Nonsteroidal Antiinflammatory Drug-Related Injury to the Gastrointestinal Tract: Clinical Picture, Pathogenesis, and Prevention
Section snippets
Epidemiology of NSAID-associated mucosal injury
In the United States, a national prescription audit showed an annual NSAID consumption of 111,400,000 at a cost of $4.8 billion, with further sales of OTC oral analgesics of $3 billion. A survey of NSAID use among people older than 65 years showed that 70% were taking an NSAID at least once a week and half of these were taking an NSAID daily.14 A study in Europe reported an NSAID consumption of 42.82 to 74.17 defined daily dose/1000 inhabitants in 2007, increasing by 25.1% between 2002 and
NSAID-associated Esophageal Injury
NSAIDs may cause damage throughout the GI tract. Although the stomach and duodenum are well-recognized sites of damage, esophageal injury is common. Despite esophageal mucosa possessing several intrinsic mechanisms of epithelial defense25 and an efficient clearing system, nearly 100 medications have been implicated as causes of esophageal mucosal damage.26 Of 92 patients with pill-induced esophageal injury, NSAIDs were causative in 41% (38 of 92) of them.27 The prevalence of esophagitis in
NSAID users: who is at risk of GI complications?
Because symptoms are not a reliable indicator of mucosal damage, it is important to identify factors that increase the risk of GI events in NSAID users. Risk factors for UGIB associated with NSAID use are well defined by several studies69 and are summarized in Fig. 1. The most important are age and prior history of complicated ulcer. Older age is common in NSAID users, and those older than 70 years carry a risk similar to those with a history of peptic ulcer. Advancing age increases risk by
General Pharmacology and Physicochemical Properties of NSAIDs
For more than 100 years, analgesic agents have been integral to the management of musculoskeletal disorders. The clinical benefits and adverse effects of aspirin, indomethacin, phenylbutazone, and the newer propionic acid drugs were well established by the end of the 1960s, but it was only after 1971 that the late Professor Sir John Vane established the key mechanism of action of NSAIDs as inhibitors of prostaglandin (PG) synthesis.76 Neither all the benefits nor untoward reactions are solely
Noninvasive Assessment
Upper GI endoscopy is the gold standard for assessing NSAID-induced GI damage, because it is generally believed that NSAID damage is usually confined to the gastroduodenal mucosa. Endoscopy is widely available, precise, sensitive, and easy to perform. However, the technique is invasive, not completely devoid of complications, and unsuitable as a routine screening test because it is time consuming and expensive. Furthermore, an ideal test should be able to detect NSAID-induced lesions before
Drug Formulations and Chemical Modification of NSAID Molecules
Attempts have been made to reduce NSAID-induced gastroduodenal damage.117, 118 These include enteric-coated preparations or soluble formulations of NSAIDs to reduce the gastric residence time (and thus contact with gastric mucosa), buffered preparations, and nonacidic prodrugs (like, for instance, droxicam and nabumetone). Rectal or parenteral administration of NSAIDs has also been advocated. Some evidence suggests that enteric coating reduces acute aspirin-induced gastric injury, whereas
Balancing GI and CV risks of nonselective and COX-2 selective NSAIDs
Several publications have raised concerns about the CV complications associated with selective COX-2 inhibitors, particularly rofecoxib, and the drug was withdrawn in 2004 because of an increase in the rate of acute myocardial infarction (AMI). The putative mechanisms involved an imbalance between antithrombotic (prostacyclin I2) and prothrombotic (thromboxane A2) prostanoids resulting in AMI.136, 137 Subsequently, these concerns were extended to all selective COX-2 inhibitors and a review and
Novel antiinflammatory compounds: a look to the future
Although cotherapy with misoprostol or PPIs is effective in preventing NSAID-induced GI damage, a more appealing approach would be to develop drugs that are devoid of, or have reduced, GI toxicity. Several attempts have been disappointing, and selective COX-2 inhibitors represent a step forward; new, potentially GI safe, antiinflammatory agents are imminent.
The protective properties of NO and H2S in the GI tract make them attractive candidates for coupling with NSAIDs. The release of small
Towards a safer antiinflammatory therapy
NSAIDs are an essential part of our therapeutic armamentarium despite their well-characterized GI and CV risk profiles. Increasing appreciation of these relationships and new knowledge, as discussed in this article, should allow a safer and more effective use of these drugs.
Physicians should not prescribe NSAIDs before taking a careful history and performing a physical examination so they have the information they need to balance the risks and benefits for individual patients. When GI and/or CV
Summary
NSAIDs are widely prescribed and, although they represent an effective class of drugs, their use is associated with a broad spectrum of untoward reactions in the liver, kidney, CV system, skin, and gut. GI problems constitute a wide range of clinical features, from symptoms of dyspepsia, heartburn, and abdominal discomfort to more serious events, including peptic ulcer and its life-threatening complications, bleeding and perforation. In the past decade, there has been a progressive change in
Acknowledgments
We are indebted to Simone Bertolini, MSc, PhD (Department of Clinical Sciences, University of Parma) for his help in drawing the figures and managing the references.
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Conflict of interest statement. The authors have received consulting and/or lecture fees from several pharmaceutical companies and other organizations. The authors have also received research support from charities and government sources at various times. No author has any direct stock holding in any pharmaceutical company.