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Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) which are widely used in clinical practice are also very well-known for their various adverse reactions. Each NSAID has its own unique safety profile and selecting an appropriate NSAID must be individualized for each patient based on his or her medical needs and risk factors. We reviewed literatures on NSAIDs, focusing on their adverse reaction profile. We reviewed and compared the incidence of adverse reaction from individual NSAIDs according to organ systems. This review includes both selective COX-2 inhibitors and non-selective NSAIDs. Based on the most up-to-date evidence, ibuprofen appears to be the preferred NSAIDs based on its favorable GI and nephrotoxicity profiles. Naproxen might be considered in patients who have greater cardiac risk. Celecoxib, at the dose of less than or equal to 200 mg day −1 , might be an option in the patients who are at high risk for GI bleeding.
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American Medical Journal 3 (2): 115-123, 2012
ISSN 1949-0070
© 2012 Science Publications
Corresponding Author: Patompong Ungprasert, Department of Internal Medicine, Bassett Medical Center and Columbia University,
College of Physicians and Surgeons, Cooperstown, New York
What Is The “Safest” Non-Steroidal Anti-Inflammatory Drugs?
Patompong Ungprasert,
Wonngarm Kittanamongkolchai,
Chrystal Price,
Supawat Ratanapo,
Napat Leeaphorn,
Daych Chongnarungsin and
Wisit Cheungpasitporn,
Department of Internal Medicine,
Bassett Medical Center and Columbia University,
College of Physicians and Surgeons, Cooperstown, New York
Abstract: Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) which are widely used in clinical
practice are also very well-known for their various adverse reactions. Each NSAID has its own unique
safety profile and selecting an appropriate NSAID must be individualized for each patient based on his
or her medical needs and risk factors. We reviewed literatures on NSAIDs, focusing on their adverse
reaction profile. We reviewed and compared the incidence of adverse reaction from individual
NSAIDs according to organ systems. This review includes both selective COX-2 inhibitors and non-
selective NSAIDs. Based on the most up-to-date evidence, ibuprofen appears to be the preferred
NSAIDs based on its favorable GI and nephrotoxicity profiles. Naproxen might be considered in patients
who have greater cardiac risk. Celecoxib, at the dose of less than or equal to 200 mg day
, might be an
option in the patients who are at high risk for GI bleeding.
Key word: Non-Steroidal Anti-Inflammatory Drugs (NSAIDs), COX-2 inhibitor, adverse drug
reaction, adverse reactions, safety profile, clinical practice, organ systems
Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)
are the most commonly used medications in the United
States (Laine, 2001). They are primarily used as pain
killer as well as anti-inflammatory agent. Currently, there
is nineteen NSAIDs available in the United States (Table
1). With the continued aging of our population, the
Center for Disease Control predicts that the prevalence of
painful degenerative joint disease will increase, which
will probably lead to an increase in the use of NSAIDs.
NSAIDs are well-known for their adverse drug
reaction. Approximately 30% of hospitalizations of
adverse drug reactions are caused by NSAIDs
(Pirmohamed et al., 2004). Adverse reactions can affect
various organ systems with gastrointestinal bleeding
and cardiovascular events being the most serious and
sometimes fatal reaction.
Most of the toxic effects of NSAIDs are a direct
result of their mode of action which includes
suppression of prostaglandins synthesis.
Cyclooxygenase (COX) is the key enzyme in
prostaglandin synthetic process that is inhibited by
Table 1: Available NSAIDs in the United States and their usual dose
Generic name Usual dose
Selective COX-2 inhibitor
Celecoxib 100-200 mg day
Non selective COX-2 inhibitor
Aspirin 2.6-6 g day 4-5 divided doses
Diclofenac 50 mg BID
Diflunisal 0.25-0.75 g BID
Etodolac 200-300 mg BID-QID
Fenoprofen 300-600 mg QID
Flurbiprofen 100 mg BID-TID
Ibuprofen 200-800 mg QID
Indomethacin 25-50 mg TID-QID
Ketoprofen 75 mg TID
Meclofenamate 50-100 mg TID-QID
Mefenamic acid 250 mg QID
Meloxicam 7.5-15 mg OD
Nabumetone 500 mg BID
Naproxen 250-500 mg BID
Oxaprozin 600 mg OD
Piroxicam 10-20 mg OD
Sulindac 150-200 mg BID
Tolmetin 400-600 mg TID
Ketorolac IV or IM 30 mg q 6hr
(max 120 mg day
COX enzyme has two isoforms COX-1 and COX-2.
COX-1 is expressed in most tissues; it serves as a
housekeeping enzyme responsible for normal cell
homeostasis. COX-2 is expressed in a limited number
Am. Med. J. 3 (2): 115-123, 2012
of organs in a normal physiologic condition but its
expression is inducible with inflammation. The
discovery of the two isoforms of the COX enzyme lead
to the development of selective anti COX-2 NSAIDs
with the hope of a reduction in adverse effects, most
specifically gastrointestinal bleeding (Flower, 2003).
Naming the universal “safest” NSAID deems
difficult because each NSAID has its own different
adverse reaction profile; “safety” priorities should be
individualized based upon patient’s concurrent
illnesses. This review will discuss the potential adverse
reactions of both conventions (non-selective) and
selective NSAIDs according to specific organ systems.
Cardiovascular effect: During the last 10 years, the
adverse cardiovascular effects of selective COX-2
inhibitors have been a highly debated issue. In October
2004, rofecoxib was withdrawn from US and world
market after a randomized placebo-controlled trial
found that it increased the incidence of Myocardial
Infarction (MI) and sudden cardiac death (Bresalier et
al., 2005). Attention has now turned to the
cardiovascular safety profile of the remaining selective
COX-2 inhibitor (celecoxib) and non-selective
NSAIDs. McGettigan and Henry (2006) conducted a
meta-analysis of an observational study and found that
celecoxib at doses of less than or equal to 200 mg day
appeared to be safe and did a not significantly increase
the risk of MI and sudden cardiac death. Conventional
NSAIDs including ibuprofen, indomethacin and
piroxicam, also did not increase the cardiac risk. Of
significant concern from this meta-analysis is,
diclofenac statistically increased the risk of
cardiovascular events with a Relative Risk (RR) of 1.36
(95% CI 1.21-1.54). A possible explanation for the
disparate result is that diclofenac is the most selective
for COX-2 compared with other conventional NSAIDs.
This study also showed a slight cardioprotective effect
of naproxen but without statistical significance (Table
2). Another meta-analysis which included only
randomized data revealed the same increased cardiac
risk from diclofenac and revealed no significant
cardioprotective benefit from naproxen. However, this
study found a significant increased risk with a daily
dose of celecoxib more than or equal 400 mg (Kearnry
et al., 2006).
Use of NSAIDs can worsen pre-existing heart
disease. The risk of worsening heart failure is well
illustrated in an observational study which found that
all the NSAIDs in the study (rofecoxib, celecoxib,
ibuprofen, diclofenac and naproxen) significantly
increased the incidence of death and re-hospitalization
because of heart failure and/or MI (Gislason et al.,
2009). The mechanism by which NSAIDs can cause
exacerbation of heart failure is related to their
vasoconstrictive effect leading to systemic hypertension
resulting in increased afterload (Dzau et al., 1984).
