Pain Ther (2018) 7:163–177 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 / Published online: June 5, 2018 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: email@example.com; firstname.lastname@example.org 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 164 Pain Ther (2018) 7:163–177 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. , (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 . 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 . Singh et al. have shown that diclofenac inhibits 90% of the PLA2 puriﬁed from snake venom , 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  (Fig. 1). human participants or animals performed by Tonussi and Ferreira  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 , 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 . Diclofenac apparently [4, 5] is 3–1000 times that of other NSAIDs , 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 . can be inhibited by an NO synthase inhibitor, a COX has two distinct isoforms : COX-1 is guanylate cyclase inhibitor, and an ATP-sensi- constitutively and relatively stably expressed in tive potassium channel opener . 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  of prostaglandin I2 (prostacyclin) ; 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 . Furthermore, DS teratogenicity increases the production of the prostaglandin, disrupts myelin sheath thickness and axon thromboxane, and leukotriene mediators of inﬂammation and pain . Diclofenac is four Pain Ther (2018) 7:163–177 165 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 , 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.  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 . 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 , is a selective and compet- itive inhibitor of NMDA receptors in rat jaw muscles , and markedly increases rat spinal cord and diencephalon concentrations of kynurenic acid, an NMDA receptor antagonist associated with antinociceptive effects . Fig. 2 Pain and new mechanisms of actions of diclofenac 166 Pain Ther (2018) 7:163–177 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 . 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 , and on spinal nociceptive processing by activating diclofenac fully blocks the synthesis of PGE2 in PPARc and inhibiting prostaglandin synthesis human chondrocytes . 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 , ﬂammatory pain . Yamazaki et al.  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 , and by 180 days’ cell proliferation by decreasing cell viability and treatment in OA patients . 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 . 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 , and it has pathway in a macrophage model  (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 . eases , 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 . 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 , 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 (2018) 7:163–177 167 Fig. 3 Inﬂamed synovium—synovitis Fig. 4 Degraded cartilage 168 Pain Ther (2018) 7:163–177 age, gender, and geographical location of the increases the sensitivity of nociceptive primary patients and the way it is deﬁned , but it has afferent neurons, and the hyperexcitability of been estimated that it affected more than 26 nociceptive neurons in the CNS . Once million people in the USA in 2005 . 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 . 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 , 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 . 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 , 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 . 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 . 