New mechanisms of action of diclofenac and the possibility of their implementation in pain treatment – narrative review

Diclofenac is a drug from the group of nonsteroidal anti-inflammatory drugs (NSAIDs) and its basic anti-inflammatory and analgesic mechanism used in the clinic is the inhibition of COX2 and COX1. This narrative review, based on a review of selected works from 1978 to May 2024, presents preclinical studies that describe new non-cyclooxygenase mechanisms of action of diclofenac. In vivo and in vitro experimental studies have shown the direct participation of diclofenac in nociceptive processes by affecting numerous ion channels – potassium, sodium, calcium, acid-sensitive ion channels. The effect on NMDA, TRP receptors, thromboxane and prostanoid receptors has been documented. The antinociceptive effect of diclofenac has been demonstrated at the spinal level through the activation of PPARgamma and the inhibition of prostaglandin synthesis and microglia activation, as well as the impact on the antinociceptive NO–cGMP pathway, the adrenergic and opioid systems. It has also been shown that diclofenac can affect the level of endorphins and arachidonic acid, regulate the synthesis of interleukins and lipoxygenase. Diclofenac in the experiment also modulates neurological processes, e.g. prevents the death of dopaminergic neurons, blocks the formation of transthyretin amyloid or reduces apoptosis after brain tissue damage. Many studies have confirmed the role of diclofenac in the regulation of the cell cycle and apoptosis, which constitutes its potential anticancer properties. In addition, it has been shown that diclofenac has antibacterial and antifungal effects. Further clinical studies are required to clarify the role of diclofenac in the mechanisms of nociception in humans, as well as the possibility of implementing diclofenac in the treatment of neurodegenerative and neoplastic diseases and their accompanying pain syndromes.