Aspirin and Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)☆

Aitor Lanas-Gimeno, Hospital Universitario de la Princesa, Madrid, Spain

Angel Lanas, Universidad de Zaragoza, Zaragoza, Spain
© 2018 Elsevier Inc. All rights reserved.

This is an update of Salahuddin Kazi, Non-Steroidal Anti-Inflammatory Drugs (NSAIDs), Editor(s): Leonard R. Johnson, Encyclopedia of Gastroenterology,
Elsevier, 2004, Pages 737–739.

Definition 1
Pharmacology 2
Nomenclature and Pharmacodynamics 2
Pharmacokinetics 2
Clinical Uses 2
Adverse Events 2
Gastrointestinal Toxicity 2
Pathogenesis 3
Risk of gastrointestinal toxicity 3
Risk factors for gastrointestinal toxicity 3
Prevention of gastrointestinal events 4
Cardiovascular Risk Events 4
References 5

Glossary
Cyclooxygenases Family of enzymes, of which at least two isoforms exist, cyclooxygenase-1 and cyclooxygenase-2. They act on
arachidonic acid to produce a number of compounds, including prostaglandins and thromboxane.
Prostaglandins One form of eicosanoids (biologically active lipids formed by the oxidation of 20-carbon fatty acids);
produced by the cyclooxygenase pathway, they are responsible for a variety of physiologic and inflammatory reactions.

Abbreviations
COX Cyclooxygenase
H2RA Histamine type 2 receptor antagonist
NSAIDs Non-steroidal anti-inflammatory drugs
PPI Proton pump inhibitor
RCT Randomized controlled trial

Definition

First acknowledgement of salicylic acid use throws us back to the ancient Egypt and Greece for its antipyretic and painkiller
properties. Acetylsalicylic acid, also known as aspirin, was first introduced by Bayer Company in 1899 thanks to Felix Hoffman and
his investigations. Since the introduction of aspirin several numbers of agents have been developed, with great changes in
prescription habits, recommendations and restrictions due to improved understanding over the last 10–20 years, of its mechanisms
of action and adverse effects. John Vane in 1971 established the mechanism of action of aspirin and NSAIDs, with the inhibition of
three enzymes, cyclooxygenase-1 (COX-1), cyclooxygenase-2 (COX-2), and cyclooxygenase-3 (COX-3) which is a recently described
variant of COX-1.
Nowadays NSAIDs are one of the most widely prescribed drugs to treat pain and inflammation, with a wide range of prescriber
specialists such as general practitioners, rheumatologists, oncologists, orthopedists, etc. It is estimated that NSAIDs are used by over
30 million people every day. Gastroenterologists have special interest in this pharmacological group in view of the gastrointestinal
adverse effects derived from their use and the recent data on colorectal cancer prevention.

☆
Change History: December 2018. This is a fully new edited chapter where the major changes have been introduced in the adverse events chapter.

Encyclopedia of Gastroenterology, 2nd Edition https://doi.org/10.1016/B978-0-12-801238-3.65620-9 1

2 Aspirin and Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)

Pharmacology
Nomenclature and Pharmacodynamics
Nonsteroidal anti-inflammatory drugs (NSAIDs) constitute a large and heterogeneous group of drugs which present a common
mechanism of action consisting of the inhibition of the enzymes responsible for prostanoid synthesis, the cyclooxygenases. There
are three principal prostanoids: prostaglandins, which are the base of both analgesic and anti-inflammatory effect, and prostacyclin
and thromboxane which are known to be involved in vascular permeability and platelet aggregation. COX-1 enzyme has a
constitutive level of expression, with a broad level of expression in most tissues including platelets and the gastrointestinal tract,
where it is involved in the mucosal integrity by facilitating mucus formation, cell replacement and maintaining blood flow. On the
other hand, COX-2 enzyme is inducible and specific to some type of cells and tissues, increasing its level of expression under
inflammatory states and regulating pain, fever, vasodilation and leukocyte infiltration. The COX-2 isozyme is also likely involved in
fluid balance and renal homeostasis (Lanas, 2016; Crofford, 1997; Bjarnason et al., 2018).
Based on their specific COX isozyme inhibition and chemical structure, NSAIDs are classified into two major classes: non-
selective NSAIDs and COX-2 selective inhibitors. Non-selective NSAIDs include aspirin and sulfasalazine, which are salicylate
derivatives, indole acetic derivatives such as indomethacin and etodolac, heteroarylacetic acid derivatives such as diclofenac.
Ibuprofen and naproxen are included in the arylpropionic acids group; piroxicam and meloxicam are enolic acids derivatives.
Most are organic acids with relatively low pKa, with their acidic nature influencing their pharmacodynamics and pharmacokinetic
profiles. Two exceptions for this particular characteristic are pyrazolic derivatives (metamizole, propyphenazone) and para-
aminophenol derivatives (paracetamol or acetaminophen). These two groups are often excluded from the NSAIDs group due to
their low anti-inflammatory activity. Selective COX-2 inhibitors were a breakthrough attempting better efficacy and lower toxicity;
sadly its deleterious cardiovascular effect seems to have stopped their progression. COX-2-selective inhibitors include rofecoxib,
celecoxib, valdecoxib, and etoricoxib, among others (Crofford, 1997).