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 : 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 . A study by van Walsem leading to peripheral sensitization. This et al.  found that diclofenac 150 mg/day and Pain Ther (2018) 7:163–177 169 etoricoxib 60 mg/day were similarly effective, but their greatest problem , 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 . 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 . 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 , 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 . is not always related to disease severity or The role of centralized pain has been con- exacerbations . 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 , 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.  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 , 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.  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 , which produce TNF-a, IL-1, and IL-6, and in an experimental model is signiﬁcantly facilitate pain transmission . 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 . 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 . Most RA patients refer to pain as are often administered to RA patients in order to 170 Pain Ther (2018) 7:163–177 manage pain . 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: . 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 , 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 . 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- . Finally, diclofenac is available for treating coxib-treated patients, and lower in those trea- pain in different formulations (oral, intramus- ted with etoricoxib . 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 , 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 . Although be sufﬁcient to exert a therapeutic effect . the analgesic effects of glucocorticosteroids may Moreover, there is good evidence that some not last more than 3 months , 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 . 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 . 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 , Pain Ther (2018) 7:163–177 171 increased risk of serious dose-related gastroin- sensitization and altered central pain processing testinal (GI), cardiovascular (CV), and renal side , 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 . injury . 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) . 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- . 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 . 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 . 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) . 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 . 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 . treatment sensitivity, which means that COX- Zerbini et al. , 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 172 Pain Ther (2018) 7:163–177 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. . 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 . 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 . 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 . 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 . 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 . 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. Single dose most relevant adverse events, and future pro- oral diclofenac for acute postoperative pain in spects of this drug in oncological ﬁeld. adults. Cochrane Database Syst Rev. 2004;2:CD004768. Pain Ther (2018) 7:163–177 173 2. Gan TJ. Diclofenac: an update on its mechanism of pharmacological agents in vitro. Scand J Clin Lab action and safety proﬁle. Curr Med Res Opin. Invest. 1997;57:401–7. 2010;26:1715–31. 15. Triggiani M, Granata F, Frattini A, et al. Activation 3. Vane JR, Botting RM. Mechanism of action of anti- of human inﬂammatory cells by secreted phos- inﬂammatory drugs. Scand J Rheum. pholipases A2. Biochim Biophys Acta. 1996;102:9–21. 2006;1761:1289–300. 