Nonsteroidal Anti-inflammatory Drugs

The importance of pain management and the use of NSAIDs in animals has increased dramatically in recent decades, with use of NSAIDs in companion animals being routine. NSAIDs have the potential to relieve pain and inflammation without the myriad potential metabolic, hemodynamic, and immunosuppressive adverse effects associated with corticosteroids. However, all NSAIDs 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, NSAIDs act primarily to reduce the biosynthesis of prostaglandins by inhibiting cyclooxygenase (COX). In general, NSAIDs do not inhibit the formation of 5-lipoxygenase (5-LOX) and hence leukotriene, or the formation of other inflammatory mediators. The novel NSAID tepoxalin is an exception in that it inhibits both COX and 5-LOX.

The discovery of the two isoforms of COX (COX-1 and COX-2) has advanced understanding of the mechanism of action and potential adverse effects of NSAIDs. COX-1, expressed in virtually all tissues of the body (eg, gut and kidney), catalyzes the formation of constitutive prostaglandins, 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 prostaglandin, 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 NSAIDs is thought to be responsible for the antipyretic, analgesic, and anti-inflammatory actions of NSAIDs. However, concurrent inhibition of COX-1 may result in many of the unwanted effects of NSAIDs, including gastric ulceration and renal toxicity. Because NSAIDs 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” NSAIDs. Although ratios of COX-1:COX-2 inhibition by various NSAIDs in people and animals have been reported, caution is advised when interpreting such ratios, because they vary greatly depending on the selectivity assay used. The COX selectivity of NSAIDs also varies by species; COX selectivity ratios reported for people 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, firocoxib, and robenacoxib, whereas 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 study that failed to demonstrate COX-2 expression in canine kidneys raised questions regarding its role. COX-2 also appears to be important in the healing of GI ulcers in people, 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.

NSAIDs enter the pocket of the COX enzyme, whereupon steric hindrance prevents entry of AA. Aspirin is unusual in that it 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) after aspirin administration, explaining the duration of aspirin's effect on hemostasis. Unlike aspirin, most other NSAIDs (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 NSAIDs, 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 NSAIDs for the relief of perioperative pain in companion animals is standard practice. In general, NSAIDs 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 indicated only against mild to moderate pain in people. However, in veterinary medicine, NSAIDs also find use in management of severe pain, optimally in combination with an opioid.

As antipyretics, NSAIDs 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, NSAIDs 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 NSAIDs 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 NSAIDs 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 people show that aspirin use is associated with a significant reduction in the incidence of colon cancer. Newer evidence suggests that the therapeutic effect of NSAIDs 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 NSAIDs are weak organic acids that are well absorbed after PO administration. However, food can impair the oral absorption of some NSAIDs (eg, phenylbutazone, meclofenamate, flunixin, and robenacoxib). Several NSAIDs are available as parenteral formulations for IV, IM, or SC administration. Some parenteral formulations are highly alkaline (eg, phenylbutazone) and may cause tissue necrosis if injected perivascularly. Once absorbed, most NSAIDs are extensively (up to 99%) bound to plasma proteins, with only a small proportion of unbound drug available to be active in the tissues. NSAIDs may also compete for binding sites with other highly protein-bound compounds, leading to some drug displacement; however, this displacement has little therapeutic consequence because it does not affect the concentration of the free drug. Because NSAIDs are highly protein bound and extravasation of protein occurs in inflammation, NSAIDs tend to concentrate in areas of inflammation. Consequently, their duration of action typically exceeds that predicted by elimination half-life.

Most NSAIDs 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. Mavacoxib is an exception, mostly being excreted unchanged in 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 NSAIDs, including naproxen, etodolac, and meclofenamic acid, undergo extensive enterohepatic recirculation in some species, resulting in prolonged elimination half-lives.