Furthermore, non-aspirin NSAIDs can interfere
with the beneficial anti-platelet effect of aspirin.
Concomitant administration of reversible COX-1
inhibitors may prevent irreversible platelet inhibition by
low-dose aspirin, due to competition between theses
drug and aspirin for a common binding site on COX-1.
At least two of conventional NSAIDs (ibuprofen and
naproxen) have been found to have this drug interaction
in vitro. This pharmacodynamic interaction is not seen
with selective COX-2 inhibitor or with diclofenac,
which has some degree of COX-2 selectivity (Catella-
Lawson et al., 2001; Capone et al., 2005). Whether this
interaction attenuates the cardioprotective benefit of
low-dose aspirin is unclear (Corman et al., 2005;
Rodiguez et al., 2004).
In conclusion, based on available data from the
mentioned study, NSAIDs should be avoided in patients
with MI or heart failure. In patients with lower cardiac
risk, NSAIDs might be used with caution with the
lowest effective dose and shortest possible duration.
Diclofenac should be avoided given the clear evidence
of increase incidence of MI and sudden cardiac death.
The only available selective COX-2 inhibitor,
Celecoxib, appears to be safe with the daily dose of not
more than 200 mg day
. Naproxen might be considered
for use in this group of patients given its slight
cardioprotective benefit, though this consideration is
based on data which lack statistical significance.
Gastrointestinal effects: Aspirin and other non-selective
NSAIDs are well-known for their gastrointestinal
toxicities ranging from asymptomatic mucosal injury to
fatal upper GI bleeding. The toxicity comes from the
mode of action of COX-1 inhibition. COX-1 is
constitutively expressed in gastric and duodenal mucosa
and is responsible for mucoprotective prostaglandins
synthesis. As a result of COX-1 inhibition and
subsequent reduction of prostaglandins synthesis, gastric
and duodenal mucosa which appears to be more
vulnerable to luminal acid and pepsin (Cryer and
Feldman, 1998; Jick, 1981). These gastrointestinal
toxicities result in more than 100,000 hospital admissions
and 7,000-10,000 deaths per year in the United States.
Aspirin, which is now widely used for coronary
artery disease treatment and prevention, can cause
significant gastric mucosa damage even at very low
doses. One study in healthy human subjects found that
aspirin at a dose of 10 mg day
reduced gastric
mucosal prostaglandins to 40% of baseline level and
induced significant gastric mucosa injury (Cryer and
Feldman, 1999). Several epidemiological and placebo-
controlled studies showed the dose-response
relationship between clinically significant gastric events
and the dose of aspirin (Jick, 1981; Farrell et al., 1991;
Weil et al., 1995; Singh and Triadafilopoulos 1999).
Am. Med. J. 3 (2): 115-123, 2012
Table 2: Relative risk and 95% confidence interval on cardiovascular events for each NSAID (adapted from Mcgettigan et al., 2006)
Celecoxib Rofecoxib Meloxicam* Naproxen Diclofenac Ibuprofen Piroxicam
Relative risk 1. 06 1.35 1.25 0.97 1.4 1.07 1.06
95% confidence interval 0. 91-1.23 1.15-1.59 1.00-1.55 0.87-1.07 1.16-1.70 0.97-1.18 0.70-1.59
*Data of meloxicam is largely based upon one single study and cannot reliably lead to any conclusion
Table 3: Relative risk and 95% confidence interval on GI complications from two systematic reviews
Study Diclofenac Ibuprofen Indomethacin Naproxen Piroxicam Sulindac Meloxicam
Hernandez-Diaz and 3.3 1.9 4.6 4 6.3 3.6 NA
Garcia-Rodriguez (2000)
(2.8-3.9) (1.6-2.2) (3.8-5.5) (3.5-4.6) (5.5-7.2) (2.8-4.7)
Richy et al. (2004) 1.7 1.2 2.3 1.8 1.7 NA 1.2
(1.2-2.5) (0.9-1.5) (1.0-5.1) (1.2-2.6) (1.1-2.4) (1.0-1.6)
Table 4: NSAIDs GI toxicity risk stratification (adapted from Lanza
et al., 2009)
High risk
History of previous complicated ulcer,
especially recent
Multiple (>2) risk factors
Moderate risk
Age >65 years
(1-2 risk factors)
High dose NSAID therapy
A previous history of uncomplicated ulcer
Concurrent use of aspirin (including low-dose),
corticosteroid or anticoagulant
Low risk No risk factors
In contrast to irreversible COX inhibition of aspirin, most
NSAIDs inhibit COX-1 and COX-2 reversibly.
Nevertheless, transient COX-1 inhibition is sufficient to
make gastric mucosa vulnerable to injury (Silverstein et
al., 2000). The risks of upper GI toxicity associated with
non-selective NSAIDs have been extensively studied. A
meta-analysis of observational studies has shown that the
risk of upper GI complications is increased 4-fold among
NSAIDs users, with the highest risk during the first
month of treatment (Hernandez-Diaz and Garcia-
Rodriguez, 2000). Risk factors for NSAIDs-related
bleeding include age > 60 years, high-dose NSAID
treatment, a previous history of peptic ulcer, concurrent
use of low-dose aspirin, anti-coagulants or steroids and
H. pylori infection (Hernandez-Diaz and Garcia-
Rodriguez, 2000; Huang et al., 2002)
From the same meta-analysis, ibuprofen was
associated with the lowest risk, followed by diclofenac,
sulindac, naproxen, indomethacin and ketoprofen, while
piroxicam conferred the highest risk (Hernandez-Diaz
and Garcia-Rodriguez, 2000). Another meta-analysis of
controlled trials revealed similar results. This study
found that ibuprofen and meloxicam were the only
commonly used non-selective NSAIDs that did not
significantly increase the risk of bleeding while
indomethacin provided the highest risk for GI
complication, followed by naproxen, diclofenac and
piroxicam as illustrated in Table 3 (Richy et al., 2004).
Selective COX-2 inhibitor has been developed to
overcome the gastrointestinal toxicities of non-selective
NSAIDs. Several studies have shown favorable safety
profile of this selective NSAID with respect to upper GI
bleeding. A systematic review of randomized controlled
trials has shown that COX-2 selective inhibitors
produced significantly fewer gastroduodenal ulcers and
clinically important ulcer complications compared with
non-selective NSAIDs (Rostom et al., 2007). However,
the co-administration of low-dose aspirin significantly
reduced this safety advantage (Rostom et al., 2007;
Singh et al., 2006). However, concerns raised regarding
cardiovascular adverse effects of selective COX-2
inhibitor have limited their clinical use.
A number of clinical trials have studied a variety of
options to prevent gastroduodenal ulcer and bleeding in
the patients indicated for NSAIDs. Two meta-analyses of
placebo-controlled studies found that the risk of
symptomatic ulcer was significantly reduced by Proton
Pump Inhibitors (PPI), misoprostol and COX-2 inhibitors
(Rostom et al., 2002; Koch et al., 1996). The evidence
for the effectiveness of Histamine-2 Receptor
Antagonists (H2RA) is still unclear. The same meta-
analysis revealed no gastric ulcer prevention benefit of a
standard dose of H2RA (Koch et al., 1996) but some
studies showed a decrease in gastric ulcer incidence with
double-dose H2RA. However, these studies were short-
term (12-24 weeks) and focused on endoscopic finding
rather than clinical endpoints (Taha et al., 1996; 2009).