4. Tegeder I, Lotsch J, Krebs S, et al. Comparison of 16. Singh N, Jabeen T, Sharma S, et al. Speciﬁc binding inhibitory effects of meloxicam and diclofenac on of non-steroidal anti-inﬂammatory drugs (NSAIDs) human thromboxane biosynthesis after single doses to phospholipase A2: structure of the complex and at steady state. Clin Pharmacol Ther. formed between phospholipase A2 and diclofenac 1999;65:533–44. at 2.7A resolution. Acta Crystallogr D. 2006;62:410–6. 5. Wittenberg RH, Willburger RE, Kleemeyer KS, et al. In vitro release of prostaglandins and leukotrienes 17. Clish CB, Sun YP, Serhan CN. Identiﬁcation of dual from synovial tissue, cartilage, and bone in degen- cyclooxygenase-eicosanoid oxidoreductase inhibi- erative joint diseases. Arthritis Rheum. tors: NSAIDs that inhibit PG-LX reductase/LTB(4) 1993;36:1444–50. dehydrogenase. Biochem Biophys Res Commun. 2001;288:868–74. 6. Ku EC, Lee W, Kothari HV, et al. Effect of diclofenac sodium on the arachidonic acid cascade. Am J Med. 18. Tonussi CR, Ferreira SH. Mechanism of diclofenac 1986;80:18–23. analgesia: direct blockade of inﬂammatory sensiti- zation. Eur J Pharmacol. 1994;251:173–9. 7. Giagoudakis G, Markantonis SL. Relationships between the concentrations of prostaglandins and 19. Fagni L, Bockaert J. Effects of nitric oxide on gluta- the nonsteroidal antiinﬂammatory drugs indo- mate-gated channels and other ionic channels. methacin, diclofenac, and ibuprofen. Pharma- J Chem Neuroanatomy. 1996;10:231–40. cotherapy. 2005;25:18–25. 20. Armstead WM. Role of ATP-sensitive Kþ channels in 8. Tegeder I, Pfeilschifter J, Geisslinger G. Cyclooxy- cGMP-mediated pial artery vasodilation. Am J genase-independent actions of cyclooxygenase Physiol. 1996;270:H423–6. inhibitors. FASEB J. 2001;15:2057–72. 21. Soares AC, Duarte ID. Dibutyryl-cyclic GMP induces 9. Warner TD, Giuliano F, Vojnovic I, et al. Nonsteroid peripheral antinociception via activation of ATP- drug selectivities for cyclooxygenase- 1 rather than sensitive K(þ) channels in the rat PGE2-induced cyclo-oxygenase-2 are associated with human gas- hyperalgesic paw. Br J Pharmacol. 2001;134:127–31. trointestinal toxicity: a full in vitro analysis. Proc Natl Acad Sci USA. 1999;96:7563–8. 22. Alves DP, Tatsuo MA, Leite R, et al. Diclofenac-in- duced peripheral antinociception is associated with 10. Dennis EA. Diversity of group types, regulation, and ATP-sensitive Kþ channels activation. Life Sci. function of phospholipase A2. J Biol Chem. 2004;74:2577–91. 1994;269:13057–60. 23. Kaplan AA, Yurt KK, Deniz OG, Altun G. Peripheral 11. Walsh CE, Dechatelet LR, Thomas MJ, et al. Effect of nerve and diclofenac sodium: Molecular and clini- phagocytosis and ionophores on release and meta- cal approaches. J Chem Neuroanat. 2018;87:2–11. bolism of arachidonic acid from human neu- trophils. Lipids. 1981;16:120–4. 24. Okuyama S, Aihara H. The mode of action of anal- gesic drugs in adjuvant arthritic rats as an experi- 12. Kothari HV, Lee WH, Ku EC. An alternate mecha- mental model of chronic inﬂammatory pain: nism for regulation of leukotriene production in possible central analgesic action of acidic nons- leukocytes: studies with an anti-inﬂammatory drug, teroidal antiinﬂammatory drugs. Jpn J Pharmacol. sodium diclofenac. Biochim Biophys Acta. 1984;35:95–103. 1987;921:502–11. 25. Sacerdote P, Monza G, Mantegazza P, et al. 13. Nevalainen TJ, Gronroos JM, Kortesuo PT. Pancre- Diclofenac and pirprofen modify pituitary and atic and synovial type phospholipases A2 in serum hypothalamic beta-endorphin concentrations. samples from patients with severe acute pancreati- Pharmacol Res Commun. 1985;17:679–84. tis. Gut. 1993;34:1133–6. 26. Bjorkman RL, Hedner T, Hallman KM, et al. Local- 14. Makela A, Kuusi T, Schroder T. Inhibition of serum ization of the central antinociceptive effects of phospholipase-A2 in acute pancreatitis by diclofenac in the rat. Brain Res. 1992;590:66–73. 