Expert Review of Clinical Pharmacology

ISSN: 1751-2433 (Print) 1751-2441 (Online) Journal homepage: http://www.tandfonline.com/loi/ierj20

NSAID induced gastrointestinal damage and

designing GI-sparing NSAIDs

Guillermo García-Rayado, Mercedes Navarro & Angel Lanas

To cite this article: Guillermo García-Rayado, Mercedes Navarro & Angel Lanas (2018): NSAID
induced gastrointestinal damage and designing GI-sparing NSAIDs, Expert Review of Clinical
Pharmacology, DOI: 10.1080/17512433.2018.1516143

To link to this article: https://doi.org/10.1080/17512433.2018.1516143

Accepted author version posted online: 23

Aug 2018.

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Review

NSAID induced gastrointestinal damage and designing GI-sparing

NSAIDs

Guillermo García-Rayado (1,2), Mercedes Navarro (1,2), Angel Lanas (1,2,3,4)

1. Hospital Clínico Universitario Lozano Blesa. Zaragoza. Spain

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2. IIS Aragón. Zaragoza. Spain

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3. CIBERehd. Madrid. Spain

4. University of Zaragoza. Zaragoza

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Address Correspondence:
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Guillermo Garcia-Rayado
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Servicio de Aparato Digestivo.

Hospital Clínico Universitario Lozano Blesa

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C/ San Juan Bosco 15

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50009 Zaragoza

Email: ggarciara@salud.aragon.es
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Abstract

NSAIDs are widely used to treat pain and rheumatic conditions, but they induce adverse

events in different body systems, although the major, most frequent events occur in the upper

and lower gastrointestinal (GI) tracts.

Areas covered: This review is focused on damage caused by NSAIDs in the upper and lower

GI tracts, the different mechanisms of damage and the GI-sparing NSAIDs designed to

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minimize adverse events based on understanding of these mechanisms.

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Expert commentary: Among the new NSAIDs, COX-2 selective inhibitors have been

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extensively investigated, and some were approved for human use. Celecoxib demonstrated its

safety for the entire GI tract, compared to traditional NSAIDs. However, coxibs, like
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traditional NSAIDs, are toxic to the cardiovascular (CV) system. Other GI-sparing agents

include nitric oxide-NSAIDs and phosphatidylcholine-associated NSAIDs. Testing in animal

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models and humans they showed some GI advantages over the parent NSAID compounds,

but none obtained regulatory approval or were further investigated. Hydrogen sulfide-
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releasing NSAIDs are currently under clinical development, and more data are needed before

clinical use. Alternative therapies, such as modulating gut microbiota, are being explored.
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Currently, clinicians must continue prescribing traditional NSAIDs or coxibs, associated

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with/without proton pump inhibitor therapy, based on the presence of GI/CV risk factors.
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Key words

NSAIDs, Gastrointestinal, COX-2 selective inhibitors, Nitric oxide, Hydrogen sulfide,

Phosphatidylcholine
1. Introduction

Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most widely used drugs

worldwide. NSAIDs are largely sold by prescription and over-the-counter (OTC) for treating

fever, acute or chronic pain, and inflammatory conditions, such as rheumatic diseases. Over

30 million people take NSAIDs each day [1]. In Europe, NSAIDs represent more than 7.7%

of all prescriptions [2]. In the United States, over 70 million NSAID prescriptions are written

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annually, and with OTC use, more than 30 billion NSAID doses are consumed annually [3].

NSAID use increases among older individuals, particularly those affected by arthritis; thus,

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use is expected to increase with an ageing population. A survey of people aged 65 years or

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older showed that 70% used NSAIDs at least once weekly, and 34% used NSAIDs daily [4].

However, like many other drugs, NSAIDs are associated with a broad spectrum of
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adverse effects, including gastrointestinal (GI) injury, cardiovascular (CV) events, renal

toxicity, congestive heart failure deterioration, and blood pressure elevation, among others.
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Recently, CV events have caused much concern [5,6], but GI toxicity is probably the most
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important adverse effect, due to its frequency and severity.

In this review, we focus on the damage caused by NSAIDs in the upper and lower GI
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tracts, the different mechanisms of damage, and the GI-sparing NSAIDs designed to avoid or

minimize GI damage.
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2. Mechanisms of GI tract damage

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Traditional NSAIDs are lipid-soluble, weak acids [7], believed to affect the GI tract by

inhibiting the two isoforms of cyclooxygenase (COX), COX-1 and COX-2, and by inducing

topical effects. Topical effects involve detergent-like interactions with phospholipids and the

uncoupling of cellular oxidative phosphorylation [7].

2.1 Inhibition of COX-1 and COX-2

NSAIDs inhibit COXs, key enzymes in the synthesis of prostaglandins derived from

arachidonic acid. Both isoforms, COX-1 and COX-2 are inhibited by traditional NSAIDs,

which include acetylsalicylic acid (ASA) at doses above 300 mg. In contrast, selective

NSAIDs only inhibit COX-2, and low-dose aspirin only inhibits COX-1 [8].

COX-1 is present in most tissues. It is associated with hemostasis regulation, GI and

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renal tract integrity, platelet function, and macrophage differentiation. COX-1 is involved in

the synthesis of prostaglandins that stimulate the production and secretion of mucus and

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bicarbonate, increase mucosal blood flow, and promote epithelial cell proliferation [8].

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COX-1 induces platelets to produce thromboxane A2, which stimulates platelet aggregation

in the presence of blood vessel damage. Blocking platelet COX-1 with aspirin is irreversible,
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and it promotes bleeding when blood vessels are damaged [9].

In contrast, COX-2 is an inducible enzyme. In most tissues, it is expressed in

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inflammatory conditions [8]. COX-2 is involved in the synthesis of prostaglandins that

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induce inflammation, pain, and fever, and are involved in cell proliferation, angiogenesis

promotion, and mucosal integrity restoration. Thus, COX-2 is the primary target of anti-
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inflammatory drugs. It provides pain relief with less adverse GI events, because it does not

affect COX-1-derived prostaglandins [10].

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NSAID inhibition of COXs has important implications in the intestinal

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microcirculation. Regulation and maintenance of intestinal microcirculation involve several

mediators, including prostaglandins (one of the most relevant), leukotrienes, nitric oxide

(NO), and hydrogen sulfide (H2S) [11]. After injury, these molecules increase microvascular

blood flow. NSAID inhibition of COXs decreases this compensatory blood flow [12].

Moreover, NSAIDs induce the expression of neutrophil adhesion molecules within the

endothelium, which could mechanically compromise microvascular blood flow. As reviewed

below, in this setting, NO and H2S can be therapeutic in preventing NSAID-induced GI

damage, because they increase mucosal blood flow and reduce leukocyte adhesion to

endothelial cells [11].

