Stuart Clark-Price
Nonsteroidal anti-inflammatory drugs (NSAIDs) are a class of drugs that produce anti-inflammatory and anti-nociceptive effects. NSAIDs are also pyretic, endotoxemic, and anti-neoplastic, and one of the fastest growing classes of drugs in veteri-nary medicine. Significant resources are being devoted to research and development, and veterinary practitioners can expect to see new and improved versions of NSAIDs in the future. When used properly, NSAIDs are a primary tool of the veterinarian for the management of pain.
HISTORY
NSAIDs are one of the oldest classes of analgesics, and their use is recorded as far back as the seventeenth century BCE. An ancient Egyptian surgical text, known as the Edwin Smith Papyrus, men-tions the use of salicylate-containing plants to relieve pain. Hip-pocrates wrote about the medicinal uses of similar agents in the fifth century BCE. In 1763, Reverend Edward Stone described the medicinal properties of willow bark in a publication of the Royal Society of England. The active agent in willow bark is salicylic acid, first isolated and described in 1828 by Henry Leroux and Raffaele Piria. In 1897, Felix Hoffman, while working for the Bayer Chem-ical Company, synthesized acetylsalicylic acid, which was later renamed aspirin, the first commercially available NSAID. In 1971, Sir John Vane described the ability of aspirin-like drugs to inhibit the production of prostaglandins (Vane, 1971). It is now understood that NSAIDs mediate their effects via a number of mechanisms.
MECHANISMS OF ACTION
NSAIDs act primarily by inhibiting the production of inflammatory mediators synthesized from arachidonic acid (AA) (Figure 5.1).
AA, a 20 carbon polyunsaturated fatty acid, is formed through the actions of the enzyme phospholipase on cellular membrane lipids in response to tissue damage or release of inflammatory mediators (Tizard, 2009). AA is derived from cellular membranes of phenotypically and functionally diverse cells, and the cell of origin determines the final disposition.
AA interacts with two enzymes, lipoxygenase (LOX) and cyclooxygenase (COX), and is oxidized to produce the eicosanoids
leukotrienes and prostaglandins (Higgins & Lees, 1984).
Leukotrienes and prostaglandins influence numerous physiologi-cal systems. Leukotrienes formed from AA include B4, A4, C4, D4, and E4. Leukotrienes mediate inflammation via inflammatory cell recruitment and activation (Tizard, 2009). Unlike prostaglandins, there are fewer clinical options for the manipulation of leukotriene concentrations for therapeutic purposes.
When presented with AA, the COX enzyme performs the first step in the synthesis of prostaglandins, cyclizing and adding a 15-hydroperoxy group to AA (Vane & Botting, 1998). This pro-duces prostaglandin G2, which is further modified by a perox-idase to form prostaglandin H2 (Vane & Botting, 1998). Addi-tional modification of prostaglandin H2 forms a number of other prostaglandins and thromboxanes. Prostaglandins formed from AA include E2, I2, D2, and F2␣, each with different effects on biological systems.
Prostaglandins are important in homeostatic mechanisms nec-essary for normal organ function. When there is tissue damage, however, these same prostaglandins can incite inflammation, fur-ther tissue damage, and pain. Prostaglandin E2(PGE2) is involved in the regulation of the reproductive, neurological, metabolic, and immune systems, bone formation and healing, temperature regula-tion, and vasomotor responses (Legler et al., 2010). PGE2is also a classic pro-inflammatory mediator, promoting redness, swelling, pain, and the development of hyperalgesia (Pratico & Dogne, 2009;
Legler et al., 2010). Prostaglandin I2 (PGI2), or prostacyclin, is an important regulatory prostaglandin and a potent vasodilator and inhibitor of platelet aggregation (Pratico & Dogne, 2009).
Prostaglandin D2 (PGD2), commonly derived from lipid mem-branes of mast cells and macrophages, causes bronchoconstriction (particularly in asthmatics and those with pulmonary inflamma-tion), vasodilation, increased capillary permeability, and mucous production (Oguma et al., 2008). Prostaglandin F2␣ (PGF2␣) is important in luteolysis, normal ovarian function, luteal mainte-nance of pregnancy, and parturition, and is used therapeutically to manipulate reproductive function. Additionally, PGF2␣is an active player in acute and chronic inflammation, and in cardiovascular and rheumatic diseases (Basu, 2007).
Regulation of the COX enzyme is the main mechanism for the therapeutic effects of NSAIDs, and first-generation NSAIDs
Pain Management in Veterinary Practice, First Edition. Edited by Christine M. Egger, Lydia Love and Tom Doherty.
C2014 John Wiley & Sons, Inc. Published 2014 by John Wiley & Sons, Inc.