174 Pain Ther (2018) 7:163–177 27. Martini A, Bondiolotti GP, Sacerdote P, et al. 39. Mahdy AM, Galley HF, Abdel-Wahed MA, et al. Diclofenac increases beta-endorphin plasma con- Differential modulation of interleukin-6 and inter- centrations. J Int Med Res. 1984;12:92–5. leukin-10 by diclofenac in patients undergoing major surgery. Br J Anaesth. 2002;88:797–802. 28. Bjorkman R, Hallman KM, Hedner J, et al. Nons- teroidal antiinﬂammatory drug modulation of 40. Sacerdote P, Carrabba M, Galante A, et al. Plasma behavioral responses to intrathecal N-methyl-D-as- and synovial ﬂuid interleukin-1, interleukin-6 and partate, but not to substance P and amino-methyl- substance P concentrations in rheumatoid arthritis isoxazole-propionic acid in the rat. J Clin Pharma- patients: effect of the nonsteroidal anti-inﬂamma- col. 1996;36:20S–6S. tory drugs indomethacin, diclofenac and naproxen. Inﬂamm Res. 1995;44:486–90. 29. Dong X-D. The analgesic action of topical diclofe- nac may be mediated through peripheral NMDA 41. Gonzalez E, de la Cruz C, de Nicolas R, et al. Long- receptor antagonism. Pain. 2009;147:36–45. term effect of nonsteroidal anti-inﬂammatory drugs on the production of cytokines and other inﬂam- 30. Adamson DJ, Frew D, Tatoud R, Wolf CR, Palmer matory mediators by blood cells of patients with CN. Diclofenac antagonizes peroxisome prolifera- osteoarthritis. Agents Actions. 1994;41:171–8. tor-activated receptor-gamma signaling. Mol Phar- macol. 2002;61:7–12. 42. Voilley N, de Weille J, Mamet J, et al. Nonsteroid anti-inﬂammatory drugs inhibit both the activity 31. Gehrmann J, Matsumoto Y, Kreutzeberg GW. and the inﬂammation-induced expression of acid Microglia: intrinsic immunoeffector cell of the sensing ion channels in nociceptors. J Neurosci. brain. Brain Res Rev. 1995;20:269–87. 2001;21:8026–33. 32. Yamazaki R, Kusunoki N, Matsuzaki T, et al. Nons- 43. Dorofeeva NA, Barygin OI, Staruschenko A, et al. teroidal anti-inﬂammatory drugs induce apoptosis Mechanisms of non-steroid anti-inﬂammatory in association with activation of peroxisome pro- drugs action on ASICs expressed in hippocampal interneurons. J Neurochem. 2008;106:429–41. liferator-activated receptor gamma in rheumatoid synovial cells. J Pharmacol Exp Ther. 2002;302:18–25. 44. Jones NG, Slater R, Cadiou H, et al. Acid-induced pain and its modulation in humans. J Neurosci. 33. Na HK, Surh YJ. Peroxisome proliferator-activated 2004;24:10974–9. receptor gamma (PPARgamma) ligands as bifunc- tional regulators of cell proliferation. Biochem 45. Sangha O. Epidemiology of rheumatic diseases. Pharmacol. 2003;66:1381–91. Rheumatology (Oxford). 2000;39:3–12. 34. Sandri A. Spinal anti-inﬂammatory action of diclo- 46. Litwic A, Edwards MH, Dennison EM, Cooper C. fenac. Minerva Med. 2016;107:167–72. Epidemiology and burden of osteoarthritis. Br Med Bull. 2013;105:185–99. 35. Ayoub SS, Botting RM, Joshi AN, et al. Activation of macrophage peroxisome proliferator-activated 47. Lawrence RC, Felson DT, Helmick CG, Arnold LM, receptor-gamma by diclofenac results in the induc- Choi H, Deyo RA, et al. Estimates of the prevalence tion of cyclooxygenase-2 protein and the synthesis of arthritis and other rheumatic conditions in the of anti-inﬂammatory cytokines. Mol Cell Biochem. United States. Part II. Arthritis Rheum. 2009;327:101–10. 2008;58:26–35. 36. O’Connor TM, O’Connell J, O’Brien DI, et al. The 48. Salafﬁ F. Pain in osteoarthritis: assessment and role of substance P in inﬂammatory disease. J Cell impact on the disability. Reumatismo. Phys. 2004;201:167–80. 2003;55(4):19–37. 