Mechanisms of Non-Opioid Analgesics Beyond Cyclooxygenase Enzyme Inhibition

Abstract

Non-opioid analgesics including both selective and non-selective cyclooxygenase (COX) inhibitors and acetaminophen are the most widely used treatments for pain. Inhibition of COX is thought to be largely responsible for both the therapeutic and adverse effects of this class of drugs. Accumulating evidence over the past two decades has demonstrated effects of non-opioids beyond the inhibition of COX and prostaglandin synthesis that might also explain their therapeutic and adverse effects. These include their interaction with endocannabinoids, nitric oxide, monoaminergic, and cholinergic systems. Moreover, the recent development of microarray technology that allows the study of human gene expression suggests multiple pathways that may be related to the analgesic and antiinflammatory effects of non-opioids. The present review will discuss the multiple actions of nonopioids and their interactions with these systems during inflammation and pain, suggesting that COX inhibition is an incomplete explanation for the actions of non-opioids and proposes the involvement of multiple selective targets for their analgesic, as well as, their adverse effects.

Short-term acetaminophen consumption enhances the exercise-induced increase in Achilles peritendinous IL-6 in humans

“…An induction of PGE 2 and other prostaglandins have several functions, including stimulating protein turnover (13,55,61,63), regulating tendon blood flow (33), and regulating the activity of matrix degrading enzymes (49,75). PGE 2 also appears to modulate the production of cytokines, including interleukin (IL)-6 (20,41,50). Interestingly, administration of COX inhibitors has been shown to increase the production of IL-6 in various models (20,22,57,71,72,75), including exercise (48).…”

Beneficial effect of aspirin against interferon‐α‐2b—induced depressive behavior in Sprague Dawley rats

“…Supportive evidence to this is the role of hyperforin, a constituent from St. John's wart inhibits prostaglandin synthesis, which is an established antidepressant agent . Studies show that aspirin and other non‐opioid derivatives affects antinociception through monoamines like serotonin . In addition to this, the latest developments suggest that aspirin decreases the risk of depression in subjects with high plasma homocysteine .…”

“…It has also been observed that lack of clinical therapeutic benefit of antidepressants is associated with overall activation of the inflammatory system, 32 which may be down Studies show that aspirin and other non-opioid derivatives affects antinociception through monoamines like serotonin. 61 In addition to this, the latest developments suggest that aspirin decreases the risk of depression in subjects with high plasma homocysteine. 56 It prevents hippocampal neuronal loss 57 and aberrant neurogenesis with omega 3 fatty acids 62 at cellular levels which can be attributed to its antidepressant action.…”

Cannabinoid Receptors Are Not Involved in Antinociception Induced by Systemic Diclofenac in Mice

“…As we have stated in the introduction, all NSAIDs have the potential of augmenting endocannabinoid levels by inhibiting COX-2 (although with a weak potential) and thereby preventing degradation of endocannabinoids (6,7,22). Inhibition of COX enzymes by NSAIDs may also elevate endocannabinoid synthesis due to the availability of arachidonic acid for endocannabinoid synthesis rather than prostaglandin synthesis (6,7,22). Moreover, some of the classical NSAIDs have been shown to inhibit FAAH directly and reduce the breakdown of endocannabinoids (9).…”

“…Recent investigations suggest that cannabinoid receptors and augmentation of endocannabinoid activity play important roles in the antinociceptive effects of both paracetamol and dipyrone (4,5). Besides paracetamol and dipyrone, all NSAIDs are expected to increase endocannabinoid tonus both by inhibiting endocannabinoid degradation and by increasing their synthesis via COX inhibition (6,7). Accordingly, it has been proposed that the endocannabinoid system appears to be involved in the antinociceptive effect of some NSAIDs, although there are contradictory findings (6)(7)(8)(9)(10)13).…”