Various studies have shown that the absence or selective inhibition of COX-1 reduced

the level of prostaglandins by 95% or more, without increasing intestinal permeability,

inflammation, or ulcers [13]. Similar effects were observed with short-term selective deletion

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or inhibition of COX-2 [14]. These effects were observed in animals, but not humans [13,14].

Therefore, it seems that “a priori” both isoenzymes must be inhibited to disrupt the GI

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mucosa. However, after this COX1/COX2 hypothesis was launched, the topical effects of

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NSAIDs (interacting with phospholipids and uncoupling oxidative phosphorylation) and

luminal aggressors were shown to play larger roles than expected [12].
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Therefore, COX inhibition is one of the most important factors to consider in the

pathogenesis of NSAID-induced GI (both upper and lower) damage, although it is probably

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not the primary, the sole, or the initiating event in NSAID-induced GI damage. We must also
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consider topical effects and luminal aggressive factors, which vary along the tract, from the

stomach to the small bowel [12].

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2.2 Topical effects: phospholipid interactions and oxidative phosphorylation uncoupling

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Mucus performs different roles in the GI tract. It acts as a lubricant between the surface

epithelium and the luminal content, and it serves as a matrix for phospholipids that maintain
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GI integrity [15]. It protects the epithelium by restricting access to different compounds, such

as digestive enzymes, bacteria, and large hydrophilic molecules. Moreover, mucus acts as a

buffer from luminal acids in the stomach [15].

Interactions between the surface epithelium and luminal aggressors, like Helicobacter

pylori, in the stomach, or bile, in the small bowel, are mediated by multiple factors. These
factors determine the production and secretion of mucus. Mucus properties, such as thickness

and composition, vary along the different GI tract regions [16].

NSAIDs interact with the mucus layer and the phospholipid bilayer of the GI tract.

NSAIDs decrease the hydrophobicity of GI mucosa, the hydrophobic lining, which leads to

mucosal exposure to different luminal aggressors, such as acid and pepsin in the stomach and

bile in the small bowel.

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On the other hand, NSAIDs uncouple mitochondrial oxidative phosphorylation, even

at millimolar concentrations [17]. This uncoupling leads to a cascade of detrimental effects

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that causes cellular ATP depletion and loss of intercellular junction integrity in the GI tract.

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These effects increase mucosal permeability, and finally, apoptosis and cell death occur.

COX-2-selective agents can also uncouple oxidative phosphorylation, but at lower potency
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than traditional NSAIDs [18].

Topical effects can initiate GI damage, but the addition of COX-1 inhibition and
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luminal aggressors causes mucosal erosions and ulcers. Uncoupling leads to increased
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intestinal permeability and low-grade inflammation. When combined with reduced mucosal

prostaglandin production and the mucosal aggressors, these effects increase the severity of
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inflammatory and ulcerative damage.

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2.3 Luminal aggressive factors

Different luminal aggressors are found in the stomach (acid, pepsin, and H. pylori) and the
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small bowel (bile, intestinal enzymes, and commensal bacteria). The importance of gastric

acid damage related to NSAIDs has been clearly proven as the incidence of damage, in short

and long-term users of these drugs, is reduced associating proton pump inhibitors (PPIs) or

high-dose histamine 2-receptor inhibitors [19,20]. Acid damage would depend on the

exposure of the mucosa to back diffusion of acid due to NSAIDs topical effects. On the other

hand, the role of H. pylori infections is unclear in the pathogenesis of NSAID-associated

gastric lesions. According to a recent systematic review and meta-analysis, in 2015, 4.4

billion individuals were infected with H. pylori [21]. These individuals develop different

types of gastritis, including pangastritis and antral predominant gastritis, with different levels

of acid secretion. The type of gastritis depends on the intrinsic virulence factors of the

bacteria and the host immune response, mediated by cytokines, which is genetically

determined. Gastric acid secretion is typically normal or reduced in patients with pangastritis

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and increased in patients with antral gastritis [22,23]. Gastric damage induced by short-term

NSAID use does not appear to be mediated by H. pylori, but damage induced by long-term

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use occurs in addition to the gastritis related to H. pylori [24]. On the other hand, gastric

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adaptation to the short-term administration of ASA could be affected by H. pylori [25].

Depending on the gastritis induced by H. pylori, we will have different findings: exacerbation
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of ASA induced gastric damage in patients with an increased acid secretion; or reduction of

the damage in those with an acid hyposecretion [26]. From a clinical perspective, a meta-
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analysis concluded that long-term NSAID use and H. pylori infections were independent,
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additive risk factors for peptic ulcer development, but they acted separately in the ulcer

complication of bleeding [27].

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Bile appears to play an important role in the pathogenesis of small bowel lesions. Bile

also contributes to NSAID-induced intestinal and gastric damage, but the biochemical
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mechanisms have not been fully established. It was reported that the severity of NSAID
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enteropathy was correlated with the amount of drug excreted in the bile and the rate of

enterohepatic circulation [28]. Indeed, a bile duct ligation almost completely abolished the

small bowel macroscopic damage from NSAIDs [29].

Some studies have suggested that the combination of bile and NSAIDs is more toxic

than either one alone [30]. For example, when bile acids were co-administered with

indomethacin in rats, the incidence and severity of gastric and small bowel damage were
significantly higher than the damage incurred by either alone [31]. On the other hand, bile

induces a biotransformation in different NSAIDs, for example diclofenac is transformed to

acyl glucuronide, which accounts for a significant part of its small bowel toxicity. Although

these conjugates can be harmful in their own way, commensal bacteria also play a role in the

metabolism of NSAID conjugates, by deconjugating them into even more toxic compounds

[32]. The interaction between biliary NSAID excretion and intestinal bacteria deconjugation

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can explain mild and distal location of NSAID enteropathy. In addition, NSAID-induced

mucosal permeability facilitates the action of bacteria. Moreover, the lipopolysaccharide

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components present in gram negative intestinal bacteria can activate the transmembrane toll-

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like receptor (TLR4) present in intestinal cells. TLR4 promotes mucosal cytokine expression,

which leads to neutrophil recruitment, and finally, the release of reactive oxygen species and
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proteases that cause mucosal injury [33].
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3. Upper gastrointestinal damage

Upper GI tract damage was the first clinically recognized adverse effect of NSAIDs [34].
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About 30 to 50% of individuals that use NSAIDs exhibit endoscopic lesions, mainly in the
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gastric antrum, often without any clinical manifestations [35,36]. In addition, up to 40% of

individuals that use NSAIDs experience upper GI symptoms, including dyspepsia or

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gastroesophageal reflux [35]. However, these symptoms are not predictive of mucosal

damage, and approximately 50% of symptomatic patients exhibited normal mucosa [37]. In
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contrast, over 50% of patients with serious peptic ulcer complications had no previous

warning symptoms [38]. About 1-2% of individuals that use NSAIDs experience a serious

complication, like bleeding, perforation, or obstruction. The use of NSAIDs has been

associated with a 3- to 5-fold increase in the risk of upper GI complications [39]. These
observations suggested that prevention therapies should be implemented based on the

presence of risk factors, not on the occurrence of dyspeptic symptoms [40].