69
70 Section 2 / Pharmacology of Analgesic Drugs
Figure 5.1. Prostaglandins and leukotrienes produced through the actions of phospholipase A2, lipoxygenase, and cyclooxygenase enzymes on cellular membrane phospholipid. Dashes represent the inhibition of phospholipase A2by corticosteroids and cyclooxygenase by NSAIDs.
nonspecifically decreased the activity of the COX enzyme, thus suppressing all prostaglandin production. In the early 1990s, it was discovered that two isoforms of the COX enzyme exist (Xie et al., 1991) and that the second isoform was inducible with stim-ulating events, such as inflammation (Kujubu et al., 1991; Xie et al., 1991). The two isoforms, cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2), are encoded by two separate genes (Warner & Mitchell, 2004). Both isoforms are membrane-bound proteins in the endoplasmic reticulum of cells, sharing approxi-mately 60% homology of amino acid structure, including nearly identical amino acid conformation at their substrate-binding sites, and similarly catalyze AA to form prostaglandins (Warner &
Mitchell, 2004). They differ, however, in the structure of their inhibitor-binding sites. For COX-1 and COX-2, AA and NSAIDs enter through a hydrophobic side channel (Khanapure et al., 2007) and NSAIDs compete with AA for this active site to inhibit produc-tion of prostaglandins. With COX-2 enzymes, valine-523 opens a
“side pocket” next to the main channel, whereas in COX-1 enzymes, isoleucine-530 effectively eliminates a “side pocket” (Khanapure et al., 2007). This results in the COX-2 site being 25% larger, making COX-2 a better competitor for AA substrate (Warner &
Mitchell, 2004). These differences in binding sites have been used to develop COX-2 selective inhibitors.
After the discovery of the COX-2 enzyme, it was postulated that COX-1 production of prostaglandins was constitutive and necessary for the normal functioning of organ systems. COX-2 was thought to be upregulated only during inflammation and other
pathologi-cal processes, and that control of inflammation and pain could be achieved with minimal side effects by suppressing COX-2. Numer-ous studies and reviews were published supporting the development of COX-2 selective/COX-1 sparing anti-inflammatory agents (Seib-ert et al., 1995; Seib(Seib-ert et al., 1997; FitzGerald & Patrono, 2001).
However, more recent research and reports of adverse events in humans have forced reconsideration of the importance of the COX-1 versus the COX-2 enzyme. For example, in human patients the use of the COX-2 selective drug, rofecoxib significantly increased the risk of thrombotic cardiovascular events such as myocardial infarction, unstable angina, cardiac thrombus, and sudden death (Mukherjee et al., 2001). Likewise, in dogs, gastrointestinal perfo-ration has been associated with the administperfo-ration of deracoxib, a COX-2 selective drug, particularly when administered at high doses or when combined with other NSAIDs (Lascelles et al., 2005a).
Based on this information, a COX-1 selective NSAID may cause more problems in certain circumstances than a COX-2 selective NSAID, and vice versa.
In 2002, a COX-3 enzyme isolated from the brains of dogs (Chan-drasekharan et al., 2002) was determined to be a splice variant of the COX-1 enzyme, with identical mRNA except for a retained intron 1.
COX-3 was selectively inhibited by acetaminophen (paracetamol), and this was thought to be the mechanism by which acetaminophen mediates analgesia. There is some debate about nomenclature and the role of COX-3, and some researchers have suggested that it be named 1b (Kis et al., 2005a; Simmons et al., 2005). The COX-3 mRNA in other species, such as humans and mice, encodes for
5 / Nonsteroidal Anti-Inflammatory Drugs and Corticosteroids 71 a nonfunctional enzyme that does not play a role in
prostaglandin-mediated fever (Kis et al., 2006). Prostaglandin production by rat cerebral endothelium is sensitive to acetaminophen, suggesting a central mechanism of action of the drug (Kis et al., 2005b). COX-3 mRNA has also been isolated from the human cerebral cortex and aorta, and rodent cerebral endothelium, heart, kidney, and neuronal tissue (Hersh et al., 2005). The role of COX-3 in inflammation, pain, and fever has yet to be completely elucidated and, to date, its clinical importance is unclear. However, synergism has been demonstrated between the COX-3 inhibitor acetaminophen and other COX iso-form selective inhibitors, suggesting there may be benefits to the use of acetaminophen in combination with other NSAID therapy (Munoz et al., 2010).
Other Mechanisms of Action
The suppression of COX is the main mechanism by which NSAIDs exert their anti-inflammatory and analgesic effects; however, non-COX mediated mechanisms contribute to the analgesic and anti-inflammatory effects of NSAIDs.
Because NSAIDs tend to be lipophilic at low pH, some anti-inflammatory action appears to be due to the insertion of NSAIDs into the lipid bilayer of cell membranes and the physical disrup-tion of cell signaling and protein-to-protein interacdisrup-tions (Dowling, 2010). This may result in decreased transmission of pain signals in the peripheral and central nervous systems.
Aspirin has been shown to have anti-inflammatory effects through inhibition of the kinase Erk, important in CD11b/CD18 integrin-dependent adhesiveness of neutrophils (Pillinger et al., 1998). This inhibition decreases neutrophil aggregation in areas of injury, reducing their inflammatory effects.
