Title

 

Authors

C. Scarpignato
 
Laboratory of Clinical Pharmacology, Division of Gastroenterology, Department of Clinical Sciences, University of Parma, Italy

 

Abstract

Although the stomach and duodenum are well-recognized sites of NSAID damage, esophageal and intestinal injuries are not uncommon. It is now widely recognized that the small bowel is more common than the stomach as a site for adverse effects of NSAIDs, giving rise to NSAID-enteropathy. The pathogenesis of small intestinal damage with NSAIDs is less well understood. Although inhibition of mucosal prostaglandin (PG) synthesis during NSAID use occurs along the entiredigestive tract, there are significant differences between the distal and proximal GI tract in the concurrence of other pathogenic factors that may add to mucosal damage. Among them, the absence of acid and the presence of bacteria and bile in the intestine, which may trigger specific NSAID-related pathogenic mechanisms in the distal GI tract, are the most evident ones. NSAID-enteropathy, rather than being life-threatening, often leads to complications that call for extensive investigation. The majority of patients with NSAID-enteropathy are asymptomatic and can be diagnosed by demonstrating increased intestinal permeability, increased fecal calprotectin or by wireless capsule enteroscopy. The spectrum of detected abnormalities range from subclinical damage, including increased mucosal permeability, mucosal inflammation, fecal occult blood loss, ileal dysfunction and malabsorption, to clinically evident conditions, including anemia, mucosal diaphragms and strictures, small bowel, colonic and rectal ulceration, colitis as well as bleeding and perforation. Increased mucosal permeability is silent and observed within 24 h of ingestion with almost all NSAIDs, except the coxibs and NSAIDs not undergoing entero-hepatic recirculation.
The lack of intestinal damage with selective COX-2 inhibitors in animal experiments has been confirmed in clinical studies. Most patients taking either meloxicam or nimesulide, two preferential COX-2 inhibitors, had normal intestinal permeability and no increase in intestinal inflammation compared to control patients. In studies in healthy volunteers rofecoxib and etoricoxib, compared with the traditional NSAID, ibuprofen, did not increase fecal blood loss. Furthermore, the incidence of anemia with celecoxib was significantly less than that seen with NSAIDs. Post hoc analysis of the VIGOR study showed that the benefits of rofecoxib over naproxen were present in both the upper and the lower GI tract with a risk reduction of 50 and 60%, respectively. In the recent CONDOR study, comparing celecoxib versus slow-release diclofenac plus omeprazole, celecoxib was superior to the NSAID plus PPI in reducing the risk of clinical outcomes throughout the entire GI tract. Interestingly, etoricoxib, which is an acidic (pKa 4.5) COX-2 selective compound, did not achieve a significant decrease in lower GI clinical events when compared with diclofenac in the RCTs of the MEDAL program. NSAID-associated intestinal damage is not pH-dependent and co-administration of antisecretory drugs neither prevents nor treats lower GI mucosal lesions beyond the proximal duodenum. Although recent experimental evidence suggests a protective activity of PPIs on indomethacin-induced intestinal damage acting through antioxidant and anti-inflammatory properties, video capsule studies show that this is not the case in humans. Since COX-2 selective inhibitors may induce less or no damage to the distal gastrointestinal tract compared to NSAIDs, their use should be viewed as a strategy of prophylaxis.
 
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