Drugs 2012; 72 (7): 873-879

CURRENT OPINION 0012-6667/12/0007-0873/$55.55/0

Adis ª 2012 Springer International Publishing AG. All rights reserved.

Coming to Terms with Nonsteroidal

Anti-Inflammatory Drug Gastropathy
Sanford H. Roth
Arizona Research and Education, Arthritis Research Laboratory, Arizona State University, Phoenix, AZ, USA

Abstract Despite well known complications, oral nonsteroidal anti-inflammatory

drugs (NSAIDs) remain the most commonly prescribed medications in the
US for musculoskeletal disorders such as osteoarthritis. Although there has
been a recent focus on the cardiovascular and renal complications associated
with these agents, NSAID gastropathy continues to be a particular concern in
many patients, especially those at increased risk for serious adverse events,
including the elderly. Complicating the diagnosis of NSAID gastropathy is its
silent course, which, up to half of the time, is asymptomatic. Several strategies
are currently employed by physicians to mitigate the risk of serious gastro-
intestinal events. These include either addition of a proton pump inhibitor
to current nonselective NSAID therapy or the use of a cyclo-oxygenase-
2-selective NSAID. Although these agents are effective at mitigating the
overall risk of gastrointestinal adverse events, they fail to address NSAID-
related cardiovascular and renal risks. Due to their reduced systemic absorp-
tion, topical NSAIDs may present a viable option for patients at increased risk
for serious NSAID-related adverse events, including gastropathy.

The catastrophe of NSAID mortality is
ultimately reduced to the individual collision
of NSAID pharmacology conflated with the
failure of host defenses.
1. Introduction
In the US, oral nonsteroidal anti-inflammatory
drugs (NSAIDs) are among the most commonly
prescribed medications, particularly for musculoskel-
etal disorders, despite the well known gastro-
intestinal complications that are commonly known
as ‘NSAID gastropathy’.[1,2] 1 NSAID gastropathy
refers to a spectrum of upper gastrointestinal com-
plications associated with NSAID use, ranging
from mild dyspepsia and abdominal discomfort
to more serious perforation, erosions, ulcers and
haemorrhage.[1] In 2005, the US Food and Drug
Administration (FDA) mandated that all marketed
prescription NSAIDs, including topicals and
cyclo-oxygenase (COX)-2-selective inhibitors, in-
clude a boxed warning emphasizing the potential
for increased risk of cardiovascular events with
NSAIDs and the well described, serious and po-
tentially life-threatening gastrointestinal bleeding
associated with their use.[5]
For decades, evidence-based research and re-
ported experience has cautioned that the chronic