Other potential mechanisms of NSAID action include interaction with the endogenous opioid system, inhibition of nuclear factorB, activation of the serotonergic bulbospinal pathway, involvement of the nitric oxide pathway, and an increase in cannabinoid/vanilloid tone (Mattia & Coluzzi, 2009; Fox, 2010). The interaction of NSAIDs with these and potentially other central nervous system receptors may be one of the reasons why human patients have a sense of well being while using these drugs.
CLASSIFICATION OF NSAIDs
No consensus currently exists on how NSAIDs should be classified, although several systems have been proposed. One method classi-fies NSAIDs based on their sequence of introduction to the market, similar to that used for antimicrobial agents (Fox, 2010). For exam-ple, first generation (e.g., aspirin, phenylbutazone, meclofenamic acid), second generation (e.g., carprofen, etodolac, meloxicam), third generation (e.g., tepoxalin, deracoxib, firocoxib), and so on.
This method does not take into account different mechanisms of action within and among generations.
Chemical composition can be used to classify NSAIDs (Table 5.1). This method also does not consider the mechanism of action and provides little clinically useful information.
Another method of classification has been based on COX-2 inhi-bition, and divides NSAIDs into COX-2 inhibitors and nonspecific NSAIDs (Stoelting & Hillier, 2006). This method presents dif-ficulties because it has been shown that although several of the newer NSAIDs, particularly the coxibs (Table 5.1), do possess very
Table 5.1. Nonsteroidal anti-inflammatory drugs used in veterinary medicine classified by chemical
composition
Chemical Composition NSAIDs
Salicylates Aspirin
Benzones Phenylbutazone
Propionic acid derivatives Carprofen Flurbiprofen Ibuprofen Ketoprofen Naproxen Vedaprofen Acetic acid derivatives Diclofenac
Etodolac Indomethacin Ketorolac
Enolic acid derivatives Meloxicam
Piroxicam
Fenamic acid derivatives Meclofenamic acid Tolfenamic acid Selective COX-2 inhibitors (coxibs) Deracoxib
Firocoxib Mavacoxib Robenacoxib
Miscellaneous Flunixin
Nimesulide Tepoxalin
strong suppression of COX-2, none of them has a complete absence of COX-1 suppression.
With the discovery of the COX-2 enzyme and the development of COX-2 preferential NSAIDs, currently the most popular method for classifying NSAIDs is based on their COX-1 versus COX-2 sup-pression profile, using the whole-blood assay as a gold standard.
This profile is often expressed as a ratio (COX-1:COX-2) which is derived from the concentration of the NSAID necessary to inhibit 50% of the activity of the COX-1 enzyme (COX-1[IC50]) and the concentration necessary to inhibit 50% of the activity of the COX-2 enzyme (COX-2[IC50]). Therefore, the ratio can be written as COX-1 [IC50]/COX-2 [IC50], or simply COX-1/COX-2 (Papich, 2008).
The greater the ratio is above 1.0, the more specific the NSAID is for the COX-2 enzyme. Using ratios derived from individual drugs, NSAIDs can be classified as COX-1 selective for ratios<1, COX-2 preferential for ratios>1–100, COX-2 selective for ratios
>100–1000, and COX-2 specific for ratios >1000 (Fox, 2010) (Table 5.2). Published studies using different inhibition assays have given conflicting results, and it is now clear that differences in testing methods and species can result in different ratios for the same NSAID (Papich, 2008). In addition, using whole blood assay data from one species to predict suppression profiles in other species should be done cautiously. It is important to note that the COX-1/COX-2 profile of an NSAID does not predict its clinical efficacy, and one NSAID may be more effective than another in an individual patient.
72 Section 2 / Pharmacology of Analgesic Drugs Table 5.2. Nonsteroidal anti-inflammatory drugs
classified by canine COX-1/COX-2 ratios
Category NSAIDs (ratio)
COX-1 selective
(COX-1/COX-2 ratio of<1)
Aspirin (0.4) Ketoprofen (0.88) COX-2 preferential
(COX-1/COX2 ratio of<1 to 100)
Carprofen (16.8) Deracoxib (48.5) Etodolac (6.6) Nimesulide (29.2) Meloxicam (7.3) COX-2 selective
(COX-1/COX-2 ratio of>100 to 1000)
Firocoxib (155) Robenacoxib (128.8) COX-2 specific
(COX-1/COX-2 ratio of>1000)
None commercially available
Sources: Streppa, H.K., Jones, C.J., & Budsberg, S.C. (2002) Cyclooxygenase selectivity of nonsteroidal anti-inflammatory drugs in canine blood. American Journal of Veterinary Research, 63, 91–94.; Li, J., Lynch, M.P., Demello, K.L., et al. (2005) In vitro and in vivo profile of 2-(3-di-fluoromethyl-5-phenylpyrazol-1-yl)-5-methanesulfonylpyridine, a potent, selective, and orally active canine COX-2 inhibitor. Bioorganic & Medicinal Chemistry, 13, 1805–1809.; King, J.N., Rudaz, C., Borer, L., et al. (2010) In vitro and ex vivo inhibition of canine cyclooxygenase isoforms by robenacoxib: a comparative study. Research in Veterinary Science, 88(3), 497–506.