Pharmacokinetics
NSAIDs present high bioavailability (80%–100%) following oral ingestion. Their absorption is generally quick with a peak plasma
concentration within 2–3 h except for some derivatives of the enolic acid (piroxicam) and certain coxibs (celecoxib and rofecoxib).
Most NSAIDs are metabolized in the liver and excreted in the urine which has important implications for patients with hepatic or
renal impairment. Nearly all NSAIDs undergo different degrees of biliary excretion and enterohepatic circulation. Some NSAIDs
such as aspirin or diclofenac have a significant first-pass hepatic effect that reduces their bioavailability while some NSAIDs need
this first-pass effect to transform into their active compound (sulindac, etoricoxib). Most NSAIDs are highly bound to plasma
proteins, mostly to serum albumin at 95%. This binding may be saturable with interactions with some drugs that compete for the
same binding site. Most compounds achieve sufficient concentrations over the majority of tissues including the central nervous
system. Their distribution among inflamed tissues seems to be affected by particular chemical characteristics like acidity, which
reduces their binding to plasma proteins and increase the free drug-fraction. Therefore, drugs like diclofenac, ibuprofen or
ketoprofen seem to easily accumulate and persist in the inflammatory loci (Bjarnason et al., 2018).

Clinical Uses
As mentioned before, NSAIDs are one of the most commonly used class of drug in developed countries. They are widely prescribed
on a daily basis for pain relief such as headaches, musculoskeletal pain after a traumatism, bone pain secondary to malignant
diseases, dysmenorrhea, biliary and renal colic or early postoperative pain. They can be prescribed as monotherapy for short-term
treatment due to the potential adverse effects. They can also be prescribed adjunct to opioids for the management of severe pain.
Due to their anti-inflammatory effect they are also indicated for the treatment of rheumatic diseases such as osteoarthritis,
rheumatoid arthritis, ankylosing spondylitis. In addition, they are effective against fever because of their antipyretic effect, which
is comparable to acetaminophen. Other recognized uses for NSAIDs are acute gout and colorectal cancer chemoprevention in
familial adenomatous polyposis. Due to aspirin’s capacity for permanent inhibition of platelet-derived thromboxane formation,
low-dose aspirin is used in preventing arterial thromboembolism such as myocardial infarction and ischemic stroke (Lanas, 2016).

Adverse Events
Gastrointestinal Toxicity
Despite being commonly prescribed, NSAIDs usage carries out substantial risk of adverse events at different organ systems (kidney,
heart, liver, central nervous system, etc.), but gastrointestinal toxicity is the most common. It is estimated that almost 30% of long-
term NSAIDs users present peptic ulcers on upper gastrointestinal endoscopy, which may be asymptomatic, and every year almost
1%–2% patients develop complications (Lanas, 2016; Laine et al., 2003). NSAIDs toxicity also affects the lower gastrointestinal tract
with almost half of chronic NSAIDs users presenting some degree of injury on the small bowel mucosa (Laine et al., 2003). Peptic
ulcer disease patterns are clearly changing due to the declining incidence of Helicobacter pylori and increased prescription of aspirin
 Aspirin and Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) 3

and NSAIDs in a continuing aging population. Also, with wide prescription of proton pump inhibitors (PPI) in patients under
NSAIDs usage, lower gastrointestinal tract complications are as frequent or even more frequent than upper GI complications. Short-
term (<4 days) and low-dose over the counter use of these compounds does not seem to be associated with serious complications
but can cause dyspepsia in some people (Lanas, 2016).