1 Roth and Bennett[3] were the first to distinguish ‘NSAID gastropathy’ from the global mid-century descriptor,
‘peptic ulcer disease’. The new nomenclature was directly inspired by a seminal literature report on unique
NSAID-associated outcomes and host risk factors by Sun et al.[4]
874
use of oral NSAID therapy for osteoarthritis (OA),
the most common form of arthritis, is inappropriate
in certain high-risk populations.[1,3,6-9] For ex-
ample, the incidence of OA increases with age, so
preventing the risk of NSAID gastropathy is of
particular concern in elderly populations, who
are already at increased risk for gastrointestinal
issues due to age-related changes in blood ves-
sels.[10-12] This review evaluates why NSAID
gastropathy persists and provides a brief over-
view of viable alternatives to traditional NSAIDs
as relates to the management of OA.
2. NSAID Gastropathy: Diagnosis
and Incidence
Gastropathy, usually in the prepyloric region,[13]
is a common complication of long-term NSAID
use.[3] Although NSAID gastropathy may su-
perficially share some common signs and symp-
toms with other gastrointestinal disorders such as
peptic ulcer disease (e.g. epigastric pain), NSAID
gastropathy differs from classic peptic ulcer dis-
ease on the basis of apparent differences in path-
ophysiology, anatomic location and clinical pattern,
and the term itself was introduced to emphasize
this distinction.[1]
Classic peptic ulcer disease is primarily acid
mediated, Helicobacter pylori related and duode-
nal, and it is most common in a younger, typically
male, demographic.[3,14] Peptic ulcer disease is also
associated with long-term NSAID use, although
non-NSAID, non-H. pylori ulcers account for
a significant proportion of all cases of peptic
ulcer disease.[15,16] The clinical presentation of
NSAID gastropathy may range from dyspepsia
and abdominal pain to serious and potentially
fatal complications such as perforation, ulceration
and haemorrhage.[3,12] In addition, asymptomatic
lesions are more common with NSAID gastropathy
than with peptic ulcer disease and put the patient at
risk for complications.[3] Although an endoscopy
could be diagnostic in such cases in which the un-
derlying diagnosis is unclear, such procedures are
expensive and are not always indicated.
The incidence of clinically significant NSAID-
related upper gastrointestinal adverse events is
four times that in the general population not
Adis ª 2012 Springer International Publishing AG. All rights reserved.
Roth
receiving NSAID therapy.[17,18] Several studies
have demonstrated a relationship between NSAID
use and the development of a life-threatening peptic
ulceration complication.[6-9] Both nonselective
and COX-2-selective NSAIDs are associated with
some degree of increased gastrointestinal risk.[19]
It is therefore important to identify patients who
are at greatest risk for gastropathy, such as
patients with OA, and to either include the use of
a cytoprotective agent or move away from the use
of oral NSAID therapy.[3]
3. Risks for Developing NSAID
Gastropathy in Patients with
Osteoarthritis
It is critical to consider individual health factors
when choosing treatment for OA (table I). Patients
with OA tend to be older and, thus, more likely to
have risk factors for NSAID-associated gastro-
intestinal complications.[12] The risk of gastric
events increases with age, rising precipitously at
age 60; the reduction in gastric microvasculature
in older individuals increases risk of ulcerative
bleeding regardless of whether other risk factors are
present.[12] A history of ulcers (particularly bleeding
ulcers) or concurrent use of antiplatelet agents and
aspirin, corticosteroids or anticoagulants further
increases the risk of gastropathy.[12,17,20]
Clinical guidelines providing recommendations
for OA management reflect the importance of as-
sessing risk factors in every patient before prescrib-
ing NSAIDs, to individualize treatment needs.[21-27]
NSAID gastropathy complications are best avoid-
ed rather than treated. Therefore, oral systemic
NSAIDs simply should not be used in certain
high-risk patient populations.[12]
4. Barriers to Mitigating
NSAID-Related Risk
NSAID gastropathy persists because NSAID
use is ubiquitous.[12,13] Because the ‘silent threat’
of NSAID gastropathy is asymptomatic, it often
progresses unrecognized.[13] Dyspeptic symptoms
commonly occur with chronic oral NSAID use,
confounding diagnosis of serious ulcers in the
absence of actual ulcer lesions and, usually, pre-
Drugs 2012; 72 (7)
Nonsteroidal Anti-inflammatory Drug Gastropathy
Table I. Risk factors for NSAID gastropathy
Older age
Female sex
Current smoker
History of ulcers and/or gastric bleeding
Combination NSAID therapy
Concurrent use of antiplatelet agents, aspirin, corticosteroids or
anticoagulants
dictable clinical symptoms.[7,12] The failure to
recognize ulcers can delay treatment, which can
lead to significant complications.
Health consumers also play a major role in the
widespread use of NSAIDs, owing to the availabil-
ity of over-the-counter NSAID products. Among
individuals with arthritis, almost 30% report daily
use of over-the-counter NSAIDs.[28] Although the
efficacy of oral NSAIDs is established, safety
often is not considered or well understood among
consumers of over-the-counter NSAIDs until
after the occurrence of adverse events such as
