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.

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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Table 1. Suggested strategies for analgesic/anti-inflammatory treatment and cardiovascular prevention among patients with inflammatory disease and different levels of risk of vascular events.
Risk of vascular event^†	Pharmacological strategies
Low (<1% per year)	tNSAID or coxib depending on GI risk
Intermediate (1–3% per year)	tNSAID (low-dose ibuprofen or naproxen + PPI); if aspirin is indicated, naproxen + PPI and aspirin, given 2 h before^‡
High (>3% per year)	Naproxen + PPI and aspirin, given 2 h before^‡

^†Vascular event is defined as the combined outcome of a nonfatal myocardial infarction, nonfatal stroke or vascular death [168].
^‡Recent findings suggest that the possible interference of naproxen on the antiplatelet effect of aspirin can be minimized by the administration of aspirin 2 h before naproxen [167]. By contrast, ibuprofen should be avoided if aspirin is indicated [165,166].
GI: Gastrointestinal; PPI: Proton pump inhibitor; tNSAID: Traditional NSAID.

Box 1. Prevention strategies in patients with gastrointestinal risk factors who need NSAIDs.
General rules Use the lowest effective dose for the shortest period of time Avoid concomitant therapy with corticosteroids, anticoagulants, low-dose aspirin or antiplatelet agents Use 'safer' NSAIDs (coxibs, diclofenac, aceclofenac and ibuprofen) Less use of NSAIDs with the highest gastrointestinal toxicity (ketorolac, piroxicam, and ketoprofen) Eradicate Helicobacter pyloriinfection in patients with prior ulcer history Use of prevention strategies No CV risk factors No gastrointestinal risk factors: use tNSAIDs (no need for prevention strategies) One or more gastrointestinal risk factors: coxib (standard dose) alone or nonselective NSAID + PPI or misoprostol If history of ulcer bleeding: coxib + PPI. Eradicate H. pyloriinfection. Avoid nonselective NSAIDs Previous CV events or risk for CV events >10% in 10 years (treatment with low-dose aspirin) One or more gastrointestinal risk factors: nonselective NSAID (naproxen) + PPI or coxib + PPI In Europe, if previous CV event exists, the European Medicine Agency contraindicates use of coxibs Avoid combining with ibuprofen since it may interfere with low-dose aspirin If history of ulcer bleeding: avoid tNSAIDs or coxib. Eradicate H. pyloriinfection If strictly necessary, celecoxib low dose + PPI. If previous CV event in Europe, coxib contraindicated
CV: Cardiovascular; PPI: Proton pump inhibitor; tNSAID: Traditional NSAID.

Sidebar

Key Issues

Conventional medical treatment for rheumatoid arthritis and osteoarthritis requires the use of NSAIDs because they provide unmistakable and significant health benefits in the treatment of pain and inflammation.
NSAIDs share both beneficial and adverse effects due to the same mechanism of action, i.e. the inhibition of cyclooxygenase (COX) activity. Their beneficial therapeutic use as antiinflammatory and analgesic agents is associated with increased risk of gastrointestinal (GI) and cardiovascular (CV) serious adverse events (i.e., upper GI bleeding and nonfatal myocardial infarction [MI]).
The risk of nonfatal MI was increased by 35% with current use of NSAIDs, but there was no increase in the risk of fatal MI. The excess risk increased with increasing treatment duration and daily dose.
The increased incidence of thrombotic events associated with profound inhibition of COX-2-dependent prostacyclin (PGI2) can be mitigated, even if not obliterated, by a complete suppression of platelet COX-1 activity.
Degree of inhibition of COX-2 for NSAIDs functionally selective for COX-2 is relevant to CV hazard and relates to drug potency (exposure). It has been proposed that the assessment of whole blood COX-2 ex vivomay represent a valid surrogate end point to predict CV risk for functionally selective COX-2 inhibitors.
NSAIDs injure the GI tract by causing topical injury to the mucosa and by systemic effects associated with mucosal prostanoid depletion derived from COX inhibition. The main clinically relevant GI side effects include GI bleeding, perforation and obstruction.
Management of patients with GI risk factors who require NSAIDs includes the use of the lowest possible dose for the shorter period of time, the use of the safest NSAIDs, the use of co-therapy with with gastroprotectants and the avoidance of co-therapy of NSAIDs with anticoagulants, antiplatelet agents or corticosteroids. Reduced incidence of GI ulcers complications compared with traditional NSAIDs (tNSAIDs) has been demonstrated for COX-2 inhibitors. COX-2 plays an important role in the healing of pre-existing ulcers. This is supported by clinical data showing that coxibs are still associated with a small risk of upper GI bleeding, though smaller than that caused by tNSAIDs.
Despite upper GI bleeding risk being multifactorial, drugs with a long half-life or slow-release formulation and/or associated with profound and coincident inhibition of both COX isozymes – which translates into deficiency of prostanoid generation in the GI tract – were associated with a greater risk of upper GI complications.
The development of biomarkers predictive of the impact of NSAIDs on COX-1 and COX-2 activities in vitro, ex vivoand in vivohas been essential to read out the clinical consequences of selective and nonselective inhibition of COX isozymes in humans. Reduction of the dose is recommended and presumably will limit, but not delete, CV or GI risk by NSAIDs and coxibs.
The use of pharmacogenomic tools to define the role of genetic factors in individual responses to drugs, in association with pharmacoepidemiological methods, represents a very promising approach to predict CV and GI risks for coxibs and tNSAIDs and to create personalized drugs with better efficacy and safety.

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