Nonsteroidal Anti-Inflammatory Drugs and Lower Gastrointestinal Complications
Section snippets
Mechanisms of intestinal damage by Nonsteroidal Anti-inflammatory Drugs
It is not completely clear how NSAIDs initiate damage in the lower GI tract. The widespread view is that upper GI toxicity by NSAIDs is mediated by both a non–prostaglandin-dependent local injury and, overall, by the systemic inhibition of the cyclooxygenase (COX) -1 enzyme.4, 6 This leads to a subsequent reduction in cytoprotective prostaglandins required for an effective mucosal defense.6 The pathogenic mechanism leading to inflammatory changes in the distal GI tract is less well known at
Lesions induced by Nonsteroidal Anti-Inflammatory Drugs in the distal gastrointestinal tract
The prevalence of NSAID-associated lower GI side effects, including both clinical and subclinical side effects, may exceed those detected in the upper GI tract and include a wide spectrum of lesions (Table 1).1, 4
Life-threatening complications from the lower gastrointestinal tract
Although increased permeability, inflammation, or even GI ulceration is the most common manifestation of NSAID toxicity, GI bleeding and perforation are the most clinically relevant side effects, since they contribute significantly to the increased risk of morbidity and mortality associated with these drugs. There is evidence that NSAIDs and/or aspirin are associated with complications from the lower GI tract since the early 1990s.37, 50, 51 Current evidence suggests that NSAIDs increase the
Lower Gastrointestinal damage with COX-2 selective inhibitors
COX-2 selective NSAIDs could be safer than tNSAIDS for the lower GI tract. The lack of intestinal damage with this type of agents in some animal experiments62 has been confirmed in preclinical study and, in 2000 and 2001, in clinical studies in humans.8, 63 In the short term, these agents do not increase mucosal permeability and have displayed a 50% reduction of serious lower GI side effects compared with tNSAIDS in some but not all post hoc analysis of outcome studies.20, 55
Smecuol and
Lower gastrointestinal damage by low-dose aspirin
It is generally believed that low-dose ASA does not cause any small bowel damage, since the drug is largely absorbed before reaching the intestine, and this would limit the topical action on the intestinal mucosa. GI injury by ASA therapy is the result of both local topical effects and a decrease in mucosal COX-1–derived prostaglandins, which could be a systemic effect. Very little clinical information is available so far. A recent study has evaluated the effect of low-dose enteric-coated
Diagnosis of Nonsteroidal Anti-Inflammatory Drug enteropathy
Probably the single most important reason for underestimating the clinical importance of NSAID enteropathy is the difficulty in making a diagnosis. Barium radiologic examination of the small-bowel mucosa is very deficient in detecting flat lesions. A number of noninvasive tests have been developed to evaluate indirect parameters of mucosal damage. Inflammatory markers (fecal calprotectin excretion) and permeability tests (urinary recovery of orally administered probes) assess the functional
Misoprostol, COX-2 Selective Inhibitors, and NO-Donating Agents
At present, effective means to prevent NSAID-associated intestinal lesions in patients are not available. The efforts to generate safer NSAIDs, including ASA, have followed different routes such as the development of enteric-coated or slow-release formulations. As commented here, these formulations could shift the problem to a more distal site within the digestive tract. Since all conventional NSAIDs appear to cause NSAID enteropathy, there is little sense to switch from one to another. The
Summary
In addition to the upper GI tract, NSAIDs can damage the small bowel and the colon. NSAID enteropathy is frequent and may be present in more than 60% of patients taking these drugs long term. In most cases, damage is subclinical, including increased mucosal permeability, inflammation, erosions, ulceration, but other more serious clinical outcomes such as anemia, and overall bleeding, perforation, obstruction, diverticulitis and deaths have also been described. The magnitude of these serious
References (89)
- et al.
Side effects of nonsteroidal anti-inflammatory drugs on the small and large intestine in humans
Gastroenterology
(1993) Mechanisms underlying intestinal injury induced by anti-inflammatory COX inhibitors
Eur J Pharmacol
(2004)- et al.
COX–1 and 2, intestinal integrity and pathogenesis of NSAID-enteropathy in mice
Gastroenterology
(2002) - et al.
Nonsteroidal anti-inflammatory drug enteropathy in rats: role of permeability, bacteria, and enterohepatic circulation
Gastroenterology
(1997) - et al.
Lower gastrointestinal events in a double-blind trial of the cyclo-oxigenase-2 selective inhibitor etoricoxib and the traditional nonsteroidal anti-inflammatory drug diclofenac
Gastroenterology
(2008) - et al.
Glucose and citrate reduce the permeability changes caused by indomethacin in humans
Gastroenterology
(1992) - et al.
Nonsteroidal anti-inflammatory drug-induced intestinal inflammation in humans
Gastroenterology
(1987) - et al.