ADVERSE EFFECTS AND CONTRAINDICATIONS The adverse effects associated with the use of NSAIDs can be seri-ous. There is a narrow therapeutic index for most NSAIDs, and a thorough knowledge of organ systems affected and associated clinical signs of toxicity is necessary for safe usage. The gastroin-testinal, renal, and hepatic systems are most commonly associated with NSAID toxicity, but the coagulation, hematopoietic, and mus-culoskeletal systems can also be affected.
Effects on the Gastrointestinal Tract
In the gastrointestinal tract both COX-1 and COX-2 are necessary for proper function, maintenance, and repair of the mucosa. COX-1 related prostaglandins help regulate mucosal blood flow, secretion of buffers and mucous, and turnover of epithelial cells (Simmons et al., 2004). It was originally thought that COX-2 was not consti-tutively expressed and was only upregulated during inflammation;
however, it is now known that COX-2 plays a role in mucosal pro-tection and repair (Halter et al., 2001) and COX-1 may not be as important (Schmassmann et al., 2006). In a recent report of 27 clin-ically normal dogs not receiving NSAIDs, 22 had histopathological evidence of gastrointestinal inflammation or erosion even though none of the dogs had gross evidence of gastrointestinal disease, and when evaluated, COX-2 expression was increased compared to COX-1, indicating COX-2 is important for healing the mucosa (Wooten et al., 2010). Thus, it stands to reason that some dogs may have undetected gastrointestinal inflammation and that they
may be more prone to gastrointestinal adverse effects after COX-2 inhibition.
The gastrointestinal tract is by far the most common site of NSAID toxicity (DeNovo, 2003). Adverse gastrointestinal events reported in dogs, cats, and horses range from mild inflammation to catastrophic ulceration and death (Hough et al., 1999; Lascelles et al., 2005a; Lascelles et al., 2007). Because COX-2 is necessary for mucosal healing, the more specific a drug is for COX-2 the more likely it is to cause gastrointestinal ulceration and prevent healing of pre-existing lesions (Goodman et al., 2009). Gastrointestinal lesions caused by NSAIDs in dogs tend to be located in the pyloric antrum, and have a poor prognosis if not identified and treated early (Las-celles et al., 2005a). In horses, ulceration can occur anywhere along the gastrointestinal tract, including the colon; however, the right dorsal colon tends to be particularly sensitive to the toxic effects of NSAIDs (McConnico et al., 2008). Clinical signs of gastroin-testinal erosions and ulcers include anorexia, depression, lethargy, diarrhea, vomiting, hematochezia, melena, abdominal pain, ane-mia, hypoproteineane-mia, leukocytosis or leukopenia, and increased blood urea nitrogen.
Effects on the Renal System
Prostaglandins regulate renal blood flow and glomerular filtration, especially during periods of systemic hypotension. Both COX-1 and COX-2 enzymes are required to maintain adequate renal perfu-sion (Fox, 2010). Renal prostaglandins work in concert with cate-cholamines to autoregulate renal blood flow and maintain renal per-fusion when mean arterial pressure is between 60 and 150 mm Hg (Cohen et al., 1983). During conditions of hypovolemia, hypoten-sion, or physiological stress, prostaglandins are upregulated in the kidneys to maintain adequate renal blood flow. Nonsteroidal anti-inflammatory suppression of renal prostaglandin production can disrupt autoregulation and result in renal ischemia. Acute renal failure, acute exacerbation of chronic renal failure, and renal papil-lary necrosis can result. Cats may be uniquely sensitive to NSAID toxicity because they possess approximately one-half the number of nephrons at birth compared to most species. Clearly, proper fluid balance and hydration are critically important when using NSAIDs, and their use should be avoided in patients with known or suspected renal disease.
Effects on the Hepatic System
NSAIDs have been implicated in hepatocellular damage and hep-atic failure in several species. Acetaminophen toxicity is one of the leading causes of acute liver failure in humans (Bernal et al., 2010).
NSAIDs are metabolized in the liver and excessive dosing can lead to hepatotoxicity. Hepatocellular toxicosis and death were reported in a dog after three different NSAIDs were administered over a 14-day period (Nakagawa et al., 2005). Idiosyncratic hepatocellu-lar toxicosis with NSAIDs can also occur, as reported in a study in dogs treated with carprofen. Interestingly, Labrador Retrievers were overrepresented in that study (MacPhail et al., 1998). Liver disease from NSAIDs is not limited to small animal patients, and excessive dosing of phenylbutazone can produce hepatotoxicity in horses (Lees et al., 1983). Liver enzyme activity should be eval-uated periodically in patients prescribed NSAIDs on a long-term basis, and a three- to fivefold increase in activity above baseline could indicate hepatotoxicity, especially if values return to normal after treatment is discontinued.
