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The importance of pain management and the use of NSAID in animals has recently increased. NSAID have the potential to relieve pain and inflammation without the immunosuppressive and metabolic side effects associated with corticosteroids. However, all NSAID have the potential for other adverse effects that should be considered in the overall management of the inflammatory process.
Mode of Action
Generally, the classification NSAID is applied to drugs that inhibit one or more steps in the metabolism of arachidonic acid (AA). Unlike corticosteroids, which inhibit numerous pathways, NSAID act primarily to reduce the biosynthesis of prostaglandins (PG) by inhibiting cyclooxygenase (COX). In general, NSAID do not inhibit lipoxygenase (and hence leukotriene) formation, or the formation of other inflammatory mediators, although tepoxalin, a recently introduced dual NSAID, does inhibit lipoxygenase.
The discovery of the 2 isoforms of COX (COX-1 and COX-2) has advanced understanding of the mechanism of action and potential adverse effects of NSAID. COX-1, expressed in virtually all tissues of the body (eg, gut and kidney), catalyzes the formation of constitutive PG, which mediate a variety of normal physiologic effects including hemostasis, GI mucosal protection, and protection of the kidney from hypotensive insult. In contrast, COX-2 is activated in damaged and inflamed tissues and catalyzes the formation of inducible PG, including PGE2, associated with intensifying the inflammatory response. COX-2 is also involved in thermoregulation and the pain response to injury. Therefore, COX-2 inhibition by NSAID is thought to be responsible for the antipyretic, analgesic, and anti-inflammatory actions of NSAID. However, concurrent inhibition of COX-1 may result in many of the unwanted effects of NSAID including gastric ulceration and renal toxicity. Because NSAID vary in their ability to inhibit each COX isoform, a drug that inhibits COX-2 at a lower concentration than that necessary to inhibit COX-1 would be considered safer. This concept has propelled the development of the “COX-2 selective” NSAID. Although ratios of COX-1:COX-2 inhibition by various NSAID in humans and animals have been reported, caution is advised when interpreting such ratios, as they vary greatly depending on the selectivity assay used. The COX selectivity of NSAID also varies by species; COX selectivity ratios reported for humans cannot be directly extrapolated to other species.
In general, drugs with ratios suggesting preferential activity against COX-2 may have fewer adverse effects due to COX-1 inhibition. In dogs, favorable ratios have been reported for carprofen, meloxicam, deracoxib, and firocoxib, while unfavorable ratios have been reported for aspirin, phenylbutazone, and vedaprofen. COX-1-sparing drugs are associated with less GI ulceration and less platelet inhibition; however, it may be an oversimplification to assume that complete COX-2 inhibition is without potential risk. Recent research has suggested that COX-2 can be induced constitutively in various organs including the brain, spinal cord, ovary, and kidney. In dogs, COX-2 mRNA is present in the loop of Henle and the maculae densa and may play an important role in the protective response to hypotension. However, a recent study failed to demonstrate COX-2 expression in canine kidneys, raising questions regarding its role. COX-2 also appears to be important in the healing of GI ulcers in humans, and certain COX-2-specific inhibitors delay ulcer healing experimentally. Although COX-1 plays a primary role in regulating homeostasis, it may play a more significant role in inflammation than originally proposed.
NSAID also vary in their mechanism of COX inhibition. Aspirin irreversibly acetylates a serine residue of COX, resulting in a complete loss of COX activity. Thus, the duration of the aspirin effect depends on the turnover rate of COX; activity is lost for the life of the platelet (7–10 days) following aspirin administration, explaining the duration of aspirin's effect on hemostasis. Unlike aspirin, most other NSAID (including salicylic acid, an active metabolite of aspirin), are reversible competitive COX inhibitors; their duration of inhibition is primarily determined by the elimination pharmacokinetics of the drug.
