Acute pain can frequently be attributed to mainly nociceptive inputs such as inflammation and/or peripheral structural damage, whereas chronic pain (usually defined as lasting for ≥ 3 months) is more probably due to inputs from the central nervous system.
OA- and RA-related pain is complex and multifactorial, and due to physiological interactions between the signaling of the central and peripheral nervous systems.
The mechanisms of action of diclofenac make it particularly effective in treating both nociceptive pain and chronic central pain. Furthermore, its new mechanisms of action suggest to clinicians to change their clinical approach for treating patients with neuropathic, central sensitization and altered central pain using an old and well-known drug but able to improve the quality of the life of these cohorts of patients.
However, diclofenac has a range of actions that are of interest in an oncological context. PGE2 is formed from the break down of arachidonic acid to prostaglandin H2 by COX-1 and COX-2 followed by further processing by microsomal prostaglandin synthase 1 (mPGES-1). Elevated levels of mPGES-1 and PGE2 are found in a range of different cancer types and are associated with the chronic inflammation that is associated with a pro-tumor microenvironment [
97]. Diclofenac, in common with other inhibitors of the COX enzymes, also acts to reduce PGE2 synthesis. Therefore it has other relevant mechanisms of anti-cancer action such as anti-angiogenic, immunomodulation, pro-apoptotic, platelet function, actions on Myc and glucose metabolism, and treatment sensitivity, which means that COX-2 expression may correlate with sensitivity to chemotherapy or radiotherapy in different cancer types, which have been confirmed by pre-clinical and clinical evidence in fibrosarcoma, neuroblastoma, and colorectal cancer, etc. [
97]. Moreover, it has been reported that actinic keratoses (AKs), intraepithelial atypical proliferations of keratinocytes that develop in skin that has undergone long-term exposure to ultraviolet radiation, can be treated with ingenol mebutate, imiquimod, and diclofenac, which can clear both visible and subclinical AK lesions and reduce the development of new lesions in the treated field [
98]. Furthermore, the efficacy of topically applied diclofenac 3% in combination with hyaluronic acid 2.5% in the treatment of AKs has been demonstrated in several clinical studies, even if the exact mode of action is still unclear [
99]. Finally, novel antitumor platinum(II) conjugates containing the nonsteroidal anti-inflammatory agent diclofenac, a drug with antiproliferative properties typical of these metallic conjugates, is potent and cancer cell selective cytotoxic agents exhibiting activity in cisplatin resistant and the COX-2 positive tumor cell lines [
100]. One of these compounds, compound 3, in which DCF molecules are coordinated to Pt(II) through their carboxylic group, is more potent than the parental conventional Pt(II) drug cisplatin, free DCF, and the congeners of 3 in which DCF ligands are conjugated to Pt(II) via a diamine. The potency of 3 is due to several factors including enhanced internalization that correlates with enhanced DNA binding and cytotoxicity [
100]. Mechanistic studies show that 3 combines multiple effects. After its accumulation in cells, it releases a Pt(II) drug capable of binding/damaging DNA and DCF ligands, which affects distribution of cells in individual phases of the cell cycle, inhibits glycolysis and lactate transport, collapses mitochondrial membrane potential, and suppresses the cellular properties characteristic of metastatic progression [
100].
In summary, in this review we tried to underline the mechanisms of diclofenac involved in chronic and acute joint pain, the most relevant adverse events, and future prospects of this drug in oncological field.