A Review of Chronic Musculoskeletal Pain: Central and Peripheral Effects of Diclofenac

A Review of Chronic Musculoskeletal Pain: Central and Peripheral Effects of Diclofenac Pain Ther https://doi.org/10.1007/s40122-018-0100-2 REVIEW A Review of Chronic Musculoskeletal Pain: Central and Peripheral Effects of Diclofenac . . Fabiola Atzeni Ignazio Francesco Masala Piercarlo Sarzi-Puttini Received: August 30, 2017 The Author(s) 2018 drug with another, or complete discontinuation ABSTRACT usually because of insufficient pain control. OA- and RA-related pain is complex and multifac- Diclofenac is widely used to manage chronic torial, and due to physiological interactions inflammatory and degenerative joint diseases between the signaling of the central and such as osteoarthritis (OA), rheumatoid arthritis peripheral nervous systems. The mechanisms of (RA), ankylosing spondylitis, and extra-articular action of diclofenac make it particularly effec- rheumatism. Its various mechanisms of action tive in treating both nociceptive pain and make it particularly effective in treating noci- chronic central pain. This review underlines the ceptive pain, but it is also an alternative for mechanisms of diclofenac involved in chronic treating spinal and chronic central pain. and acute joint pain, the most relevant adverse Osteoarthritis and rheumatoid arthritis are the events. most frequently encountered arthritic condi- tions in adults. The management of nociceptive pain requires a sequential hierarchical Keywords: Chronic pain; Diclofenac; approach, with the initial NSAID treatment Musculoskeletal pain; NSAIDs; Spinal pain being characterized by the replacement of one Enhanced digital features To view enhanced digital features for this article go to https://doi.org/10.6084/ INTRODUCTION m9.figshare.6061397. Fabiola Atzeni and Ignazio Francesco Masala contributed Diclofenac, ibuprofen, and ketoprofen are non- equally to this paper. steroidal anti-inflammatory drugs (NSAIDs) that have been widely used to manage chronic F. Atzeni (&) inflammatory and degenerative joint diseases Rheumatology Unit, University of Messina, and treat pain for the last 30 years. Their mul- Messina, Italy tifactorial anti-inflammatory and analgesic e-mail: atzenifabiola@hotmail.com; fatzeni@unime.it activities not only involve cyclo-oxygenase (COX) inhibition, but also a series of pain and I. F. Masala inflammatory mediators and intracellular Orthopedic and Trauma Unit, Santissima Trinita pathways. Hospital, Cagliari, Italy Diclofenac (2-[2,6-dichloranilino]pheny- P. Sarzi-Puttini lacetic acid) is available in oral sodium, potas- Rheumatology Unit, L. Sacco University Hospital, sium, sodium/misoprostol, and Milan, Italy Pain Ther hydroxyethylpyrrolidine formulations, and is times more selective for COX-2 than other indicated for the treatment of osteoarthritis NSAIDs but, as pointed out by Warner et al. [9], (OA), rheumatoid arthritis (RA), ankylosing therapeutic concentrations (i.e., IC ) also spondylitis, extra-articular rheumatism, and inhibit 70% of COX-1, which may explain its postoperative pain [1]. Its main mechanism of balanced effect against adverse cardiovascular analgesic action is COX inhibition, which events. decreases the production of prostaglandin E2 It was initially thought that diclofenac does (PGE2) and thromboxane, but it also has other not directly inhibit phospholipase A2 (PLA2) peripheral and central mechanisms [2, 3]. [10–12], but a recent study has shown that rel- The aim of this review is to underline the atively high doses inhibit 93% of extra-pancre- mechanisms of actions of diclofenac subdivided atic PLA2 in patients with acute pancreatitis into well-known and then recently discovered [13, 14]. This still controversial finding may be mechanisms of action. Furthermore, the mech- due to its different isoforms in intra- and extra- anisms responsible for the acute and chronic cellular spaces (secreted or group II PLA2s), pain in rheumatoid arthritis and in which can promote inflammation by con- osteoarthritis and the management of pain have tributing to eicosanoid production and directly been described. activating pro-inflammatory cells [15]. Singh et al. have shown that diclofenac inhibits 90% of the PLA2 purified from snake venom [16], MECHANISMS OF ACTION and other studies have found that it also inhi- bits dehydrogenase and hydroxydehydrogenase This article is based on previously conducted enzymes, thus inactivating eicosanoid-related studies and does not contain any studies with anti-inflammatory mediators [17] (Fig. 1). human participants or animals performed by Tonussi and Ferreira [18] used two animal any of the authors. models of pain to show that in addition to inhibiting COX, diclofenac apparently down- Well-Known Mechanisms regulates the function of sensitized peripheral pain receptors by stimulating the L-arginine/ nitric oxide(NO)/cyclic guanosine monophos- Peripheral Mechanisms phate (cGMP) pathway. It is known that an NO- Various in vitro models and in vivo tissue induced increase in cGMP facilitates the open- studies have shown that NSAIDs inhibit pros- ing of various ion channels [19, 20], and it has taglandin and thromboxane synthesis [3], but it been shown that a cGMP analogue induces has been reported that the efficacy of diclofenac peripheral anti-nociception by activating the in inhibiting blood and synovial tissue COX adenosine triphosphate(ATP)-sensitive potas- levels (and consequently the synthesis of pro- sium channel in rats with hyperalgesic paws inflammatory and nociceptive prostaglandins) induced by PGE2 [21]. Diclofenac apparently [4, 5] is 3–1000 times that of other NSAIDs [6], has the same effect as the diclofenac-induced and that its inhibition of PGE2 correlates with activation of ATP-sensitive potassium channels plasma drug levels [7]. can be inhibited by an NO synthase inhibitor, a COX has two distinct isoforms [8]: COX-1 is guanylate cyclase inhibitor, and an ATP-sensi- constitutively and relatively stably expressed in tive potassium channel opener [22]. Diclofenac most tissue types, where it mediates normal sodium (DS) may accelerate nerve regeneration platelet function, regulates renal blood flow, and its effects on healing, as well as cause and cytoprotects the gastric mucosa by means deleterious effects in the developing nerves [23] of prostaglandin I2 (prostacyclin) [8]; COX-2 in neuropathic pain that occurs after injury and expression increases in the presence of damaged leads to dysfunction of the peripheral nervous tissue and pro-inflammatory mediators, which system [23]. Furthermore, DS teratogenicity increases the production of the prostaglandin, disrupts myelin sheath thickness and axon thromboxane, and leukotriene mediators of inflammation and pain [8]. Diclofenac is four Pain Ther Fig. 1 Pain and old mechanisms of actions of diclofenac structure, but its possible benefits and limita- pathways is supported by the fact that tions are still unknown (Fig. 2). intraperitoneally administered diclofenac decreases the concentration of pituitary b-en- dorphin (an endogenous opioid) in rats within Central Mechanisms 30 min [25], and this is associated with an The results of animal and human studies sug- increase in plasma b-endorphin levels (an index gest that diclofenac may act directly or indi- of nociceptive input into the CNS); it has also rectly on the CNS [24, 25]. Bjorkman et al. [26] been reported that diclofenac increases plasma found that injecting diclofenac 1-10 ng into b-endorphin concentrations in humans unaf- different areas of mouse brain dose-dependently fected by pain [27]. reduced ethacrynic acid levels and induced Synaptic nociceptive transmission in the writhing, and that diclofenac’s central anti-no- spinal cord involves N-methyl-D-aspartate ciceptive effects in rat could be partially (NMDA) receptors, and it has been shown that reversed by naloxone, an opioid receptor diclofenac attenuates NMDA receptor-mediated antagonist. The possible role of central opioid hyperalgesia via the L-arginine/NO/cGMP pathway in rats [28], is a selective and compet- itive inhibitor of NMDA receptors in rat jaw muscles [29], and markedly increases rat spinal cord and diencephalon concentrations of kynurenic acid, an NMDA receptor antagonist associated with antinociceptive effects [2]. Fig. 2 Pain and new