Use and Development of NSAIDs Should Consider More Than Just a Single Feature

LAS VEGAS—It's time to refocus on NSAIDs beyond only COX-1 versus COX-2 inhibition.

That's the conclusion of Robert B. Raffa, PhD, of the School of Pharmacy and School of Medicine, Temple University, Philadelphia, Pennsylvania, who said to attendees of PAINWeek 2014 that reemphasis on pharmacokinetic and pharmacodynamic concepts “beyond just COX-1 versus COX-2 might hold promise for NSAID discovery, development, and clinical use.”

Although discovery of the cyclooxygenase (COX) enzyme advanced understanding of arachidonic acid metabolism, prostaglandin physiology, and pain-modulating pathways— which was further advanced with the discovery of COX-2—“arguably, COX-2 inhibitors did not provide significant new insight into painmodulating pathways or analgesic mechanisms of action and may have inadvertently resulted in a hiatus in NSAID analgesia research,” he said.

This hiatus is due, in part, to the time spent (lost?) in the almost exclusive interest in developing potentially revolutionizing COX-2 inhibitors and the unfortunate recognition of increased risk of heart attacks and stroke observed after several COX-2 agents were approved, which resulted in rofecoxib being withdrawn in 2004 and valdecoxib in 2005. Celecoxib remains on the market, and all NSAIDs now carry a warning of the potential for cardiovascular and gastrointestinal risks. Other NSAIDs that may be prescribed include ibuprofen, naproxen, indomethacin, diclofenac, and meloxicam. Even inhibitor “selectivity” needs a better measure, he argued, noting that the commonly used ratio of IC50/IC50, which measures the concentrations that inhibit both COX-1 and COX-2 equally (50%), is not a good measure; rather, the ratio IC80/IC50, is both more biochemically accurate and clinically relevant.

Other factors can be equally or more important. For example, non-acidic NSAIDs distribute almost equally throughout the body, while acidic NSAIDs have high plasma protein binding, predominantly to albumin and NSAIDs have varying access to synovial fluid and the brain. Such pharmacokinetic properties suggest that peripheral tissue or CNS may be targeted with newer agents. Animal studies have shown evidence of central action, with indomethacin, ibuprofen, and diclofenac depressing C fiber-evoked activity in the rat thalamus and spinal cord, while sodium  salicylate was found to inhibit GABAA current in rat spinal cord neuron cells.

Dr. Raffa noted that “it is important to recognize that there can be other than COX activity.” For example, the antinociceptive effect of one newer NSAID, a ‘preferential COX-2 inhibitor', actually also includes bradykinin induced effects on AMPA currents via inhibition of protein kinase C.

Thinking beyond just COX-1 vs COX-2 can inform clinical practice and suggest possible drug development directions, he said.

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