Adverse Effects

All NSAIDs have the potential to induce adverse reactions, some of which can be life threatening. Many reactions to NSAIDs 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 prostaglandins 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, NSAIDs, especially aspirin, may also cause direct chemical irritation of the GI mucosa. The enterohepatic recirculation of certain NSAIDs 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 be more severe, resulting in vomiting, hematemesis, and melena. Horses may develop oral, lingual, or colonic ulceration with accompanying signs of colic, weight loss, and diarrhea.

GI blood loss may be further complicated by impaired platelet function; NSAIDs, by inhibiting COX-1, 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 people. Animals with underlying renal compromise receiving NSAIDs could experience exacerbation or decompensation of their disease. It is important to maintain hydration and renal perfusion in animals receiving NSAIDs, especially those undergoing anesthesia or surgery and in horses with colic.

Hepatopathies are relatively common in people and animals receiving NSAIDs. NSAID administration routinely induces mild hepatic changes characterized primarily by increases in liver enzymes without clinical signs or hepatic dysfunction. Rare reports of idiosyncratic reactions resulting in hepatic dysfunction or failure have been reported in people (acetaminophen and others), dogs (acetaminophen, carprofen, etodolac), and horses (phenylbutazone). Cytopathic (hepatocellular injury, necrosis), cholestatic, and mixed histopathologic patterns of injury have been documented. NSAIDs should be used with caution in animals with preexisting hepatic disease.

Specific Nonsteroidal Anti-inflammatory Drugs

Based on structure, most NSAIDs can be divided into two 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), fenemates (tolfenamic and meclofenamic acids), phenylacetic acids (acetaminophen), and aminonicotinic acids (flunixin). The newer coxib class of selective COX-2 inhibitors includes a diaryl-substituted pyrazole (celecoxib) and a diaryl-substituted isoxazole (valdecoxib), both available for human use. Four NSAIDs of the coxib class, deracoxib, firocoxib, robenacoxib, and mavacoxib have been introduced in veterinary medicine.

Aspirin

By far the most widely used NSAID in people, 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. After 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, salicylic acid is considered the main active substance in the systemic circulation. Aspirin primarily inhibits COX-1, whereas salicylic acid has more balanced COX-1/COX-2 activity. In addition, aspirin may irreversibly bind to COX-1 through acetylation of a serine residue near the enzyme active site. Because of 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. Approximately 80%–90% of salicylate is bound to plasma proteins. Metabolism and elimination is via hepatic conjugation with glucuronic acid, followed by renal excretion. Cats, which lack glucuronyl transferase, metabolize salicylates slowly. 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, whereas it is ~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/day, PO. In cats, aspirin may be used for its antiplatelet effects in thromboembolic disease at a dosage of 10 mg/kg, PO, every 48 hr, to allow for prolonged metabolism. Adverse effects are common after 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 decrease GI ulceration associated with aspirin and other NSAIDs. 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 analgesic and antipyretic effects similar to those of aspirin, but it has weaker anti-inflammatory effects than does aspirin and other NSAIDs. The reason for this anomaly is that acetaminophen's selective COX-2 inhibition is via enzyme reduction; the high levels of peroxides in areas of inflammation are thought to interfere with COX-2 reduction peripherally, whereas the low peroxide levels in the brain and spinal cord account for any centrally mediated analgesia. Acetaminophen does not inhibit neutrophil activation, has little ulcerogenic potential, and has no effect on platelets or bleeding time. 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 because of their deficiency of glucuronyl transferase, which makes them susceptible to methemoglobinemia and centrilobular hepatic necrosis.

