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Adverse effects of non-steroidal anti-inflammatory drugs (NSAIDs, aspirin and coxibs) on upper gastrointestinal tract

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Non-steroidal anti-inflammatory drugs (NSAIDs) are one of the most widely prescribed medication in the world. Their main benefit derives from their anti-inflammatory and analgesic effect, but the use of these agents is not innocuous since they mainly increase the risk of gastrointestinal (GI) and cardiovascular complications compared with non-NSAID users. NSAIDs injures the upper and lower gut by depleting COX-1 derived prostaglandins and causing topical injury to the mucosa. The risk of upper GI complications varies, depending on the presence of one or more risk factors. Among them, the three main risk factors are prior history of peptic ulcer, the single most important risk factor, age, the most common, and concomitant aspirin use, due to their GI and cardiovascular implications. Those individuals at-risk should be considered for alternatives to NSAID therapy and modifications of risk factors. If NSAID therapy is required, patients at risk will need prevention strategies including co-therapy of NSAID with gastroprotectants (PPI or misoprostol) or the prescription of COX-2 selective inhibitors. The probable introduction of NO-NSAIDs in the market in the near future may open a new therapeutic option for patients with hypertension who need NSAIDs.

Introduction

More than one hundred years have passed since Felix Hoffman in 1897 synthesised acetylsalicylic acid (ASA) as the first non-steroidal anti-inflammatory drug. Approximately 40 years pass before Douthwaite and Lintott provided endoscopic evidence that aspirin could cause gastrointestinal injury and it is in the early 1970s when investigators began to understand how aspirin works by showing that ASA inhibits the production of prostaglandins, that are involved in inflammations.

Today, NSAIDs are among the most commonly used drugs in the world. In Europe, NSAIDs represents more than 7.7% of all prescriptions and it is probably that these figures are underestimated because of over-the-counter use is not included [1]. In absolute terms, in the year 2004, a total of 111 million NSAID prescriptions were written in the United States [2], and it is expected that the use of NSAIDs will increase because the incidence of rheumatic diseases also is increasing. Their use is more frequent among women and increases with age, as does the incidence of rheumatic diseases. Indeed more than 90% of prescriptions for NSAIDs are made to patients aged >65 years.

The major problem with the use of these drugs is that adverse events are common, especially gastrointestinal morbidities, including complications in both upper and lower gastrointestinal tract.

Section snippets

Mechanisms of gastrointestinal (GI) injury

NSAIDs injure the gut by causing topical injury to the mucosa and a systemic effects associated with mucosal prostaglandin depletion derived from COX-1. The systemic effects of NSAIDs appear to have the predominant role. Because of that the use of enteric-coated aspirin preparations and parenteral or rectal administration of NSAIDs in order to prevent topical mucosal injury has failed to prevent the development of ulcers.

Upper gastrointestinal effects of NSAIDs

NSAIDs can adversely affect both the upper and lower gastrointestinal tract. The clinical significance and frequency of adverse events with NSAIDs in the lower GI tract have been increasingly reported, but are less characterised than those from the upper GI tract. A recent study from Lanas et al [8] have shown that the frequency of hospitalisations due to upper GI complications decreasing for the last 10 years, whereas those from the lower GI tract are increasing. In this article, we will focus

The role of cyclooxygenase 2 inhibitors

The identification of the COX-2 isoenzyme opened the door to development of NSAIDs which selectively inhibit COX-2. The main goal of which was to decrease the GI toxicity. Coxib spare COX-1 and primarily inhibit COX-2 function therefore decrease but do not eliminate NSAIDs associated GI toxicity and are efficacious as tNSAIDs in relieving pain [15].

Data from large GI outcomes studies have characterised the GI effects of coxib. The Celecoxib Long-term Arthritis Safety Study (CLASS Study) that

Risk factors for gastrointestinal complications

Dyspeptic symptoms are not a trustworthy warming sign; because of that it is important to identify factors that increase the risk of GI events in NSAIDs users. Several studies have demonstrated which are the major risk factors for GI event associated with NSAID therapy. (Table 1) [50], [51], [52], [23].

Among them, the two main are prior history of complicated ulcers, the most important one, and age. Older age is the most common in NSAIDs users and those age >70 years are considered to carry a

Management

The main goal in the management of patients receiving NSAIDS is the prevention of GI complications. Other objectives are the treatment of GI mucosal lesions and the treatment and prevention of NSAID-induced dyspepsia. Finally, due to the association of NSAID and coxib use with CV risk, this factor should also be taken into account in the management of patients who need NSAIDs.

Conflict of interest

Dr Angel Lanas is consultant or has received research grants from AstraZeneca, Pfizer, Bayer and Nicox. Dr Carlos Sostres, Dr Carla J. Gargallo and Dr María T. Arroyo reports no conflict of interest.

Acknowledgements

This study was funded by grants from the Carlos III, FIS PI08/1301 and Gobierno de Aragón. B01

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