mechanisms of actions of diclofenac Pain Ther More Recently Discovered Mechanisms Initial inflammation involves a very large number of cytokines: the release of IL-6 is reg- ulated by prostaglandins, and its expression as Inflammatory processes and fatty acid metabo- well as that of other pro-inflammatory cytoki- lism involve gamma peroxisome proliferator- nes is down-regulated by IL-10. NSAIDs may activated receptors (PPARc), which also control reduce the levels of pro-inflammatory cytokines adipocyte and macrophage differentiation, and by means of a prostaglandin-independent play a role in suppressing tumor cell prolifera- mechanism because the expression and pro- tion [8]. It has been reported that the affinity of duction of IL-6 is down-regulated by ketopro- diclofenac for PPARc is 50 times greater than fen, indomethacin, and diclofenac regardless of that of other NSAIDs, and that diclofenac acts human T cell PGE2 production [37], and on spinal nociceptive processing by activating diclofenac fully blocks the synthesis of PGE2 in PPARc and inhibiting prostaglandin synthesis human chondrocytes [38]. Major surgery [2, 30]. Furthermore, as the activation of PPARc patients treated with diclofenac for 12 h have suppresses microglia activation, diclofenac may significantly lower IL-6 and significantly higher be beneficial in the case of chronic neuro-in- IL-10 levels than those receiving placebo [39], flammatory pain [31]. Yamazaki et al. [32] have and the plasma and synovial fluid IL-6 levels are shown that diclofenac increases PPARc activity significantly lowered by 7 days’ diclofenac in the synovial cells of RA patients, and reduces treatment of RA patients [40], and by 180 days’ cell proliferation by decreasing cell viability and treatment in OA patients [41]. inducing apoptosis. It has also been shown that Tissue acidosis directly excites nociceptive PPARc ligands have anti-inflammatory effects sensory neurons via acid-sensing ion channels by blocking the activation of the nuclear factor (ASICs), and thus contributes to the sensation of kappa-light-chain-enhancer of activated B cells pain. Voilley et al. have shown that diclofenac (NF-jB) and activation protein 1 (AP1), and can and ibuprofen are respectively selective inhibi- bind to specific sequences in the promoter ele- tors of ASIC3 and ASIC1a in a simian virus ments of inflammatory response genes [33, 34]. 40-transformed simian cell line (COS cells), and Finally, diclofenac induces the release of a that both prevent the inflammation-induced number of anti-inflammatory cytokines, expression of ASICs in sensory neurons [42]. including interleukin-10 (IL-10) and trans- They both also inhibit proton-induced currents forming growth factor-b (TGF-b) via a PPARc in rat hippocampal interneurons [43], and it has pathway in a macrophage model [35] (Fig. 3). been shown that topical diclofenac decreases Substance P, a pro-inflammatory neuropep- acid-evoked pain in humans, probably by tide associated with various inflammatory dis- attenuating ASIC activity [44]. eases [36], is found in the plasma and synovial fluid of patients with arthritis. It has been hypothesized that as NSAIDs are used to treat CHRONIC MUSCULOSKELETAL arthritis-related pain, they may also interfere PAIN with the chemotactic effect of substance P on monocytes and polymorphonuclear (PMN) Osteoarthritis and rheumatoid arthritis are the cells, which is a crucial step in arthritic disease. most frequently encountered arthritic condi- A study of RA patients has shown that diclofe- tions in adults [45]. nac sodium 50 mg and naproxen 250 mg three times a day for 7 days (but not indomethacin 25 mg) significantly decreases synovial fluid Osteoarthritis substance P levels [2], which suggests that the analgesic effect of diclofenac may be at least The prevalence of OA, which is a major cause of partially due to the inhibition of the leukotriene musculoskeletal pain and the main cause of pathway induced by substance P depletion disability and handicap in Western industrial- (Fig. 4). ized countries, varies widely depending on the Pain Ther Fig. 3 Inflamed synovium—synovitis Fig. 4 Degraded cartilage Pain Ther age, gender, and geographical location of the increases the sensitivity of nociceptive primary patients and the way it is defined [46], but it has afferent neurons, and the hyperexcitability of been estimated that it affected more than 26 nociceptive neurons in the CNS [54]. Once million people in the USA in 2005 [47]. It has a cartilage damage has occurred, the release of severe impact on the patients’ health-related bradykinin, substance P, and the other media- quality of life (HRQoL) [48, 49], and is a con- tors by chondrocytes decreases nociceptive siderable socio-economic burden as it leads to thresholds and increases neuronal membrane lost working days and early retirement, and excitability, which causes hyperalgesia and significantly increases welfare costs. allodynia, and therefore further contributes to OA-related pain is due to complex interac- the vicious circle [50, 51]. tions between local tissue damage, inflamma- Macrophage-mediated inflammation can tion, and the peripheral and central nervous induce endothelial cells and fibroblasts to pro- systems, and is induced by nociceptive and duce angiogenic factors such as vascular neuropathic mechanisms [50, 51]. Nociceptive endothelial growth factor, and inflamed tissue pain arises from stimulated peripheral nocicep- hypoxia can also stimulate angiogenesis and tors, and the signals transmitted by various cause further inflammation [55]. neurotransmitters (glutamate, aspartate, sub- Finally, although OA-related pain is mainly a stance P, etc.) travel to the brain via the combination of nociception and local inflam- ascending pathway in the spinal cord [52], mation, neuropathic mechanisms may also be which they reach by means of three types of involved. fibers. Myelinated Ad (group III) and unmyeli- nated C fibers (group IV) innervate the synovial Managing OA-Related Pain membrane, joint capsule, periarticular liga- The Effects of NSAIDs on Nociceptive and ments, menisci, and the adjacent periosteum Central Pain The management of nociceptive and subchondral bone, whereas myelinated Aß pain requires a sequential hierarchical approach fibers (group II) innervate the synovial mem- [56, 57], with the initial NSAID treatment being brane, joint capsule, periarticular bursae, fat characterized by the replacement of one drug pad, ligaments, menisci, and adjacent bony with another, or complete discontinuation periosteum [21, 22]. Aß fibers are mainly acti- usually because of insufficient pain control [58]. vated by moving joints, whereas Ad and C fibers A number of systematic reviews have com- are activated by means of mechanical, chemi- pared the pain-reducing effects of NSAIDs and cal, or thermal stimuli [50, 51]. placebo [59, 60]. One concluded that there is no OA is a form of non-inflammatory arthritis clear difference among NSAIDs [61], and another, but, although defects in central pain processing which considered 93 randomized clinical trials are suggested by the fact that OA patients are (RCTs), found no difference between non-selec- sensitive to pressure at many sites, there is tive and COX-2-selective NSAIDs [62]. A recent growing evidence that inflammation occurs meta-analysis comparing the effectiveness of because of the release of cytokines and metal- different NSAIDs and paracetamol found that loproteinases within joints [53]. It seems that is paracetamol is clinically ineffective regardless of an interaction between inflammation and pain dose, and that diclofenac at a daily dose of insofar as inflammation increases pain sensi- 150 mg/dayis moreeffective intreating painand tivity, and this may stimulate inflammatory physical disability than high doses of ibuprofen, responses [50, 51]. The markers of joint naproxen, or celecoxib. Etoricoxib 60 mg/day is inflammation are involved in the degraded as effective as diclofenac 150 mg/day in treating matrix characterizing typical OA-related carti- nociceptive pain, but estimates of its effects on lage degeneration [53]: cytokines such as TNF, physical disability are imprecise, although etori- and pro-inflammatory ILs, chemokines, NGF, coxib 90 mg/day and rofecoxib 50 mg/day (both leukotrienes, prostaglandins, and matrix