Phenylbutazone

Phenylbutazone toxicity (colitis), horse

One of the earliest NSAIDs approved for use in horses and dogs, phenylbutazone (PBZ) is a pyrazolone derivative available in tablet, paste, gel, and parenteral formulations. The plasma half-life of PBZ is 5–6 hr in horses and dogs and >30 hr in cattle (a reason that PBZ is not approved for use in cattle). When given PO, PBZ adsorbs to hay in the diet, to then be released during fermentation in the hindgut. Although this potentially may reduce GI absorption and bioavailability, the clinically relevant effect is a delay in absorption. Once absorbed, binding to plasma proteins is high (99% in horses). 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 PBZ is to treat acute laminitis in horses. Laminitis is treated initially with injectable PBZ 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 PBZ is relatively narrow (PBZ exhibits zero order metabolism), 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 PBZ. Ulcers may develop in the mouth, stomach, cecum, and right dorsal colon. The ulcerogenic potential of PBZ in horses is greater than that of flunixin and ketoprofen. Phenylbutazone dosages of 3–7 mg/kg, PO, tid, are recommended in dogs. In dogs, PBZ has been associated with bleeding dyscrasias, hepatopathies, nephropathies, and rare cases of irreversible bone marrow suppression.

Meclofenamic Acid

Meclofenamic acid is a fenemate (anthranilic acid) NSAID available for horses as a granular preparation and for dogs as an oral tablet. The recommended dosage is 2.2 mg/kg/day for 5–7 days in horses and 1.1 mg/kg/day 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 before dosing may delay absorption. The onset of action is slow, requiring 2–4 days of dosing for a clinical effect. Although it is effective in the treatment of chronic laminitis, meclofenamic acid has a therapeutic index that may be lower than that of other NSAIDs.

Tolfenamic acid

Tolfenamic acid is an anthranilic (fenemate) NSAID class approved for use in Europe and other countries. It is used for fever, postoperative pain, and acute and chronic inflammatory conditions in cats, dogs, cattle, and pigs.

Flunixin

In the USA, the nicotinic acid derivative flunixin (as the meglumine salt) is approved for use in horses as PO and parenteral formulations. The recommended dosage is 1.1 mg/kg/day for 5 days, IV or PO. Flunixin is rapidly absorbed after PO or IM administration, and the elimination half-life is short (~2–3 hr). Elimination is primarily by renal excretion. Flunixin is effective for the treatment of visceral pain associated with colic in horses. It is also used to reduce the inflammatory-mediated hemodynamic response to endotoxin, although it is unlikely to reduce mortality associated with endotoxemic shock. 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 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

Carprofen is an NSAID of the arylpropionic acid class 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/day or divided bid, PO. In Europe and other countries, carprofen is also registered for use in horses and 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 NSAIDs, 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 selectivity 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 NSAIDs (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 adverse effects are rare, as with other NSAIDs. 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/day for up to 5 days, IV or PO, in dogs and cats; 2.2 mg/kg/day for up to 5 days, IV, in horses; and 3 mg/kg/day for 1–3 days, IV or IM, 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 after orthopedic and soft-tissue surgery in dogs. After administration PO, ketoprofen is rapidly absorbed and has a terminal half-life in cats and dogs of 2–3 hr. As with other NSAIDs, 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 NSAIDs. Other adverse effects, including hepatopathies and renal disease, have been reported in animals. Because of 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/day, PO. 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, etodolac 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 three 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 those of other NSAIDs.

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. Vedaprofen is indicated for the treatment of pain and inflammation associated with musculoskeletal disorders in dogs (0.5 mg/kg/day) 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). After administration PO, vedaprofen is rapidly absorbed. Bioavailability 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

Meloxicam is an oxicam NSAID available as an oral syrup and injectable solution. It is approved for human use in the USA and Canada and for use in dogs in the USA. In Europe and other countries, it is approved for use in dogs, cats, cattle, and horses. 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/day, PO. 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 NSAIDs, 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. Deracoxib is indicated for the control of postoperative pain and inflammation associated with orthopedic surgery at a dosage of 3–4 mg/kg/day for up to 7 days, PO, and for the control of pain and inflammation associated with osteoarthritis at a dosage of 1–2 mg/kg/day, PO. Once absorbed, protein binding is >90%, and the elimination half-life is 3 hr.