gastropathy.[12]
5. Other Avenues to Prevent
NSAID Gastropathy
5.1 Cyclo-Oxygenase (COX)-2-Selective
NSAIDs
Traditional nonselective NSAIDs block both
COX-1 and COX-2 enzymes. When the COX-1
enzyme is blocked, inflammation is reduced, but
the protection of the stomach lining is lost. COX-2
inhibitors are oral NSAIDs that preferentially
block the COX-2 enzyme. Unlike COX-1, the
COX-2 enzyme does not play a role in gastro-
protection; therefore, COX-2 inhibitors have been
shown to decrease the incidence of gastrointestinal
adverse effects and reduce toxicity associated
with nonselective NSAIDs while effectively reduc-
ing pain and inflammation.[29] Gastrointestinal
risk is not entirely eliminated with COX-2-selective
agents, however, particularly in patients who have
other risk factors.[29] COX-2 inhibition also sup-
presses some inflammatory mediators involved in
the progression of atherogenesis and ischaemic
myocardial damage and appears to alter the bal-
ance between antithrombotic prostacyclin and
Adis ª 2012 Springer International Publishing AG. All rights reserved.
875
prothrombotic thromboxane A2, thereby in-
creasing the risk of thrombosis.[30]
Celecoxib is the only COX-2 inhibitor cur-
rently available in the US. Two COX-2-selective
NSAIDs were withdrawn from the market – ro-
fecoxib in 2004 and valdecoxib in 2005 – because
they increased the risk of cardiovascular events
associated with long-term use.[31,32] Treatment
with COX-2-selective NSAIDs has been associated
with increased risk of myocardial infarction,
peripheral oedema, renal toxicity and increases in
blood pressure that are potentially clinically rel-
evant.[31,33] The use of nonselective NSAIDs is
also associated with an increased risk of cardio-
vascular events; in fact, recent results from both a
systematic review of population-based, control-
led, observational studies[34] and a meta-analysis
of randomized, controlled, clinical trials[35] indicated
that cardiovascular risk can, in some instances,
be as high with oral nonselective NSAIDs as with
COX-2-selective NSAIDs. These considerations,
particularly the cardiovascular concerns related
to the use of COX-2-selective NSAIDs, prompt-
ed the FDA to require that all NSAIDs include a
boxed warning highlighting the increased risk of
gastrointestinal bleeding and cardiovascular
events associated with their use.[5]
Celecoxib is a sulfonamide and should be
avoided in patients with sulfonamide allergies
because it could trigger hypersensitivity reactions.[36]
Although COX-2 inhibitors are associated with
fewer gastrointestinal complications than non-
selective NSAIDs, the addition of a proton pump
inhibitor (PPI) is recommended by some pain
management guidelines and has been shown to be
more effective than COX-2 inhibitors alone in pre-
venting ulcerative bleeding in high-risk patients.[37]
5.2 Addition of a Proton Pump Inhibitor to
Traditional NSAIDs
NSAID-induced gastropathy is difficult to
manage through the use of traditional peptic ulcer
therapy.[38] The addition of a PPI to an NSAID
has been shown to protect against both short-term
and long-term gastrointestinal effects associated
with the use of NSAIDs alone.[39] Although some
data indicate that misoprostol, a prostaglandin
Drugs 2012; 72 (7)
876
E1 analogue, is effective for the prevention of
NSAID gastropathy, data from comparative studies
have demonstrated that PPIs are therapeutically
superior.[38] Long-term use of PPIs, however, is
associated with risks, including a dose-related
increase in risk of osteoporotic hip fractures
among the elderly.[40] PPIs may cause low serum
magnesium levels if taken for prolonged periods,
which can lead to increased cardiovascular risk.
The addition of a PPI to NSAID-based therapy
imposes a polypharmacy burden, which increases
risk of drug interactions, adverse events, non-
adherence and costs to the patient.[12,41]
A fixed-dose combination of enteric-coated na-
proxen 500 mg and immediate-release esomeprazole
20 mg (taken twice daily) is a possible solution
to reduce the polypharmacological burden.[39]
Two randomized, double-blind, parallel-group,
placebo-controlled, multicentre phase III trials in
patients with OA of the knee showed significant
improvements with naproxen/esomeprazole mag-
nesium versus placebo in both studies (p < 0.05).
Naproxen/esomeprazole magnesium was associ-
ated with improvements in scores on the Western
Ontario and McMaster Universities Arthritis
Index (WOMAC) pain and physical function
subscales and the Patient Global Assessment
(visual analogue scale). The most common treat-
ment-related adverse event was dyspepsia, which
was reported in 3.6–10.3% of patients treated
with naproxen/esomeprazole magnesium com-
pared with 10.5–12.3% of patients who received
placebo. Gastrointestinal disorders were the most
frequent adverse events associated with study
discontinuation (2.5%).[39]
5.3 Addition of a Histamine H2-Receptor
Antagonist to Traditional NSAIDs
Histamine H2-receptor antagonists combat the
gastrointestinal effects of NSAIDs by blocking
the action of histamine on parietal cells in the
stomach, thereby decreasing the production of
acid by these cells.[42] Several randomized trials
have shown that high-dose H2-receptor antagonists
can effectively reduce the incidence of ulcers in