37. Tsuboi I, Tanaka H, Nakao M, et al. Nonsteroidal 49. Salafﬁ F, Carotti M, Stancati A, Grassi W. Health- anti-inﬂammatory drugs differentially regulate related quality of life in older adults with symp- cytokine production in human lymphocytes: up- tomatic hip and knee osteoarthritis: a comparison regulation of TNF, IFN-gamma and IL-2, in contrast with matched healthy controls. Aging Clin Exp Res. to down-regulation of IL-6 production. Cytokine. 2005;17(4):255–63. 1995;7:372–9. 50. Mease PJ, Hanna S, Frakes EP, Altman RD. Pain 38. Henrotin Y, de Leval X, Mathy-Hartet M, et al. mechanisms in osteoarthritis: understanding the In vitro effects of aceclofenac and its metabolites on role of central pain and current approaches to its the production by chondrocytes of inﬂammatory treatment. J Rheumatol. 2011;38:1546–51. mediators. Inﬂamm Res. 2001;50:391–9. Pain Ther (2018) 7:163–177 175 51. Dray A, Read SJ. Arthritis and pain. Future targets to 64. van Walsem A, Pandhi S, Nixon RM, Guyot P, control osteoarthritis pain. Arthritis Res Ther. Karabis A, Moore RA. Relative beneﬁt–risk compar- 2007;9:212. ing diclofenac to other traditional non-steroidal anti-inﬂammatory drugs and cyclooxygenase-2 52. Schaible HG, Schmelz M, Tegeder I. Pathophysiol- inhibitors in patients with osteoarthritis or ogy and treatment of pain in joint disease. Adv rheumatoid arthritis: a network meta-analysis. Drug Deliv Rev. 2006;58:323–42. Arthritis Res Ther. 2015;17:66. 53. Salafﬁ F, Ciapetti A, Carotti M. The sources of pain 65. Latremoliere A, Woolf CJ. Central sensitization: a in osteoarthritis: a pathophysiological review. Reu- generator of pain hypersensitivity by central neural matismo. 2014;66:57–71. plasticity. J Pain. 2009;10:895–926. 54. Schaible HG, Ebersberger A, von Banchet GS. 66. Treede RD, Kenshalo DR, Gracely RH, Jones AK. The Mechanisms of pain in arthritis. Ann N Y Acad Sci. cortical representation of pain. Pain. 2002;966:343–54. 1999;79:105–11. 55. Bonnet CS, Walsh DA. Osteoarthritis, angiogenesis 67. Phillips K, Clauw DJ. Central pain mechanism in and inﬂammation. Rheumatology. 2005;44:7–16. the rheumatic diseases. Arth Rheum. 2013;65:291–302. 56. Porcheret M, Jordan K, Jinks C, Croft P. Primary care treatment of knee pain—a survey in older adults. 68. Burian M, Tegeder I, Seegel M, Geisslinger G. Rheumatology (Oxford). 2007;46:1694–700. Peripheral and central antihyperalgesic effects of diclofenac in a model of human inﬂammatory pain. 57. Juni P, Reichenbach S, Dieppe P. Osteoarthritis: Clin Pharmacol Ther. 2003;74:113–20. rational approach to treating the individual. Best Pract Res Clin Rheumatol. 2006;20:721–40. 69. Vellani V, Franchi S, Prandini M, Moretti S, Castelli M, Giacomoni C, Sacerdote P. Effects of NSAIDs and 58. Gore M, Sadosky A, Leslie D, Tai KS, Seleznick M. paracetamol (acetaminophen) on protein kinase C epsilon translocation and on substance P synthesis Patterns of therapy switching, augmentation, and and release in cultured sensory neurons. J Pain Res. discontinuation after initiation of treatment with 2013;6:111–20. select medications in patients with osteoarthritis. Clin Ther. 2011;33:1914–31. 70. Kazis LE, Meenan RF, Anderson JJ. Pain in the rheumatic diseases. Investigation of a key health 59. McAlindon TE, Bannuru RR, Sullivan MC, et al. status component. Arthritis Rheum. OARSI guidelines for the non-surgical management of knee osteoarthritis. Osteoarthritis Cartilage. 1983;26:1017–22. 2014;22:363–88. 71. Atzeni F, Masala IF, Salafﬁ F, Di Franco M, Casale R, 60. Bjordal JM, Klovning A, Ljunggren AE, Slordal L. Sarzi-Puttini P. Pain in systemic inﬂammatory Short-term efﬁcacy of pharmacotherapeutic inter- rheumatic diseases. Best Pract Res Clin Rheumatol. ventions in osteoarthritic knee pain: A meta-anal- 2015;29(1):42–52. ysis of randomised placebo-controlled trials. Eur J Pain. 2007;11(2):125–38. 