Firocoxib

Firocoxib is a coxib-class NSAID 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. After 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/day, PO. COX-1:COX-2 ratios from in vitro canine whole blood assays indicate it is 384-fold more selective for COX-2. As with other NSAIDs, protein binding is high, at ~96%. GI safety appears to be greater than that of nonspecific NSAIDs.

Robenacoxib

Robenacoxib is a coxib-class highly selective COX-2 inhibitor, structurally related to the human NSAIDs diclofenac and lumiracoxib. Robenacoxib is approved in the USA and Europe for the control of pain and inflammation associated with osteoarthritis, orthopedic and soft-tissue surgery in dogs, and musculoskeletal disorders and soft-tissue surgeries in cats. Dosage is 2 mg/kg, PO, initially and then 1–2 mg/kg/day thereafter (for up to 6 days in cats). COX-1:COX-2 ratios from in vitro canine whole blood assays indicate it is 128-fold more selective for COX-2. As with other NSAIDs, protein binding is high, at ~98%. GI safety appears to be greater than that of nonselective NSAIDs. The elimination half-life is 1 hr after oral administration. Administration with food decreases bioavailability of robenacoxib.

Mavacoxib

Mavacoxib is a new coxib-class COX-2 inhibitor recently approved in Europe and Australia for the control of pain and inflammation associated with degenerative joint disease in dogs. Mavacoxib is structurally related to the human NSAID celecoxib; however, substitution of a methyl group with a single fluorine atom has conferred great resistance to metabolism, resulting in an elimination half-life of 17 days in young Beagle dogs. Unlike the major route of elimination of other NSAIDs, that of mavacoxib is biliary excretion of the parent molecule. In field trials conducted in aged dogs with osteoarthritis, the half-life was found to be even longer at 44 days, and in these older dogs, approximately 1 in 20 exhibited a half-life of >80 days. These population pharmacokinetic studies in target patients were used to optimize the dose regimen. The long half-life means mavacoxib has a unique dose regimen: the initial dose is 2 mg/kg, PO, repeated 14 days later; thereafter, the dosing interval is 1 mo, with the total course not exceeding seven doses (6.5 mo). Food significantly increases bioavailability. COX-1:COX-2 ratios from in vitro canine whole blood assays indicate it is 128-fold more selective for COX-2. As with other NSAIDs, protein binding is high, at ~98%. GI safety appears to be greater than that of nonselective NSAIDs. The elimination half-life is 1 hr after oral administration.

Tepoxalin

Tepoxalin is a dual inhibitor of both cyclooxygenases (COX-1 and COX-2) and 5-lipoxygenase (5-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/day. Tepoxalin is rapidly absorbed and reaches peak plasma concentration 2–3 hr after administration. Its plasma half-life is short (2 hr), but it is metabolized to a carboxylic active metabolite (tepoxalin pyrazol acid) that has a long half-life (12–15 hr). The metabolite, tepoxalin pyrazol acid, lacks the LOX activity of the parent molecule. Both tepoxalin and its active metabolite are highly bound to plasma protein (98%–99%). The most commonly reported adverse effects are GI related (eg, diarrhea and vomiting in ~20% of dogs treated for 4 wk).

Other NSAIDs

A large number of prescription and nonprescription NSAIDs are available for human use. However, because of 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 seen in dogs receiving piroxicam at dosages of 0.3–1 mg/kg/day.

Ibuprofen is an arylpropionic acid derivative used in dogs as an anti-inflammatory agent. However, dogs are much more sensitive to the development of GI adverse effects from ibuprofen administration than are people. At therapeutic doses, adverse effects seen 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, once to twice daily. Bioavailability is lower (~50%) for naproxen than for other NSAIDs, and the elimination half-life is ~5 hr in horses. In dogs, the elimination half-life of naproxen is 35–74 hr, presumably because of extensive enterohepatic recirculation. The pharmacokinetics in dogs also appear to be breed dependent. Because of the prolonged half-life of naproxen, dogs are extremely sensitive to its adverse 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 April 2014 by Scott H. Edwards, BSc, BVMS, PhD, MANZCVSc