Several risk factors are related to NSAID-induced GI complications (Table 1),

including a history of peptic ulcer, age >65 years, severe illness, H. pylori infection, and the

use of concomitant therapy with other potentially damaging gastrotoxic drugs, including

other NSAIDs [41]. Some risk factors can be modified, and should be taken into account

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before starting NSAID therapies. The different available NSAIDs carry different risks of GI

bleeding. A 2012 systematic review and meta-analysis of observational studies (SOS project)

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confirmed the variability in the risk of upper GI complications among NSAIDs used in

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clinical practice. The pooled relative risks (RRs) were <2 for aceclofenac, celecoxib, and

ibuprofen, 2-4 for rofecoxib, sulindac, diclofenac, meloxicam, nimesulide, and ketoprofen, 4-
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5 for tenoxicam, naproxen, indomethacin, and diflunisal, and >5 for piroxicam, ketorolac, and

azapropazone [42]. The doses and durations of individual NSAIDs that are linked to upper GI
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damage should be addressed in future studies.

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Table 1. Risk factors for NSAID-related GI complications

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Risk factors

Age (>65 years, specially >70 years)

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History of peptic ulcer

Severe illness
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Concomitant therapy with antiplatelet agents, anticoagulants, selective serotonin reuptake

inhibitors or corticosteroids

H. pylori infection

Use of two or more NSAIDs at the same time

Use of other gastro-erosive agents

 Before prescribing NSAIDs, one should consider the concomitant use of other drugs,

such as antiplatelets, anticoagulants, or selective serotonin reuptake inhibitors (SSRIs). A

recent retrospective cohort study examined the comparative safety of individual NSAIDs

when given concomitantly with clopidogrel. They concluded that the bleeding risks of

individual NSAIDs varied more markedly than thrombotic risks, when used concomitantly

with clopidogrel. Indomethacin, diclofenac, naproxen, and rofecoxib showed statistically

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significantly higher bleeding risks than ibuprofen, but valdecoxib showed significantly

reduced bleeding risk. Moreover, in the presence of clopidogrel, the bleeding and thrombotic

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risks of individual NSAIDs did not appear to be inversely related [43].

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Also of interest, a 2014 systematic review and meta-analysis of observational studies

evaluated the risk of upper GI bleeding with SSRIs, with or without concurrent NSAID use.
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They concluded that SSRIs were associated with a modest increase in the risk of upper GI

bleeding (odds ratio [OR]: 1.66, 95% CI: 1.44-1.92), and the risk was significantly higher
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when SSRIs were combined with NSAIDs (OR: 4.25, 95% CI: 2.82-6.42) [44].
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H. pylori infection and NSAID use seem to have synergistic effects on the risk of

upper GI bleeding. A meta-analysis of 16 studies showed that, among patients with H. pylori
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infection that used NSAIDs, the OR for peptic ulcer was 61.1 (95% CI: 9.98-373), compared

to individuals without H. pylori that did not use NSAIDs [27]. Similarly, Sostres and
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colleagues performed a case control study that included 1332 patients, 666 with peptic ulcer
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bleeding. They concluded that NSAIDs, low-dose ASA use, and H. pylori infections were

independent risk factors for the development of peptic ulcer bleeding. However, they found

different interaction effects. They found that an H. pylori infection did not interact with

low-dose ASA use, but had additive effects with NSAID use (RR: 8, 95% CI: 5.0-12.8) [45].

Of note, the best available evidence regarding NSAID-related GI bleeding is from

randomized controlled trials with patients that used NSAIDs to manage chronic rheumatic
diseases. However, a recent Spanish study analyzed the characteristics of patients

hospitalized for upper GI bleeding in clinical practice and found that the majority reported

short-term NSAID use for reasons other than rheumatic disease. That finding suggested that

current prevention strategies may not reach a substantial population that use NSAIDs for

short-term treatments [46].

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4. Lower GI damage

Over the last decades, hospitalization rates have changed due to GI complications [47,48]. In

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a multicenter study, annual hospitalization rates for NSAID gastropathy increased from 0.6%

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in 1981, to a peak of 1.5% in 1992, and then decreased to 0.5% in 2000 [47]. The latter

reduction could be explained by the use of lower NSAIDs doses, PPIs, and less toxic
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NSAIDs, in addition to a decreasing prevalence of H. pylori infection.

Along the same lines, in 2011, Lanas and colleagues conducted a population-based
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study and found that the incidences (per 100 000 person-years) of upper GI bleeding and

perforations decreased over time, respectively, from 54.6 and 3.9 in 1996, to 25.8 and 2.9 in
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2005. In contrast, the incidences (per 100 000 person-years) of colonic diverticular bleeding
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and angiodysplasia bleeding increased over time, respectively, from 3.3 and 0.9 in 1996, to

8.0 and 2.6 in 2005. In addition, a small increase in intestinal perforations was reported [48].
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Increasing evidence has suggested that NSAIDs also damage the lower GI tract,

although this damage has not been characterized as well as the damage caused in the upper
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GI tract. Many recent studies have focused on the damage induced by NSAIDs in the small

bowel where mechanistic studies (see above) and evidence is now greater than that obtained

for the colon. Video capsule endoscopy (VCE) for evaluation of the small bowel helped to

improve the study of the side effects of NSAIDs in the lower GI tract. One study with

hundred twenty and forty patients on long-term NSAIDs and COX-2 selective agents
respectively and sixty healthy volunteers as controls, showed that 62% of patients on

conventional NSAIDs and 50% of patients on selective COX-2 inhibitors had abnormal VCE

studies which differed significantly (P < 0.001) from controls. The main pathology related

were reddened folds, denuded areas and mucosal breaks [49]. These findings were also found

on short-term diclofenac treatment. Many other studies are consistent with these findings

[50,51]. This NSAID effect in the small bowel might, at least in part, explain the increased

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rate of hospitalizations due to lower GI bleeding. Indeed, the prevalence of NSAID-

associated adverse effects, including both clinical and subclinical effects, might be higher in

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the small bowel than in the upper GI tract. In the lower GI, NSAIDs cause a wide spectrum of

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lesions, which includes increased gut permeability, inflammation, blood loss, anemia,

malabsorption, protein loss, and mucosal ulceration (Table 2).

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Table 2. Prevalence of main NSAID-associated lower GI side-effects. Adapted from
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Lanas et al [52].