Pathogenesis
As mentioned earlier, gastrointestinal toxicity related to NSAIDs is mediated by the inhibition of cyclooxygenase enzyme activity.
While the analgesic and antiinflammatory effect arise from the inhibition of COX-2, gastrointestinal toxicities are mediated through
the COX-1 inhibition. COX-1 is a constitutive enzyme expressed all along the gastrointestinal tract, where it helps maintain the
integrity of the epithelium and the mucous barrier in the stomach and small and large bowel (Crofford, 1997). NSAID-induced
inhibition of prostaglandins in the gastrointestinal mucosa reduces the quantity of mucus and bicarbonate secretion and also
decreases cell proliferation and mucosal blood flow.
There is also another topical pathogenic pathway of gastrointestinal toxicity involving NSAIDs and aspirin. These drugs can
diffuse through the gastric and intestinal mucous, disrupting the first phospholipid layer thanks to their lipophilic chemical
properties. They reach the surface gastrointestinal epithelium, where they expose the mucosa to direct luminal aggressors (acid,
pepsin and H. pylori in the gastric lumen and bile, bacteria, and intestinal and pancreatic secretions in the small bowel) and also turn
into dissociate ionized forms and trap hydrogen ions that cause direct mucosal damage (Bjarnason et al., 2018). Enterohepatic
recirculation and biliary excretion of NSAIDs contribute to enhance this topical cytotoxicity. NSAIDs gastrointestinal toxicity is also
related to their capacity to uncouple the mitochondrial oxidative phosphorylation. This effect leads to depletion of cellular ATP
levels which contributes to cell apoptosis and increased mucosal permeability due to loss of intercellular junctions (Bjarnason
et al., 2018).

Risk of gastrointestinal toxicity

Multiple studies estimate that after 1 year of NSAID use, almost 30% of patients show peptic ulcers on upper gastrointestinal
endoscopy (most of these lesions are asymptomatic), whereas 1%–2% of patients will develop complications. Dyspepsia associated
with NSAID use is also common but is not necessarily associated with mucosal lesions (Laine et al., 2003). Compared to non-use,
there is a fourfold increased risk of upper gastrointestinal complications with these compounds. This effect is dose dependent
(Masclee et al., 2014). Also, this risk seems to be highest among new users in the first 2 months, remaining elevated after 2 months
of discontinuation (Hernandez-Diaz and Rodriguez, 2000). NSAIDs which have a long half-life and profound inhibition of both
COX-enzymes such as naproxen and piroxicam are associated with a greater risk. Low-dose aspirin use is associated to a 1.5–2-fold
increased risk of upper gastrointestinal event with an estimated number needed to harm of 833 patients (Laine et al., 2006).
NSAIDs can also damage the lower gastrointestinal tract with a wide spectrum of manifestations ranging from silent mucosal
injury to significant ulceration with bleeding and even perforation. Studies involving capsule endoscopy showed that NSAID could
induce mucosal injury in up to 75% and macroscopic ulcers in 40% of patients under chronic NSAID treatment (Laine et al., 2003).
NSAIDs can also cause, in up to 40% of users, gastrointestinal symptoms such as nausea and vomiting, dyspepsia and
abdominal pain (Lanas, 2016).

Risk factors for gastrointestinal toxicity

The main risk factors for gastrointestinal toxicity include advanced age over 65 years, multiples comorbidities, prior history of peptic
ulcer or H. pylori infection, concomitant use of aspirin or another NSAID, concomitant use of anticoagulant agents, selective
serotonin reuptake inhibitors or corticosteroids (Lanas, 2016).
The most important risk factor for adverse gastrointestinal events appears to be a prior history of peptic ulcer with an estimated
risk of over 38 cases per 100 patient-years (Langman et al., 1994). Advanced age over 65 years, and especially over 70 years, is
associated with a risk increase of 4% per year. Therefore, the incidence of serious gastrointestinal events in patients between 70 and
80 years of age would be around 16 cases per 100 patients-year (Gabriel et al., 1991).
H. pylori infection and NSAIDs treatment are both independent factor for upper gastrointestinal disease with an increased risk of
1.79 and 4.85-fold respectively. When each of these risk factors collide, the risk of upper gastrointestinal hemorrhage reaches a
relative risk of 6.13. That is the reason why prior to initiating chronic treatment with NSAIDs or aspirin, H. pylori infection should be
screened for and treated. H. pylori eradication among NSAID chronic users would decrease the risk of peptic ulcer up to 57% (Huang
et al., 2002).
Nowadays, with a wide increased use of low-dose aspirin for cardiovascular indications, concomitant use with NSAIDs is
becoming more common (almost 20% of aspirin consumers). Concomitant treatment with aspirin and another NSAID is
associated with a risk of ulcer bleeding that is greater than aspirin or NSAID treatment alone respectively. Major risk seems to
appear with a concomitant use of aspirin and a traditional NSAID, although patients taking COX-2 inhibitors in combination with
aspirin are also at increased risk (Masclee et al., 2014; Weil et al., 1995).
Oral anticoagulants increase the risk of developing an NSAID related peptic ulcer bleeding. In a study conducted by Masclee et al.
(Lanas-Gimeno and Lanas, 2017) including a database analysis of over 110,000 patients, concomitant use of oral anticoagulants
with aspirin and other NSAIDs led to an increased risk of upper ulcer bleeding of 8.7 and 6.9-fold respectively. Novel oral
anticoagulants such as dabigatran, rivaroxaban and apixaban are becoming popular in the past decade due to their similar efficacy
to warfarin in terms of cardiovascular risk with no need for typical blood test monitoring. Concomitant use of these novel oral
4 Aspirin and Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)