Pharmacologic Effects
All NSAID, except for acetaminophen (also named paracetamol), are antipyretic, analgesic, and anti-inflammatory. They are routinely used for the relief of pain and inflammation associated with osteoarthritis in dogs and horses and for colic, navicular disease, and laminitis in horses. The use of NSAID for the relief of perioperative pain in companion animals is increasing. In general, NSAID provide only symptomatic relief from pain and inflammation and do not significantly alter the course of pathologic damage. As analgesics, they are generally less effective than opioids and are therefore generally only indicated against mild to moderate pain.
As antipyretics, NSAID reduce body temperature in febrile states. Although the beneficial effects of the febrile response usually outweigh the negative effects, NSAID inhibition of PGE2 activity in the hypothalamus may provide symptomatic relief and improve appetite. In Europe, NSAID have been used in conjunction with antibiotics for treatment of acute respiratory diseases in cattle. They may reduce morbidity through their antipyretic and anti-inflammatory effects and prevent development of irreversible lung lesions.
The effects of some NSAID on chondrocyte metabolism have been investigated. Some, including aspirin, naproxen, and ibuprofen, are considered chondrotoxic because they inhibit the synthesis of cartilage proteoglycans. Others, including carprofen and meloxicam, may be considered chondroneutral, or depending on dose, actually stimulate the production of cartilage matrix. The potential beneficial or deleterious effects of NSAID on chondrocyte metabolism remain to be clarified.
A therapeutic area in which NSAID use may become important is in the treatment and prevention of cancer. Epidemiologic studies in humans show that aspirin use is associated with a significant reduction in the incidence of colon cancer. Newer evidence suggests that the therapeutic effect of NSAID on colon cancer is mediated by inhibition of COX-2, which may be upregulated in many premalignant and malignant neoplasms. In veterinary medicine, piroxicam has been shown to reduce the size of tumors such as transitional cell carcinoma in dogs. Specific COX-2 inhibitors may prove useful as a primary or adjunctive therapy in the management of cancer.
Administration and Pharmacokinetics
Most NSAID are weak organic acids that are well absorbed following PO administration. However, food can impair the oral absorption of some NSAID (eg, phenylbutazone, meclofenamate, flunixin meglumine) in horses and ruminants. Several NSAID are available as parenteral formulations for IV, IM, or SC administration. Some parenteral formulations are highly alkaline and may cause tissue necrosis if injected perivascularly. Once absorbed, most NSAID are extensively (up to 99%) bound to plasma proteins, with only a small proportion of unbound drug available to be active in the tissues. NSAID may also compete for binding sites with other highly protein-bound compounds, leading to some drug displacement; however, this displacement has no therapeutic consequences because it does not affect the concentration of the free drug.
Most NSAID are biotransformed in the liver to inactive metabolites that are excreted either by the kidney via glomerular filtration and tubular secretion or by the bile. Biotransformation and elimination half-lives vary significantly by species (and in some cases by breed or strain, as is the case for some COX-2 inhibitors in Beagles), so it is not possible to safely extrapolate dosages from one species or animal to another. Some NSAID, including naproxen, etodolac, and meclofenamic acid, undergo extensive enterohepatic recirculation in some species, resulting in prolonged elimination half-lives.
Adverse Effects
All NSAID have the potential to induce adverse reactions, some of which can be life threatening. Many reactions to NSAID are dose-related and are typically reversible with discontinuation of therapy and supportive care.
Vomiting is the most common adverse effect. GI ulceration is the most common life-threatening adverse effect. Loss of GI protective mechanisms results from inhibition of constitutive PG that regulate blood flow to the gastric mucosa and stimulate bicarbonate and mucus production. This disrupts the alkaline protective barrier of the gut, allowing diffusion of gastric acid back into the mucosa, injuring cells and blood vessels and causing gastritis and ulceration. As organic acids, NSAID, especially aspirin, may also cause direct chemical irritation of the GI mucosa. The enterohepatic recirculation of certain NSAID may result in high biliary concentrations that increase ulcerogenic potential in the gut. NSAID-induced GI bleeding may be occult, leading to iron-deficiency anemia, or more severe, resulting in vomiting, hematemesis, and hematochezia. Horses may develop oral, lingual, or colonic ulceration with accompanying signs of colic, weight loss, or loose manure.