met- above the approved maximum daily doses) may alloproteinases initiate a cascade of events be more effective [63]. A study by van Walsem leading to peripheral sensitization. This et al. [64] found that diclofenac 150 mg/day and Pain Ther etoricoxib 60 mg/day were similarly effective, but their greatest problem [71], and pain may be the former was more effective than other NSAID even more disabling than structural joint dam- regimens, including diclofenac 100 mg/day. age [72]. Pain is not only a marker of the However, OA-related pain is also influenced inflammation associated with disease activity, it by local inflammation, and various studies have is also a consequence of radiographically shown that central pain sensitization may detected changes in joint structure [73]. develop and be maintained by an excessive It has been shown in clinical trials that, nociceptive ascending input and deficient particularly if disease activity is regularly mon- inhibitory input [65, 66]. Moreover, changes in itored, intensive early treatment with disease- the regulatory tone normally governed by modifying anti-rheumatic drugs (DMARDs) and supraspinal descending pathways may sensitize corticosteroids improve pain levels [74], bone marrow neurons and stimulate peripheral although this effect may not be complete or nociceptive signals, thus indicating that permanent. There have also been reports of supraspinal center stimulation or reduced inhi- referred pain syndromes because pain intensity bitory activity may alter pain thresholds [66]. is not always related to disease severity or The role of centralized pain has been con- exacerbations [75]. firmed by RCTs showing the efficacy of dulox- RA-related pain may have different causes in etine and tricyclic antidepressants in altering the early and later stages of the disease, during pain neurotransmitters [67], and NSAIDs can inflammatory flares and in the intervening also act on this pathway. Using the experimental periods, and between one patient and another. freeze lesion model, Burian et al. [68] found that Synovial inflammation stimulates pros- oral diclofenac was much more effective than taglandins, bradykinin, and pro-inflammatory topical diclofenac even if tissue concentrations cytokines such as TNF-a, IL-1, IL-6, and TGF-b, at the site of injury were almost the same; given which sensitize peripheral nerves and signifi- the negligible systemic concentrations produced cantly contribute to generating and maintain- by topically applied diclofenac, they concluded ing pain [76, 77]. Furthermore, sensory nerves that a non-peripheral (presumably central) are also found in joint capsules, ligaments, the component was involved in the antinociceptive outer parts of the menisci, sub-chondral bone, effect of oral diclofenac. These findings suggest tendon sheaths, and muscles [76], although the that diclofenac may have an effect on substance usually aneural articular cartilage and inner P, which plays an important role in the CNS by two-thirds of the menisci may allow pain-free sensitizing spinal neurons and causing vasodi- joint movement and weight bearing. latation, decreases nociceptive thresholds, and Synovitis is associated with activated spinal contributes to neurogenic inflammation in the cord microglia and astrocytes, and altered c- peripheral nervous system. Furthermore, Vellani aminobutyric acid (GABA), substance P, calci- et al. [69] have shown that the up-regulated tonin gene-related peptide (CGRP) neurotrans- expression of preprotachykinin (PPT, a precursor mitters, and their receptors in the spinal cord of substance P) mRNA induced by inflammation [78], which produce TNF-a, IL-1, and IL-6, and in an experimental model is significantly facilitate pain transmission [77]. Transmission reduced by nimesulide, paracetamol, celecoxib, may be further increased by more descending and diclofenac, whereas ibuprofen is ineffective. activation and less descending inhibition, and central sensitization may affect more than the nerves in the inflamed joint and reduce pain Rheumatoid Arthritis thresholds in adjacent tissues [71]. RA is a frequent inflammatory joint disease that Managing RA-Related Pain has a profound effect on the quality of life and The Effects of NSAIDs on Nociceptive and working productivity of patients, and accounts Central Pain Although NSAIDs are not for a considerable amount of healthcare appropriate for long-term disease control, they resources [70]. Most RA patients refer to pain as are often administered to RA patients in order to Pain Ther manage pain [79]. It is very important to start many of which are based on a series of system- DMARDs promptly and, in the case of pain, the atic Cochrane database reviews carried out in European League Against Rheumatism (EULAR) 2011–2012, suggest using paracetamol and recommends NSAIDs for patients with early NSAIDs to control chronic pain. disease whose gastrointestinal, renal, and car- The results of clinical trials of using tricyclic diovascular status has been carefully evaluated antidepressants in RA patients are equivocal: [79]. one systematic Cochrane review of eight RCTs A systematic review of the literature in which antidepressant therapy was compared describing the efficacy, safety, and tolerability with placebo or an active intervention found of NSAIDs in 146,524 patients participating in that the evidence was insufficient [85], but 176 studies included in a network meta-analysis adjuvant tricyclic antidepressants are included showed that diclofenac 150 mg/day was likely in the 3e recommendations for a subset of to be more effective in alleviating pain than patients with inflammatory arthritis [84]. celecoxib 200 mg/day, naproxen 1000 mg/day, Diclofenac can also be suggested because of its or ibuprofen 2400 mg/day, and as effective as effects on substance P, b-endorphin, and NMDA etoricoxib 60 mg/day, and that the effect of a receptors, and the fact that many clinical stud- lower diclofenac dose of 100 mg/day was com- ies have demonstrated that it relieves pain. It parable with that of all of the other treatments. has been shown that patients suffering from The rate of major adverse cardiovascular events migraine who experience central sensitization was similar with all of the active treatments, but with allodynia and do not achieve pain relief diclofenac caused fewer major upper gastroin- with other medications may benefit from the testinal events than naproxen or ibuprofen, cyclooxygenase-blocking activity of diclofenac although their frequency was similar in cele- [86]. Finally, diclofenac is available for treating coxib-treated patients, and lower in those trea- pain in different formulations (oral, intramus- ted with etoricoxib [64]. cular, topical, etc.). The sparse data available Glucocorticosteroids and traditional indicate that topical diclofenac can penetrate DMARDs such as methotrexate can be used to and permeate to deeper tissues, with a lower control most cases of RA [80], and biological plasma-to-tissue ratio than oral diclofenac, but drugs should only be used to treat patients with where it reaches a concentration that appears to very advanced or severe disease [81]. Although be sufficient to exert a therapeutic effect [87]. the analgesic effects of glucocorticosteroids may Moreover, there is good evidence that some not last more than 3 months [82], the early formulations of topical diclofenac and keto- suppression of inflammatory disease activity profen are useful in acute pain conditions such can avoid the development of worse pain as sprains or strains, with low (good) number- 12 months after diagnosis, and combined needed-to-treat (NNT) values, while in chronic DMARD treatment may be more effective than musculoskeletal conditions with assessments using one DMARD alone. over 6–12 weeks, topical diclofenac and keto- However, as inflammation is only one factor profen had limited efficacy in hand and knee contributing to pain, symptomatic relief is osteoarthritis, as did topical high-concentration often only partial even when the reduction in capsaicin in postherpetic neuralgia [88]. swollen joint counts and acute-phase reactant Though NNTs were higher, this still indicates levels, and ultrasound findings show that that a small proportion of people had good pain inflammatory disease activity is under control. relief. This