THE MECHANISMS OF ACTION OF NSAIDS IN ANALGESIA

Traditionally, the analgesic action of nonsteroidal anti-inflammatory drugs (NSAIDs) has been explained on the basis of their inhibition of the enzymes that synthesise prostaglandins. However, it is clear that NSAIDs exert their analgesic effect not only through peripheral inhibi tion of prostaglandin synthesis but also through a variety of other pe ripheral and central mechanisms. It is now known that there are 2 stru cturally distinct forms of the cycle-oxygenase enzyme (COX-I and COX-2 ). COX-1 is a constitutive member of normal cells and COX-2 is induced in inflammatory cells. Inhibition of COX-2 activity represents the mo st likely mechanism of action for NSAID-mediated analgesia, while the ratio of inhibition of COX-1 to COX-2, by NSAIDs should determine the likelihood of adverse effects. In addition, some NSAIDs inhibit the li poxygenase pathway, which may itself result in the production of algog enic metabolites. Interference with G-protein-mediated signal transduc tion by NSAIDs may form the basis of an analgesic mechanism unrelated to inhibition of prostaglandin synthesis. There is increasing evidence that NSAIDs have a central mechanism of action that augments the peri pheral mechanism. This effect may be the result of interference with t he formation of prostaglandins within the CNS. Alternatively the centr al action may be mediated by endogenous opioid peptides or blockade of the release of serotonin (5-hydroxytryptamine; 5-HT). A mechanism inv olving inhibition of excitatory amino acids or N-methyl-D-aspartate re ceptor activation has also been proposed.