GI blood loss may be further complicated by impaired platelet function. Platelet function is inhibited because NSAID prevent platelets from forming TXA2, a potent aggregating agent. Because TXA2 inhibition causes prolonged bleeding, evaluation of buccal mucosal bleeding time is advised in animals for which surgery is anticipated. Blood dyscrasias after longterm NSAID therapy have been reported in cats, dogs, and horses. Acetaminophen (paracetamol) administration in cats is associated with Heinz body anemia, methemoglobinemia, hepatic failure, and death. Bone marrow dyscrasias associated with phenylbutazone administration have also been reported.
Nephropathies associated with chronic NSAID use are common in humans. Animals with underlying renal compromise receiving NSAID could experience exacerbation or decompensation of their disease. It is important to maintain hydration and renal perfusion in animals receiving NSAID, especially those undergoing anesthesia or surgery and in horses with colic.
Hepatopathies are relatively common in both humans and animals receiving NSAID. NSAID administration routinely induces mild hepatic changes characterized primarily by elevation in liver enzymes without clinical signs or hepatic dysfunction. Rare reports of idiosyncratic reactions resulting in hepatic dysfunction or failure have been reported in humans (acetaminophen and others), dogs (acetaminophen, carprofen, etodolac), and horses (phenylbutazone). Cytopathic (hepatocellular injury, necrosis), cholestatic, and mixed histopathologic patterns of injury have been documented. NSAID should be used with caution in animals with pre-existing hepatic disease.
Specific Nonsteroidal Anti-inflammatory Drugs
Based on structure, most NSAID can be divided into 2 broad groups—carboxylic acid and enolic acid derivatives. The main subgroups of enolic acids are the pyrazolones (phenylbutazone) and the oxicams (meloxicam, piroxicam). Carboxylic acid subgroups include the salicylates (aspirin), propionic acids (ibuprofen, naproxen, carprofen, ketoprofen, and vedaprofen), anthranilic acids (tolfenamic and meclofenamic acids), phenylacetic acids (acetaminophen), and aminonicotinic acids (flunixin). The newer coxib class of selective COX-2 inhibitors includes a diaryl-substituted furanone (rofecoxib), a diaryl-substituted pyrazole (celecoxib), and a diaryl-substituted isoxazole (valdecoxib), all available for human use. Three NSAID of the coxib class, deracoxib, firocoxib, and robenacoxib, have been introduced in veterinary medicine.
Aspirin
By far the most widely used anti-inflammatory drug in humans, aspirin is primarily used in veterinary medicine for relief of mild to moderate pain associated with musculoskeletal inflammation or osteoarthritis. The salicylic ester of acetic acid, aspirin (acetylsalicylic acid) is available in several different dosage forms including bolus (for cattle), oral paste (for horses), oral solution (for poultry), and tablets (for dogs). Enteric-coated products used in human medicine are not recommended in dogs because gastric retention may lead to erratic plasma exposure. Following PO administration, aspirin is rapidly absorbed from the stomach and upper small intestine. Aspirin is subjected to a large first-pass effect in the liver to yield salicylic acid, its main active metabolite. In addition, the aspirin fraction that gains access to the systemic circulation is also rapidly hydrolyzed to salicylic acid with a half-life of ~15 min. After oral aspirin administration, saliylic acid is considered the main active substance in the systemic circulation. Aspirin primarily inhibits COX-1, while salicylic acid has more balanced COX-1/COX-2 activity. In addition, aspirin may irreversibly bind to COX-1 through acetyl-ation of a serine residue near the enzyme active site. Due to this irreversible binding, the anticoagulant activity of aspirin lasts far longer than its anti-inflammatory effect; a single aspirin dose of 20 mg/kg in a horse may prolong bleeding for 48 hr. Depending on its route of administration, aspirin may have different pharmacologic effects. For irreversible platelet COX-1 inhibition (to treat a thromboembolic condition), aspirin given IV is more efficient than aspirin given PO because, for the same dose, aspirin exposure is greater for the IV route of administration.