Increased gut permeability 44-70%

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Gut inflammation 60-70%

Blood loss and anemia 30%

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Malabsorption 40-70%
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Protein loss 10%

Mucosal ulceration 30-40%

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The development of mucosal inflammation and increased gut permeability are the

most frequent abnormalities associated with NSAID use [53]. Small bowel mucosal

inflammation is present in 60-70% of patients that take NSAIDs, and it can be detected up to

3 years after long-term NSAID treatment has been interrupted. Inflammation is associated

with protein and blood loss, but it is often silent [54]. Increased gut permeability can be
observed 12 h after NSAID ingestion, but is not observed in NSAIDs that do not undergo

enterohepatic circulation [53]. Some studies have suggested that COX-2-selective agents do

not increase intestinal permeability [55]. NSAID use can induce erythema, mucosal

hemorrhage, erosions, and ulceration in the small bowel. Mucosal ulceration was observed in

up to 40% of patients that use NSAIDs [52], and it could be associated with occult bleeding,

major GI bleeding, or perforation [56].

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When taken long-term, NSAIDs can induce enteropathy associated with continuous,

mild blood loss, which might result in anemia or iron deficiency. The precise burden and

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clinical impact of this problem in patients taking NSAIDs or ASA has not been well

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established. A systematic review of randomized trials that included 1162 subjects found that

most individuals taking NSAIDs and low-dose ASA exhibited a small average increase in
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fecal blood loss of 1 to 2 ml/day, from about 0.5 ml/day at baseline. Some individuals lost

much more blood than average; 5% of individuals taking NSAIDs had blood losses of 5
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ml/day or more, and 1% of individuals lost 10 ml/day or more. With daily doses of 1800 mg
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ASA or greater, daily blood loss of 5 ml/day and 10 ml/day occurred in 31% and 10% of

individuals, respectively [57].

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In 2008, the Multinational Etoricoxib and Diclofenac Arthritis Long-Term (MEDAL)

program was designed to evaluate the incidence of CV events in patients taking either
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etoricoxib or diclofenac. That trial also evaluated the occurrence of severe upper and lower
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GI events in 34 701 patients with rheumatoid arthritis or osteoarthritis, aged 50 years or

older, with a mean therapy duration of 18 months. Lower GI complication rates (including

perforation, obstruction, or bleeding) were 0.32 and 0.38 per 100 patients, for etoricoxib and

diclofenac, respectively (HR: 0.84, 95% CI: 0.63-1.13). Bleeding occurred most commonly,

at rates of 0.19 and 0.23 per 100 patient-years, for etoricoxib and diclofenac, respectively.
Finally, a multivariable analysis revealed two significant risk factors: prior lower GI event(s)

(HR: 4.06, 95% CI: 2.93-5.62) and age above 65 years (HR: 1.98, 95% CI: 1.45-2.71) [58].

A 2014 prospective study evaluated the risk of lower GI bleeding associated with

NSAIDs, low-dose ASA, thienopyridine, and other antiplatelet drugs. They concluded that

nonselective or selective NSAID use was associated with lower GI bleeding (OR: 2.3, 95%

CI: 1.6-3.2) [59]. In addition, a recent case-control study associated NSAID use with

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increased risks of both upper (RR: 2.6, 95% CI: 2.0-3.5) and lower GI bleeding (RR: 1.4,

95% CI: 1.0-1.9) [60].

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Complicated colonic diverticular disease is another clinical adverse effect associated

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with NSAIDs in the lower GI tract. In 2011, a cohort study that included 47 210 men, ages

40-75 years at baseline, identified 939 cases of diverticulitis and 256 cases of diverticular
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bleeding during a 22-year follow-up. After adjusting for risk factors, individuals that

regularly used NSAIDs had an increased risk of diverticulitis (HR: 1.72, 95% CI: 1.40-2.11)
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and diverticular bleeding (HR: 1.74, 95% CI: 1.15-2.64), compared to men that denied using
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these medications [61]. That finding was confirmed in a 2014 systematic review and meta-

analysis of observational studies; they concluded that ASA and NSAID use were strongly and
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consistently associated with an increased risk of colonic diverticular bleeding (RR: 2.48, 95%

CI: 1.86-3.31) [62]. In addition, a prospective study investigated the risk factors associated
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with transfusion, further bleeding, and prolonged length of stay in patients with acute
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episodes of diverticular bleeding. Multivariate analyses revealed that NSAID use (OR: 5.9;

p=0.04) and stigmata of bleeding (OR: 11; p <0.01) were significant risk factors for further

bleeding. Moreover, age >70 years (OR: 2.1; p =0.04) and NSAID use (OR: 2.7; p =0.03)

were independent risk factors for prolonged hospitalization [63].

5. Designing GI-sparing NSAIDs

Information gained over the last decades on the biochemical characteristics of NSAIDs and

the mechanism of damage to the GI tract mucosa has initiated a search for NSAIDs with low

or no capacity to induce gastric or intestinal mucosal damage. Multiple studies have

investigated new or complex compounds, but few have passed testing in humans, and much

fewer have been commercialized or used in clinical practice.

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5.1 COX-2-selective agents

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The discovery of the gene encoding the COX-2 iso-enzyme opened the door to the

development of NSAIDs that selectively inhibited COX-2, or preferentially inhibited COX-2

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over COX-1, at doses commonly used in clinical practice. Selective and preferential COX-2
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inhibitors induce pain relief, reduce inflammation, and cause fewer GI adverse events than

traditional NSAIDs. Although COX-1 inhibition is not the only mechanism involved in
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NSAID-related GI toxicity, these data reinforced the hypothesis that COX-1 inhibition is

important in NSAID-induced GI damage.

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NSAIDs are classified according to their specific inhibition of COX-2 [64].

“Preferential” COX-2 inhibitors, such as meloxicam, mainly inhibit COX-2, but they show
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some inhibition of COX-1 at clinically effective doses. “Selective” COX-2 agents (also called
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coxibs) only inhibit COX-2 at clinically effective doses, but they may inhibit COX-1 at high

doses (Table 3). Coxibs on the market include celecoxib and etoricoxib; other coxibs, such as
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rofecoxib or lumiracoxib, were withdrawn from the market due to concerns about increased

CV risk (rofecoxib) or liver damage (lumiracoxib) [65].

Table 3. NSAID selectivity according to COX-1 and COX-2 inhibition

Dual inhibition COX-1 and COX-2 Naproxen, ibuprofen, ketoprofen,

indomethacin, piroxicam, diclofenac

COX-1 Selective inhibition Low-dose ASA

COX-2 Preferential inhibition Nimesulide, meloxicam, nabumetone

COX-2 Selective inhibition Celecoxib, rofecoxib

lumiracoxib, valdecoxib, etoricoxib

Coxib effects on the GI have been characterized in large GI outcome studies over the

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last 15 years . A systematic review of randomized controlled trials showed that, compared to

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non-selective NSAIDs, coxibs produced significantly fewer gastroduodenal ulcers (RR: 0.26,

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95% CI: 0.23-0.3), fewer clinically important ulcer complications (RR: 0.39, 95% CI: 0.31-

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0.5), and better GI tolerability [66]. The CONDOR trial was a multi-center, double-blind

study. They randomly assigned 4484 patients to receive celecoxib or diclofenac slow release
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plus PPI, and evaluated the risk of GI events in each group. The risk of clinically significant

upper and lower GI events was higher with diclofenac plus PPI than with celecoxib (HR: 4.3,
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95% CI: 2.6–7.0; p<0.0001). Importantly, patients taking concomitant aspirin were excluded

from the trial [67].