In 2009, the American College of Gastroenterology
issued an official guideline for prevention of NSAID-
related ulcer complications. This guideline emphasizes
on balancing between patient’s cardiovascular risk and
GI toxicity risk. Patients are stratified into low,
moderate and high GI toxicity risk based upon the
number of risk factors they have as illustrated in Table
4. Cardiovascular risk is arbitrarily categorized into low
and high risk based upon the patients’ need to use low-
dose aspirin to prevent serious cardiovascular events.
These recommendations are summarized in Table 5.
In general, patient with low cardiac risk and
without GI risk factors can use non-selective NSAID
alone without protective measures. The least
ulcerogenic NSAIDs like ibuprofen and meloxicam are
Am. Med. J. 3 (2): 115-123, 2012
preferable. In the patient without GI risk factors but is
at high risk for cardiovascular events, naproxen is
preferred based upon their more favorable cardiac
safety profile. In this group of patient, protective
measure either PPI or misoprostal should be employed
because naproxen confers more considerable GI
toxicity compared with ibuprofen.
A patient who is classified as moderate risk should
have mucoprotective agent, either PPI or mesoprostal,
while using conventional NSAIDs. If a patient has low
cardiac risk, COX-2 inhibitor alone can be used as an
alternative. Again, naproxen is the preferable if the
patient has high cardiac risk. For the patient who is
at high risk for both GI and cardiac event, NSAIDs
should be entirely avoided. If the patient has only
high GI risk but has low cardiac risk, COX-2
inhibitor plus PPI or mesoprostal can be used with
caution (Lanza et al., 2009).
In addition, Helicobacter pylori infection is another
independent risk factor. Several studies suggest that H.
pylori infection increases the risk of peptic ulcer disease
in patients taking NSAIDs (Chan, 2001; Bazzoli et al.,
2001 ; Huang et al., 2002) and eradication of H. pylori
decreased the incidence of NSAID-related ulcer
(Hawkey et al., 1998; Chan et al., 2001). Based on
these evidences, it is advisable that all the patients who
require long-term NSAIDs should be tested and treated
for H. Pylori.
Hepatotoxicity: Hepatic adverse reaction is relatively
uncommon. The incidence of serious reaction requiring
hospitalization ranges from 3-23 cases per 100,000
person-year (Rodriguez et al., 1992; Traversa et al.,
2003). Hepatotoxicity from NSAIDs (except for
aspirin) appears to be idiosyncratic and can present with
either hepatocellular or cholestatic pattern (Rubenstein
and Laine, 2004). Nimesulide, which has never been
approved by FDA and not available in the United
States, is particularly associated with increased risk of
hepatic injury. A recent large cohort study showed that
only nimesulide significantly increased the risk of
hepatic injury while other NSAIDs in the study,
including diclofenac, piroxicam, ketoprofen, ketorolac,
ibuprofen, naproxen, celecoxib, meloxicam,
cinnoxicam and flurbiprofen, tended to increase the risk
but without statistical significance (Traversa et al.,
2003). Another large case-control trial which studied on
diclofenac, piroxicam, ibuprofen, naproxen, celecoxib
and meloxicam showed that only sulindac significantly
increased the incidence of hepatitis required
hospitalization while the rest tended to increase the
incidence but, again, without statistical significance
(Gutthann and Rodigruez, 1993).
In the light of evidence of risk of hepatotoxicity
and availability of alternative NSAIDs, nimesulide and
sulindac should not be prescribed especially in patient
with known liver disease such as chronic viral hepatitis,
concurrent use of other hepatotoxic medications
including alcohol and cirrhosis.
Nephrotoxicity: One of the most recognized adverse
effects of NSAIDs is nephrotoxicity. Inhibition of COX
can lead to renal impairment and dysregulation of water
and electrolyte homeostasis. COX regulates renal
hemodynamics, Glomerular Filtration Rate (GFR) and
mediates salt and water excretion. Prostaglandins,
generated through the action of COX, dilate the renal
vascular bed, lower renal vascular resistance and
increase renal perfusion (Dunn et al., 1998). However,
they play only a minor role in maintaining renal blood
flow in healthy persons. These prostaglandins will be
critically important in maintaining the GFR in the
situation of decreased effective circulatory volume.
Thus, inhibiting prostaglandins by NSAIDs can
contribute to a further decrease in overall renal
perfusion causing renal impairment (Patrono and Dunn,
1987). Nevertheless, these renal effects are usually
completely reversible following prompt discontinuation
of the offending NSAIDs.
COX-2 inhibitors appear to have similar renal
effects as nonselective NSAIDs and do not offer any
renal safety benefits over nonselective NSAIDs. A
recent large nested case-control study demonstrated a
comparable relative risk of acute renal failure among
rofecoxib user (RR = 2.31), naproxen user (RR = 2.42)
and other nonselective NSAIDs user (RR = 2.30)
though the relative risk of celecoxib was marginally
lower (RR =1. 54) (Schneider et al., 2006).
Although there is no large epidemiological study to
compare the relative risk of NSAIDs, low dose over-
the-counter ibuprofen appears to be safe in most healthy
subjects (Mann et al., 1993). Sulindac has its unique
metabolic pathway that may spare renal oxygenase by
oxidizing sulindac sulfide to an inactive metabolite in
the kidney. Nonetheless, this capacity varies between
individuals, which may explain conflicting reports on
the effects of sulindac on urinary prostaglandins and
renal function (Brandli et al., 1991).
Acute Interstitial Nephritis (AIN) is another
common renal adverse effect. The mechanism by which
NSAIDs can induce AIN is not well understood. One
explanation is that inhibition of COX causes
preferential conversion of arachidonic acid to
leukotrienes resulting in helper T-cell activation and
inflammation. Affected patients typically present with
markedly elevated serum creatinine and proteinuria that
occur several months after the introduction of NSAIDs.
Renal function usually improves within 1-3 months
after discontinuing the drug (Brezin et al., 1979).
Am. Med. J. 3 (2): 115-123, 2012
Table 5: Summary of recommendations for prevention of NSAIDs-related ulcer complications (adapted from Lanza et al., 2009)
GI risk
Low Moderate High
Low CV risk NSAID alone (the
least ulcerogenic NSAID SAID + PPI or Alternative therapy if possible or
at the lowest
effective dose) misoprostal COX-2
inhibitor + PPI or misoprostal
High CV risk Naproxen + PPI or
misoprostal Naproxen + PPI or Avoid NSAIDs and
COX-2 inhibitors.