After absorption, both aspirin and salicylate are widely distributed through most tissues and fluids and readily cross the placental barrier. About 80–90% of salicylate is bound to plasma proteins. Metabolism and elimination is via hepatic conjugation with glucoronic acid, followed by renal excretion. Cats, which lack glucuronyl transferase, slowly metabolize salicylate. In addition, salicylate metabolism is saturable and, if overexposure due to an aspirin overdose occurs, plasma salicylate elimination may follow a zero order and slower elimination kinetics. The elimination half-life of salicylic acid in cats approaches 40 hr, compared with 7.5 hr in dogs.
Because aspirin is not approved for veterinary use, definitive efficacy studies have not been performed to establish effective dosages. Recommended dosages in dogs are 10–40 mg/kg, PO, bid-tid. Aspirin has been used for its anticlotting effect in the treatment of laminitis in horses at a dosage of 10 mg/kg, PO, sid. In cats, aspirin may be used for its anti-platelet effects in thromboembolic disease at a dosage of 10 mg/kg, PO, every 48 hr, to allow for prolonged metabolism. Adverse effects are common following aspirin administration and appear to be dosage dependent. Even at therapeutic dosages of 25 mg/kg, plain aspirin may induce mucosal erosion and ulceration in dogs. Vomiting and melena may be seen at higher doses. The PGE1 analog misoprostol may be effective in decreasing GI ulceration associated with aspirin and other NSAID. Aspirin overdose in any species can result in salicylate poisoning, characterized by severe acid-base abnormalities, hemorrhage, seizures, coma, and death.
Acetaminophen
Acetaminophen (paracetamol) is a para-aminophenol derivative with antipyretic and analgesic activity, but minimal anti-inflammatory effects. Acetaminophen does not inhibit neutrophil activation, has little ulcerogenic potential, and has no effect on platelets or bleeding time. The pharmacologic effect of acetaminophen may vary from that of other NSAID because acetaminophen is more effective in inhibiting COX in the brain rather than in the periphery. It has been suggested that acetaminophen may act by inhibiting COX-3, a splice variant of COX-1, but this hypothesis has been challenged. The recommended dosage of acetaminophen in dogs is 10–15 mg/kg, PO, tid. Dose-dependent adverse effects include depression, vomiting, and methemoglobinemia. Use in cats is contraindicated due to a lack of glucuronosyl transferase and the potential for hemolytic anemia and centrilobular hepatic necrosis.
Phenylbutazone
One of the earliest NSAID approved for use in horses and dogs, phenylbutazone is a pyrazolone derivative available in tablet, paste, gel, and parenteral formulations. The plasma half-life of phenylbutazone is 5–6 hr in horses and dogs and >30 hr in cattle. When given PO, phenylbutazone absorbs to hay in the diet, which may reduce GI absorption and bioavailability. Once absorbed, binding to plasma proteins is high (99% in horses, 93% in cattle). Phenylbutazone is metabolized by the liver to several active (oxyphenbutazone) and inactive metabolites, which are excreted in urine. One of the major therapeutic uses of the drug is the treatment of acute laminitis in horses. Laminitis is treated initially with injectable phenylbutazone at dosages up to 8.8 mg/kg, followed by therapy PO at 2.2–4.4 mg/kg, bid. Because the therapeutic index for phenylbutazone is relatively narrow, the dosage should be adjusted to the minimum possible to maintain comfort and avoid toxicity. GI effects (eg, anorexia) and depression are the most frequent adverse effects associated with phenylbutazone. Ulcers may occur in the mouth, stomach, cecum, and the right dorsal colon. The ulcerogenic potential of phenylbutazone in horses is greater than that of flunixin meglumine and ketoprofen. Phenylbutazone dosages of 3–7 mg/kg, PO, tid, are recommended in dogs. In dogs, phenylbutazone has been associated with bleeding dyscrasias, hepatopathies, nephropathies, and rare cases of irreversible bone marrow suppression.