5 / Nonsteroidal Anti-Inflammatory Drugs and Corticosteroids 73 Effects on Platelet Function
Thromboxane is necessary for proper platelet function and is pro-duced via the 1 enzyme. NSAIDs that strongly suppress COX-1 could have significant effects on platelets and clot formation. It is well known that aspirin can inhibit platelet aggregation and it is used therapeutically for that purpose (Smith et al., 2003; Brainard et al., 2007; Lamont & Mathews, 2007). In normal dogs, meloxi-cam had minimal effects on platelet function, whereas carprofen decreased clot strength and platelet aggregation (Brainard et al., 2007). It is not clear if the effect of carprofen on platelets is clin-ically significant. However, ketoprofen has been shown clinclin-ically to affect hemostasis, and should be avoided in cases where surgical bleeding may be difficult to control, such as in laparoscopic proce-dures (Lamont & Mathews, 2007). The coxib-type NSAIDs do not affect platelet function (Brainard et al., 2007).
Effects on Bone Healing
Bone healing after fracture or surgical osteotomy is a complex process that is affected by numerous variables including fracture gap, comminution, disturbance of blood flow, degree of soft tissue damage, mechanical stability, nutrition, and age (Pountos et al., 2012). Several drug classes slow or inhibit bone healing including corticosteroids, chemotherapeutics, and some antibiotics (Pountos et al., 2008; Pountos et al., 2011). Debate continues as to the effect of NSAIDs on bone healing, with several published studies supporting both sides of the argument. Prostaglandins play an important role in bone healing, directly induce osteogenesis, and help increase cortical and trabecular mass (Pountos et al., 2012). Physiologically, it makes sense to use NSAIDs judiciously in patients recovering from bone injury. However, the analgesic and anti-inflammatory properties of NSAIDs make them particularly useful in this set of patients. The use of NSAIDs for the treatment of bone pain has been demonstrated to be as effective as opioids, and some human studies have shown a greater reduction in pain scores (Camu et al., 2002; Monaon, 2010; Pountos et al., 2012). Currently, in human medicine, evidence suggests COX-2 inhibition may affect early fracture healing, but the evidence is not considered conclusive and therefore short term NSAID use is considered a safe and effective supplement for pain management (Kurmis et al., 2012). Studies in veterinary medicine regarding the use of NSAIDs and bone healing are sparse. One study demonstrated that long-term administration (120 days) of carprofen appeared to inhibit bone healing in dogs after tibial osteotomy (Ochi et al., 2011). Overall, the short-term use of NSAIDs after bone injury probably has minimal long-term effects on bone healing and should be considered in an analgesic plan in such patients.
CLINICAL USE OF NSAIDs
NSAIDs are one of the most commonly used classes of analgesics in veterinary medicine and are principally used to reduce effects of the primary disease, such as acute and chronic pain, inflammation, fever, endotoxemia, and hypercoagulability, but are also used to treat some neoplastic processes (Lascelles et al., 2005b). When NSAIDs are combined with other classes of drugs, such as opioids, there is a synergistic effect because each mediates anti-nociception via a different mechanism (Hellyer et al., 2007). Co-administration of NSAIDs with opioids enhances analgesia and reduces the dose of opioid required (Salerno & Hermann, 2006).
Care should be taken with patient selection when prescribing NSAIDs. In general, this class of drugs should be reserved for patients without renal, gastrointestinal, or hepatic dysfunction. In equine and bovine patients, however, NSAIDs may be used in conjunction with other treatments to relieve pain associated with gastrointestinal distress. NSAIDs should be avoided in immature animals in which organ maturation is not complete. General guide-lines suggest that NSAIDs should be avoided in patients less than six weeks of age (Lamont & Mathews, 2007); however, many NSAIDs have not been evaluated in animals less than 1 year of age.
When prescribing NSAIDs, owner education regarding the signs of toxicity, such as vomiting, depression, or diarrhea, is critical. Fol-lowup physical examination and blood evaluation should continue on a regular basis, especially if treatment is prolonged.
Peri-operative use of NSAIDs requires careful consideration of not only the patient’s preoperative physical status and history but also the nature and length of the general anesthetic event. Most anesthetic agents can affect cardiac output, blood pressure, and tis-sue perfusion. Consequently, the adverse effects of NSAIDs may be magnified in patients administered NSAIDs prior to anesthe-sia. Post-surgical administration of NSAIDs rather than preoper-ative administration may be more appropriate; that way, NSAIDs can be withheld from patients who experience hypotension, hypo-volemia, or other adverse events that may exacerbate NSAID-induced adverse effects. If NSAIDs are used preoperatively, blood pressure monitoring and support is essential.
SELECTED NSAIDs
The following sections are general descriptions of the use of selected NSAIDs in dogs, cats, horses, and cattle. Detailed pharma-cokinetic and pharmacodynamic data for many of the NSAIDs is available for several species and can be found in subsequent chap-ters. Several excellent reviews of NSAID use in dogs (Lascelles et al., 2005b; Papich, 2008; Sanderson et al., 2009), cats (Lascelles et al., 2007; Papich, 2008), horses (Goodrich & Nixon, 2006), and cattle (Smith et al., 2008) are available.