Misoprostal use alternative
Table 6: Relative risk and 95% confidence interval on cerebrovascular events from observational studies (adapted from Roumie et al., 2008)
Study N stokes Celecoxib Rofecoxib Naproxen Ibuprofen Diclofenac Indomethacin
Bak et al. (2003)
Hemorrhagic 867 NA NA 0.8 (0.3-2.1) 1.3 (0.9-2.0) 1.3 (0.6-2.8) 1.3 (0.5-3.7)
Bak et al. (2003) Ischemic 2171 NA NA 0.7 (0.4- 1.1) 1.3 (1.0- 1.6) 1.1 (0.7- 1.7) 1.4 (0.8-2.4)
Andersohn et al. (2006) 3094 1.07 (0.79 -1.44) 1.71 (1.33 -2.18) 1.16 (0.80 -1.70) 1.12 (0.91 -1.37) 1.32 (1.10 -1.57) NA
Solomon et al. (2006) 3552 1.00 (0.92 -1.09 1.15 (1.04 -1.26) 0.83 (0.67 -1.04) 0.95 (0.78 -1.16) 0.98 (0.75 -1.29) NA
Lee et al. (2007) 4787 0.97 (0.68 - 1.37) 1.45 (1.10 -1.92) 1.15 (1.01 -1.31) 1.11 (0.99 -1.25) 1.24 (0.95 -1.63) 1.13 (0.86-1.50)
Roumie et al. (2008) 4354 1.12 (0.83 -1.52) 1.46 (1.08 -1.98) 1.02 (0.73 -1.42) 1.26 (0.87 -1.81) 0.31 (0.04 -2.18) 1.29 (0.53-3.09)
Virtually all NSAIDs can cause AIN but fenoprofen
appears to be associated with a higher risk. It is
responsible for 47% of AIN caused by NSAIDs in a
case series (Porile et al., 1990).
Nephrotic syndrome is also well-known to be
associated with the use of NSAIDs. Renal pathology
typically reveals minimal change disease though
membranous nephropathy has been reported (Warren
et al., 1989; Radford et al., 1996). Papillary necrosis,
though rare nowadays, is the only permanent
complication of NSAIDs and usually occurs after
long-term use.
NSAIDs can interfere with normal electrolyte and
water homeostasis but usually without significant
clinical outcomes. NSAIDs reduces sodium excretion
and blunt the diuretic effect of loop diuretics, but these
effects are usually mild and subclinical (Clive and
Stoff, 1984). NSAIDs attenuate the release of renin and
hence reduce aldosterone production, results in
decrease potassium excretion. The risks of
hyperkalemia are further potentiated by renal
dysfunction, diabetes, congestive heart failure and the
use of potassium supplement, ACE inhibitors and/or
potassium sparing diuretics (Whelton and Hamilton,
1991). Last, long term use of NSAIDs can slightly
increase mean arterial pressure by 5 mmHg and
interfere with several antihypertensive medications
such as diuretics, beta-blockers and ACE inhibitors
(Johnson et al., 1994).
Central nervous system: The same study that has led
to withdrawal of rofecoxib from worldwide market also
revealed an increased incidence of stroke among
rofecoxib users though without statistical significance
(Bresalier et al., 2005). Subsequent observational
studies showed a significant increase of cerebrovascular
risk among rofecoxib user and did not show any
significant increase of the risk among celecoxib user
(Andersohn et al., 2006; Solomon et al. 2006; Lee et
al., 2007; Roumie et al., 2008). The results regarding
conventional non-aspirin NSAIDs were less consistent.
Though the majority of studies did not show any
increased risk for either ischemic or hemorrhagic stroke
with the use of any conventional non-aspirin NSAIDs
(Bak et al., 2003; Solomon et al., 2006; Roumie et al.,
2008) Andersohn et al. (2006) reported an increased
risk for ischemic stroke with the use of diclofenac and
Lee et al. (2007) reported an increased risk for
cerebrovascular events among users of naproxen.
Result from these studies are summarized in Table 6.
In addition to cerebrovascular events, NSAIDs
can cause other CNS adverse effects. Aseptic
meningitis is the infrequent adverse effect of NSAID.
It is found most commonly in patients with lupus
treated with ibuprofen, but it should be considered in
any patient with meningitis if the patient has used
NSAIDs. Psychosis and cognitive impairment in
association with NSAIDs use have been reported,
particularly in elderly patient started on a regimen of
indomethacin. Thus, NSAIDs (especially
indomethacin) should be prescribed with caution in
this population with close attention to mental status
changes (Hoppmann et al., 1991).
Hematologic effect: The most significant hematologic
effect of NSAID use is the anti-platelet by inhibition of
COX-1 which is responsible for Thromboxane A2
(TXA2) production. TXA2 is synthesized and released
by platelets in response to a variety of stimuli and
provides a mechanism for amplifying the platelet
response leading to platelet aggregation (Hamburg et
al., 1975). This anti-platelet effect of TXA2 inhibition
provides therapeutic applications for thrombosis
prevention in patients with coronary artery disease or
peripheral vascular disease. Selective COX-2 inhibitors
have minimal to no effect on platelet function since
matured platelet expresses only COX-1.
Am. Med. J. 3 (2): 115-123, 2012
In the patient with thrombocytopenia (platelet
count < 50,000/microL) or platelet dysfunction, non-
selective NSAIDs should be avoided; COX-2 inhibitors
are considered as a safer option. Conventional NSAIDs
should be discontinued four to five times their half-life
before surgery to avoid an increased intra-operative and
post-operative bleeding risk. Aspirin should be
discontinued at least one week before surgery to allow
the bone marrow to produce new platelets.
Neutropenia, although uncommon, is another
adverse hematologic effect from NSAID use. A case-
control study showed a significant increase in incidence
of neutropenia among NSAID users, although no single
class of NSAID or any individual NSAIDs was
associated with a unique risk.
Cutaneous reaction: NSAIDs can cause several kinds of
drug eruptions ranging from a mild pruritic rash to more
severe skin reactions such as Toxic Epidermal Necrolysis
(TEN) and Steven Johnson Syndrome (SJS). The true
incidence of skin reactions related to NSAIDs is difficult
to estimate, as these medications are commonly
purchased over-the-counter, with minor skin side effects
going quite often underreported. However, in one
prospective study of nearly 20,000 inpatients who were
prescribed NSAIDs, 0.3% of the participants were found
to have a NSAIDs-related skin reaction. Maculopapular
rash was the most common skin reaction, followed by
urticaria, angioedema, serum sickness syndromes and
erythema nodosum (Kaiser et al., 1987).
Hypersensitivity reaction is a unique skin condition
caused by NSAIDs. Symptoms include facial
angioedema, urticaria, conjunctivitis as well as
respiratory symptoms such as rhinorrhea, cough and
bronchospasm. Again, one explanation is that inhibition
of COX-1 leads to a shunting of arachidonic acid
metabolism, causing overproduction of leukotrienes
consequently resulting in allergy-like effects (Keane et
al., 1984). However, the reasons why only a certain
number of people react to NSAIDs are not completely
clear. The known predisposing factors putting certain
people at risk for skin reactions include an atopic
diathesis, female sex, young adulthood, chronic
urticaria and the use of the NSAIDS for the relief of
acute pain (Sanchez-Borges et al., 2002). Drugs that
inhibit COX-2 with higher specificity than classic
NSAIDs are more tolerated by the majority of classic
NSAID-sensitive patients. Nevertheless,
hypersensitivity reactions have been reported with
COX-2 inhibitors as well (Dona et al., 2011).
Pseudoporphyria is a photosensitive reaction of
skin with tense bullae and erosions which is clinically
indistinguishable from true cutaneous porphyria tarda.
However, there is no abnormality detected in porphyrin
metabolism with pseudoporphyria. It has been found to
be associated with several NSAIDs, including
naproxen, nabumetone and ketoprofen (Green and
Manders, 2001). This reaction is believed to be caused
by the photosensitizing drug that behaves in a similar
fashion to photoactivated endogenous porphyrins and
target similar structures in the skin (Zelickson, 1964).
