Variability in the response to non-steroidal anti-inflammatory drugs: mechanisms and perspectives

Non-steroidal anti-inflammatory drugs (NSAIDs) are a chemically heterogeneous group of compounds that provide unmistakable and significant health benefits in the treatment of pain and inflammation. They include traditional NSAIDs (tNSAIDs), which act by inhibiting both cyclooxygenase (COX)-1 and COX-2 and selective COX-2 inhibitors (coxibs). The development of biomarkers predictive of the impact of NSAIDs on COX-1 and COX-2 activities in vitro, ex vivo and in vivo has been essential to read out the clinical consequences of selective and non-selective inhibition of COX isozymes in human beings. The analgesic and anti-inflammatory effects of NSAIDs are COX-2-dependent effects, unrelated to COX-2 selectivity. The intensity and duration of these effects are influenced by dose and half-life of the NSAID. However, the inhibition of COX-1 in cells of the gastrointestinal (GI) system and COX-2 in vascular cells translates into increased risk of serious GI adverse events and atherothrombosis and hypertension, respectively. The COX-2 selectivity of NSAIDs can predict, at least in part, the GI toxicity. In contrast, the CV effects are largely COX-2-dependent effects, unrelated to COX-2 selectivity but are dose dependent. The reduction in the dose is recommended and presumably will limit the number of patients exposed to a CV or a GI hazard by NSAIDs and coxibs. It will not, however, eliminate the risk on an individual level because there is a marked variability in how different people react to these drugs, based on their genetic background. The challenge of the next future will be to develop biomarkers useful to identify the individuals who react abnormally to COX inhibition.