NSAID users.[43] A single-tablet combination of
ibuprofen (800 mg) and the H2-receptor antag-
Adis ª 2012 Springer International Publishing AG. All rights reserved.
Roth
onist, famotidine (26.6 mg), has been approved
recently for symptoms of rheumatoid arthritis and
OA to decrease the risk of upper gastrointestinal
ulcers associated with NSAID use alone.[42] Results
of two 24-week, double-blind, randomized trials
using ibuprofen/famotidine combination therapy,
given three times daily, demonstrated significantly
less dyspepsia when compared with ibuprofen alone
(5% vs 8%, respectively; p = 0.0086).[42,43] However,
as with all NSAIDs, this therapy carries a class-
wide boxed warning that details the increased risk
of serious gastrointestinal and cardiovascular
events.[5]
5.4 Topical NSAID Therapy
Topical analgesics are an effective treatment
for localized pain in superficial joints, partic-
ularly the hands and knees.[21-23] There are two
topical NSAID formulations available in the US
and approved by the FDA for the management of
OA in the knee and/or other joints: diclofenac
sodium 1% gel and diclofenac sodium topical
solution 1.5% in 45.5% dimethyl sulfoxide (DMSO)
solution.[44,45]
NSAIDs in topical formulations deliver the
drug directly to the local target tissue and result
in significantly lower levels of systemic absorp-
tion relative to oral therapy.[46] Peak plasma
concentrations of diclofenac from the gel and
topical solution formulations are less than those
with oral diclofenac.[47,48] Studies have shown
that topical NSAIDs exhibit comparable efficacy
and reduced incidence of systemic adverse events
versus oral diclofenac.[49-52] Therefore, low blood
levels of NSAID medications may reduce the
incidence of systemic adverse events such as gas-
trointestinal adverse events, increased liver en-
zyme levels and decreased haemoglobin levels.[53]
Application-site reactions are commonly asso-
ciated with topical NSAIDs. A meta-analysis of
19 randomized controlled trials evaluated the in-
cidence of adverse events among elderly adults
with OA who were treated with a topical NSAID.
The most frequently reported application-site
reaction was dry skin, reported by 0.79–39.3%
of study participants treated with diclofenac so-
dium topical solution, and this may be caused by
Drugs 2012; 72 (7)
Nonsteroidal Anti-inflammatory Drug Gastropathy
the DMSO vehicle, which is known to dissolve
lipids on the skin surface.[54] Although topical
NSAIDs have shown reduced rates of serious
gastrointestinal and cardiovascular events, as
compared with oral NSAIDs, all formulations
currently carry the same boxed warning.[5]
6. Conclusion
Although many variations of NSAIDs have
evolved in the past 25 years to treat inflammatory
symptoms and OA pain, these agents are asso-
ciated with the risk of serious gastrointestinal
adverse events.[1,2,6-9] The asymptomatic nature
of NSAID gastropathy makes it challenging to
mitigate risks because the most serious con-
sequences often occur without warning.[12,13]
Because the prevalence of OA increases with
age, the safety of prescribed NSAIDs warrants
careful consideration of benefits versus risks,
particularly in an ageing patient population.[10,11,17]
The continued use of NSAIDs in the elderly
population has led to an increased incidence of
NSAID-induced gastropathy. Per clinical guide-
lines, prescribing NSAIDs in an elderly pop-
ulation continues to be discouraged due to these
significant risks.[21-27] Indeed, recently updated
guidelines by the American College of Rheuma-
tology recommend topical NSAIDs rather than
oral NSAIDs for the treatment of OA of the hand
or knee in patients aged 75 years or older.[22]
Despite well known adverse effects and guidelines
to assist in treatment options, many physicians
are not using appropriate clinical judgement
when prescribing OA therapy to high-risk popu-
lations. The use of over-the-counter NSAIDs in
addition to prescription NSAID treatment in-
creases the risk of these adverse effects.
Among other avenues discussed, topical
NSAIDs are associated with a reduced incidence
of gastropathy, and one has evidence of equivalent
efficacy.[49-52] Physicians should consider the im-
portance of mitigating safety risks in high-risk pop-
ulations while providing effective pain relief in these
patients. The ultimate goal through these efforts is to
fulfill the immortal symmetry of the yin and yang of
Hippocrates’ admonitions to physicians: ‘‘first do no
harm’’ and yet ‘‘relieve pain and suffering.’’
Adis ª 2012 Springer International Publishing AG. All rights reserved.
877
Acknowledgements
Technical editorial and medical writing assistance for the
preparation of this manuscript was provided by Lauren
Burawski, MA, Synchrony Medical LLC, West Chester, PA,
USA. Funding for this support was provided by Mallinckrodt
Inc., a Covidien company, Hazelwood, MO, USA.
Dr Roth is a current stakeholder in Transdel Pharmaceu-
ticals and serves as a consultant and speaker for Covidien.
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Correspondence: Dr Sanford H. Roth, MD, Medical Director
and Adjunct Professor, Arizona Research and Education,
Arthritis Research Laboratory, Arizona State University,
6831 North 58th Place, Paradise Valley, AZ 85253, USA.
E-mail: sroth16@cox.net
Drugs 2012; 72 (7)
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.