Acetaminophen (Paracetamol)
Although classified as an NSAID, acetaminophen may not impart its clinical effect through COX-1 or COX-2 inhibition. There is evidence that acetaminophen inhibits the COX-1 variant known as COX-3 (Chandrasekharan et al., 2002). It has been demonstrated that acetaminophen has minimal to no anti-inflammatory action because of its poor ability to inhibit COX in the presence of inflam-matory mediators and byproducts of inflammation (Burk et al., 2006). One report demonstrated anti-inflammatory effects in dogs after orthopedic surgery, but the dose of acetaminophen used was higher than recommended (Mburu et al., 1988). Acetaminophen also has a disproportionate effect on COX in the brain, which may explain its strong anti-pyretic effects (Boutaud et al., 2002).
Because acetaminophen has minimal effects on the gastrointesti-nal and regastrointesti-nal systems when compared with classic NSAIDs, there are some who believe that acetaminophen works through non-COX pathways to provide analgesia (Papich, 2008). Acetaminophen has been used in dogs for analgesia and can be found in commer-cially available combinations with opioids, such as codeine, oxy-codone, and hydrocodone. There is limited bioavailability of orally administered opioids in dogs, but there are anecdotal reports of
74 Section 2 / Pharmacology of Analgesic Drugs efficacy of these combinations in some animals. Acetaminophen
also has other uses. In dogs with certain ventricular arrhyth-mias, acetaminophen reduced the number of ectopic beats that developed during ischemia and reperfusion (Merrill et al., 2007).
Acetaminophen has demonstrated anti-oxidant effects on low-density lipoproteins, also resulting in cardioprotection (Merrill &
Goldberg, 2001; Chou & Greenspan, 2002).
There is the potential for serious adverse effects with the use of acetaminophen in veterinary patients. Acetaminophen is not approved for use in animals, and under no circumstances should acetaminophen be administered to a cat, domestic, exotic, or wild.
A single 325 mg over-the-counter tablet may be lethal to the average domestic cat. Due to deficiencies in hepatic glucuronidation cats cannot metabolize acetaminophen in the liver with glucuronic acid.
N-acetyl-p-benzoquinone forms and binds covalently to cellular molecules, ultimately resulting in hepatic necrosis. Other adverse effects that can occur in cats and dogs include methemoglobine-mia and Heinz-body formation (McConkey et al., 2009). There is a case report of a dog that developed methemoglobinemia and Heinz-body hemolytic anemia after ingesting a toxic amount of acetaminophen. That dog was successfully treated with S-adenosyl-L-methionine and supportive care; thus, S-adenosyl-S-adenosyl-L-methionine may be an appropriate antidote for animals with acetaminophen toxicity (Wallace, 2002). There are minimal reports of the use of acetaminophen in horses, and its use in cattle is prohibited in the United States.
Aspirin
Aspirin is mainly a COX-1 inhibitor, and it irreversibly inactivates COX enzymes via acetylation (Dowling, 2010). This is distinct from other NSAIDs, and the duration of aspirin’s effect is related to the turnover rate of the COX enzymes (Burk et al., 2006). Conversely, other NSAIDs work via competition with AA for binding sites, and their duration of action is related to drug concentration and dispo-sition. Aspirin can be used as an analgesic for osteoarthritis in dogs (Lamont & Mathews, 2007), although it should be used cautiously as therapeutic concentrations are very close to toxic concentrations (Morton & Knottenbelt, 1989). Aspirin is associated with chon-drodestruction, irreversible platelet dysfunction, and gastrointesti-nal bleeding and ulceration (Fox, 2010). Aspirin is also unique in that it induces the production of aspirin-triggered lipoxin (ATL) by the COX-2 enzyme in humans, and possibly in dogs (Papich, 2008).
During chronic use of aspirin, ATL has a protective role in reduc-ing inflammation and enhancreduc-ing healreduc-ing in the gastrointestinal tract (Papich, 2008). Production of ATL is thought to decrease the poten-tial for further injury to the gastrointestinal tract with long-term use of aspirin (Souza et al., 2003). The addition of a stronger COX-2 inhibiting drug can result in loss of this adaptation and catastrophic ulceration. In cats, aspirin frequently causes gastric ulceration, does not predictably reduce thrombosis at therapeutic doses, and has not been evaluated for efficacy or safety for treatment of pain, fever, or inflammation (Lascelles et al., 2007). Aspirin has been used specif-ically for its effects on platelets in horses, and of all of the avail-able NSAIDs, aspirin is the most effective for antiplatelet therapy (Cambridge et al., 1991). Suppression of COX-1 via aspirin also inhibits thromboxane A2production, which is necessary for platelet aggregation. In the equine, platelet thromboxane A2plays a minor role in aggregation of platelets, but aspirin still effectively abolishes aggregation (Heath et al., 1994). The antiplatelet effects of aspirin
have been used for the treatment of laminitis, disseminated intravas-cular coagulation, venous thrombosis, and equine verminous arteri-tis (Dowling, 2010). In cattle, aspirin has been used as an antipyretic and for inflammation associated with lower respiratory tract infec-tions (Smith et al., 2008; Woolums et al., 2009). Aspirin has also been shown to reduce plasma cortisol concentrations in calves fol-lowing castration (Coetzee et al., 2007). It is important to note that aspirin in not labeled for use in any animal in the United States, and its use in cattle is not recommended by the food animal residue avoidance and depletion (FARAD) program.
