Recent Developments in Nonsteroidal Antiinflammatory Drugs in Cats
Pain, particularly chronic pain, is an underestimated ailment in cats. Veterinarians tend to under-diagnose and under-treat pain in this aloof and stoic species. Until recently, there was only one analgesic (i.e., butorphanol) approved in the United States for use in cats; but many analgesics, particularly opioids, have been used extra-label for this purpose. Nonsteroidal antiinflammatory drugs (NSAIDs) have been used sparingly in cats because of safety concerns, which are less of an issue with the newer agents. Meloxicam is the only NSAID labeled for use in cats in the United States, but other agents are available in this country and are labeled for use in cats in other countries.
Introduction
Nonsteroidal antiinflammatory drugs (NSAIDs) have been used since the discovery that willow tree bark controlled colic.1 Aspirin was soon synthetically prepared. Aspirin as well as other NSAIDs (e.g., flunixin, piroxicam, phenylbutazone, dipyrone) have been historically administered to cats, but safety concerns have limited their use.2–5 Cats are more sensitive to the side effects of NSAIDs than are many species.6–10 It is essential that NSAIDs only be administered after their safety and efficacy have been determined in cats. Even when the pharmacokinetics and pharmacodynamics of an NSAID in the target species are known, careful patient selection is critical. Owners must be advised of potential side effects and clinical signs of toxicity.
The purpose of this article is to discuss the newer NSAIDs recently approved for use in cats in the United States (e.g., meloxicam) and other countries (e.g., meloxicam, carprofen, ketoprofen, tolfenamic acid).4–5,8,11–13 Even though a diligent effort has been made to provide current information regarding mechanisms of action, safety, and efficacy of NSAIDs, rapid advances in knowledge dictate that new developments may be omitted from this review. For example, the previous belief that NSAIDs act peripherally through either constituitive cyclooxygenase (COX)-1 or inflammatory COX-2 now appears to be an oversimplification. Improved reporting of adverse drug reactions to the Food and Drug Administration’s (FDA) Center for Veterinary Medicine (CVM) and continued vigilance conducted by the pharmaceutical industry will assist practitioners in making appropriate decisions about NSAID administration in cats. The onus of determining the risk to benefit ratio for each cat, however, rests with the individual practitioner.
Mechanisms of Action
Nonsteroidal antiinflammatory drugs act centrally (e.g., analgesic, antipyretic actions) and peripherally (e.g., analgesic, antithrombotic actions).1,5,14–16 Phospholipase A2 catalyzes arachidonic acid release from the cell membrane. Originally, NSAIDs were believed to act only peripherally through the inhibition of the arachidonic acid cascade. Arachidonic acid may be catalyzed by four enzyme groups: COX, 5-lipoxygenase (5-LOX), 12-LOX, and 15-LOX.14 Cyclooxygenase enzymes COX-1 or COX-2 catalyze the conversion of arachidonic acid to prostaglandin (PG) G2 and H2.17 Prostaglandin H2 is converted to assorted eicosanoids (i.e., 20 carbon fatty acids such as PGE2, PGD2, PGF2α, PGI2, and thromboxane [TX] A2).17 The particular PG produced is determined by the cell type. Prostaglandins have a primary role in inflammation but are also critical to many physiological responses. Diverse functions, including blood clotting, reproduction (e.g., ovulation, initiation of labor), bone metabolism, nerve development and growth, wound healing, kidney function and development, vascular tone, and immune response may be ascribed to PGs.17
Historically, COX-1 has been considered constituitive and mainly responsible for certain normal physiological functions (e.g., renal and gastrointestinal protection, blood clotting), and its inhibition has been the main cause of most NSAID-induced side effects (e.g., gastric ulcers, renal failure, blood dyscrasias).14 The COX-2 enzyme is usually induced by inflammation, and its inhibition has been considered to be responsible for most therapeutic effects (e.g., analgesic, antiinflammatory effects).14 As a result, drugs have been developed with greater COX-2 specificity in an attempt to make them safer. Drugs with partial specificity for COX-2 are labeled COX-2 preferential, and those with no COX-1 activity are termed COX-2 selective. Although COX-1 is mostly constituitive and COX-2 is mostly inflammatory, the complete picture is not yet clear. The COX-2 inhibitors are more gastroprotective, but they may also induce side effects since COX-2 is constituitive in the kidney, brain, and reproductive tract.15 In chronic inflammation, the role of COX-1 may also be important.16 Recent discovery of COX-3, a COX isoform derived from the same gene as COX-1, may explain the action of acetaminophen and dipyrone.18
The lipoxygenase (LOX) pathway is the second arm of the arachidonic acid pathway producing 5-LOX, 12-LOX, and 15-LOX.14 Of particular interest is the 5-LOX pathway, which produces inflammatory mediators such as leukotrienes (LT) A4, B4, C4, D4, and E4, and 5-hydroxy-(HETE) and 5- hydroperoxy-(HPETE) icosatetraenoic acids.2,14,15 If inhibition of COX occurs, arachidonic acid may be shunted to the LOX pathway, making 5-LOX inhibitors an attractive class of NSAIDs for use against inflammation.13,14,19,20
A group of newly developed NSAIDs may offer increased protection from gastric ulcers. Cyclooxygenase-inhibiting nitric oxide donors are believed to be gastroprotective through the release of nitric oxide and have improved analgesic and antiinflammatory properties.3,14–16,19 Currently there are no COX-inhibiting nitric oxide donors available for use in animals.
