Managing the Adverse Effects of Nonsteroidal Anti-inflammatory Drugs

^†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.

Authors and Disclosures

Paola Patrignani^†1, Stefania Tacconelli¹, Annalisa Bruno¹, Carlos Sostres² and Angel Lanas<sup>2

1</sup>Department of Medicine and Center of Excellence on Aging, "G. d'Annunzio" University, and CeSI, Via dei Vestini 31, 66100 Chieti, Italy
²University of Zaragoza School of Medicine, University Hospital Lozano Blesa, IIS Aragón, CIBERehd, Zaragoza, Spain

^†Author for correspondence
Tel.: +39 087 154 1473 Fax: +39 087 135 56718 ppatrignani@unich.it

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.