Inhibition of COXI and not COX2 enzyme potentiates the opioid induced analgesia in rats

Opioids are widely used in the treatment of various types of pain and hyperalgesic states. However, opioid related side effects are well known and are representing a great challenge in using these drugs for the management of pain. A combined use of opioids with nonsteroidal anti-inflammatory drugs [NSAIDs] has been advocated in clinical practice to potentiate each other analgesic effect and to reduce the dose and related side effects of both drugs. Several studies on animal and human models have shown that such combination provides greater efficacy in pain relief. Reducing the doses of opioids used, due to the presence of N'SAIDs, ultimately reduces potential for side effects. It is unclear whether NSAIDs induces its opioid analgesic potentiating effect through inhibition of COX1 or COX2 enzymes. Both isoforms contribute to the inflammatory process, but COX2 is of considerable therapeutic interest as its induction, results in an enhanced formation of prostaglandins, during acute as well as chronic inflammation. It is generally assumed t hat NSAIDs anti-inflammatory and analgesic activity is mediated via COX2 inhibition. In contrast, it has been reported that the potencies of various NSAIDs to potentiate opioid induced presynaptic inhibitory effect nearly matched their inhibitory potencies at COX1. The present study was designed to study the effect of co-administration of the non selective COX inhibitor, indomethacin or diclofenac with pentazocine on pain relief and to compare it with the effect of its coadministration with the selective COX2 inhibitors, rofecoxib and meloxicam. Tail flick and hot plate assays were used asmodels o f central nociception. Non selective COX inhibitors, indomethacin and diclofenac potentiated the antinoceceptive effect of the opioid agonist pentazocine, an effect that was abolished by naloxone. The selective COX2 inhibitors, rofecoxib and meloxicam failed to modify the analgesic effect of pentazocine. These results suggest that analgesia potentiating effect of NSAIDs is mediated through inhibition of COX1 rather COX2 enzyme. The finding support a novel therapeutic intervention by which reduced doses of opioids can be used in the presence of NSAIDs that act preferentially on COX1 to produce effective pain relief with reduced side effects

Effect of the selective cox 2 inhibitor, rofecoxib versus the non selective cox inhibitor, indomethacin on renal hemodynamics and tubular excretion

Nonsteroidal anti-inflammatory drugs [NSAIDs] are among the most widely prescribed medications worldwide. The mechanism through which NSAIDs provide analgesia and suppress inflammation is the inhibition of the enzyme cyclooxygenase [COX] with subsequent suppression of the prostanoids synthesis. The suppression of prostanoids synthesis can also produce gastric and renal toxicity, as we!l as impair normal platelet function. Two distinct but related enzymes, cyclo-oxygenase-1 [COX-1] and cyclooxygenase-2 [COX-2] mediate prostanoids synthesis and contribute to the inflammatory process. However, it is generally assumed that NSAIDs anti-inflammatory and analgesic activity is mediated via COX-2 inhibition while Inhibition of COX-1 is thought to be responsible for the gastric toxicity and bleeding complications. It is unclear whether NSAID-induced renal toxicity is attributable to inhibition of COX-1 or COX-2. The present study was designed to compare the effect of chronic administration of selective COX-2 inhibitor, rofecoxib with that of the non selective COX inhibitor, in-domethacin on renal hemodynamics and tubular excretion. Thus, changes in mean arterial pressure [MAP], renal blood flow [RBF], glomerular filtration rate [GFR], urine volume and urinary Na 4 and K excretion ratio, hematocrite value, serum Na +.K +,urea and crearinine concentrations were all detected after IM injection of rofecoxib [1 umol/kg], indomethacin [3 umol/kg] or the vehicle for three weeks. Results from the present study showed that three weeks treatment with both indomethacin and rofecoxib induced a decrease in urine volume and Na + and K + excretion. Indomethacin but not rofecoxib reduced RBF and GFR. No significant change was observed in MAP, hematocrite value or serum Na + serum. Serum K + urea and creatinine levels were all elevated suggesting impairment in the renal functions. It seems likely that COX-2 inhibition causes acute salt and water retention, whereas the decline in RBF and GFR is caused by the blockade of COX-1. COX-2 inhibitors should be used with caution since they are, like traditional NSAIDs, can induce renal function impairment