Indications and Contraindications
Until recently, NSAIDs were used primarily as antiinflammatory agents for osteoarthritis, as antipyretics to treat fever, as analgesics for mild to moderate pain, and as anticoagulants for thromboembolic disease.2,4,6 Increasingly, NSAIDs are being used for moderate to severe pain, especially to provide perioperative analgesia in cats.2,11,22–26 Although NSAIDs do not replace opioids in the perioperative setting, they are excellent adjunctive agents. Because most NSAIDs have a longer onset than opioids, when given perioperatively, the lag time should be covered with opioids.3,12
Administration of NSAIDs should be reserved for normotensive, normovolemic, adult cats with no history of bleeding diatheses or renal, hepatic, or gastrointestinal disease. Screening blood work, a urinalysis, and perhaps blood pressure measurements should be performed prior to instituting NSAID therapy and should be monitored regularly during chronic treatment. In some populations of cats, the benefits of NSAID therapy may outweigh the risks, as the importance of quality of life may supersede the desire for continued longevity. Although the risk of idiosyncratic drug reactions cannot be predicted, the best way to avoid adverse events is to be educated about the signs of toxicity.
Nonsteroidal antiinflammatory drugs are highly protein bound (>90%), and they bind in most instances to albumin.27 Once binding sites are saturated, the concentration of free drug (active form) rapidly increases. Displacement from binding sites may occur with NSAIDs, but more frequently NSAIDs displace less tightly bound drugs, which may potentiate the effects of the displaced drug.27 Treatment with NSAIDs should not be initiated if steroids or other NSAIDs are being administered, because of a higher risk of side effects.6 Appropriate withdrawal periods have not been established for situations when steroids or other NSAIDs are being given, but since cats cannot conjugate glucuronide well, other classes of analgesics (e.g., opioids) should be used to cover a reasonably long withdrawal interval. The elimination half-life is known for most NSAIDs in cats and may be used to estimate appropriate withdrawal times.
Nonsteroidal antiinflammatory drugs interact with other drugs in several ways.6 Drugs with a narrow therapeutic index (e.g., digoxin, cisplatin, methotrexate, oral anticoagulants) carry the greatest risk of increased toxicity when used with NSAIDs.6 Some drugs, such as diuretics, angiotensin-converting enzyme inhibitors, or beta-blockers may have decreased effectiveness when administered with NSAIDs.6
Nonsteroidal antiinflammatory drugs are contraindicated in cats with dehydration, renal or hepatic insufficiency, hypotension, congestive heart failure, ascites, thrombocytopenia, blood dyscrasias, gastrointestinal disease, shock, and possibly asthma.3,6,12,28 Because the course of any general anesthetic cannot always be predicted (e.g., episodes of hypotension, hemorrhage), the use of NSAIDs may best be saved for postoperative administration. In breeding and pregnant cats, the use of NSAIDs should be avoided, because COX-2 may be required for normal reproduction.29 In very young and very old cats, the ability to metabolize and excrete NSAIDs may be compromised, so extra care must be taken when prescribing NSAIDs for these cats.6
Adverse Effects
Although NSAID toxicity can occur in any species, cats are particularly sensitive.6–10,12 Decreased glucuronide conjugation in the cat is genetic and may result from the lack of evolutionary pressure on cats to metabolize phytoalexens from cruciferous plants, since cats are obligate carnivores.7,10 If glucuronide synthesis is the major method of drug inactivation (e.g., aspirin, carprofen) and alternate pathways are less efficient, the drug accumulates.10,27,30
Exposure to an NSAID may be accidental (i.e, cat consumes an NSAID on its own), appropriate (i.e., correct dose and drug administered under the direction of a veterinarian), or inappropriate (i.e., cat was medicated with the wrong drug or dose). As human usage of NSAIDs has increased, so have reports of companion animal toxicity.27 Isolated reports of toxicity in cats have been published in different states and countries. In the United States, reports of adverse drug events to the FDA-CVM for all veterinary drugs have increased from 4000 in 1997 to about 24,000 in 2001, 2002, and 2003; reports may be found on their web site.a,31 A review of earlier adverse drug events indicated cats were ingesting and being administered over-the-counter NSAIDs as well as those prescribed by veterinarians.32 In a 1987 report from the Illinois Animal Poison Information Center, 25% of the calls involving possible NSAID exposure pertained to cats, but specific numbers of cats exposed to each NSAID were unavailable.27