Meclofenamic Acid
This anthranilic NSAID is available for horses as a granular preparation and for dogs as an oral tablet. The recommended dosage is 2.2 mg/kg, sid for 5–7 days in horses and 1.1 mg/kg, sid, for 5–7 days in dogs. In cattle, administration of meclofenamic acid results in a biphasic pattern of absorption, with an initial peak plasma concentration reached at ~30 min and a secondary peak 4 hr after dosing. In horses, meclofenamic acid is rapidly absorbed, but feeding prior to dosing may delay absorption. The onset of action is slow, requiring 2–4 days of dosing for a clinical effect. While it is effective in the treatment of chronic laminitis, meclofenamic acid has a therapeutic index that may be lower than that of other NSAID.
Flunixin Meglumine
In the USA, the nicotinic acid derivative flunixin meglumine is approved for use in horses as PO and parenteral formulations. The recommended dosage is 1.1 mg/kg, IV or PO, sid for 5 days. Flunixin meglumine is rapidly absorbed following PO or IM administration, and the elimination half-life is short (~2–3 hr). Elimination is primarily by renal excretion. Flunixin meglumine is effective for the treatment of visceral pain associated with equine colic and may have anti-endotoxic activity. The dosage recommended in horses is 1.1 mg/kg, bid, or 0.25 mg/kg, tid. Toxicity in horses is relatively uncommon, but GI ulceration and erosion may develop. Flunixin has been used to treat mastitis and acute pulmonary emphysema in cattle although it is not approved for these indications. Chronic administration of flunixin meglumine to dogs may result in severe GI ulceration and renal damage. Flunixin is not marketed in the USA for dogs, but it is approved in Europe and other countries.
Carprofen
This NSAID of the arylpropionic acid class is available in the USA in caplet and chewable tablet formulations. An injectable formulation is also available in the USA and Europe. Carprofen is approved by the FDA to manage pain and inflammation associated with osteoarthritis and acute pain associated with soft-tissue and orthopedic surgery in dogs. The recommended dosage is 4.4 mg/kg, PO, sid or divided bid. In Europe and other countries, carprofen is also registered for use in cattle and for short-term therapy in cats. In dogs, oral bioavailability is high (90%) and plasma concentrations peak ~2–3 hr after dosing. The elimination half-life is ~8 hr. As with other NSAID, carprofen is highly (99%) protein bound. Elimination is via hepatic biotransformation with excretion of the resulting metabolites in feces and urine. Some enterohepatic recycling occurs. The exact mechanism of action of carprofen is unclear. Although it has greater selec-tivity for COX-2 over COX-1, carprofen is considered a weak COX inhibitor. In vitro assays with canine cell lines indicate that it is 129-fold more selective for COX-2, whereas in vitro assays with canine whole blood indicate that it is 7- to 17-fold more selective for COX-2. Equine whole blood assays indicate that it is 1.6-fold more selective for COX-2, and feline whole blood assays indicate it is >5.5-fold more selective for COX-2. Other mechanisms of action, including inhibition of PA2, may be responsible for its anti-inflammatory effects. Carprofen has been used extensively in dogs since its introduction, and adverse events have been comparable to those of other NSAID (ie, ~2 events/1,000 dogs treated). Approximately one-fourth of the adverse reactions reported were GI signs, including vomiting, diarrhea, and GI ulceration. Renal and hepatic side effects are rare, as with other NSAID. Potentially serious idiosyncratic hepatopathies, characterized by acute hepatic necrosis, have been reported in some dogs. Approximately one-third of the dogs developing hepatopathies while receiving carprofen were Labrador Retrievers, although a true breed predisposition has not been established. As with any NSAID therapy, clinical laboratory monitoring for hepatic damage is advised, especially in geriatric animals that may be predisposed to more serious complications.
