Nonsteroidal Antiinflammatory Drug-Related Injury to the Gastrointestinal Tract: Clinical Picture, Pathogenesis, and Prevention

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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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References (170)

  • R.H. Hunt et al.

    A randomized trial measuring fecal blood loss after treatment with rofecoxib, ibuprofen, or placebo in healthy subjects

    Am J Med

    (2000)
  • L. Laine et al.

    Serious lower gastrointestinal clinical events with nonselective NSAID or coxib use

    Gastroenterology

    (2003)
  • F.K. Chan et al.

    Celecoxib versus omeprazole and diclofenac in patients with osteoarthritis and rheumatoidarthritis (CONDOR): a randomised trial

    Lancet

    (2010)
  • L. Laine et al.

    Lower gastrointestinal events in a double-blind trial of the cyclo-oxygenase-2 selective inhibitor etoricoxib and the traditional non steroidal anti-inflammatory drug diclofenac

    Gastroenterology

    (2008)
  • K. Kurahara et al.

    Clinical and endoscopic features of nonsteroidal anti-inflammatory drug-induced colonic ulcerations

    Am J Gastroenterol

    (2001)
  • R.W. Lengeling et al.

    Ulcerative ileitis encountered at ileo-colonoscopy: likely role of nonsteroidal agents

    Clin Gastroenterol Hepatol

    (2003)
  • G.F. Bonner et al.

    Tolerance of nonsteroidal antiinflammatory drugs in patients with inflammatory bowel disease

    Am J Gastroenterol

    (2000)
  • U. Mahadevan et al.

    Safety of selective cyclooxygenase-2 inhibitors in inflammatory bowel disease

    Am J Gastroenterol

    (2002)
  • W.J. Sandborn et al.

    Safety of celecoxib in patients with ulcerative colitis in remission: a randomized, placebo-controlled, pilot study

    Clin Gastroenterol Hepatol

    (2006)
  • L. Laine et al.

    Stratifying the risk of NSAID-related upper gastrointestinal clinical events: results of a double-blind outcomes study in patients with rheumatoid arthritis

    Gastroenterology

    (2002)
  • J.Q. Huang et al.

    Role of Helicobacter pylori infection and non-steroidal anti-inflammatory drugs in peptic-ulcer disease: a meta-analysis

    Lancet

    (2002)
  • J.L. Wallace

    Pathogenesis of NSAID-induced gastroduodenal mucosal injury

    Best Pract Res Clin Gastroenterol

    (2001)
  • J.L. Wallace et al.

    Nitric oxide in mucosal defense: a little goes a long way

    Gastroenterology

    (2000)
  • N.J. Wight et al.

    Rofecoxib, a COX-2 inhibitor, does not inhibit human gastric mucosal prostaglandin production

    Gastroenterology

    (2001)
  • J.L. Wallace et al.

    Lipoxins in gastric mucosal health and disease

    Prostaglandins Leukot Essent Fatty Acids

    (2005)
  • J.L. Goldstein et al.

    Video capsule endoscopy to prospectively assess small bowel injury with celecoxib, naproxen plus omeprazole, and placebo

    Clin Gastroenterol Hepatol

    (2005)
  • J.B. Meddings et al.

    Sucrose: a novel permeability marker for gastroduodenal disease

    Gastroenterology

    (1993)
  • R. Jones

    Nonsteroidal anti-inflammatory drug prescribing: past, present, and future

    Am J Med

    (2001)
  • N.J. Shaheen et al.

    The burden of gastrointestinal and liver diseases, 2006

    Am J Gastroenterol

    (2006)
  • T. Pincus et al.

    Patient preference for placebo, acetaminophen (paracetamol) or celecoxib efficacy studies (PACES): two randomised, double blind, placebo controlled, crossover clinical trials in patients with knee or hip osteoarthritis

    Ann Rheum Dis

    (2004)
  • G.P. Geba et al.

    Efficacy of rofecoxib, celecoxib, and acetaminophen in osteoarthritis of the knee

    JAMA

    (2002)
  • K.M. Jordan et al.

    EULAR recommendations 2003: an evidence based approach to the management of knee osteoarthritis: report of a task force of the standing committee for international clinical studies including therapeutic trials (ESCISIT)

    Ann Rheum Dis

    (2003)
  • American College of Rheumatology Subcommittee on Osteoarthritis Guidelines

    Recommendations for the medical management of osteoarthritis of the hip and knee: 2000 update

    Arthritis Rheum

    (2000)
  • J.K. Aronson

    Meyler’s side effects of analgesics and anti-inflammatory drugs

    (2010)
  • C. Scarpignato et al.

    Working team report: towards a GI safer antiinflammatory therapy

    Gastroenterology International

    (1999)
  • A. Lanas et al.

    Prevention of anti-inflammatory drug-induced gastrointestinal damage: benefits and risks of therapeutic strategies

    Ann Med

    (2006)
  • M.R. Tramèr et al.

    Comparing analgesic efficacy of non-steroidal anti-inflammatory drugs given by different routes in acute and chronic pain: a qualitative systematic review

    Acta Anaesthesiol Scand

    (1998)
  • K. Baxter

    Stockley’s drug interactions

    (2010)
  • A.M. Marchiando et al.

    Epithelial barriers in homeostasis and disease

    Annu Rev Pathol

    (2010)
  • A. Inotai et al.

    Trends in the non-steroidal anti-inflammatory drug market in six central-eastern European countries based on retail information

    Pharmacoepidemiol Drug Saf

    (2010)
  • N.S. Abraham et al.

    National mortality following upper gastrointestinal or cardiovascular events in older veterans with recent nonsteroidal anti-inflammatory drug use

    Aliment Pharmacol Ther

    (2008)
  • S. Straube et al.

    Mortality with upper gastrointestinal bleeding and perforation: effects of time and NSAID use

    BMC Gastroenterol

    (2009)
  • J.D. Greenberg et al.

    The COX-2 inhibitor market withdrawals and prescribing patterns by rheumatologists in patients with gastrointestinal and cardiovascular risk

    Clin Exp Rheumatol

    (2009)
  • A. Lanas et al.

    Time trends and impact of upper and lower gastrointestinal bleeding and perforation in clinical practice

    Am J Gastroenterol

    (2009)
  • R.H. Hunt et al.

    Review article: should NSAID/low-dose aspirin takers be tested routinely for H. pylori infection and treated if positive? Implications for primary risk of ulcer and ulcer relapse after initial healing

    Aliment Pharmacol Ther

    (2004)
  • U. Kiltz et al.

    Use of NSAIDs and infection with Helicobacter pylori - what does the rheumatologist need to know?

    Rheumatology (Oxford)

    (2008)
  • C.W. Helsper et al.

    Trends and determinants of adequate gastroprotection in patients chronically using NSAIDs

    Pharmacoepidemiol Drug Saf

    (2009)
  • R.C. Orlando

    The pathogenesis of gastroesophageal reflux disease: the relationship between epithelial defense, dysmotility, and acid exposure

    Am J Gastroenterol

    (1997)
  • S. Abid et al.

    Pill-induced esophageal injury: endoscopic features and clinical outcomes

    Endoscopy

    (2005)
  • B. Avidan et al.

    Risk factors of oesophagitis in arthritic patients

    Eur J Gastroenterol Hepatol

    (2001)
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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.

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