With regards to severe skin reactions, the risk of SJS
and TEN caused by NSAIDs is extremely low, which is
less than 1-2 per 1 million users per week. Oxicam
derivatives appear to have the greatest association with
SJS and TEN (Ward et al., 2010). There is also a strong
association between SJS/TEN and the use of the
sulfonamide COX-2 inhibitors, particularly valdecoxib
(Grenade et al., 2005). Aspirin is not associated with a
measurable increase in the risk of these rare but severe
reactions (Kaufman and Kelly, 2001).
As with most drug-induced skin reactions, the best
approach to the management of NSAD-induced skin
reactions is to withdraw the trigger medication. This
sometimes results in resolution of the rash, although
this may take some months and is often not universal.
Pulmonary effect: Non-aspirin NSAIDs rarely causes
adverse pulmonary effects, though they can precipitate
acute exacerbations of airway inflammation in patients
with Aspirin Exacerbated Respiratory Disease (AERD).
AERD is characterized by persistent and severe
inflammation of the upper and lower respiratory tracts
manifested as asthma and chronic rhinosinusitis with
nasal polyposis inducible by aspirin or NSAIDs
ingestion. This reaction is directly related to COX-1
inhibition; selective COX-2 inhibitors are much less
likely to trigger AERD (Palikhe et al., 2009).
Selecting the most appropriate NSAIDs for each
patient should be tailored to each individual patient
based on the patient’s medical background. In general,
ibuprofen is the preferred NSAIDs based on its favorable
GI and nephrotoxicity profiles. Naproxen might be
considered in patients who have greater cardiac risk.
Celecoxib, at the dose of less than or equal to 200 mg
, might be an option in the patients who are at high
risk for GI bleeding. However, both selective and non-
selective NSAIDs should be avoided in patients who
have a MI, heart failure and chronic kidney disease.
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... При высоком гастроинтестинальном и сердечно-сосудистом риске -отказ от НПВП, использование других лекарственных средств для анальгезии (см. рисунок) [2,[10][11][12]. ...
... пациентолет) и обусловлено идиосинкразией. Чаще всего поражение печени бывает вызвано приемом нимесулида и сулиндака [12]. Гепатопатия, обусловленная приемом аспирина (чаще при использовании больших доз), обычно протекает бессимптомно, развитие печеночной недостаточности встречается редко. ...
... Каким препаратам отдать предпочтение: при низком кардиоваскулярном риске -напроксену, низким дозам ибупрофена (не более 1200 мг/сут), целекоксибу; при умеренном риске возможно использование целекоксиба или напроксена + ИПП; при высоком -целекоксиба + ИПП (лучше пантопразол); при очень высоком риске -отказ от любых НПВП [2,5,10,[12][13][14][15][16][17][18][19][20][21][22][23][24]. ...
Full-text available
The literature review presents the possibilities of using non-steroidal anti-inflammatory drugs (NSAIDs) for polymorbid pathology. The mechanism of NSAIDs action, risk factors for the development of undesirable effects on the cardiovascular, digestive, urinary and other systems are considered; prevention measures and drug selection options are discussed, NSAIDs prescribing algorithm is considered.
... Among chronic inflammatory diseases, rheumatoid arthritis comprises one of the most common forms of inflammatory joint disease that affects the quality of life of millions of people around the world, causing significant morbidity and considerable economic/social impact, since it leads to brief or permanent physical inability (Smolen et al. 2016). Therapies currently available for the treatment of chronic inflammatory diseases are not always effective and adverse effects such as lesions in the gastric mucosa and liver, kidney toxicity, and increased risk of cardiovascular events often limit cure (Ungprasert et al. 2012;Harirforoosh et al. 2013). Therefore, the search for new effective analgesic and/or antiinflammatory agents that cause the least possible adverse effects has become a major challenge for the pharmaceutical industry (Manjiani et al. 2014). ...
... Considering that the prolonged use of anti-inflammatory agents can lead to significant adverse effects (Ungprasert et al. 2012;Harirforoosh et al. 2013) and that medications available for the treatment of rheumatoid arthritis carry with them adverse effects related mainly to lesions in the gastrointestinal tract and hepatic and renal dysfunctions (Crofford 2013), it was also evaluated the effect of treatment with repeated doses of CGE on different toxicity indicators. For this, the animals were weighed during all the days of the experiment and histopathological analyses of the stomach, liver, and kidney tissues were done. ...
The antinociceptive and anti-inflammatory activities of a polysaccharide-free extract of the cashew gum obtained from Anacardium occidentale L., Anacardiaceae, in a chronic model of complete Freund’s adjuvant-induced arthritis were investigated, as well as the possible adverse effects caused by continued administration of this extract. The cashew gum extract was obtained after the precipitation and removal of polysaccharides using acetone. The chemical characterization of this extract was performed with liquid chromatography coupled to mass spectrometry and tandem mass spectrometry analyses. In the complete Freund’s adjuvant-induced arthritis model, the experimental groups (number = 8) were orally treated once daily for 15 days with vehicle (5 ml/kg) or extract (75 mg/kg). Pain, edema joint, and cell migration to synovial fluid were assessed. Alterations in the body weight and organ weight of the animals were evaluated and histopathological analyses of the stomach, liver, and kidney were performed. Liquid chromatography coupled to mass spectrometry basically identified and quantified seven anacardic acids as the predominant constituents of the extract. The polysaccharide-free cashew gum reduced the prostration, joint edema, and migration of polymorphonuclear cells; in addition, this extract did not alter body or organ weight. The histopathological analysis showed promoted gastroprotective and hepatoprotective effects against damage caused by adjuvant injection. These findings support the use of cashew gum in popular medicine and demonstrate that part of its effects is independent of the presence of polysaccharides, evidencing its therapeutic potential for the future development of new analgesic and anti-inflammatory drugs.
... 1) Non-steroidal anti-inflammatory drugs (NSAIDs) are used to treat mild-to-moderate pain as first-line postoperative analgesics and antipyretics despite their several adverse effects, including gastrointestinal disorders and renal impairment. 2,3) Acute kidney injury (AKI) is a severe postoperative complication associated with increased duration of hospital stay, rates of readmission, and hospital mortality. [4][5][6] Minor changes in serum creatinine (SCr) levels are significantly linked to the length of stay and mortality. ...
