIDs may cause
gastrointestinal ulcers which may be complicated by ulcer
bleeding. High dose of nonselective NSAIDs and COX-2
selective may cause serious cardiovascular events like
myocardial infarction and are also related with development
of hypertension, acute renal failure and worsening pre-
existing heart failure. Patient with both, cardiovascular and
316 Current Drug Safety, 2011, Vol. 6, No. 5
gastrointestinal risk should avoid NSAID therapy. If an anti-
inflammatory drug is needed, the choice lies between those
that are more likely to cause gastrointestinal side effects
(which can be fairly severe) or those that may cause more
cardiovascular problems. The "right" decision will vary from
patient to patient, and will require an informed patient as
well as an informed doctor. In a pain-producing condition or
an inflammatory disease like arthritis an estimate of the risk
vs benefit of taking NSAIDs needs to be forecasted.
CONFLICT OF INTEREST
Authors have no conflict of interest
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Received: August 4, 2011 Revised: November 10, 2011 Accepted: November 21, 2011