Carprofen
The use of carprofen in dogs was first reported in the early 1990s (Schmitt & Guentert, 1990; Nolan & Reid, 1993; Lascelles et al., 1994), and it is presently one of the most commonly used NSAIDs in dogs. Carprofen is the only NSAID licensed in the United States for dogs as both an oral and an injectable formulation, making it prac-tical for perioperative use. In a review paper systemaprac-tically eval-uating study design, quality, criteria, consistency, relevance, and strength of evidence relating to management of canine osteoarthri-tis, the use of carprofen resulted in significant improvement and was supported by moderate evidence that the results could be extrapo-lated to the target population of dogs with osteoarthritis (Sanderson et al., 2009). Carprofen is considered more potent than aspirin or phenylbutazone for treatment of pain and inflammation, and may be safer than older NSAIDs (Fox & Johnston, 1997). The antithrom-boxane activity of carprofen appears to be minimal, suggesting that induced coagulopathy is less likely in patients with normal coagulation (Lamont & Mathews, 2007).
Shortly after carprofen was introduced there were several anec-dotal reports of hepatic failure in dogs. Subsequently, a scientific report was published citing hepatocellular toxicosis in 21 dogs, 13 of which were Labrador Retrievers (MacPhail et al., 1998). It is believed that carprofen-associated hepatic toxicosis is idiosyn-cratic, and, when identified early, usually resolves after discontinu-ation of carprofen and administrdiscontinu-ation of supportive care (MacPhail et al., 1998). It is recommended that dogs be prescreened for liver dysfunction prior to administration of carprofen, that owners be counseled as to clinical signs of toxicosis, and that carprofen be discontinued immediately if such signs are observed.
The use of carprofen in cats has been studied and pharmacoki-netic data are available (Lascelles et al., 2007). Carprofen is labeled for single injection in cats in many European countries, Australia, and New Zealand. Carprofen is effective in cats for soft tissue and orthopedic pain (Al-Gizawiy & Rude, 2004; Mollenhoff et al., 2005). In healthy cats, a single dose of carprofen does not appear to cause gastrointestinal or renal lesions; however, toxicity is more likely with prolonged administration or in cats with concurrent systemic disease (Lascelles et al., 2007).
The use of carprofen in horses has been documented and it is licensed for use in horses in Europe. Pharmacokinetic and pharma-codynamic data for carprofen in horses are available (Lees et al., 1994). Carprofen is effective for treating visceral pain in horses (Schatzmann et al., 1992), and the duration of action is about 12 hours (Johnson et al., 1993). Carprofen may be most benefi-cial in the treatment of osteoarthritis (Clark-Price, 2009). When applied to chondrocytes, carprofen decreases production of inflam-matory mediators, increases proteoglycan synthesis, and decreases glycosaminoglycan loss from cartilage (Armstrong & Lees, 1999;
5 / Nonsteroidal Anti-Inflammatory Drugs and Corticosteroids 75 Frean et al., 1999). In some European countries, carprofen is
licensed for use in cattle for control of fever. In the United States, however, it would be difficult to justify its use over flunixin meg-lumine and, therefore, would most likely not be legal (Smith et al., 2008).
Deracoxib
Deracoxib was one of the first coxib-type drugs approved for vet-erinary use in the United States, and is approved as an oral formu-lation for control of postoperative and osteoarthritis pain in dogs.
Deracoxib is effective in decreasing lameness and pain associated with synovitis, and pre-emptive administration decreased lameness scores in experimentally induced lameness in dogs (Millis et al., 2002). When first discovered, the coxib class of drugs was thought to have a decreased incidence of gastrointestinal adverse effects due to their relative COX-1 sparing effects. However, deracoxib has been associated with gastrointestinal perforation (Case et al., 2010), and it is recommended that deracoxib should only be used at approved dosages and never co-administered with corticosteroids or other NSAIDs (Lascelles et al., 2005a). The pharmacokinetics, but not clinical use, of deracoxib has been described in cats (Gassel et al., 2006).