Non-steroidal anti-inflammatory medications are associated with renal impairment. However, there is little information on whether these medications affect postoperative renal function compared with acetaminophen. The objective of this study was to compare the effects of acetaminophen and loxoprofen, used as postoperative analgesic, effect on postoperative analgesia using propensity score matching analysis. We retrospectively enrolled 328 patients treated with loxoprofen or acetaminophen after open radical prostatectomy between October 2017 and February 2020. We analyzed postoperative pain intensity, the incidence rate of acute kidney injury, drug-induced liver injury, and rate of elevation in serum creatinine after open radical prostatectomy. Eighty-one matched pairs of patients treated with loxoprofen or acetaminophen were selected using propensity score matching analysis. The postoperative numerical rating scale was significantly higher in the acetaminophen group than in the loxoprofen group on postoperative day 5. The use of patient-controlled anesthesia and rescue analgesics was significantly higher in the acetaminophen group than in the loxoprofen group. The loxoprofen group had a significantly higher postoperative increase in serum creatinine than the acetaminophen group on postoperative days 5 and 8. The incidence of acute kidney injury was 4.9% in the loxoprofen group and 0% in the acetaminophen group, while the incidence of drug-induced liver injury was 0% in both groups. Acetaminophen appears to be safer than loxoprofen in terms of effects on renal function. Nevertheless, the number of acetaminophen doses and the dose per dose may need to be increased for patients with significant postoperative pain. Fullsize Image
... 7 The widespread use of NSAIDs is associated with a number of serious side effects and complications observed for both selective and non-selective COX inhibitors. 8 Therefore, the search for new COX inhibitors, which along with their effectiveness will have minimal side effects, is a very important and urgent task. Work is underway to find potential NSAIDs among substances of natural origin, 9 as well as synthetic derivatives of azepine, 10 benzimidazole, 11,12 triazole, 13-15 1,3,4-oxadiazole, [16][17][18][19][20] xanthone, 21 coumarin, [22][23][24] quinazoline, 25,26 pyrrolidinone, 27,28 pyrrolisine, 29 pyrazole, 30-32 1,3-thiazole, 33 pyridazine, 34 and other cyclic and acyclic systems. ...
Full-text available
Background: Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most commonly used drugs in the world. The widespread use of NSAIDs is associated with a number of serious side effects and complications observed for both selective and non-selective COX inhibitors. Therefore, the search for new COX inhibitors, which along with their effectiveness will have minimal side effects, is a very important and urgent task. Methods: This work studied the synthesis of new 1,4,5,6-tetrahydropyrimidine-2-carboxamides based on the reaction of 2-morpholin-4-yl-N-(het)aryl-2-thioxoacetamides with 1,3-diaminopropane. All obtained compounds were tested for anti-inflammatory activity in vivo and in silico conditions. All synthesized 1,4,5,6-tetrahydropyrimidine-2-carboxamides were tested for influence on the course of the exudative phase of the inflammatory process based on the carrageenan model of paw edema of laboratory nonlinear heterosexual white rats weighing 220-250 g, using Diclofenac as a reference. Optimization of the geometry of the studied structures and molecular docking was carried out using the ArgusLab 4.0.1 software package. Results: The target products were obtained with yields of 71-98% and easily isolated from the reaction mixture. The best anti-inflammatory activity was found in N-(4-chlorophenyl)-1,4,5,6-tetrahydropyrimidine-2-carboxamide and in N-[4-chloro-3-(trifluoromethyl)phenyl]-1,4,5,6-tetrahydropyrimidine-2-carboxamide, suppression of the inflammatory response was 46.7% and 46.4%, respectively. The results of molecular docking with COX-1 and COX-2 enzymes were in good agreement with the experimental data, R 2 > 0.92 and R 2 > 0.83, respectively. Conclusion: The compounds under study were shown to be promising as potential anti-inflammatory agents.
... Walsh et al. 17 showed the increased prevalence of abomasal ulceration in Holstein calves when treated with IBF (10-day course). Ungprasert et al. 18 showed that IBF appears to be the preferred NSAIDs based on its favorable gastrointestinal and nephrotoxicity profiles. ...
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The incorporation of drugs and bioactive compounds in the natural rubber latex (NRL) matrix has been an alternative for the development of transdermal release membranes. Ibuprofen (IBF) is known to be used to treat inflammatory diseases, but when administered orally, high concentrations can cause some adverse problems. In this work, the incorporation of IBF in the NRL membranes was evaluated by physical-chemical, in vitro permeation, hemocompatibility and molecular modeling assays. In addition, the in vitro release profile of IBF in acid and basic media was analyzed during 96 h. The IBF-NRL membrane exhibited the absence of intermolecular bonding that could hinder drug release and presented compatible mechanical properties for applications as a cutaneous adhesive (0.58 and 1.12 MPa to Young’s modulus and rupture tension, respectively). The IBF-NRL system did not present a significant hemolysis degree (1.67%) within 24 h. The release test indicated that in the first hours of the study, 48.5% IBF was released at basic pH and 22.5% at acidic pH, which is characteristic of a burst effect. Then, a stable release profile was observed until the end of the assay, with total IBF release of 60% in alkaline medium and 50% in acidic medium. The drug permeation results indicated that the IBF-NRL membranes can be used for the local skin treatment with permeation of 3.11% of IBF. Dynamic Molecular simulations indicated a pronounced electric dipole in the ionized form of IBF, which suggests a more effective interaction with water, explaining the efficient drug release in alkaline solutions. In general, the results demonstrate that the IBF-NRL membrane has great potential for a new adhesive that can be used for the treatment of inflammatory processes and injuries.
... We believe that in our patient skin ulcers may be related to the vasoconstrictive effect of nonsteroid anti-inflammatory drugs including diclofenac sodium. 9 Patient history is the major factor in the diagnosis of skin popping and histopathological examination is usually not performed in these patients. Especially in cases who presented with multiple scars and multiple and/or giant ulcers with irregular borders, a histopathological examination should be performed. ...
... НпВп и сердечная недостаточность Согласно данным метаанализа P. Ungprasert и соавт., у пациентов, принимающих НПВП, наблюдалось повышение риска возникновения СН на 17 %, причем при использовании неселективных НПВП риск был более высокий, чем при использовании ингибиторов ЦОГ-2 [32]. Причинами этого повышенного риска могут быть вазоконстрикция, АГ, задержка жидкости, которая приводит к увеличению объема крови, клинически выраженная СН, особенно у больных с имеющейся дисфункцией миокарда [33][34][35]. В связи с тем, что уровень ингибирования простагландина, опосредованный НПВП, возрастает с увеличением дозы препарата, повышается и риск клинически выраженной СН [36]. Согласно результатам метаанализа A. Arfè и соавт., включавшего 92 163 случая госпитализаций (8 246 403 -на контроле) из-за СН больных, принимающих НПВП, риск СН возрастает на 24 % [37]. ...