Blood and protein loss via small intestinal inflammation induced by nonsteroidal antiinflammatory drugs
Lancet
(1987) - et al.
Enteroscopic diagnosis of small bowel ulceration in patients receiving non-–steroidal antiinflammatory drugs
Lancet
(1991) - et al.
A prospective trial comparing small bowel radiographs and video capsule endoscopy for suspected small bowel disease
Gastroenterology
(2002)
Visible small-intestinal mucosal injury in chronic NSAID users
Clin Gastroenterol Hepatol
Clinical and endoscopic features of nonsteroidal anti-inflammatory drug-induced colonic ulcerations
Am J Gastroenterol
Objective evidence of aspirin use in both ulcer and non–ulcer upper and lower gastrointestinal bleeding
Gastroenterology
Evidence of aspirin use in both upper and lower gastrointestinal perforation
Gastroenterology
Epidemiology of lower gastrointestinal bleeding
Best Pract Res Clin Gastroenterol
Effects of nonsteroidal antiinflammatory drugs on inflammatory bowel disease: a case control study
Am J Gastroenterol
Safety of celecoxib in patients with ulcerative colitis in remission: a randomized, placebo-controlled, pilot study
Clin Gastroenterol Hepatol
Colonic release and reduced intestinal tissue damage of coated tablets containing naproxen inclusion complex
Int J Pharm
Surgical complications of non–steroidal anti-inflammatory drug-induced small bowel ulceration
J Am Coll Surg
Risk of aspirin-associated major upper-gastrointestinal bleeding with enteric-coated or buffered product
Lancet
Serious lower gastrointestinal clinical events with nonselective NSAID or coxib use
Gastroenterology
MEDAL Steering Committee. Assessment of upper gastrointestinal safety of etoricoxib and diclofenac in patients with osteoarthritis and rheumatoid arthritis in the Multinational Etoricoxib and Diclofenac Arthritis Long-term (MEDAL) programme: a randomised comparison
Lancet
A randomized trial measuring fecal blood loss after treatment with Rofecoxib, Ibuprofen, or Placebo in healthy subjects
Am J Med
Video capsule endoscopy to prospectively assess small bowel injury with celecoxib, naproxen plus omeprazole, and placebo
Clin Gastroenterol Hepatol
Less small-bowel injury with lumiracoxib compared with naproxen plus omeprazole
Clin Gastroenterol Hepatol
Long-term effects of nonsteroidal anti-inflammatory drugs and cyclooxygenase–2 selective agents on the small bowel: a cross-sectional capsule enteroscopy study
Clin Gastroenterol Hepatol
Response to Ray and colleagues: the called-for large clinical trial is already ongoing
Gastroenterology
Clinically significant small-bowel pathology identified by double-balloon enteroscopy but missed by capsule endoscopy
Gastrointest Endosc
A quantitative analysis of NSAID-induced small bowel pathology by capsule enteroscopy
Gastroenterology
Management of lower gastrointestinal bleeding
Best Pract Res Clin Gastroenterol
Small bowel injury by low-dose enteric-coated aspirin and treatment with misoprostol: a pilot study
Clin Gastroenterol Hepatol
Is non–steroidal anti-inflammatory drug (NSAID) enteropathy clinically more important than NSAID gastropathy?
Postgrad Med J
High prevalence of NSAID enteropathy as shown by a simple faecal test
Gut
Clinical implications of COX-1 and/or COX-2 inhibition for the distal gastrointestinal tract
Curr Pharm Des
Systematic review: the lower gastrointestinal adverse effects of non–steroidal anti-inflammatory drugs
Aliment Pharmacol Ther
Importance of local versus systemic effects of non–steroidal anti-inflammatory drugs in increasing small intestinal permeability in man
Gut
Acute gastrointestinal permeability responses to different non–steroidal anti-inflammatory drugs
Gut
Role of leukocytes in indomethacin-induced small bowel injury in the rat
Am J Phys
Neutrophil migration into indomethacin induced rat small intestinal injury is CD11a/CD18 and CD11b/CD18 codependent
Gut
Role of unbalanced growth of gram-negative bacteria in ileal ulcer formation in rats treated with a nonsteroidal anti-inflammatory drug
J Med Invest
NSAID-induced intestinal damage: are luminal bacteria the therapeutic target?
Gut
Microbial flora in NSAID induced intestinal damage: a role for antibiotics?
Digestion
Nonsteroidal anti-inflammatory drug-induced small intestinal damage is toll-like receptor 4 dependent
Gut
Nonsteroidal anti-inflammatory drugs and the small intestine
Curr Opin Gastroenterol
Cited by (0)
Funding Support: This manuscript has been supported by funds from the Government of Aragón (B01) and grant from Fondo de Investigaciones Sanitarias (FIS 05/2445).