Diclofenac
There are few publications describing the clinical use of diclofenac in dogs and cats, and with the approval of newer NSAIDs in these species, diclofenac is not commonly used. In the United States, diclofenac is approved for use in horses as a topically applied 1%
liposomal cream. This formulation was developed for topical appli-cation to a localized area of inflammation, reducing frequency and severity of toxicity (Lynn et al., 2004); however, there is evidence of systemic absorption of the drug and the potential for systemic toxicity exists (Anderson et al., 2005). Diclofenac cream is effi-cacious for the treatment of osteoarthritis in horses (Frisbie et al., 2009), and may also be effective when applied over areas of soft tissue inflammation (Caldwell et al., 2004). It has also been used to decrease inflammation over catheter insertion sites (Levine et al., 2009). No formulation of diclofenac is approved for use in cattle in the United States.
Dipyrone
Dipyrone is thought to have a mechanism of action similar to acetaminophen. It is not approved for use in the United States;
however, it is available by prescription in several European coun-tries including Germany, Hungary, Italy, Portugal, and Spain. It is available as an over-the-counter preparation in Brazil, Bulgaria, Egypt, India, Israel, Mexico, Poland, Russia, and Turkey. Dipyrone is best used as an antipyretic, and is used in bacteremic neona-tal foals. Dipyrone has been shown to induce blood dyscrasias in human patients, and should not be used in any animal that may enter the human food chain (Garbe, 2007).
Etodolac
Etodolac is labeled for use in dogs in the United States, and is effective for treatment of orthopedic conditions (Budsberg et al., 1999). Adverse effects of the drug appear to occur primarily in the gastrointestinal tract (Lamont & Mathews, 2007). Publications of use of etodolac in other veterinary species are sparse.
Firocoxib
Firocoxib is the only coxib-type NSAID approved for use in horses in the United States. It is available in tablet form for dogs and as an oral paste and intravenous injectable formulation for horses.
Firocoxib is the most COX-1 sparing NSAID available in the United States for dogs. It is approved for osteoarthritis in dogs, and is effective in decreasing urate-induced synovitis, pain, inflammation, and lameness (Drag et al., 2007). In horses, the pharmacokinetics after single (Kvaternick et al., 2007) and multiple (Letendre et al., 2008) oral dosing have been described, and firocoxib is comparable in efficacy to phenylbutazone for treatment of osteoarthritis (Doucet et al., 2008). For horses with small intestinal colic, firocoxib may be preferred over flunixin meglumine, as it inhibits recovery of ischemia-injured mucosa to a lesser degree (Cook et al., 2009).
Flunixin Meglumine
Flunixin is considered moderately effective for the control of both soft tissue and orthopedic pain (Mathews et al., 1996), and decreases intraocular inflammation after ophthalmic surgery (Krohne &
Vestre, 1987) in dogs. The systemic use of flunixin in dogs results in severe adverse effects including gastric ulceration, perforation, and peritonitis, increased plasma alanine aminotransferase activ-ity and creatinine, and renal failure (Elwood et al., 1992; McNeil, 1992; Vonderhaar & Salisbury, 1993; Mathews et al., 1996). Flu-nixin meglumine has been used in cats and pharmacokinetic data are available (Lascelles et al., 2007); however, with the availability of safer NSAIDs approved for use in cats its use cannot be rec-ommended. Flunixin is one of the more commonly used NSAIDs in horses (Hubbell et al., 2010), and can be administered orally, intravenously, or intramuscularly. Cases of myonecrosis have been reported with intramuscular use (Peek et al., 2003). Flunixin is effi-cacious for the treatment of osteoarthritic conditions (Goodrich &
Nixon, 2006), and is comparable to phenylbutazone for the treat-ment of navicular syndrome (Erkert et al., 2005). When flunixin and phenylbutazone are combined, they are more effective in treat-ing lameness than either NSAID administered alone (Keegan et al., 2008). Extreme caution should be used with concurrent administra-tion as gastrointestinal ulceraadministra-tion and hypoproteinemia can result (Reed et al., 2006). Flunixin is mainly used for pain associated with gastrointestinal disease in the horse. In acute equine colic, flunixin provides less satisfactory analgesia than that obtained with the ␣-2 agonist detomidine (Jochle et al., 1989). Flunixin is currently the most commonly used NSAID in horses undergoing exploratory laparotomy for abdominal pain. There are conflicting reports of its effects on the intestinal mucosa after ischemic injury. One report demonstrated delayed recovery of the jejunal mucosa after ischemia and flunixin administration (Cook et al., 2009), whereas another study was not able to document an effect of flunixin on the recov-ery of colonic mucosa after ischemia (Matyjaszek et al., 2009).
Concurrent administration of lidocaine ameliorated any inhibitory effects of flunixin meglumine on recovery of mucosa from ischemic injury, which may warrant the use of lidocaine as an adjunctive treatment to flunixin in horses with intestinal injury (Cook et al., 2008). Flunixin is also used in endotoxemic horses to decrease eicosanoid production. Administration of small doses of flunixin suppresses thromboxane B2and 6-keto-prostaglandin F1␣ produc-tion associated with endotoxin administraproduc-tion, without masking the physical signs of endotoxemia that aid clinical evaluation of patient status (Semrad et al., 1987). In the United States, flunixin