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A common clinical scenario is the patient that takes low-dose ASA for primary or,

more commonly, secondary CV prevention and also needs to take NSAIDs for an arthritic
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condition. Low-dose ASA acts as a selective COX-1 inhibitor [10] and the combination of
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coxib plus low-dose ASA should act as a dual COX inhibitor. This scenario raised the

question of whether low-dose ASA combined with a coxib was better or worse than low-dose
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ASA combined with a traditional NSAID. Evidence from several studies [67-70], suggested

that co-administration of ASA reduced the GI-safety of coxibs. However, a more recent

meta-analysis of randomized controlled trials showed that coxib plus low-dose ASA was

associated with a lower risk of upper GI complications, compared to non-selective NSAIDs

plus low-dose ASA [71]. Nevertheless, those data must be interpreted with caution, because

patients had not been randomly assigned to the different groups, and the risk of bias could not
be ruled out. The PRECISION (Prospective Randomized Evaluation of Celecoxib Integrated

Safety versus Ibuprofen or Naproxen) trial evaluated the global safety (i.e., major adverse CV

events, noncardiovascular death, and GI or renal events) of naproxen, ibuprofen, and

celecoxib when co-administered with low-dose ASA. Without aspirin, celecoxib had a better

overall safety profile than the other drugs. This difference was attenuated by adding ASA, but

celecoxib remained associated with fewer renal events than ibuprofen and fewer GI events

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than ibuprofen or naproxen [72].

Prior to choosing a NSAID, one should weigh the GI benefits of selective COX-2

cr
agents against the known CV risks, although CV toxicity is not exclusively a property of

us
selective COX-2 NSAIDs. The mechanism of CV damage remains unclear, though it might

be partly explained by the inhibitory effect of traditional NSAIDs and coxibs on the COX-2-
an
mediated endothelial cardioprotective pathway. These drugs counteract the COX-2 inhibition

of PGI2 in the vasculature, which releases the constraints on platelet function, and leads to a
M

prothrombotic situation. Moreover, a recent study showed that NSAIDs potently induced
ed

reactive oxygen species (ROS) in cardiac cells, which could lead to cardiotoxicity through a

ROS-dependent mechanism involving mitochondrial and proteasome dysfunction [73].

pt

Unlike most other NSAIDs, naproxen, particularly at high doses (500 mg), causes an

antiplatelet effect through a persistent, but reversible, inhibition of platelet COX-1 activity.
ce

This naproxen effect might improve its CV tolerability, but also increase the risk of GI
Ac

adverse events [10].

In a 2013 meta-analysis of randomized trials that evaluated the vascular and upper GI

effects of NSAIDs, naproxen did not significantly increase major vascular events (RR: 0.93,

95% CI: 0.69-1.27). However, vascular death was increased significantly by coxibs (RR:

1.58, 99% CI 1.0-2.49; p=0.0103) and diclofenac (RR: 1.65, 0.95-2.85; p=0.0187), only non-
significantly by ibuprofen (RR: 1.9, 0.56-6.41; p=0.17), and naproxen had no effect (RR:

1.08, 0.48-2.47; p=0.8) [5].

The PRECISION trial also compared the CV safety of celecoxib, ibuprofen, and

naproxen in patients that needed NSAIDs for treating rheumatic diseases. That study mainly

aimed to assess the non-inferiority of celecoxib with regard to CV death, nonfatal stroke, or

myocardial infarction. Celecoxib at moderate doses was found to be non-inferior to ibuprofen

t
ip
or naproxen with regard to CV safety (HR for celecoxib vs. naproxen, 0.93, 95% CI: 0.76-

1.13; HR for celecoxib vs. ibuprofen, 0.85, 95% CI: 0.70-1.04; P<0.001 for non-inferiority in

cr
both comparisons) [6]. As a secondary objective, they evaluated GI safety. Patients taking

us
NSAIDs plus PPI had infrequent clinically significant GI events. Celecoxib plus PPI had

better overall GI safety compared to ibuprofen or naproxen, despite the co-administration of

an
corticosteroids or low-dose ASA [74]. However, that trial had several limitations: two-thirds

of the patients interrupted treatment with the assigned drug; almost 30% of patients were lost
M

to follow-up; and patients assigned to naproxen and ibuprofen received the highest doses
ed

within the protocol-specified range. These factors could have led to overestimations of

adverse event rates with these drugs [75]. A post-hoc analysis of this trial reported that
pt

naproxen or ibuprofen experienced a significantly higher risk of major toxicity than those that

used celecoxib [76].

ce

Finally, another recent double-blind randomized trial (CONCERN study) evaluated

Ac

the GI safety of celecoxib versus naproxen in patients at high risk of both CV and GI events.

The 514 patients enrolled received either celecoxib 100 mg twice per day plus PPI or

naproxen 500 mg twice per day plus PPI for 18 months. The cumulative incidence of

recurrent bleeding was significantly higher (p=0.008) with naproxen (12.3%, 95% CI: 8.8-

17.1) than with celecoxib (5.6%, 95% CI: 3.3-9.2). The appearance of serious CV events was

not significantly different between groups, though that was not the endpoint of the study [77].
The major criticism of the trial was the different doses of celecoxib (low) and naproxen

(high).

In summary, the available evidence favors the use of coxibs instead of traditional

NSAIDs, when considering the safety of the entire GI tract. However, the use of coxibs

should be balanced against the CV risk, particularly in patients at high risk of CV disease.

When needed, one should prescribe the shortest duration and lowest effective dose of either a

t
ip
traditional NSAID or a coxib [75].

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5.2 Nitric oxide-, carbon monoxide- and hydrogen sulfide-releasing NSAIDs

To counteract the harmful effects on intestinal microcirculation produced by NSAIDs, a

us
traditional NSAID can be coupled with a donor molecule that releases a gaseous mediator,
an
like NO or H2S. Reports of adverse CV effects associated with coxibs motivated the

investigation and development of compounds coupled with NO and H2S, which are
M
cardioprotective agents. NO- and H2S-releasing drugs can prevent endothelial dysfunction

and myocardial ischemia and they provide significant benefits to patients with congestive
ed

heart failure [78,79]. Moreover, H2S has anti-atherosclerotic effects, by inhibiting neointimal

hyperplasia, vascular calcification, and vascular inflammation [80]. These beneficial vascular
pt

effects extend to the GI tract; NO and H2S reduce NSAID-induced GI damage by increasing
ce

mucosal microvascular blood flow. In addition, these compounds increase mucus and

bicarbonate secretion in the GI tract and reduce leukocyte adhesion to endothelial cells [81]
Ac

(Table 4).

Table 4. Biological effects of NO, H2S and CO in the GI tract.

