Non-steroidal anti-inflammatory drugs have a direct action on spinal nociceptive processing in vivo with a relative order of potency which correlates with their capacity as inhibitors of cyclooxygenase activity. However, recent clinical surveys and new in vivo evidence strongly suggest that for some of these agents, centrally mediated analgesia may also be achieved by additional mechanisms, which are independent of prostaglandin synthesis inhibition. In this review we explore the likelihood for such mechanisms following an extensive survey of existing data. The implications of these mechanisms are discussed in the light of our current understanding of spinal nociceptive processing.