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Medicinal Management Nonsteroidal Anti Medicinal management 43 foundation for treating OA, and are likely to be the drugs, every NSAID has the potential for patient- foundation for some years to come. Many clinicians dependent intolerance. Further, NSAID adverse manage the elusive pain of OA simply by sequenc- responses are over-represented by excessive dos- ing different NSAIDs until satisfactory patient ing30,31. As OA patients age, and possibly experience results are found or unacceptable adverse reactions underlying subclinical renal and/or hepatic com- are experienced. However, optimal clinical results promise, it is imperative that their maintenance are most frequently obtained by implementing a NSAID administration be at the minimal effec- multimodal protocol for OA, as has been proved for tive dose. A multimodal OA treatment protocol is multimodal perioperative analgesia. anchored on this tenet of minimal effective dose. Although contemporary experience precedes pub- NSAIDs relieve the clinical signs of pain. This is lished literature, there is a growing evidence base for achieved by suppression of prostaglandins (PGs), the multimodal management of OA. This evidence is primarily PGE2, produced from the substrate ara- a collation of clinical expertise, client/patient pref- chidonic acid within the prostanoid cascade. PGE2 erences, available resources, and research evidence, plays a number of roles in OA including: 1) lowering positioned on the evidence pyramid. the threshold of nociceptor activation; 2) promot- ing synovitis in the joint lining; 3) enhancing the MEDICINAL MANAGEMENT formation of degradative metalloproteinases (MMPs); and 4) depressing cartilage matrix syn- Medicinal management consists of three parts: (1) thesis by chondrocytes. In contrast, PGs also play NSAIDs, (2) chondroprotectants, and (3) adjunct positive metabolic roles such as enhancing platelet medications/treatments (3.3). aggregation (to prevent excessive bleeding), main- taining integrity of the gastrointestinal (GI) tract, NONSTEROIDAL ANTI-INFLAMMATORY and facili tating renal function. Eicosanoid activity DRUGS is tissue dependent. It is the goal of NSAID manage- ment to inhibit PG formation that contributes to the NSAIDs will likely remain the foundation for treat- clinical signs and pathways of OA, while sparing PG ing canine OA based on their anti-inflammatory, production associated with beneficial physiologic analgesic, and antipyretic properties. As with all functions (3.4)32. Therefore, maintaining an optimal balance of PG production in the body is the ‘NSAID challenge’. NSAIDs and the COX-1:COX-2 ratio NSAID The IC50 is defined as the concentration of drug (NSAID) needed to inhibit the activity of the enzyme cyclo-oxygenase (COX) by 50%. In keeping Multimodal with the above rationale, one would like to have a management high concentration of NSAID before causing 50% of canine inhibition of COX-1 (‘good guy’, or beneficial PGs) osteoarthritis and a low concentration of NSAID to reach the IC50 (pharmacologic) Adjunct for COX-2 (‘bad guy’, or PGs associated with the pain Chondro- and pathology of OA): protectant IC50 of COX-1 (good) HIGH IC50 of COX-2 (bad) LOW 3.3 The medicinal management triangle comprises nonsteroidal anti-inflammatory drugs (NSAIDs), The higher the numerator and lower the denomin- chondroprotectants, and adjunct medications. ator, the higher the absolute value. Therefore, a 44 Multimodal Management for Canine Osteoarthritis 3.4 Cyclo-oxygenase-mediated prostanoids play a variety COX-1 gene COX-2 gene of physiologic roles, some constitutive, some pathologic32. GI: gastrointestinal; PG: prostaglandin; COX-1 COX-2b? COX-2 COX-2 COX: cyclo-oxygenase; constitutive inducible constitutive inducible NSAID: nonsteroidal anti- COX-3 inflammatory drug; constitutive TX: thromboxane. Traditional NSAIDs Acetaminophen COX-2 selectives GI tract (PGE2, PGI2 – mucosal protection) Inamed Kidney (PGE2/I2 – Kidney (PGE2 – uid renal blood ow) balance) tissue (e.g. Circulation (PGI2) PGE2) Platelets CNS (PGE2 – pain, fever) (TXA2 – aggregation) Physiology Pathophysiology greater COX-1/COX-2 ratio suggests (theoretically) COX-2. This has driven the creation of coxib-class the more optimal performing NSAID. With this in NSAIDs, which are COX-2-selective and (relatively) mind, pharmaceutical companies began designing COX-1-sparing (3.5). NSAIDs for which it takes a low concentration to inhibit COX-2, but a high concentration to inhibit Arachidonic acid pathway COX-1. Many factors such as species, incubation In most respects NSAIDs can be characterized as a time, and enzyme source can influence the data class, whereas there are molecule-specific charac- obtained from enzyme preparations and in vitro teristics. NSAIDs manifest their mode of action