means that analgesic drugs such as parac- etamol are often used even though there is no ADVERSE EFFECTS supporting evidence from RCTs [83]. However, recently published recommendations from the Diclofenac has shown to be effective and is 17-country 3e (evidence, expertise, exchange) widely used in the treatment of OA and RA, but collaborative project designed to promote evi- similar to other NSAIDs, is associated with an dence-based practices in rheumatology [84], Pain Ther increased risk of serious dose-related gastroin- sensitization and altered central pain processing testinal (GI), cardiovascular (CV), and renal side [96], compared diclofenac 150 mg/day versus effects [2, 89–91]. The GI adverse events (AEs) etoricoxib 60 mg/day for 4 weeks and found no occur due to reduced synthesis of prostanoids, differences in adverse events (gastrointestinal limiting secretion of mucus and bicarbonate adverse events in particular) between the two that normally protect the gastric mucosa from cohorts [95]. injury [92]. Consistent with the hypothesis that NSAIDs associated with the highest COX-1 CONCLUSIONS selectivity are more likely to be associated with an increased risk of GI toxicity, diclofenac ranks Acute pain can frequently be attributed to low in terms of relative risk for GI complica- mainly nociceptive inputs such as inflamma- tions, especially when administered at low tion and/or peripheral structural damage, doses (B 75 mg daily) [93]. According to data whereas chronic pain (usually defined as lasting from a meta-analysis of 280 trials of NSAIDs for C 3 months) is more probably due to inputs versus placebo (124,513 participants, 68,342 from the central nervous system. person-years) and 474 trials of one NSAID versus OA- and RA-related pain is complex and another NSAID (229,296 participants, 165,456 multifactorial, and due to physiological inter- person-years), the relative risk of upper gas- actions between the signaling of the central and trointestinal complications compared with pla- peripheral nervous systems. cebo was similar for diclofenac (RR 1.89) and The mechanisms of action of diclofenac coxibs (RR 1.81), while it was higher for make it particularly effective in treating both ibuprofen (RR 3.97) and naproxen (RR 4.22) nociceptive pain and chronic central pain. Fur- [91]. PGI2, a major product of COX-2—medi- thermore, its new mechanisms of action suggest ated metabolism of arachidonic acid in vascular to clinicians to change their clinical approach endothelial cells, serves a physiologic function for treating patients with neuropathic, central as a potent vasodilator and platelet inhibitor. sensitization and altered central pain using an Both preclinical and clinical evidence indicates old and well-known drug but able to improve that suppression of PGI2 synthesis increases the the quality of the life of these cohorts of risk for hypertension and thrombosis. The CV patients. hazard of diclofenac at doses C 150 mg daily is However, diclofenac has a range of actions estimated to be comparable to that of rofecoxib that areof interestinanoncological context. and celecoxib, as well as ibuprofen administered PGE2 is formed from the break down of at high doses [94]. The variable risk of myocar- arachidonic acid to prostaglandin H2 by COX- dial infarction (MI) due to NSAIDs that do not 1and COX-2followedbyfurther processing by completely inhibit COX-1 is largely related to microsomal prostaglandin synthase 1 (mPGES- their extent of COX-2 inhibition [2, 94]. The 1). Elevated levels of mPGES-1 and PGE2 are best safety profile related to MI was found for found in a range of different cancer types and naproxen, while diclofenac, ibuprofen, and are associated with the chronic inflammation coxibs increased the risk. The relative risk of that is associated with a pro-tumor microen- major coronary events compared with placebo vironment [97]. Diclofenac, in common with was similar for diclofenac (RR 1,70) coxibs (RR other inhibitors of the COX enzymes, also acts 1,76), and ibuprofen (RR 2.22) [89]. There was to reduce PGE2 synthesis. Therefore it has only limited evidence for an increased risk of other relevant mechanisms of anti-cancer major vascular events during the first 6 months action such as anti-angiogenic, immunomod- for coxibs and diclofenac [89]. Data for all other ulation, pro-apoptotic, platelet function, NSAIDs were not available because of the lack of actions on Myc and glucose metabolism, and well-designed RCTs [89]. treatment sensitivity, which means that COX- Zerbini et al. [95], in a trial including 440 2 expression may correlate with sensitivity to participants affected by chronic low back pain chemotherapy or radiotherapy in different (LBP), which is an example of central Pain Ther cancer types, which have been confirmed by ACKNOWLEDGEMENTS pre-clinical and clinical evidence in fibrosar- coma, neuroblastoma, and colorectal cancer, The authors wish to thank to Dr. Kevin Smart etc. [97]. Moreover, it has been reported that for the mother tongue revision. actinic keratoses (AKs), intraepithelial atypical proliferations of keratinocytes that develop in Funding. No funding or sponsorship was skin that has undergone long-term exposure to received for this study or publication of this ultraviolet radiation, can be treated with inge- article. The article processing charges were nol mebutate, imiquimod, and diclofenac, funded by the authors. which can clear both visible and subclinical AK lesions and reduce the development of new Authorship. All named authors meet the lesions in the treated field [98]. Furthermore, International Committee of Medical Journal the efficacy of topically applied diclofenac 3% Editors (ICMJE) criteria for authorship for this in combination with hyaluronic acid 2.5% in article, take responsibility for the integrity of the treatment of AKs has been demonstrated in the work as a whole, and have given their several clinical studies, even if the exact mode approval for this version to be published. of action is still unclear [99]. Finally, novel antitumor platinum(II) conjugates containing Disclosures. Fabiola Atzeni, Ignazio Fran- the nonsteroidal anti-inflammatory agent cesco Masala, and Piercarlo Sarzi-Puttini have diclofenac, a drug with antiproliferative prop- nothing to disclose. erties typical of these metallic conjugates, is potent and cancer cell selective cytotoxic Compliance with Ethics Guidelines. This agents exhibiting activity in cisplatin resistant article is based on previously conducted studies and the COX-2 positive tumor cell lines [100]. and does not contain any studies with human One of these compounds, compound 3, in participants or animals performed by any of the which DCF molecules are coordinated to Pt(II) authors. through their carboxylic group, is more potent than the parental conventional Pt(II) drug cis- Data Availability. Data sharing is not platin,freeDCF,and thecongeners of 3in applicable to this article, as no datasets were which DCF ligands are conjugated to Pt(II) via generated or analyzed during the current study. a diamine. The potency of 3 is due to several Open Access. This article is distributed factors including enhanced internalization under the terms of the Creative Commons that correlates with enhanced DNA binding Attribution-NonCommercial 4.0 International and cytotoxicity [100]. Mechanistic studies License (http://creativecommons.org/licenses/ show that 3 combines multiple effects. After its by-nc/4.0/), which permits any noncommer- accumulation in cells, it releases a Pt(II) drug cial use, distribution, and reproduction in any capable of binding/damaging DNA and DCF medium, provided you give appropriate credit ligands, which affects distribution of cells in to the original author(s) and the source, provide individual phases of the cell cycle, inhibits a link to the Creative Commons license, and glycolysis and lactate transport, collapses indicate if changes were made. mitochondrial membrane potential, and sup- presses the cellular properties characteristic of metastatic progression [100]. In summary, in this review we tried to REFERENCES underline the mechanisms of diclofenac involved in chronic and acute joint pain, the 1. Moore RA, McQuay HJ, Derry P, et al. 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A Review of Chronic Musculoskeletal Pain: Central and Peripheral Effects of Diclofenac