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Nonsteroidal anti-inflammatory drugs (NSAIDs) are the most commonly used pain relievers. However, their use often threatens with serious undesirable effects, associated mainly with damage to cardiovascular system (CVS), gastrointestinal tract, kidneys and liver. Contraindications to NSAIDs prescription are clearly regulated, algorithms for their personalized appointment are determined taking into account risk factors for cardiovascular and gastrointestinal adverse events. The severity of NSAIDs side effects is mainly due to the selectivity to cyclooxygenase-2 (COX-2), as well as the physicochemical properties of various drugs. Cardiovascular adverse events differ among various NSAIDs both within commonly used drugs and among COX-2 inhibitors. It is well known that NSAIDs selective for COX-2 are safer in terms of the effect on the gastrointestinal tract than non-selective drugs. A meta-analysis showed that relatively selective COX-2 inhibitors (meloxicam, etodolac) were associated with a comparable risk of developing symptomatic ulcers and ulcers identified by endoscopy, and safety and tolerability profiles of the drugs were similar.All NSAIDs are associated with cardiovascular toxicity, however, different drugs have significant risk differences. The mechanism of NSAIDs cardiovascular adverse effects is associated with an increase of blood pressure, sodium retention, vasoconstriction, platelet activation, and prothrombotic state. It has been shown that the risk of cardiovascular adverse events when taking COX-2 inhibitors (celecoxib, etoricoxib) significantly increases. According to a study of more than 8 million people, it was found that the risk of myocardial infarction was increased in patients taking ketorolac. Further, highest to lowest risk authors list indomethacin, etoricoxib, rofecoxib (not currently used), diclofenac, a fixed combination of diclofenac with misoprostol, piroxicam, ibuprofen, naproxen, celecoxib, meloxicam, nimesulide and ketoprofen. When taking NSAIDs, the risk of heart failure decompensation increases, and it turned out to be the greatest for ketorolac, etoricoxib, and indomethacin. Meloxicam, aceclofenac, ketoprofen almost did not increase heart failure risk. It should be noted that when using the drugs (except for indomethacin and meloxicam), there is a tendency to increase the total cardiovascular and renal risks with increasing doses. Thus, it is obvious that a very careful approach is required when choosing NSAIDs. If there is an increased risk of gastrointestinal complications associated with NSAIDs, selective NSAIDs are preferred, with both coxibs and traditional selective NSAIDs showing the best safety profile in the studies. To minimize cardiovascular side effects specialists should consider the risk level of cardiovascular complications, as well as results of large clinical studies where particular NSAIDs are compared.
Pain management in the geriatric population is challenging. The high stakes involved with pain in older adults can be daunting with significant disability due to reduced mobility, falls and anxiety. Chronic pain is widespread and affects up to 25% of the older adult population. This chapter explores chronic pain in older person and how it differs from the general population. We outline the epidemiology of chronic pain in the elderly and the changes in pain physiology. We discuss the challenging nature of pain assessment and pain management in the geriatric population. In the older adults, a multimodal approach to pain that include both pharmaceutical and non-pharmaceutical modalities is key to optimising clinical outcome. Although the use of physical and psychological rehabilitation to restore function is crucial, we will focus on the use of pharmaceutical treatment and increasing armamentarium of interventional pain strategies for the pain management of the elderly patient.
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The antinociceptive and anti-inflammatory activities of crude ethanolic extract of Celtis iguanaea leaves and their active fractions are reported. The oral treatment with crude ethanolic extract (CEE; 100, 300 or 1000 mg/Kg) inhibited the number of writhings in a dose-dependent manner. The intermediate dose also inhibited formalin-induced nociception in both phases. The oral treatment with dichloromethane fraction (DF; 9 mg/Kg) produced antinociceptive effect in both phases of formalin test; however, the treatment with ethyl acetate fraction (EAF; 16 mg/Kg) reduced pain only in the second phase of this test. The oral treatments with CEE (300 mg/Kg) or DF (9 mg/Kg) reduced the nociception induced by capsaicin and pre-treatment with naloxone did not change these effects. The oral administration of CEE (300 mg/Kg), DF (9 mg/Kg) or ethyl EAF (16 mg/Kg) reduced ear edema, leukocytes migration and myeloperoxidase activity. Furthermore, the oral treatment with CEE (300 mg/Kg) or EAF (16 mg/Kg) reduced the level of Tumor Necrosis Factor - Alpha (TNF-α) in the pleurisy test. In conclusion, the DF showed antinociceptive activity that involves the vanilloid system as well as anti-inflammatory effect and the EAF showed anti-inflammatory activity involving the reduction of TNF-α cytokine.
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In subjects with hypersensitivity reactions with cross-intolerance to nonsteroidal anti-inflammatory drugs (NSAIDs), tolerance to selective COX-2 inhibitors has not been evaluated in large series of well-phenotyped cases. We evaluated 252 patients with urticaria and/or angioedema caused by hypersensitivity owing to cross-intolerance to NSAIDs. In addition to the clinical history, diagnosis was confirmed by provocation to an alternative NSAID. Two groups were considered: (A) patients with cross-intolerance to NSAIDs and intolerance to paracetamol and (B) patients with cross-intolerance to NSAIDs and good tolerance to paracetamol. Etoricoxib was administered to Group A patients and to a representative sample of Group B patients. In the event of a positive response, serum tryptase levels were determined and skin biopsy was performed in five patients in each group. Ibuprofen was the most commonly implicated drug, followed by acetylsalicylic acid (ASA). Urticaria was the most common manifestation, followed by angioedema. Most of the patients developed symptoms within 1 h. Twenty-five percent in Group A (n = 47) and 6% in Group B (n = 50) were intolerant to etoricoxib. Skin biopsy showed mast cell activation with the release of tryptase to the extracellular space but without the increase in serum tryptase levels. Selective COX-2 inhibitors may be unsafe in subjects with urticaria and/or angioedema caused by hypersensitivity reactions to NSAIDs with cross-intolerance if they are intolerant to paracetamol. A quarter of patients who were intolerant to this drug were also intolerant to etoricoxib. In subjects with hypersensitivity to NSAIDs and intolerance to paracetamol, selective COX-2 inhibitors should be administered as a controlled, incremental dose provocation test to assess tolerance.
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Aspirin intolerant asthma (AIA) is frequently characterized as an aspirin (ASA)-exacerbated respiratory disease (AERD). It is a clinical syndrome associated with chronic severe inflammation in the upper and lower airways resulting in chronic rhinitis, sinusitis, recurrent polyposis, and asthma. AERD generally develops secondary to abnormalities in inflammatory mediators and arachidonic acid biosynthesis expression. Upper and lower airway eosinophil infiltration is a key feature of AERD; however, the exact mechanisms of such chronic eosinophilic inflammation are not fully understood. Cysteinyl leukotriene over-production may be a key factor in the induction of eosinophilic activation. Genetic studies have suggested a role for variability of genes in disease susceptibility and response to medication. Potential genetic biomarkers contributing to the AERD phenotype include HLA-DPB1*301, LTC4S, ALOX5, CYSLT, PGE2, TBXA2R, TBX21, MS4A2, IL10 -1082A > G, ACE -262A > T, and CRTH2 -466T > C; the four-locus SNP set was composed of B2ADR 46A > G, CCR3 -520T > G, CysLTR1 -634C > T, and FCER1B -109T > C. Management of AERD is an important issue. Aspirin ingestion may result in significant morbidity and mortality, and patients must be advised regarding aspirin risk. Leukotriene receptor antagonists (LTRA) that inhibit leukotriene pathways have an established role in long-term AERD management and rhinosinusitis. Aspirin desensitization may be required for the relief of upper and lower airway symptoms in AERD patients. Future research should focus on identification of biomarkers for a comprehensive diagnostic approach.
Conference Paper
Nonsteroidal antiinflammatory drugs (NSAID) are one of the most commonly used classes of medications worldwide. It is estimated that more than 30 million people take NSAID daily. Gastrointestinal (GI) complications related to NSAID therapy are the most prevalent category of adverse drug reactions. Patients with arthritis are among the most frequent users of NSAID and are therefore particularly at risk for these side effects. To evaluate the nature of NSAID-related GI complications and to determine how their frequency can be reduced, a series of studies of such complications in patients with rheumatic disease have been carried out based on data from the Arthritis, Rheumatism, and Aging Medical Information System (ARAMIS). This report briefly reviews the literature and presents recent findings from the ARAMIS studies, which provide an update on published information. It addresses whether CI side effects such as dyspepsia can serve as warning symptoms for life-threatening GI complications and describes the risk factors for these events. It also summarizes a study that investigated whether H-2-receptor antagonists and antacids affect the development of serious GI complications. In addition, ongoing research and topics to be addressed in future studies are described.