72. Odegard S, Finset A, Mowinckel P, Kvien TK, Uhlig T. Pain and psychological health status over a 61. Chen YF, Jobanputra P, Barton P, et al. Cyclooxy- 10-year period in patients with recent onset genase-2 selective non-steroidal anti-inﬂammatory rheumatoid arthritis. Ann Rheum Dis. drugs (etodolac, meloxicam, celecoxib, rofecoxib, 2007;66:1195–201. etoricoxib, valdecoxib and lumiracoxib) for osteoarthritis and rheumatoid arthritis: a systematic 73. Atzeni F, Sarzi-Puttini P. Rheumatoid arthritis: why review and economic evaluation. Health Technol wait? Explaining delays in seeking therapy for early Assess. 2008;12:1–278. arthritis. Nat Rev Rheumatol. 2012;8:190–1. 62. Chou R, McDonagh MS, Nakamoto E, Grifﬁn J. 74. Andersson ML, Svensson B, Bergman S. Chronic Analgesics for osteoarthritis: an update of the 2006 widespread pain in patients with rheumatoid comparative effectiveness review. Rockville: Agency arthritis and the relation between pain and disease for Healthcare Research and Quality (US), 2011. activity measures over the ﬁrst 5 years. J Rheumatol. 2013;40:1977–85. 63. da Costa BR, Reichenbach S, Keller N, Nartey L, Wandel S, Ju ¨ ni P, Trelle S. Effectiveness of non- 75. Atzeni F, Cazzola M, Benucci M, Di Franco M, Salafﬁ steroidal anti-inﬂammatory drugs for the treatment F, Sarzi-Puttini P. Chronic widespread pain in the of pain in knee and hip osteoarthritis: a network spectrum of rheumatological diseases. Best Pract Res meta-analysis. Lancet. 2016;387(10033):2093–105. Clin Rheumatol. 2011;25:165–71. 176 Pain Ther (2018) 7:163–177 76. Woolf CJ. Central sensitization: implications for the 87. Hagen M, Baker M. Skin penetration and tissue diagnosis and treatment of pain. Pain. permeation after topical administration of diclofe- 2010;152:S2–15. nac. Curr Med Res Opin. 2017;33:1623–34. 77. Raychaudhuri SP, Raychaudhuri SK, Atkuri KR, 88. Derry S, Wiffen PJ, Kalso EA, et al. Topical analgesics Herzenberg LA, Herzenberg LA. Nerve growth fac- for acute and chronic pain in adults—an overview tor: a key local regulator in the pathogenesis of of Cochrane Reviews. Cochrane Database Syst Rev. inﬂammatory arthritis. Arthritis Rheum. 2017;5:CD008609. 2011;63:3243–52. 89. Coxib and traditional NSAID Trialists’ (CNT) Col- 78. Schaible HG, von Banchet GS, Boettger MK, et al. laboration Vascular and upper gastrointestinal The role of proinﬂammatory cytokines in the gen- effects of non-steroidal anti-inﬂammatory drugs: eration and maintenance of joint pain. Ann N Y meta-analyses of individual participant data from Acad Sci. 2010;1193:60–9. randomised trials. Lancet. 2013;382:769–79. 79. Sarzi-Puttini P, Atzeni F, Lanata L, Bagnasco M. 90. Kuo HW, Tsai SS, Tiao MM, Liu YC, Lee IM, Yang Efﬁcacy of ketoprofen vs. ibuprofen and diclofenac: CY. Analgesic use and the risk for progression of a systematic review of the literature and meta- chronic kidney disease. Pharmacoepidemiol Drug analysis. Clin Exp Rheumatol. 2013;31(5):731–8. Saf. 2010;19:745–51. 80. Boers M, Verhoeven AC, Markusse HM, et al. Ran- 91. Kontogiorgis C, Valikeserlis I, Hadjipavlou-Litina D, domized comparison of combined step-down Nena E, Constantinidis TC. Use of non-selective prednisolone, methotrexate, and sulphasalazine non-steroidal anti-inﬂammatory drugs in relation with sulphasalazine alone in early rheumatoid to cardiovascular events. A systematic pharma- arthritis. Lancet. 1997;350:309–18. coepidemiological review. Curr Vasc Pharmacol. 2016;14:502–13. 81. Emery P. Optimizing outcomes in patients with rheumatoid arthritis and an inadequate response to 92. Warner TD, Giuliano F, Vojnovic I, Bukasa A, anti-TNF treatment. Rheumatology. 2012;51(Suppl Mitchell JA, Vane JR. Nonsteroid drug selectivities 5):v22–30. for cyclo-oxygenase-1 rather than cyclo-oxygenase- 2 are associated with human gastrointestinal toxi- 82. Ramiro S, Radner H, van der Heijde D, et al. Com- city: a full in vitro analysis. Proc Natl Acad Sci. bination therapy for pain management in inﬂam- 1999;96:7563–8. matory arthritis (rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, other spondy- 93. Laporte JR, Ibanez L, Vidal X, Vendrell L, Leone R. loarthritis). Cochrane Database Syst Rev. Upper gastrointestinal bleeding associated with the 2011;(10):CD008886. use of NSAIDs: newer versus older agents. Drug Saf. 2004;27:411–20. 