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Pain Ther https://doi.org/10.1007/s40122-018-0100-2 REVIEW A Review of Chronic Musculoskeletal Pain: Central and Peripheral Effects of Diclofenac . . Fabiola Atzeni Ignazio Francesco Masala Piercarlo Sarzi-Puttini Received: August 30, 2017 The Author(s) 2018 drug with another, or complete discontinuation ABSTRACT usually because of insufficient pain control. OA- and RA-related pain is complex and multifac- Diclofenac is widely used to manage chronic torial, and due to physiological interactions inflammatory and degenerative joint diseases between the signaling of the central and such as osteoarthritis (OA), rheumatoid arthritis peripheral nervous systems. The mechanisms of (RA), ankylosing spondylitis, and extra-articular action of diclofenac make it particularly effec- rheumatism. Its various mechanisms of action tive in treating both nociceptive pain and make it particularly effective in treating noci- chronic central pain. This review underlines the ceptive pain, but it is also an alternative for mechanisms of diclofenac involved in chronic treating spinal and chronic central pain. and acute joint pain, the most relevant adverse Osteoarthritis and rheumatoid arthritis are the events. most frequently encountered arthritic condi- tions in adults. The management of nociceptive pain requires a sequential hierarchical Keywords: Chronic pain; Diclofenac; approach, with the initial NSAID treatment Musculoskeletal pain; NSAIDs; Spinal pain being characterized by the replacement of one Enhanced digital features To view enhanced digital features for this article go to https://doi.org/10.6084/ INTRODUCTION m9.figshare.6061397. Fabiola Atzeni and Ignazio Francesco Masala contributed Diclofenac, ibuprofen, and ketoprofen are non- equally to this paper. steroidal anti-inflammatory drugs (NSAIDs) that have been widely used to manage chronic F. Atzeni (&) inflammatory and degenerative joint diseases Rheumatology Unit, University of Messina, and treat pain for the last 30 years. Their mul- Messina, Italy tifactorial anti-inflammatory and analgesic e-mail: atzenifabiola@hotmail.com; fatzeni@unime.it activities not only involve cyclo-oxygenase (COX) inhibition, but also a series of pain and I. F. Masala inflammatory mediators and intracellular Orthopedic and Trauma Unit, Santissima Trinita pathways. Hospital, Cagliari, Italy Diclofenac (2-[2,6-dichloranilino]pheny- P. Sarzi-Puttini lacetic acid) is available in oral sodium, potas- Rheumatology Unit, L. Sacco University Hospital, sium, sodium/misoprostol, and Milan, Italy Pain Ther hydroxyethylpyrrolidine formulations, and is times more selective for COX-2 than other indicated for the treatment of osteoarthritis NSAIDs but, as pointed out by Warner et al. [9], (OA), rheumatoid arthritis (RA), ankylosing therapeutic concentrations (i.e., IC ) also spondylitis, extra-articular rheumatism, and inhibit 70% of COX-1, which may explain its postoperative pain [1]. Its main mechanism of balanced effect against adverse cardiovascular analgesic action is COX inhibition, which events. decreases the production of prostaglandin E2 It was initially thought that diclofenac does (PGE2) and thromboxane, but it also has other not directly inhibit phospholipase A2 (PLA2) peripheral and central mechanisms [2, 3]. [10–12], but a recent study has shown that rel- The aim of this review is to underline the atively high doses inhibit 93% of extra-pancre- mechanisms of actions of diclofenac subdivided atic PLA2 in patients with acute pancreatitis into well-known and then recently discovered [13, 14]. This still controversial finding may be mechanisms of action. Furthermore, the mech- due to its different isoforms in intra- and extra- anisms responsible for the acute and chronic cellular spaces (secreted or group II PLA2s), pain in rheumatoid arthritis and in which can promote inflammation by con- osteoarthritis and the management of pain have tributing to eicosanoid production and directly been described. activating pro-inflammatory cells [15]. Singh et al. have shown that diclofenac inhibits 90% of the PLA2 purified from snake venom [16], MECHANISMS OF ACTION and other studies have found that it also inhi- bits dehydrogenase and hydroxydehydrogenase This article is based on previously conducted enzymes, thus inactivating eicosanoid-related studies and does not contain any studies with anti-inflammatory mediators [17] (Fig. 1). human participants or animals performed by Tonussi and Ferreira [18] used two animal any of the authors. models of pain to show that in addition to inhibiting COX, diclofenac apparently down- Well-Known Mechanisms regulates the function of sensitized peripheral pain receptors by stimulating the L-arginine/ nitric oxide(NO)/cyclic guanosine monophos- Peripheral Mechanisms phate (cGMP) pathway. It is known that an NO- Various in vitro models and in vivo tissue induced increase in cGMP facilitates the open- studies have shown that NSAIDs inhibit pros- ing of various ion channels [19, 20], and it has taglandin and thromboxane synthesis [3], but it been shown that a cGMP analogue induces has been reported that the efficacy of diclofenac peripheral anti-nociception by activating the in inhibiting blood and synovial tissue COX adenosine triphosphate(ATP)-sensitive potas- levels (and consequently the synthesis of pro- sium channel in rats with hyperalgesic paws inflammatory and nociceptive prostaglandins) induced by PGE2 [21]. Diclofenac apparently [4, 5] is 3–1000 times that of other NSAIDs [6], has the same effect as the diclofenac-induced and that its inhibition of PGE2 correlates with activation of ATP-sensitive potassium channels plasma drug levels [7]. can be inhibited by an NO synthase inhibitor, a COX has two distinct isoforms [8]: COX-1 is guanylate cyclase inhibitor, and an ATP-sensi- constitutively and relatively stably expressed in tive potassium channel opener [22]. Diclofenac most tissue types, where it mediates normal sodium (DS) may accelerate nerve regeneration platelet function, regulates renal blood flow, and its effects on healing, as well as cause and cytoprotects the gastric mucosa by means deleterious effects in the developing nerves [23] of prostaglandin I2 (prostacyclin) [8]; COX-2 in neuropathic pain that occurs after injury and expression increases in the presence of damaged leads to dysfunction of the peripheral nervous tissue and pro-inflammatory mediators, which system [23]. Furthermore, DS teratogenicity increases the production of the prostaglandin, disrupts myelin sheath thickness and axon thromboxane, and leukotriene mediators of inflammation and pain [8]. Diclofenac is four Pain Ther Fig. 1 Pain and old mechanisms of actions of diclofenac structure, but its possible benefits and limita- pathways is supported by the fact that tions are still unknown (Fig. 2). intraperitoneally administered diclofenac decreases the concentration of pituitary b-en- dorphin (an endogenous opioid) in rats within Central Mechanisms 30 min [25], and this is associated with an The results of animal and human studies sug- increase in plasma b-endorphin levels (an index gest that diclofenac may act directly or indi- of nociceptive input into the CNS); it has also rectly on the CNS [24, 25]. Bjorkman et al. [26] been reported that diclofenac increases plasma found that injecting diclofenac 1-10 ng into b-endorphin concentrations in humans unaf- different areas of mouse brain dose-dependently fected by pain [27]. reduced ethacrynic acid levels and induced Synaptic nociceptive transmission in the writhing, and that diclofenac’s central anti-no- spinal cord involves N-methyl-D-aspartate ciceptive effects in rat could be partially (NMDA) receptors, and it has been shown that reversed by naloxone, an opioid receptor diclofenac attenuates NMDA receptor-mediated antagonist. The possible role of central opioid hyperalgesia via the L-arginine/NO/cGMP pathway in rats [28], is a selective and compet- itive inhibitor of NMDA receptors in rat jaw muscles [29], and markedly increases rat spinal cord and diencephalon concentrations of kynurenic acid, an NMDA receptor antagonist associated with antinociceptive effects [2]. Fig. 2 Pain and new mechanisms of actions of diclofenac Pain Ther More Recently Discovered