Effect on mucosal blood flow Increased

Effect on bicarbonate and mucus secretion Increased

Effect on acid secretion Minimal effect

Cytoprotection Yes

Effect on leukocytes adhesion to endothelial cells Reduced

Aspirin and several NSAIDs, like naproxen or diclofenac, have been coupled to a

nitroxybutyl or nitrosothiol moiety to generate molecular hybrids that release NO [11]. These

NO-releasing NSAIDs have been investigated in preclinical studies and clinical trials.

t
ip
Fiorucci and colleagues showed, in 40 healthy subjects, that NO-aspirin decreased gastric and

duodenal endoscopic injury after 7 days of treatment [82]. However, the most investigated

cr
NO-releasing NSAID is NO-naproxen (also called naproxcinod).

us
In preclinical studies, NO-naproxen caused less upper GI damage than naproxen. For

example, in a proof-of-concept study with 31 healthy volunteers, NO-naproxen (AZD3582)

an
or naproxen was administered at equimolar doses for 12 days. The mean total number of

gastroduodenal erosions was 11.5 with naproxen and 4.1 with NO-naproxen (p <0.0001), and
M

more than half the NO-naproxen group had no erosions [83]. Despite these promising initial

results, phase II studies could not confirm a lower gastrolesive profile for NO-naproxen. In a
ed

double blind phase II trial [84], 970 patients with hip or knee osteoarthritis were randomized
pt

to 750 mg AZD3582 twice daily, 500 mg naproxen twice daily, or placebo twice daily.

Although AZD3582 was favored for some secondary endpoints, like the endoscopy Lanza
ce

score, the primary end point (6-week endoscopic gastroduodenal ulcer incidence) was not

significantly different between AZD3582 and naproxen. The incidence of gastroduodenal

Ac

ulcers was 9.7% with AZD3582 and 13.7% with naproxen (p = 0.07, not significant).

Because long-term clinical trials did not show a significant difference between these two

drugs, the FDA denied approval of AZD3582 in 2010. In addition, the FDA requested a

broader safety assessment of NO-naproxen [11] that covered other adverse effects, such as

drops in blood pressure, which could have a major impact in older individuals.
 H2S can have beneficial effects on different systems damaged by NSAIDs (Figure 1).

In the GI tract plays a key role in maintaining mucosal integrity and it can protect the

stomach from damage [85]. Various NSAIDs have been designed, for example, H2S was

coupled with diclofenac, aspirin, and naproxen. These compounds reduced GI toxicity in

rodent models by preventing reductions in gastric mucosal blood flow [86], inhibiting tumor

necrosis factor-α expression, and inhibiting leukocyte adherence to vascular endothelium

t
ip
[87]. H2S might also confer gastroprotection by upregulating the Nrf-2/HO-1 pathway [88].

H2S-naproxen (ATB-346) was also tested in rats with compromised gastric mucosal defense

cr
systems, which mimicked the use of NSAIDs by humans at high risk. ATB-346 did not

us
induce significant GI damage; in fact, it accelerated the healing of pre-existing gastric ulcers

in these models of impaired mucosal defense [89,90]. In addition to the upper GI tract, H2S-
an
donor treatments reduced NSAID-induced enteropathy in rats [91], promoted the resolution

of colonic inflammation [92], and prevented intestinal polyp formation in an APCMin+mouse

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model [93].
ed

However, H2S-releasing NSAIDs must be assessed in clinical trials to determine

whether their GI safety might diminish in long-term real life settings. Currently, several
pt

proof-of-concept clinical studies with ATB-346 have been initiated in humans, mainly by the

Antibe Therapeutics company [79,94]. A phase 2A effectiveness study in patients with

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osteoarthritis of the knee showed that ATB-346 (250 mg once daily) reduced pain with
Ac

equivalent or better efficacy than that provided by naproxen or celecoxib. In a phase 2B GI

safety study, ATB-346 was tested in 244 healthy volunteers. One group received ATB-346

(250 mg once daily), and the other group received naproxen (500 mg twice daily) for 14 days.

Results were announced by Antibe in March, 2018. The gastric or duodenal ulceration rate

was 2.5% (3/118) with ATB-346 and 42.1% (53/126) with naproxen (p<0.001). Other H2S-
releasing NSAIDs, like ketoprofen for acute pain (ATB-352) and low-dose ASA (ATB-340),

are currently under investigation by the same company in pre-clinical stages [94].

A third gaseous mediator of GI mucosal integrity is carbon monoxide (CO). CO

production occurs via the enzymes, hemoxygenase-1 (HO-1, constitutive) and

hemoxygenase-2 (HO-2, inducible). CO is more biologically stable than NO and H2S. It acts

as a signaling molecule, and it has anti-inflammatory and cytoprotective properties. An

t
ip
important limitation to studying CO effects in vivo has been the lack of suitable CO donors

[81]. The most useful tools are a group of molecules called ‘‘CORMs’’ (CO-releasing

cr
molecules), developed in the laboratory of R. Motterlini [95]. A pharmacological CO donor,

us
known as the tricarbonyldichlororuthenium (II) dimer (CORM-2), protected against gastric

damage and accelerated the healing of pre-existing gastric ulcers in animal models [96,97]. In
an
animal models of ethanol-induced gastric damage and administration of different NSAIDs,

CORM-2 pretreatment reduced the number of gastric lesions and improved gastric blood flow
M

[96]. However, human studies on CO in GI diseases remain limited.

ed

5.3 Phosphatidylcholine-associated NSAIDs

As highlighted above, COX inhibition is not the only mechanism of NSAID-induced GI

pt

damage. Prostaglandin-independent mechanisms are also important; mainly the interaction

ce

between NSAIDs and the phospholipids of GI layers. The most abundant phospholipid in the

GI mucosa is phosphatidylcholine (PC), which plays a key role in preserving the hydrophobic
Ac

GI barrier. When NSAIDs disrupt phospholipid layers, luminal aggressors can gain access to

the epithelium [98]. On the other hand, PC is the major phospholipid in bile and able to

prevent bile injury in the lower GI tract. NSAIDs combined with bile salts increase GI

damage by forming toxic mixed micelles. In addition, NSAIDs may bind to PC, which

increases the amount of unbound toxic bile acid [99].