Non-steroidal anti-inflammatory drugs (NSAIDs) are important agents in the management of arthritic and inflammatory conditions, and are among the most frequently prescribed medications in North America and Europe. However, there is overwhelming evidence linking these agents to a variety of gastrointestinal (GI) toxicities. To review the effectiveness of common interventions for the prevention of NSAID induced upper GI toxicity. A literature search was conducted, according to the Cochrane methodology for identification of randomized controlled trials in electronic databases, including MEDLINE from 1966 to January 2000, Current Contents for 6 months prior to January 2000, Embase to Febuary 1999, and a search of the Cochrane Controlled Trials Register from 1973 to 1999. Recent conference proceedings were reviewed and content experts and companies were contacted. Randomized controlled clinical trials (RCTs) of prostaglandin analogues (PA), H2-receptor antagonists (H2RA) or proton pump inhibitors (PPI) for the prevention of chronic NSAID induced upper GI toxicity were included. Two independent reviewers extracted data regarding population characteristics, study design, methodological quality and number of patients with endoscopic ulcers, ulcer complications, symptoms, overall drop-outs, drop outs due to symptoms. Dichotomous data was pooled using Revman V3.1. Heterogeneity was evaluated using a chi square test. Thirty-three RCTs met the inclusion criteria. All doses of misoprostol significantly reduced the risk of endoscopic ulcers. Misoprostol 800 ug/day was superior to 400 ug/day for the prevention of endoscopic gastric ulcers (RR=0.18, and RR=0.38 respectively, p=0.0055). A dose response relationship was not seen with duodenal ulcers. Misoprostol caused diarrhea at all doses, although significantly more at 800ug/day than 400ug/day (p=0.0012). Misoprostol was the only prophylactic agent documented to reduce ulcer complications. Standard doses of H2RAs were effective at reducing the risk of endoscopic duodenal (RR=0.24; 95% CI: 0.10-0.57) but not gastric ulcers(RR=0.73; 95% CI:0.50-1.09). Both double dose H2RAs and PPIs were effective at reducing the risk of endoscopic duodenal and gastric ulcers (RR=0.44; 95% CI:0.26-0.74 and RR=0.37;95% CI;0.27-0.51 respectively for gastric ulcer), and were better tolerated than misoprostol. Misoprostol, PPIs, and double dose H2RAs are effective at preventing chronic NSAID related endoscopic gastric and duodenal ulcers. Lower doses of misoprostol are less effective and are still associated with diarrhea. Only Misoprostol 800ug/day has been directly shown to reduce the risk of ulcer complications.
Aims  Various nonsteroidal anti-inflammatory drugs are known to increase the risk of Stevens–Johnson syndrome and toxic epidermal necrolysis. The relationship between salicylate treatment and these conditions is not known.Methods  A case-control study was conducted in four countries in Europe from 1989 to 1995.Results  Among 373 cases and 1720 controls, the multivariate relative risk estimate for any salicylate use in the previous week was 1.3 (95% confidence interval, 0.8–2.2); no statistically significant elevations were observed for single ingredient preparations or for salicylate-containing combination products.Conclusions  Acetylsalicylic acid and other salicylates are not associated with a measurable increase in the risk of these rare but severe reactions.
Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) associated with the use of nonsteroidal antiinflammatory drugs (NSAIDs) are described. A search of the English- language medical literature was conducted to identify studies and cases of SJS and TEN associated with NSAIDs and cyclooxygenase-2-selective NSAIDs available in the United States. Several epidemiologic studies, case reports, and case series involving SJS and TEN associated with NSAIDs were identified. Of the available NSAIDs, oxicam derivatives appeared to have the greatest association with SJS and TEN. The relative risks reported with other NSAIDs are much lower. The risk with cyclooxygenase-2-selective NSAIDs and meloxicam is less clear, since all were introduced after the completion of the epidemiologic studies. SJS or TEN from NSAIDs and cyclooxygenase-2-selective NSAIDs appears to affect the same patient population as other medications that cause SJS or TEN. The risk of SJS or TEN caused by NSAIDs is extremely low (less than 2 per 1 million users per week for oxicam derivatives, less than 1 per 1 million users per week for other NSAIDs, and 6 cases per 1 million person-years for celecoxib). Aspirin is not typically associated with SJS or TEN. Of the other salicylates, SJS or TEN has only been reported with diflunisal. The risk of SJS or TEN in patients receiving NSAIDs is extremely low; older patients, women, and patients within the first month of treatment initiation appear to have the greatest risk. Health care providers and patients should be aware of the signs and symptoms of SJS and TEN.
There are few therapeutic options for the prevention of gastrointestinal mucosal damage caused by low-dose aspirin. We therefore investigated the efficacy of famotidine, a well-tolerated histamine H(2)-receptor antagonist, in the prevention of peptic ulcers and erosive oesophagitis in patients receiving low-dose aspirin for vascular protection. Adult patients (aged >/=18 years) from the cardiovascular, cerebrovascular, and diabetes clinics at Crosshouse Hospital, Kilmarnock, UK, were eligible for enrolment in this phase III, randomised, double-blind, placebo-controlled trial if they were taking aspirin 75-325 mg per day with or without other cardioprotective drugs. Patients without ulcers or erosive oesophagitis on endoscopy at baseline were randomly assigned by computer-generated randomisation sequence to receive famotidine 20 mg twice daily (n=204) or placebo twice daily (n=200). Patients had a final endoscopic examination at 12 weeks. The primary endpoint was the development of new ulcers in the stomach or duodenum or erosive oesophagitis at 12 weeks after randomisation. Analysis was by intention to treat, including all randomised patients who received at least one dose of study drug (famotidine or placebo). This trial is registered as an International Standard Randomised Clinical Trial, number ISRCTN96975557. All randomised patients received at least one dose and were included in the ITT population. 82 patients (famotidine, n=33; placebo, n=49) did not have the final endoscopic examination and were assumed to have had normal findings; the main reason for participant withdrawal was refusal to continue. At 12 weeks, comparing patients assigned to famotidine with patients assigned to placebo, gastric ulcers had developed in seven (3.4%) of 204 patients compared with 30 (15.0%) of 200 patients (odds ratio [OR] 0.20, 95% CI 0.09-0.47; p=0.0002); duodenal ulcers had developed in one (0.5%) patient compared with 17 (8.5%; OR 0.05, 0.01-0.40; p=0.0045); and erosive oesophagitis in nine (4.4%) compared with 38 (19.0%; OR 0.20, 0.09-0.42; p<0.0001), respectively. There were fewer adverse events in the famotidine group than in the placebo group (nine vs 15); four patients in the placebo group were admitted to hospital with upper gastrointestinal haemorrhage. The other most common adverse event was angina (famotidine, n=2; placebo, n=4). Famotidine is effective in the prevention of gastric and duodenal ulcers, and erosive oesophagitis in patients taking low-dose aspirin. These findings widen the therapeutic options for the prevention of gastrointestinal damage in patients needing vascular protection. Merck Laboratories and Astellas Pharma.