Ketoprofen
Ketoprofen is another propionic acid derivative available in the USA and other countries as a 10% injectable solution for horses, and in Europe and Canada as tablets and a 1% injectable solution for dogs and cats. Ketoprofen is recommended for acute pain (up to 5 days) in both dogs and cats. In horses, it is used for pain and inflammation associated with osteoarthritis and for visceral pain associated with colic. The recommended dosage is 1 mg/kg, IV or PO, sid for up to 5 days in dogs and cats, 2.2 mg/kg, IV, sid for up to 5 days in horses, and 3 mg/kg, IV or IM, sid for 1–3 days in cattle. Ketoprofen is a potent inhibitor of COX and bradykinin and may also inhibit some lipoxygenases. Its efficacy is comparable to that of opioids in the management of pain following orthopedic and soft-tissue surgery in dogs. Following administration PO, ketoprofen is rapidly absorbed and has a terminal half-life in cats and dogs of 2–3 hr. As with other NSAID, ketoprofen is metabolized in the liver to inactive metabolites that are eliminated by renal excretion. Adverse effects, including GI upset, are similar to those of other NSAID. Other side effects, including hepatopathies and renal disease, have been reported in animals. Due to potential antiplatelet effects, care should be exercised when using ketoprofen perioperatively.
Etodolac
The pyranocarboxylic acid etodolac is approved for use in dogs in the USA. The elimination half-life is ~8–12 hr, allowing dosing at 10–15 mg/kg, PO, sid. Extensive enterohepatic recirculation has been reported in dogs, followed by elimination of etodolac and its metabolites in the liver and feces. In in vitro studies, eto-dolac was more selective in inhibiting COX-2 than COX-1, although in vitro canine whole blood assays have also shown it to be nonselective. Etodolac has been shown to inhibit macrophage chemotaxis and has demonstrated efficacy for the treatment of lameness associated with hip dysplasia. Although the risk of GI ulceration is low at therapeutic doses, administration of 3 times the label dosage resulted in GI ulceration, vomiting, and weight loss in toxicity studies. GI, hepatic, and renal adverse reactions have been reported after administration of etodolac, similar to other NSAID.
Vedaprofen
The arylpropionic acid derivative vedaprofen is available in Europe in a gel formulation for horses and dogs and in an injectable formulation for horses. The drug is indicated for the treatment of pain and inflammation associated with musculoskeletal disorders in dogs (0.5 mg/kg, sid) and horses (1 mg/kg, bid) and for the treatment of pain associated with colic in horses (2 mg/kg, IV, as a single injection). Following administration PO, vedaprofen is rapidly absorbed. Biovailability is generally high, but may be reduced if the drug is administered with food. The terminal half-life is 10–13 hr in dogs and 6–8 hr in horses. Vedaprofen undergoes extensive biotransformation to hydroxylated metabolites, which are excreted in urine and feces.
Meloxicam
Approved for use in Canada and Europe in dogs, cats, and cattle, the oxicam NSAID meloxicam is available as an oral syrup and injectable solution. Meloxicam is also approved for human use in the USA and Canada and is approved for use in dogs in the USA. A potent inhibitor of prostaglandin synthesis, meloxicam is used for the treatment of acute and chronic inflammation associated with musculoskeletal disease, and for the management of postoperative pain. In dogs, a one-time loading dose of 0.2 mg/kg, PO, is recommended, followed by 0.1 mg/kg, PO, sid. Once a therapeutic effect is seen, the dosage can be titrated to the lowest possible dose. COX-1: COX-2 ratios reported for meloxicam suggest the drug is COX-2 selective, with in vitro canine whole blood assays indicating it is 2.7- to 10-fold more selective for COX-2. Once absorbed, meloxicam is highly protein bound (97%) and has a relatively long elimination half-life (12+ hr). GI safety appears to be greater for meloxicam than for nonselective NSAID, and meloxicam has been shown to be chondroneutral in rodent studies.
Deracoxib
Deracoxib, the first NSAID of the coxib class approved for use in dogs, is available in a beef-flavored chewable tablet formulation in the USA. Deracoxib has been shown to inhibit COX-2-mediated PGE2 production. COX-1:COX-2 ratios reported for deracoxib in in vitro cloned canine cell assays indicate it is 1,275-fold more selective for COX-2, whereas in vitro canine whole blood assays indicate it is 12- to 37-fold selective for COX-2. The drug is indicated for the control of postoperative pain and inflammation associated with orthopedic surgery at a dosage of 3–4 mg/kg, PO, sid for up to 7 days and for the control of pain and inflammation associated with osteoarthritis at a dosage of 1–2 mg/kg, PO, sid. Once absorbed, protein binding is >90%, and the elimination half-life is 3 hr.