 Extensive studies and associated knowledge gained on this mechanism of topical

damage induced by NSAIDs opened the door to the development of therapeutic strategies

based on PC co-administration. New PC-associated NSAIDs (PC-NSAIDs) were designed as

safer drugs for the upper and lower GI tracts that lacked the potential CV damage associated

with COX-2 selective inhibitors. PC-NSAIDs were tested first in animal models and later in

human pilot clinical trials, mostly conducted by Lichtenberger and colleagues [100-106].

t
ip
In rodent models, oral or parenteral administration of PC-NSAIDs reduced the

NSAID-induced GI injury without affecting therapeutic activity [100,101]. In an

cr
experimental study, rats received acute intravenous or chronic subcutaneous PC-associated

us
indomethacin or indomethacin alone. PC-indomethacin produced less GI bleeding and

intestinal damage than indomethacin alone, but they had similar analgesic and anti-
an
inflammatory activities [101]. These protective effects were also investigated with a coxib

combined with aspirin treatment in rats. The gastric toxicity of aspirin combined with a coxib
M

was obviated with PC-associated aspirin, due to the maintenance of the stomach’s
ed

hydrophobic properties. Moreover, aspirin and PC-aspirin equally inhibited gastric mucosal

PGE2 concentrations [102]. PC also reduced the small bowel damage induced by
pt

indomethacin in rats. Administration of PC-indomethacin resulted in significantly fewer

erosions (>50% reduction) and bleeding (>80% reduction), compared to indomethacin alone.
ce

However, neither omeprazole nor lansoprazole protected against indomethacin-induced small

Ac

bowel injury [103].

Those results in animals motivated evaluations of PC-NSAIDs in humans. PC-aspirin

and PC-ibuprofen have been tested. In a pilot randomized, double-blind study [104], 16

healthy volunteers received aspirin or PC-aspirin for 3 days. Endoscopy on day 4 showed

significantly fewer gastric erosions with PC-aspirin than with aspirin alone (2.9 ± 4.3 vs. 8.7

± 10.7; p <0.025). In a larger, randomized, single blind, active-controlled study, 204 healthy
subjects (ages 50-74 years) received 7-day treatments with once daily 325 mg aspirin or PC-

aspirin [105]. Gastroduodenal erosions and/or ulcers were observed in 42.2% of the aspirin-

treated group and 22.2% of the PC-aspirin-treated group (p=0.0027). Finally, PC-ibuprofen

was also assessed in humans [106]. In this randomized, double-blind trial, 125 patients with

osteoarthritis received 2400 mg/day ibuprofen or an equivalent dose of PC-ibuprofen for 6

weeks. A trend was observed in improved GI safety in the PC- ibuprofen group compared to

t
ip
the ibuprofen group, but the difference was not statistically significant. However, in patients

over age 55 years, PC-ibuprofen treatment provided a significant benefit compared to

cr
ibuprofen in the prevention of NSAID-induced upper GI damage. Therefore, PC-ibuprofen

us
reduced upper GI injury, but only in patients at risk that were over 55 years old. These

satisfactory results with PC-NSAIDs in humans should be confirmed in long-term studies that
an
assess clinical GI events.

5.4 Other GI-sparing NSAIDs

M

In addition to coxibs and combinations of NSAIDs with gaseous mediators and

ed

phosphatidylcholine, other GI-sparing NSAIDs have been studied but most of them are in a

preclinical phase and have only been tested in animal models. Examples of these are
pt

encapsulated NSAIDs and combinations of glucosamine hydrochloride (GS-HCl) and

NSAID.
ce

Various vectors as polymer-based nanoparticles, liposomes and solid lipid

Ac

nanoparticles have been designed to encapsulate NSAIDs and decrease their GI side effects.

Both nanoparticles and liposomes have been studied in rodents or in rabbits. Most common

actives that have been tested in animals include flurbiprofen, diclofenac, indomethacin and

oxicams and the most targeted ways of administration routes were ocular and intravenous.

Some outcomes of these in vivo studies showed a bioavailability enhancement, improvement

of drug accumulation in targeted site and prolonged release with a well security profile [107].
Although it will be necessary to conduct similar studies in humans and specifically assess GI

damage outcomes. On the other hand, GS-HCl in combination with NSAID has been tested in

mice to try decrease GI injury of NSAIDs. Combination of GS-HCl and indomethacin

showed significantly decrease of gastric lesions in comparison with indomethacin alone. This

GI sparing effect could be due to inhibit COX-2 N-glycosylation by GS-HCl. GS-HCl

significantly attenuated TNF-a-induced COX-2 expression and also significantly reduced the

t
ip
expressions of other molecules like ICAM-1, VCAM-1, IL-8 and IL-1b [108].

cr
us
6. Expert commentary

The analgesic and anti-inflammatory efficacies of NSAIDs are well proven. NSAIDs remain
an
one of the most common prescriptions worldwide; millions of people take NSAIDs every

day, and NSAIDs will probably remain in use for years. In addition, NSAIDs have potential
M

anti-neoplastic effects, and they prevent colorectal adenomas. Unfortunately, like most

prescribed medications, their use is associated with adverse effects. This review described
ed

NSAID-induced adverse effects in the GI, CV, hepatic, and renal systems. Short- and long-
pt

term use of NSAIDs can produce upper and lower GI damage, mainly in patients with risk

factors, which include a history of peptic ulcer, concomitant therapy with antiplatelet or
ce

anticoagulant agents, older age, and severe comorbidity. NSAIDs-induced GI damage arises

from COX inhibition and topical effects, in addition to luminal GI aggressor actions. The
Ac

principal luminal aggressors include acid, pepsin, and H. pylori, in the upper GI tract, and

bile and bacteria, in the lower GI tract [12].

Investigations have focused for years on finding compounds to minimize adverse

effects, mainly in the GI tract. Several compounds were designed based on the growing

knowledge of the damage mechanisms (Figure 2). The most important development was the
design and introduction of COX-2-selective inhibitors. Coxibs were shown to be safer than

traditional NSAIDs in both the upper and lower GI tracts, but they were toxic to the CV

system. This discovery led to the finding that essentially all NSAIDs could induce CV events,

at least partly due to their effects on COX-2-dependent prostacyclin endothelial secretion.

After decades of NSAID use, this CV effect was not clearly detected until coxibs were

introduced to the market. This prompted the development of new guidelines that included

t
ip
both GI and CV risk factors for patients that needed NSAIDs. However, the beneficial effect

of coxibs in the GI tract, compared to traditional NSAIDs, was reduced when they were co-

cr
administered with low-dose ASA, a common clinical scenario. Consequently, because coxibs

us
did not fulfill initial expectations, other compounds with the potential to reduce both upper

and lower GI adverse events were developed and clinically tested, after successful preclinical
an
studies (Table 5).
M

Table 5: GI and CV risk associated to different NSAIDs. Evidence in humans with

ed

GI-sparing agents different to coxibs is limited or non-existing. The risk expressed are

estimations based on their parent compounds and/or animal data (*).

pt

CV: Cardiovascular. COX: Cyclooxygenase. GI: Gastrointestinal. H2S: Hydrogen

sulfide. PC: Phosphatidylcholine. NO: Nitric oxide. NSAIDs: Non-steroidal anti-

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inflammatory drugs.
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GI Risk CV Risk

Traditional NSAIDs ++ ++
(except naproxen)