Mechanisms Initial inflammation involves a very large number of cytokines: the release of IL-6 is reg- ulated by prostaglandins, and its expression as Inflammatory processes and fatty acid metabo- well as that of other pro-inflammatory cytoki- lism involve gamma peroxisome proliferator- nes is down-regulated by IL-10. NSAIDs may activated receptors (PPARc), which also control reduce the levels of pro-inflammatory cytokines adipocyte and macrophage differentiation, and by means of a prostaglandin-independent play a role in suppressing tumor cell prolifera- mechanism because the expression and pro- tion [8]. It has been reported that the affinity of duction of IL-6 is down-regulated by ketopro- diclofenac for PPARc is 50 times greater than fen, indomethacin, and diclofenac regardless of that of other NSAIDs, and that diclofenac acts human T cell PGE2 production [37], and on spinal nociceptive processing by activating diclofenac fully blocks the synthesis of PGE2 in PPARc and inhibiting prostaglandin synthesis human chondrocytes [38]. Major surgery [2, 30]. Furthermore, as the activation of PPARc patients treated with diclofenac for 12 h have suppresses microglia activation, diclofenac may significantly lower IL-6 and significantly higher be beneficial in the case of chronic neuro-in- IL-10 levels than those receiving placebo [39], flammatory pain [31]. Yamazaki et al. [32] have and the plasma and synovial fluid IL-6 levels are shown that diclofenac increases PPARc activity significantly lowered by 7 days’ diclofenac in the synovial cells of RA patients, and reduces treatment of RA patients [40], and by 180 days’ cell proliferation by decreasing cell viability and treatment in OA patients [41]. inducing apoptosis. It has also been shown that Tissue acidosis directly excites nociceptive PPARc ligands have anti-inflammatory effects sensory neurons via acid-sensing ion channels by blocking the activation of the nuclear factor (ASICs), and thus contributes to the sensation of kappa-light-chain-enhancer of activated B cells pain. Voilley et al. have shown that diclofenac (NF-jB) and activation protein 1 (AP1), and can and ibuprofen are respectively selective inhibi- bind to specific sequences in the promoter ele- tors of ASIC3 and ASIC1a in a simian virus ments of inflammatory response genes [33, 34]. 40-transformed simian cell line (COS cells), and Finally, diclofenac induces the release of a that both prevent the inflammation-induced number of anti-inflammatory cytokines, expression of ASICs in sensory neurons [42]. including interleukin-10 (IL-10) and trans- They both also inhibit proton-induced currents forming growth factor-b (TGF-b) via a PPARc in rat hippocampal interneurons [43], and it has pathway in a macrophage model [35] (Fig. 3). been shown that topical diclofenac decreases Substance P, a pro-inflammatory neuropep- acid-evoked pain in humans, probably by tide associated with various inflammatory dis- attenuating ASIC activity [44]. eases [36], is found in the plasma and synovial fluid of patients with arthritis. It has been hypothesized that as NSAIDs are used to treat CHRONIC MUSCULOSKELETAL arthritis-related pain, they may also interfere PAIN with the chemotactic effect of substance P on monocytes and polymorphonuclear (PMN) Osteoarthritis and rheumatoid arthritis are the cells, which is a crucial step in arthritic disease. most frequently encountered arthritic condi- A study of RA patients has shown that diclofe- tions in adults [45]. nac sodium 50 mg and naproxen 250 mg three times a day for 7 days (but not indomethacin 25 mg) significantly decreases synovial fluid Osteoarthritis substance P levels [2], which suggests that the analgesic effect of diclofenac may be at least The prevalence of OA, which is a major cause of partially due to the inhibition of the leukotriene musculoskeletal pain and the main cause of pathway induced by substance P depletion disability and handicap in Western industrial- (Fig. 4). ized countries, varies widely depending on the Pain Ther Fig. 3 Inflamed synovium—synovitis Fig. 4 Degraded cartilage Pain Ther age, gender, and geographical location of the increases the sensitivity of nociceptive primary patients and the way it is defined [46], but it has afferent neurons, and the hyperexcitability of been estimated that it affected more than 26 nociceptive neurons in the CNS [54]. Once million people in the USA in 2005 [47]. It has a cartilage damage has occurred, the release of severe impact on the patients’ health-related bradykinin, substance P, and the other media- quality of life (HRQoL) [48, 49], and is a con- tors by chondrocytes decreases nociceptive siderable socio-economic burden as it leads to thresholds and increases neuronal membrane lost working days and early retirement, and excitability, which causes hyperalgesia and significantly increases welfare costs. allodynia, and therefore further contributes to OA-related pain is due to complex interac- the vicious circle [50, 51]. tions between local tissue damage, inflamma- Macrophage-mediated inflammation can tion, and the peripheral and central nervous induce endothelial cells and fibroblasts to pro- systems, and is induced by nociceptive and duce angiogenic factors such as vascular neuropathic mechanisms [50, 51]. Nociceptive endothelial growth factor, and inflamed tissue pain arises from stimulated peripheral nocicep- hypoxia can also stimulate angiogenesis and tors, and the signals transmitted by various cause further inflammation [55]. neurotransmitters (glutamate, aspartate, sub- Finally, although OA-related pain is mainly a stance P, etc.) travel to the brain via the combination of nociception and local inflam- ascending pathway in the spinal cord [52], mation, neuropathic mechanisms may also be which they reach by means of three types of involved. fibers. Myelinated Ad (group III) and unmyeli- nated C fibers (group IV) innervate the synovial Managing OA-Related Pain membrane, joint capsule, periarticular liga- The Effects of NSAIDs on Nociceptive and ments, menisci, and the adjacent periosteum Central Pain The management of nociceptive and subchondral bone, whereas myelinated Aß pain requires a sequential hierarchical approach fibers (group II) innervate the synovial mem- [56, 57], with the initial NSAID treatment being brane, joint capsule, periarticular bursae, fat characterized by the replacement of one drug pad, ligaments, menisci, and adjacent bony with another, or complete discontinuation periosteum [21, 22]. Aß fibers are mainly acti- usually because of insufficient pain control [58]. vated by moving joints, whereas Ad and C fibers A number of systematic reviews have com- are activated by means of mechanical, chemi- pared the pain-reducing effects of NSAIDs and cal, or thermal stimuli [50, 51]. placebo [59, 60]. One concluded that there is no OA is a form of non-inflammatory arthritis clear difference among NSAIDs [61], and another, but, although defects in central pain processing which considered 93 randomized clinical trials are suggested by the fact that OA patients are (RCTs), found no difference between non-selec- sensitive to pressure at many sites, there is tive and COX-2-selective NSAIDs [62]. A recent growing evidence that inflammation occurs meta-analysis comparing the effectiveness of because of the release of cytokines and metal- different NSAIDs and paracetamol found that loproteinases within joints [53]. It seems that is paracetamol is clinically ineffective regardless of an interaction between inflammation and pain dose, and that diclofenac at a daily dose of insofar as inflammation increases pain sensi- 150 mg/dayis moreeffective intreating painand tivity, and this may stimulate inflammatory physical disability than high doses of ibuprofen, responses [50, 51]. The markers of joint naproxen, or celecoxib. Etoricoxib 60 mg/day is inflammation are involved in the degraded as effective as diclofenac 150 mg/day in treating matrix characterizing typical OA-related carti- nociceptive pain, but estimates of its effects on lage degeneration [53]: cytokines such as TNF, physical disability are imprecise, although etori- and pro-inflammatory ILs, chemokines, NGF, coxib 90 mg/day and rofecoxib 50 mg/day (both leukotrienes, prostaglandins, and matrix met- above the approved maximum daily doses) may alloproteinases initiate