Managing the Adverse Effects of Nonsteroidal Anti-inflammatory Drugs

Paola Patrignani; Stefania Tacconelli; Annalisa Bruno; Carlos Sostres; Angel Lanas


Expert Rev Clin Pharmacol. 2011;4(5):605-621. 

In This Article

NSAIDs & Lower GI Damage

The clinical significance and frequency of adverse events with tNSAIDs in the lower GI tract have been increasingly reported, but are much more poorly characterized than those from the upper GI tract. Increased mucosal permeability and mucosal inflammation are often silent but occur with most tNSAIDs.[145,53–56] Other findings include anemia, occult blood loss, malabsorption and protein loss. Video capsule endoscopy studies have shown that more than 50% of patients on NSAIDs or low-dose aspirin may have mucosal lesions or mucosal breaks in the small bowel.[57] Clinically significant GI bleeding and perforation, diarrhoea, mucosal ulceration, symptomatic diverticular disease and strictures due to fibrous diaphragms may occur.[58] Two recent studies[146,147] have reported either similar or higher mortality frequency for complications from the lower GI tract when compared with those from the upper GI tract. NSAID use might damage the lower GI tract (small bowel, colon or anus), with a rate of bleeding events that is believed to be approximately a third of that of upper GI bleeding.

When comparing COX-2-selective NSAIDs with nonselective NSAIDs, the incidence of lower GI tract injury and clinical events with COX-2-selective NSAIDs is lower but less well characterized than those in the upper GI tract. Sigthorsson et al. demonstrated a significantly higher small intestinal permeability with indomethacin versus rofecoxib 25 and 50 mg.[55] Atherton et al. found that naproxen significantly increased small intestinal permeability when compared with lumiracoxib.[53] Small intestinal permeability was not significantly different when comparing COX-2-selective NSAID and placebo in these two studies. Two randomized clinical controlled trials in which healthy subjects receiving either celecoxib or a nonselective NSAID (naproxen or ibuprofen) or placebo underwent video capsule endoscopy, have shown that the percentage of subjects with intestinal mucosal breaks and the number of mucosal breaks per patient were significantly lower in the celecoxib groups versus naproxen or ibuprofen groups.[148,149] In terms of clinically relevant outcomes have shown less consistent results. Post hoc analysis of the VIGOR trial showed a lower incidence of serious lower GI clinical events (gross rectal bleeding other than melena, intestinal perforation, obstruction, diverticulitis) when compared rofecoxib versus naproxen;[27] however post-hoc analysis of the Multinational Etoricoxib and Diclofenac Arthritis Long-term program[150] have shown similar rates of lower GI events between etoricoxib and diclofenac. Chan et al. have recently published the first large, double-blind, randomized clinical trial to assess upper and lower GI events in patients needing chronic NSAID therapy.[151] In this study, diclofenac plus omeprazole was compared with celecoxib alone. The GI end point was the combination of gastroduodenal, small-bowel or large-bowel hemorrhage or perforation, gastric outlet obstruction or clinically significant anemia. They concluded that the risk of clinical outcomes throughout the GI tract was lower in patients treated with celecoxib 200 mg twice daily versus diclofenac SR 75 mg twice daily plus omeprazole 20 mg/day after 6 months of therapy.

At present, effective means to prevent NSAID-associated intestinal lesions in patients are not available. The efforts to generate safer NSAIDs, including aspirin, have followed different routes such as the development of enteric-coated or slow-release formulations or switch to a COX-2-selective agent, since these drugs have been found in some studies to be safer to the lower GI tract compared with tNSAIDs.[59,114,149,151–154] However, their long-term safety requires appropriate study.

If NSAID enteropathy is to be prevented, celecoxib seems a reasonable alternative based on the available data commented above. It may also be reasonable to coadminister misoprostol with the NSAID, as this reduces the permeability changes caused by NSAIDs. However, although misoprostol improves anemia in patients with proven NSAID enteropathy,[155] the evidence is poor and its ability to reverse intestinal permeability changes induced by indomethacin or naproxen for example is still controversial and needs further investigation.

Some attention is being focused on NO-donating NSAIDs. Preclinical studies with these compounds have demonstrated reduced intestinal adverse effects (i.e., ulceration and bleeding) compared with those of parent compounds.[75] Although NO–naproxen failed to increase intestinal permeability in healthy volunteers,[156] no clinical data regarding the lower GI tract are available in these patients. A good number of other potential approaches are being tested, but they are still in preclinical development.[157,158]

Pathologic similarities between NSAID enteropathy and inflammatory bowel disease have led to the suggestion that sulfasalazine may be a possible therapeutic option in NSAID enteropathy. Hayllar and colleagues assessed the use of disease-modifying antirheumatic drugs, including sulfasalazine, in patients taking NSAIDs. Sulphasalazine significantly reduced intestinal inflammation and blood loss, whereas other second-line antirheumatic drugs did not.[159]

Experimental and clinical investigations indicate that in the short term, antibacterial agents either reduce or abolish NSAID enteropathy.[160,161] The evidence from animal experiments has been confirmed in human studies, showing that metronidazole, an antimicrobial mainly targeted against anaerobic organisms, significantly prevented indomethacin-induced increase in intestinal permeability in healthy volunteers and reduced inflammation and blood loss in rheumatic patients taking NSAIDs.[162] Despite all the aforementioned evidence, no clinical trials have been formally performed in humans to evaluate the effect of antibiotics in the prevention of intestinal damage induced by NSAIDs.


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