83. Wienecke T, Gotzsche PC. Paracetamol vs nons- teroidal anti-inﬂammatory drugs for rheumatoid 94. Altman R, Bosch B, Brune K, Patrignani P, Young C. arthritis. Cochrane Database Syst Rev. Advances in NSAID development: evolution of 2004;1:CD003789. diclofenac products using pharmaceutical technol- ogy. Drugs. 2015;75:859–77. 84. Whittle SL, Colebatch AN, Buchbinder R, et al. Multinational evidence-based recommendations for 95. Zerbini C, Ozturk ZE, Grifka J, Maini M, Nilganu- pain management by pharmacotherapy in inﬂam- wong S, Morales R, et al. Efﬁcacy of etoricoxib matory arthritis: integrating systematic literature 60 mg/day and diclofenac 150 mg/day in reduction research and expert opinion of a broad panel of of pain and disability in patients with chronic low rheumatologists in the 3e initiative. Rheumatology back pain: results of a 4-week, multinational, ran- (Oxford). 2012;51:1416–25. domized, double-blind study. Curr Med Res Opin. 2005;21(12):2037–49. 85. Richards BL, Whittle SL, Buchbinder R. Neuro- modulators for pain management in rheumatoid 96. Roussel NA, Nijs J, Meeus M, Mylius V, Fayt C, arthritis. Cochrane Database Syst Rev. Oostendorp R. Central sensitization and altered 2012;1:CD008921. central pain processing in chronic low back pain: fact or myth? Clin J Pain. 2013;29(7):625–38. 86. Joshi S, Rapoport AM. Diclofenac potassium for oral solution (CAMBIA ) in the acute management of a 97. Pantziarka P, Sukhatme V, Bouche G, Meheus L, migraine attack: clinical evidence and practical Sukhatme VP. Repurposing Drugs in Oncology experience. Ther Adv Neurol Disord. (ReDO)-diclofenac as an anti-cancer agent. 2017;10(4):217–26. Ecancermedicalscience. 2016;10:610. Pain Ther (2018) 7:163–177 177 98. Stockﬂeth E. The importance of treating the ﬁeld in 100. Intini FP, Zajac J, Novohradsky V, Saltarella T, actinic keratosis. J Eur Acad Dermatol Venereol. Paciﬁco C, Brabec V, Natile G, Kasparkova J. Novel 2017;31(Suppl 2):8–11. antitumor platinum(II) conjugates containing the nonsteroidal anti-inﬂammatory agent diclofenac: 99. Maltusch A, Ro ¨ wert-Huber J, Matthies C, Lange- synthesis and dual mechanisms of antiproliferative Asschenfeldt S, Stockﬂeth E. Modes of action of effects. Inorg Chem. 2017;56(3):1483–97. diclofenac 3%/hyaluronic acid 2.5% in the treat- ment of actinic keratosis. J Dtsch Dermatol Ges. 2011;9(12):1011–7.
Pain and Therapy – Springer Journals
Published: Jun 5, 2018
It’s your single place to instantly
discover and read the research
that matters to you.
Enjoy affordable access to
over 18 million articles from more than
15,000 peer-reviewed journals.
All for just $49/month
Query the DeepDyve database, plus search all of PubMed and Google Scholar seamlessly
Save any article or search result from DeepDyve, PubMed, and Google Scholar... all in one place.
Get unlimited, online access to over 18 million full-text articles from more than 15,000 scientific journals.
Read from thousands of the leading scholarly journals from SpringerNature, Wiley-Blackwell, Oxford University Press and more.
All the latest content is available, no embargo periods.
“Hi guys, I cannot tell you how much I love this resource. Incredible. I really believe you've hit the nail on the head with this site in regards to solving the research-purchase issue.”Daniel C.
“Whoa! It’s like Spotify but for academic articles.”@Phil_Robichaud
“I must say, @deepdyve is a fabulous solution to the independent researcher's problem of #access to #information.”@deepthiw
“My last article couldn't be possible without the platform @deepdyve that makes journal papers cheaper.”@JoseServera