a cascade of events be more effective [63]. A study by van Walsem leading to peripheral sensitization. This et al. [64] found that diclofenac 150 mg/day and Pain Ther etoricoxib 60 mg/day were similarly effective, but their greatest problem [71], and pain may be the former was more effective than other NSAID even more disabling than structural joint dam- regimens, including diclofenac 100 mg/day. age [72]. Pain is not only a marker of the However, OA-related pain is also influenced inflammation associated with disease activity, it by local inflammation, and various studies have is also a consequence of radiographically shown that central pain sensitization may detected changes in joint structure [73]. develop and be maintained by an excessive It has been shown in clinical trials that, nociceptive ascending input and deficient particularly if disease activity is regularly mon- inhibitory input [65, 66]. Moreover, changes in itored, intensive early treatment with disease- the regulatory tone normally governed by modifying anti-rheumatic drugs (DMARDs) and supraspinal descending pathways may sensitize corticosteroids improve pain levels [74], bone marrow neurons and stimulate peripheral although this effect may not be complete or nociceptive signals, thus indicating that permanent. There have also been reports of supraspinal center stimulation or reduced inhi- referred pain syndromes because pain intensity bitory activity may alter pain thresholds [66]. is not always related to disease severity or The role of centralized pain has been con- exacerbations [75]. firmed by RCTs showing the efficacy of dulox- RA-related pain may have different causes in etine and tricyclic antidepressants in altering the early and later stages of the disease, during pain neurotransmitters [67], and NSAIDs can inflammatory flares and in the intervening also act on this pathway. Using the experimental periods, and between one patient and another. freeze lesion model, Burian et al. [68] found that Synovial inflammation stimulates pros- oral diclofenac was much more effective than taglandins, bradykinin, and pro-inflammatory topical diclofenac even if tissue concentrations cytokines such as TNF-a, IL-1, IL-6, and TGF-b, at the site of injury were almost the same; given which sensitize peripheral nerves and signifi- the negligible systemic concentrations produced cantly contribute to generating and maintain- by topically applied diclofenac, they concluded ing pain [76, 77]. Furthermore, sensory nerves that a non-peripheral (presumably central) are also found in joint capsules, ligaments, the component was involved in the antinociceptive outer parts of the menisci, sub-chondral bone, effect of oral diclofenac. These findings suggest tendon sheaths, and muscles [76], although the that diclofenac may have an effect on substance usually aneural articular cartilage and inner P, which plays an important role in the CNS by two-thirds of the menisci may allow pain-free sensitizing spinal neurons and causing vasodi- joint movement and weight bearing. latation, decreases nociceptive thresholds, and Synovitis is associated with activated spinal contributes to neurogenic inflammation in the cord microglia and astrocytes, and altered c- peripheral nervous system. Furthermore, Vellani aminobutyric acid (GABA), substance P, calci- et al. [69] have shown that the up-regulated tonin gene-related peptide (CGRP) neurotrans- expression of preprotachykinin (PPT, a precursor mitters, and their receptors in the spinal cord of substance P) mRNA induced by inflammation [78], which produce TNF-a, IL-1, and IL-6, and in an experimental model is significantly facilitate pain transmission [77]. Transmission reduced by nimesulide, paracetamol, celecoxib, may be further increased by more descending and diclofenac, whereas ibuprofen is ineffective. activation and less descending inhibition, and central sensitization may affect more than the nerves in the inflamed joint and reduce pain Rheumatoid Arthritis thresholds in adjacent tissues [71]. RA is a frequent inflammatory joint disease that Managing RA-Related Pain has a profound effect on the quality of life and The Effects of NSAIDs on Nociceptive and working productivity of patients, and accounts Central Pain Although NSAIDs are not for a considerable amount of healthcare appropriate for long-term disease control, they resources [70]. Most RA patients refer to pain as are often administered to RA patients in order to Pain Ther manage pain [79]. It is very important to start many of which are based on a series of system- DMARDs promptly and, in the case of pain, the atic Cochrane database reviews carried out in European League Against Rheumatism (EULAR) 2011–2012, suggest using paracetamol and recommends NSAIDs for patients with early NSAIDs to control chronic pain. disease whose gastrointestinal, renal, and car- The results of clinical trials of using tricyclic diovascular status has been carefully evaluated antidepressants in RA patients are equivocal: [79]. one systematic Cochrane review of eight RCTs A systematic review of the literature in which antidepressant therapy was compared describing the efficacy, safety, and tolerability with placebo or an active intervention found of NSAIDs in 146,524 patients participating in that the evidence was insufficient [85], but 176 studies included in a network meta-analysis adjuvant tricyclic antidepressants are included showed that diclofenac 150 mg/day was likely in the 3e recommendations for a subset of to be more effective in alleviating pain than patients with inflammatory arthritis [84]. celecoxib 200 mg/day, naproxen 1000 mg/day, Diclofenac can also be suggested because of its or ibuprofen 2400 mg/day, and as effective as effects on substance P, b-endorphin, and NMDA etoricoxib 60 mg/day, and that the effect of a receptors, and the fact that many clinical stud- lower diclofenac dose of 100 mg/day was com- ies have demonstrated that it relieves pain. It parable with that of all of the other treatments. has been shown that patients suffering from The rate of major adverse cardiovascular events migraine who experience central sensitization was similar with all of the active treatments, but with allodynia and do not achieve pain relief diclofenac caused fewer major upper gastroin- with other medications may benefit from the testinal events than naproxen or ibuprofen, cyclooxygenase-blocking activity of diclofenac although their frequency was similar in cele- [86]. Finally, diclofenac is available for treating coxib-treated patients, and lower in those trea- pain in different formulations (oral, intramus- ted with etoricoxib [64]. cular, topical, etc.). The sparse data available Glucocorticosteroids and traditional indicate that topical diclofenac can penetrate DMARDs such as methotrexate can be used to and permeate to deeper tissues, with a lower control most cases of RA [80], and biological plasma-to-tissue ratio than oral diclofenac, but drugs should only be used to treat patients with where it reaches a concentration that appears to very advanced or severe disease [81]. Although be sufficient to exert a therapeutic effect [87]. the analgesic effects of glucocorticosteroids may Moreover, there is good evidence that some not last more than 3 months [82], the early formulations of topical diclofenac and keto- suppression of inflammatory disease activity profen are useful in acute pain conditions such can avoid the development of worse pain as sprains or strains, with low (good) number- 12 months after diagnosis, and combined needed-to-treat (NNT) values, while in chronic DMARD treatment may be more effective than musculoskeletal conditions with assessments using one DMARD alone. over 6–12 weeks, topical diclofenac and keto- However, as inflammation is only one factor profen had limited efficacy in hand and knee contributing to pain, symptomatic relief is osteoarthritis, as did topical high-concentration often only partial even when the reduction in capsaicin in postherpetic neuralgia [88]. swollen joint counts and acute-phase reactant Though NNTs were higher, this still indicates levels, and ultrasound findings show that that a small proportion of people had good pain inflammatory disease activity is under control. relief. This means that analgesic drugs such as parac- etamol are often used