Firocoxib
Firocoxib is a coxib-class NSAID that is approved in the USA and Europe for the control of pain and inflammation associated with osteoarthritis and for the control of postoperative pain and inflammation associated with soft-tissue and orthopedic surgery in dogs. In Canada, Australia, and New Zealand, it is approved for use in osteoarthritis and soft-tissue and orthopedic surgery. It is available in a chewable tablet formulation. Following administration PO, firocoxib is rapidly absorbed and then eliminated by hepatic metabolism and fecal excretion. The elimination half-life is ~8 hr, allowing dosing at 5 mg/kg, PO, sid. COX-1:COX-2 ratios from in vitro canine whole blood assays indicate it is 384-fold more selective for COX-2. Like other NSAID, protein binding is high, at ~96%. GI safety appears to be greater than that of nonspecific NSAID.
Tepoxalin
Tepoxalin is a dual inhibitor of both cyclooxygenases (COX-1 and COX-2) and 5-lipoxygenase (LOX). From a mechanistic perspective, its LOX activity (reduction of leukotriene production) may reduce components of inflammation not controlled by COX isoenzyme inhibition. It is available for dogs as an oral tablet. The initial dosage is 20 mg/kg, followed by a maintenance dosage of 10 mg/kg sid. Tepoxalin is rapidly absorbed and reaches peak plasma concentration 2–3 hr post administration. Its plasma half-life is short (2 hr), but it is metabolized to a carboxylic active meta-bolite (tepoxalin pyrazol acid) with a long half-life (12–15 hr). Both tepoxalin and its active metabolite are highly bound to plasma protein (98–99%). The most commonly reported adverse effects are GI (eg, diarrhea, vomiting in ~20% of dogs treated for 4 wk).
Other NSAID
A large number of prescription and nonprescription NSAID are available for human use. However, due to species differences in metabolism, efficacy, and toxicity, many are not recommended for use in animals. For example, in dogs, indomethacin is highly toxic to the GI tract and may result in severe ulceration, hematemesis, and melena at therapeutic doses. Piroxicam undergoes extensive enterohepatic recycling in dogs, resulting in a prolonged plasma half-life. GI ulceration and bleeding and renal papillary necrosis have been observed in dogs receiving piroxicam dosages of 0.3–1 mg/kg, sid.
Ibuprofen is an arylpropionic acid derivative that has been used in dogs as an anti-inflammatory agent. However, dogs are much more sensitive to the development of GI side effects from ibuprofen administration than are humans. At therapeutic doses, adverse effects observed in dogs include vomiting, diarrhea, GI bleeding, and renal infection. Ibuprofen is not recommended for use in dogs or cats.
Naproxen has been used in horses at a dosage of 5–10 mg/kg, sid-bid. Bioavailability is lower (~50%) for naproxen than for other NSAID, and the elimination half-life is ~5 hr in horses. In dogs, the elimination half-life of naproxen is 35–74 hr, presumably due to extensive enterohepatic recirculation. The pharmacokinetics in dogs also appear to be breed dependent. Due to the prolonged half-life of naproxen, dogs are extremely sensitive to its toxic effects.
Coxib class drugs, including celecoxib, and valdecoxib, developed for use in human medicine are COX-2 selective. In clinical studies, the incidence of GI ulceration in patients receiving valdecoxib or celecoxib was significantly less than that of those receiving naproxen. The use of these drugs in animals has yet to be fully investigated. One pharmacokinetic study with celecoxib in Beagles demonstrated variability in drug elimination between dogs. In that study, one subgroup of Beagles metabolized celecoxib much more rapidly than the other, with elimination half-lives of ~2 and 18 hr, respectively. Until further data are available regarding the pharmacokinetics and safety of these drugs in animals, their use in veterinary medicine is not recommended.
Last full review/revision March 2012 by Pierre-Louis Toutain, DVM, PhD, DECVPT
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