anticoagulant agents with NSAIDs and aspirin seems to increase the risk of major bleeding by 45% (Lanas-Gimeno and
Lanas, 2017).
Concomitant use of NSAIDs and corticosteroids is associated with an increased risk of peptic ulcer compared to the use of either
compound alone. Corticosteroids inhibit ulcer healing, which seems to explain the increased risk of major risk of upper gastroin-
testinal bleeding and perforation (Piper et al., 1991).

Prevention of gastrointestinal events

There are two main strategies to prevent gastrointestinal events among NSAIDs users: concomitant use of NSAIDs with one
gastroprotective agent such as histamine-2 receptor antagonist, misoprostol or, better, a proton pump inhibitor. The other suitable
strategy is to prescribe a COX-2 inhibitor instead of a non-selective NSAID (Lanas, 2016).
Histamine-2 receptor antagonist (H2RAs) have been widely tested for gastrointestinal prevention in patients taking NSAIDs with
controversial results. In a Cochrane analysis of five pooled RCTs for the prevention of ulcers among NSAIDs users, H2RAs showed
reduced incidence of duodenal ulcers but failed to prevent the appearance of gastric ulcers (Rostom et al., 2002). Another meta-
analysis showed that H2RAs might not significantly reduce the risk of symptomatic ulcers (Hooper et al., 2004).
One meta-analysis of misoprostol’s effectiveness in preventing NSAID-induced gastrointestinal toxicity showed that doses
ranging from 400 to 800 mg a day could reduce the risk of NSAID-induced ulcers on endoscopy. However, almost 30% of
misoprostol users experienced some form of gastrointestinal upset (Rostom et al., 2002).
Concomitant use of PPIs and NSAIDs is the most effective strategy in NSAIDs gastrointestinal adverse event prevention. Two
randomized RCTs comparing omeprazole 20 mg daily, ranitidine 150 mg twice daily and misoprostol 400 mg a day showed
omeprazole to be more effective than the other two options (Yeomans et al., 1998; Hawkey et al., 1998). A large meta-analysis
comparing different gastroprotective agents of 849 trials including over 140,000 patients, also showed proportionately greater
reductions in upper GI bleeding and ulcer healing with PPI than with other prevention strategies (Scally et al., 2018).
The benefits of COX-2 inhibitors in the gastrointestinal tract has been studied in many RCTs and meta-analyses, showing
significant reduced risk compared to traditional NSAIDs. The risk reduction of gastrointestinal ulcer incidence and ulcer compli-
cations was 74% and 61% respectively. When we compare a traditional NSAID associated to a PPI versus COX-2 inhibitors alone,
the reduction in ulcer bleeding risk seems to be similar (Rostom et al., 2007). In an RCT conducted by Chan FK et al. comparing
celecoxib alone versus celecoxib plus esomeprazole among patients with prior history of NSAID-induced ulcer bleeding, celecoxib
alone showed 8.9% of bleeding recurrence while the group with concomitant PPI had no recurrent ulcer bleeding (Chan et al.,
2007). The benefit of COX-2 inhibitors appear to extend to patients taking aspirin. Although concomitant use of COX-2 inhibitors
and aspirin does increase the gastrointestinal risk, it appears to be less so than the concomitant use of NSAIDs and aspirin (Laine
et al., 2007). In addition, compared to traditional NSAIDs, COX-2 inhibitors appear to cause less lower gastrointestinal events
(Chan et al., 2010).

