Abstract
The action of NSAIDs is characterized by a certain selectivity in their effects. They produce reversible cyclo-oxygenase (COX) inhibition by competing with the substrate arachidonic acid for the active site of the enzyme. NSAIDs thus prevent the pathological production of prostaglandins (PGs) by COX-2 and the physiological formation of prostanoids by COX-1. Their gastrointestinal toxicity arises from inhibition of PGE2 and PGI2 due to inducing COX-1 formation. The kidney is a rich source of COX-1 produced PGs which are necessary for keeping its normal function. Most of unwanted renal effects of NSAIDs, such as reduction of renal blood flow and glomerular filtration rate, sodium retention and hyperkalemia, have been attributed to inhibition of PG synthesis. Selective COX-2 inhibitors appear to be so largely devoid of unwanted renal and gastrointestinal effects that we can prescribe COX-2 selective NSAIDs quite safely recently.
The activity and metabolism of peripheral afferent sensory fibers is altered by chemical mediators generated by inflammation following tissue injury. PGs enhance local nociceptors and some of them sensitize sensory neurons to other stimuli and contribute to mechanism of peripheral hyperalgesia. The interrelationship between NMDA receptor-induced activation of the NO system and expression of COX is believed today an important part in the development of neuronal plasticity and central sensitization. These suggest that NSAIDs should have new and more active role in the treatment of neuropathicpain such as CRPS after tissue injury or nerve injury.
If it is definitely established that COX-2 and PGE2 are expressed in the central nervous system and related with the central sensitization or inflammatory hyperalgesia, this may offer implications for therapy with NSAIDs in neuropathicpain. After C-fiber stimulation, there is evidence of prostanoid release in the spinal cord and COX inhibition blocks the hyperalgesia induced by both substance P and NMDA. Repetitive C-fiber stimulation evokes a state of spinal facilitation referred to as wind up and an increase in the size of their respective fields. In spite of appropriate preclinical toxicity testing has not been performed for any commercially available NSAIDs and intraspinal application is premature, one report has showed the excellent efficacy of administration of infra epidural NSAIDs for cancer pain. Intraspinal NSAIDs applications should be advanced therapy for neuropathicpain and other pain such as cancer pain in the near future.