Naproxen ++ +

COX-2 selective agents + ++

NO and H2S-NSAIDs + +

PC-NSAIDs + ++
 One of those compounds, naproxcinod, reached a significant clinical development,

because it combined the NSAID with the best CV profile with NO, an agent shown to be

beneficial for both the GI and CV systems. Unfortunately, in phase III studies, naproxcinod

did not show sufficient advantage over the current drugs, and both the EMA and FDA raised

safety concerns. Other compounds, like PC-associated NSAIDs or PC-aspirin, were also

t
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tested in humans with good results, but longer-term studies that assess clinically relevant GI

events are lacking. No new studies or applications for marketing approval are on the horizon.

cr
Currently, the only of new compounds undergoing clinically testing are H2S-releasing

us
NSAIDs. In a very recent phase 2B GI safety study, H2S-naproxen showed significantly

lower gastric and duodenal ulceration rates than naproxen alone in a 14-day treatment [94].
an
We must await results from clinical studies to ascertain whether these new H2S-releasing

NSAIDs will be given the green light to be marketed as a new drug for patients that need
M

NSAIDs.
ed

Currently, clinicians must choose from the available strategies, although other

options, different from GI-sparing NSAIDs, are being tested. One strategy for reducing
pt

NSAID-induced GI damage is to interfere with luminal aggressors. In the upper GI tract, the

most important aggressor is gastric acid. Indeed, PPIs were shown to be highly effective for
ce

reducing NSAID-related complications in the upper GI tract in all populations tested

Ac

[23,109,110]. However, PPIs do not reduce NSAID-induced lower GI injuries. In fact, they

might exacerbate small intestinal damage by inducing dysbiosis [111]. In addition, some

concern remains about the potential side effects of PPIs in long-term use and in drug

interactions. However, much of the current evidence linking PPI use to serious long-term

adverse consequences is weak and not well substantiated [112].

 To avoid or minimize NSAID-induced lower GI damage, new strategies, other than

COX-2 selective agents, are needed. Again, it might be beneficial to interfere with luminal

aggressors; in this case, bile and bacteria play relevant roles in the lower GI tract [12].

Bacterial β-glucuronidase in bile can deconjugate NSAIDs, and metabolites can be toxic to

GI mucosa. Some animal studies have shown that specific inhibitors of bacterial β-

glucuronidase [113,114] could reduce small bowel lesions induced by NSAIDs. These

t
ip
compounds have not been tested in human clinical trials. Other investigators have tested

antibiotics and/or probiotics in animal models and humans. One study in thirteen patients

cr
showed that metronidazole reduced intestinal inflammation and blood loss in NSAID-induced

us
enteropathy [115]. However, extensive clinical use of these drugs is limited by potential

negative effects on intestinal microbiota and the occurrence of extragastrointestinal drug

an
resistance. One recent proof-of-concept study was conducted with rifaximin, a poorly

absorbed, effective drug against enterobacteria [116]. In that placebo-controlled study, 60

M

healthy volunteers (median age 26 years) were given diclofenac plus omeprazole, with either
ed

rifaximin (400 mg) or placebo, twice daily for 14 days. Subjects were assessed with video-

capsule endoscopy. Mucosal breaks were detected in 20% of subjects given rifaximin and
pt

43% of subjects given placebo. None of the subjects in the rifaximin arm developed large

lesions, but 9 volunteers developed large lesions in the placebo arm (p<0.001). To confirm
ce

the clinical usefulness of rifaximin, a phase III study should be conducted in patients given
Ac

long-term NSAID treatments. Finally, other studies have tested probiotics, like VSL-3 and

Lactobacillus casei [117,118], for reducing NSAID-induced enteropathy in patients.

However, larger, more consistent clinical trials with probiotics are necessary to translate their

use into clinical practice.

7. Five-year view
Over the past decades, we have observed an important reduction in NSAIDs-induced peptic

ulcer disease [48, 119], mainly due to the widespread use of anti-secretory drugs, like PPIs,

and a reduction in H. pylori prevalence. However, the occurrence of lower GI damage and

complications associated with NSAIDs has become more apparent, and it presents a clear

clinical problem. From that perspective, we need new compounds and/or new therapeutic

strategies that aim to prevent not only upper but also lower GI tract damage these events.

t
ip
Some of the GI-sparing agents developed in the last decades have fulfilled partially this target

(coxibs) and others failed or have not been approved for human use. In 5 years time we will

cr
know whether the new H2S-releasing NSAIDs may be one of those compounds, and will

us
have a better understanding of the role of the microbiome on the damage or protection of the

gastrointestinal tract in patients taking NSAIDs. More effort and funding are needed to
an
investigate both the mechanisms of damage and to develop novel treatment strategies that

target the whole GI tract.

M
ed

8. Key issues

• NSAIDs are associated with a broad spectrum of adverse effects, but GI toxicity is the
pt

most important, due to its frequency and severity. NSAIDs cause damage in the upper

but also in the lower GI tract.

ce

• COX inhibition is one of the most important factors to consider in the pathogenesis of

NSAID-induced GI damage, although we must also consider topical effects of

Ac

NSAIDs and luminal aggressive factors.

• Coxibs are safer than traditional NSAIDs in both the upper and lower GI tracts, but

they are toxic to the CV system, therefore the use of coxibs should be balanced

against the CV risk.

 • NO-releasing NSAIDs and PC-associated NSAIDs showed a better GI profile over

the parent NSAID compounds in animals and humans studies, but they did not show

sufficient advantages and did not obtained regulatory approval or were further

investigated.

• H2S-naproxen is currently under clinical development and has showed significantly

less GI damage in a recent phase 2B GI safety study, although more data are needed

t
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before clinical use.

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Lower GI damage associated with NSAIDs has become more important, and novel

treatment strategies that target NSAID-induced lower GI tract should be developed.

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Larger and more consistent clinical trials with antibiotics like rifaximin or probiotics

that modulate gut microbiota are needed.

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Funding

This paper was not funded.

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Declaration of Interest
ed

The authors have no relevant affiliations or financial involvement with any organization or

entity with a financial interest in or financial conflict with the subject matter or materials
pt

discussed in the manuscript. This includes employment, consultancies, honoraria, stock

ownership or options, expert testimony, grants or patents received or pending, or royalties.

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Reviewer disclosures
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Peer reviewers on this manuscript have no relevant financial or other relationships to

disclose.
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* of interest
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Declaration of conflict of interest:
Guillermo Garcia-Rayado, Mercedes Navarro and Angel Lanas declare not to have conflict of
interests

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 Legends off Figures:

Figure 1: Adverse
A effe
fects of NSA
AIDs in diffferent system
ms and som
me of suggessted

beneficial effects
e of H2S in these systems. *M
Most of data from anim
mal models or

preclinical studies in humans.

h

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 Figure 2: Mechanisms
M s of pathogeenesis of GII damage by
y NSAIDs aand strategies to

reduce this injury (greeen boxes). C

COX: Cyclo
ooxygenasee. GI: Gastroointestinal.

H2RAs: Hiistamine H2
2 receptor anntagonists. H2S: Hydro
ogen sulfidee. NO: Nitriic oxide.

PPIs: Protoon pump inh

hibitors.

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