Cardiovascular Risk Events

Emerging data of increased risk of cardiovascular events involving NSAIDs and COX-2 inhibitors started when one RCT regarding
the preventative effect of rofecoxib on gastrointestinal toxicity showed a fourfold increased risk of acute myocardial events as
compared to naproxen (Bombardier et al., 2000). This increased risk was further reported in one placebo-controlled trial. The
cardiovascular effect of celecoxib seems to be dose-dependent with no significant increased risk of cardiovascular events among
patients taking 200 mg a day (Bresalier et al., 2005).
A meta-analysis evaluating the cardiovascular risk of traditional non-selective NSAIDs and COX-2 inhibitors showed similar
cardiovascular risk among patients taking high doses of diclofenac, ibuprofen and COX-2 inhibitors but a low risk of cardiovascular
events among patients taking naproxen. Table 1 presents the relative gastrointestinal and cardiovascular risks of some NSAIDs and
coxibs (Bhala et al., 2013). One RCT compared celecoxib versus naproxen in patients with arthritis at high risk of both upper GI
bleeding and cardiothrombotic disease. The study concluded that in patients who require aspirin and NSAID, celecoxib 100 mg
daily plus a PPI is the preferred treatment over naproxen 500 mg twice a day plus PPI, in terms of GI toxicity. The study was
underpowered to provide reliable cardiovascular (CV) outcomes (Chan et al., 2017). Also, the recent PRECISION trial, conducted in

Table 1 Gastrointestinal and cardiovascular risk of some NSAIDs and coxibs

Drug Gastrointestinal risk Cardiovascular risk (major vascular events)

Diclofenac [RR] 1.89, 95% CI 1.16–3.09 [RR] 1.41, 95% CI 1.12–1.78

Ibuprofen [RR] 3.97, 95% CI 2.2–7.1 [RR] 1.44, 95% CI 0.89–2.33
Naproxen [RR] 4.22, 95% CI 2.71–6.56 [RR] 0.93, 95% CI 0.69–1.27
Coxibs [RR] 1.81, 95% CI 1.17–2.81 [RR] 1.37, 95% CI 1.14–1.66

Modified from reference Bhala, N., Emberson, J., Merhi, A., Abramson, S., Arber, N., Baron, J.A., et al. (2013) Vascular
and upper gastro-intestinal effects of non-steroidal anti-inflammatory drugs: Meta-analyses of individual participant data
from randomised trials. Lancet 382, 769–779.
 Aspirin and Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) 5

Table 2 Best prescription option balancing gastrointestinal and cardiovascular risks

Cardiovascular risk Gastrointestinal risk

Low GI risk (no risk factors) Moderate GI risk (1–2 risk factors) High GI risk (3 or more risk factors
or history of ulcer complications)

Low CV risk NSAID at lowest effective dose NSAIDs plus PPI/misoprostol or celecoxib COX-2 inhibitor plus PPI
High CV risk Naproxen Naproxen plus PPI/misoprostol or low-dose celecoxib Avoid NSAID/COX2 if possiblea
High CV risk on aspirin —b Low-dose Celecoxib plus PPIc Avoid NSAID/COX if possiblea
a
When NSAID treatment cannot be avoided consider low-dose celecoxib plus PPI with the restrictions commented above.
b
Patients on low-dose aspirin who need NSAIDs are not considered at low-GI risk.
c
Some regulatory agencies do not recommend or contraindicate the use of coxibs in patients at high CV risk or with previous CV events. Consider the potential interaction of naproxen
with the antiplatelet effect of aspirin. Also test and treat for H. pylori if ulcer history.

patients who required NSAIDs for osteoarthritis or rheumatoid arthritis and who were at increased cardiovascular risk, concluded
that celecoxib plus esomeprazole had a lower incidence of GI events compared to naproxen or ibuprofen combined with
esomeprazole and no increase in CV events (Nissen et al., 2016). However, these results have to be interpreted with caution
given the high number of patients who stopped taking the drug (68.8%) and that almost a third of patients were lost to follow-up
and the imbalance in anti-inflammatory doses between the treatment arms. Table 2 is a summary of current recommendations of
NSAIDs prescriptions based on both GI and cardiovascular risk and an update of a recommendation derived from a consensus
meeting (Scarpignato et al., 2015).

References

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