on testing. the arachidonic acid (AA) cascade (3.6). It is import- NSAID selection based upon the IC50 ratio can ant to note that the function of many prostanoids easily be misinterpreted. Firstly, IC50 ratio data is tissue-dependent, e.g. PGs may contribute to pain are generated in vitro. Secondly, the optimal ratio and inflammation in the arthritic joint, while they is unknown. It is known that a NSAID can be too enhance normal homeostatic functions of vascu- COX-2-selective, but the actual magnitude is as yet larization and bicarbonate and mucus secretion in unknown. What is undisputed is that the optimal the GI tract. At one time it was believed that block- NSAID should be COX-1-sparing, appreciating that ing the COX pathway results in a build-up of the COX-1 is more responsible for normal constitutive substrate AA, which would then lead to increased functions such as platelet aggregation, normal production of leukotrienes. This has been refuted renal function, and normal GI function than is by some33, while supported by others34. Nonsteroidal anti-inflammatory drugs 45 Membrane phospholipid Arachidonic acid COX-1 sparing and Nonselective NSAID block COX-2 selective COX-1 COX-2 Eicosanoids Physiologic Pain and function inammation Traditional NSAID Coxib-class NSAID 3.5 Summary of the cyclo-oxygenase pathway and nonselective vs. cyclo-oxygenase (COX)-1 sparing and COX-2 selective nonsteroidal anti-inflammatory drugs (NSAIDs). The coxib-class NSAIDs were designed to be too large to fit into the COX-1 receptor site (at label doses), but fit well into the COX-2 receptor site, thereby blocking pathologic COX-2-mediated prostaglandins (PGs), while sparing physiologic COX-1-mediated PGs. This is in contrast to traditional (nonselective) NSAIDs, which fit into both the COX-1 and COX-2 receptors, blocking both COX-1- and COX-2-mediated PGs. NSAID efficacy and safety The most common complications documented To date, only one study has compared the relative with NSAID use in the dog are associated with over- efficacy of multiple contemporary NSAIDs in dogs dosing and the concurrent use with other NSAIDs (n=8)3. This study received no commercial funding and/or corticosteroids35,36. Because corticosteroids and used objective assessment (force plate gait have their mode of action at a location higher in the analysis). A noteworthy finding in this study was AA cascade than do NSAIDs, it is redundant to use that every dog in the study responded to a NSAID, them concurrently, and doing so markedly increases but not every dog responded to each NSAID (3.7). the severity of adverse reactions30,37,38. Data from Currently, several NSAIDs (aspirin, carprofen, humans show that the risk of NSAID-induced GI cinchophen, deracoxib, etodolac, firocoxib, flunixin, complications is doubled when a NSAID is used ketoprofen, meloxicam, phenylbutazone, tepox- concurrently with a corticosteroid39. Of adverse alin, tolfenamic acid, robenacoxib, mavacoxib, and reactions reported, as a class of drug, NSAIDs are vedaprofen) have approval for the control of canine most commonly associated with adverse reactions perioperative and/or chronic pain in various coun- to the GI tract (64%), renal system (21%), and liver tries. NSAIDs approved for feline use are far more (14%)40. There is no published information relating restricted. to similar feline adverse drug events. 46 Multimodal Management for Canine Osteoarthritis Phospholipids • Chemotaxis • Immune reactions • Inammation Phospholipases Injury • Pain Glycerol • Allergies and asthma Lipoxygenase Arachidonic acid Inhibition site of corticosteroids • Inammation Cyclo-oxygenase • Exogenous chemical Leukotrienes metabolism Lipoxins • Steroid biosynthesis P450 PGG • Cholesterol catabolism 2 Inhibition site of NSAIDs • Vascular tone modulation • Glomerular dynamics Epoxides Cyclo-oxygenase • Apoptosis inhibition • Mitogenesis regulation PGH2 PGI1 Dierent PGE1 TXA PGE synthases and 1 2 isomerases Pain PGD2 Inammation TXA2 Pro-oncogenesis PGF2α Vasoconstriction Vasodilatation Vasoconstriction Antiplatelet aggregation Fever GI protection Wakefulness Temperature Pro-platelet GI motility control aggregation Sleep Bronchodilatation Bronchoconstriction Vasodilatation Penile erection Uterine contraction 3.6 The arachidonic acid pathway produces a number of eicosanoids that impact on the physiology of joint inflammation. GI: gastrointestinal; PG: prostaglandin; NSAID: nonsteroidal anti-inflammatory drug; TX: thromboxane. 115 110 105 Control Tepoxalin Etodolac Meloxicam (as % baseline) Carprofen Firocoxib Peak vertical force 100 Aspirin Deracoxib Acetaminophen 95 0 7 14 Time (days) 3.7 Relative efficacy of several contemporary nonsteroidal anti-inflammatory drugs (NSAIDs) used in veterinary medicine to treat stifle osteoarthritis.
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