even though there is no ADVERSE EFFECTS supporting evidence from RCTs [83]. However, recently published recommendations from the Diclofenac has shown to be effective and is 17-country 3e (evidence, expertise, exchange) widely used in the treatment of OA and RA, but collaborative project designed to promote evi- similar to other NSAIDs, is associated with an dence-based practices in rheumatology [84], Pain Ther increased risk of serious dose-related gastroin- sensitization and altered central pain processing testinal (GI), cardiovascular (CV), and renal side [96], compared diclofenac 150 mg/day versus effects [2, 89–91]. The GI adverse events (AEs) etoricoxib 60 mg/day for 4 weeks and found no occur due to reduced synthesis of prostanoids, differences in adverse events (gastrointestinal limiting secretion of mucus and bicarbonate adverse events in particular) between the two that normally protect the gastric mucosa from cohorts [95]. injury [92]. Consistent with the hypothesis that NSAIDs associated with the highest COX-1 CONCLUSIONS selectivity are more likely to be associated with an increased risk of GI toxicity, diclofenac ranks Acute pain can frequently be attributed to low in terms of relative risk for GI complica- mainly nociceptive inputs such as inflamma- tions, especially when administered at low tion and/or peripheral structural damage, doses (B 75 mg daily) [93]. According to data whereas chronic pain (usually defined as lasting from a meta-analysis of 280 trials of NSAIDs for C 3 months) is more probably due to inputs versus placebo (124,513 participants, 68,342 from the central nervous system. person-years) and 474 trials of one NSAID versus OA- and RA-related pain is complex and another NSAID (229,296 participants, 165,456 multifactorial, and due to physiological inter- person-years), the relative risk of upper gas- actions between the signaling of the central and trointestinal complications compared with pla- peripheral nervous systems. cebo was similar for diclofenac (RR 1.89) and The mechanisms of action of diclofenac coxibs (RR 1.81), while it was higher for make it particularly effective in treating both ibuprofen (RR 3.97) and naproxen (RR 4.22) nociceptive pain and chronic central pain. Fur- [91]. PGI2, a major product of COX-2—medi- thermore, its new mechanisms of action suggest ated metabolism of arachidonic acid in vascular to clinicians to change their clinical approach endothelial cells, serves a physiologic function for treating patients with neuropathic, central as a potent vasodilator and platelet inhibitor. sensitization and altered central pain using an Both preclinical and clinical evidence indicates old and well-known drug but able to improve that suppression of PGI2 synthesis increases the the quality of the life of these cohorts of risk for hypertension and thrombosis. The CV patients. hazard of diclofenac at doses C 150 mg daily is However, diclofenac has a range of actions estimated to be comparable to that of rofecoxib that areof interestinanoncological context. and celecoxib, as well as ibuprofen administered PGE2 is formed from the break down of at high doses [94]. The variable risk of myocar- arachidonic acid to prostaglandin H2 by COX- dial infarction (MI) due to NSAIDs that do not 1and COX-2followedbyfurther processing by completely inhibit COX-1 is largely related to microsomal prostaglandin synthase 1 (mPGES- their extent of COX-2 inhibition [2, 94]. The 1). Elevated levels of mPGES-1 and PGE2 are best safety profile related to MI was found for found in a range of different cancer types and naproxen, while diclofenac, ibuprofen, and are associated with the chronic inflammation coxibs increased the risk. The relative risk of that is associated with a pro-tumor microen- major coronary events compared with placebo vironment [97]. Diclofenac, in common with was similar for diclofenac (RR 1,70) coxibs (RR other inhibitors of the COX enzymes, also acts 1,76), and ibuprofen (RR 2.22) [89]. There was to reduce PGE2 synthesis. Therefore it has only limited evidence for an increased risk of other relevant mechanisms of anti-cancer major vascular events during the first 6 months action such as anti-angiogenic, immunomod- for coxibs and diclofenac [89]. Data for all other ulation, pro-apoptotic, platelet function, NSAIDs were not available because of the lack of actions on Myc and glucose metabolism, and well-designed RCTs [89]. treatment sensitivity, which means that COX- Zerbini et al. [95], in a trial including 440 2 expression may correlate with sensitivity to participants affected by chronic low back pain chemotherapy or radiotherapy in different (LBP), which is an example of central Pain Ther cancer types, which have been confirmed by ACKNOWLEDGEMENTS pre-clinical and clinical evidence in fibrosar- coma, neuroblastoma, and colorectal cancer, The authors wish to thank to Dr. Kevin Smart etc. [97]. Moreover, it has been reported that for the mother tongue revision. actinic keratoses (AKs), intraepithelial atypical proliferations of keratinocytes that develop in Funding. No funding or sponsorship was skin that has undergone long-term exposure to received for this study or publication of this ultraviolet radiation, can be treated with inge- article. The article processing charges were nol mebutate, imiquimod, and diclofenac, funded by the authors. which can clear both visible and subclinical AK lesions and reduce the development of new Authorship. All named authors meet the lesions in the treated field [98]. Furthermore, International Committee of Medical Journal the efficacy of topically applied diclofenac 3% Editors (ICMJE) criteria for authorship for this in combination with hyaluronic acid 2.5% in article, take responsibility for the integrity of the treatment of AKs has been demonstrated in the work as a whole, and have given their several clinical studies, even if the exact mode approval for this version to be published. of action is still unclear [99]. Finally, novel antitumor platinum(II) conjugates containing Disclosures. Fabiola Atzeni, Ignazio Fran- the nonsteroidal anti-inflammatory agent cesco Masala, and Piercarlo Sarzi-Puttini have diclofenac, a drug with antiproliferative prop- nothing to disclose. erties typical of these metallic conjugates, is potent and cancer cell selective cytotoxic Compliance with Ethics Guidelines. This agents exhibiting activity in cisplatin resistant article is based on previously conducted studies and the COX-2 positive tumor cell lines [100]. and does not contain any studies with human One of these compounds, compound 3, in participants or animals performed by any of the which DCF molecules are coordinated to Pt(II) authors. through their carboxylic group, is more potent than the parental conventional Pt(II) drug cis- Data Availability. Data sharing is not platin,freeDCF,and thecongeners of 3in applicable to this article, as no datasets were which DCF ligands are conjugated to Pt(II) via generated or analyzed during the current study. a diamine. The potency of 3 is due to several Open Access. This article is distributed factors including enhanced internalization under the terms of the Creative Commons that correlates with enhanced DNA binding Attribution-NonCommercial 4.0 International and cytotoxicity [100]. Mechanistic studies License (http://creativecommons.org/licenses/ show that 3 combines multiple effects. After its by-nc/4.0/), which permits any noncommer- accumulation in cells, it releases a Pt(II) drug cial use, distribution, and reproduction in any capable of binding/damaging DNA and DCF medium, provided you give appropriate credit ligands, which affects distribution of cells in to the original author(s) and the source, provide individual phases of the cell cycle, inhibits a link to the Creative Commons license, and glycolysis and lactate transport, collapses indicate if changes were made. mitochondrial membrane potential, and sup- presses the cellular properties characteristic of metastatic progression [100]. In summary, in this review we tried to REFERENCES underline the mechanisms of diclofenac involved in chronic and acute joint pain, the 1. Moore RA, McQuay HJ, Derry P, et al. 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Pain and TherapySpringer Journals

Published: Jun 5, 2018

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