Over a 19-month period (1989 to 1990) in Georgia, 50 cases of NSAID toxicity were reported in cats, and 20 additional cats had no signs of toxicity at the time of the call.32 Of these cats, 25 were exposed to ibuprofen, 31 to acetaminophen, nine to aspirin, and three to indomethacin.32 Interestingly, most of the exposures to ibuprofen were accidental, with only 19% being inappropriate. For other drugs, most of the exposures were inappropriate (e.g., acetaminophen 56%, aspirin 100%, indomethacin 100%).32
In Australia, a commercial preparation of hyoscin and dipyrone was implicated in the deaths of three cats that appeared to have hypersensitivity reactions (e.g., cyanosis, dyspnea, pulmonary effusion, congestion).33 The manufacturer removed cats from the label of the combination, yet it was used in an extra-label fashion after the labeling change.33,34 A Swedish review of reports by veterinarians from 1991 to 1995 listed adverse events from NSAIDs in horses and dogs, but not in cats.35
One report of a duodenal perforation in a cat associated with extended carprofen administration has been published.36 Injectable carprofen (4 mg/kg subcutaneously [SC]) is approved for one-time use preoperatively in the United Kingdom, France, Germany, Netherlands, Italy, Belgium, Australia, and New Zealand. In New Zealand, a second dose of carprofen (2 mg/kg) has also been considered if additional postoperative analgesia is required, but currently only one dose of carprofen is recommended in cats.37 Chronic administration of carprofen is not recommended until appropriate safety studies have been conducted.21,25,26,38–42
A thorough description of the NSAIDs available in the United States has been published.30 The monographs included label and extra-label indications and dosages; withdrawal times; information about products approved in the United States and Canada; definitions of usages that are accepted, not established, or unaccepted; and relevant information for extra-label use.30 The monographs also included reviews by an FDA liaison and the Veterinary Medicine Expert Committee.30 A description of the process the FDA uses to record and report adverse drug events has been summarized in a special report by the American Veterinary Medical Association (AVMA).31 The FDA-CVM offers postmarketing information to veterinarians through FDA surveillance news on the AVMA web site.b,43 The four most commonly reported adverse events associated with NSAIDs are vomiting, anorexia, depression, and diarrhea.43 Gastric ulceration, intestinal ulceration, renal and hepatic failure, and death are also reported.43
Although inhibition of COX-1 increases the likelihood of gastrointestinal toxicity, claims of increased safety based on COX specificity may be misleading.44 The COX selectivity of different species varies widely and can only be determined using an assay specific for the species of interest. In addition, there is much confusion with the way the ratios of COX selectivity are determined. It is important to note that the selectivity of an agent depends on the species and may be affected by the laboratory performing the testing, the assay used, the definition of inhibition used, and, for racemic mixtures, whether the whole compound or one of its enantiomers is compared.1,14,44–46
Although it may not be applicable to cats, recent information about COX-2 inhibitors has revealed some unexpected side effects. An increased risk for gastroduodenal lesions occurred in people when aspirin was administered with a selective COX-2 inhibitor.47 Higher risks for hypertension, fluid retention, and cerebrovascular events may also exist in people receiving COX-2 selective inhibitors.48,49
Treatment of Toxicosis
An emetic is recommended following NSAID toxicity if the initial exposure was <1 hour ago. If exposure was >1 hour, activated charcoal is recommended.50 Clinical signs of NSAID toxicosis in cats include loss of appetite, vomiting, dehydration, lethargy, hematemesis, melena, and anemia.50 Tachycardia, weak to bounding pulses, abdominal pain, hypothermia, and brick-red mucous membranes may be present if gastrointestinal perforation has occurred. With suspected exposures, a complete blood count, biochemical panel (with electrolytes), urinalysis, arterial blood pressure, and an electrocardiogram are recommended. Abdominocentesis may confirm a gastrointestinal perforation. If a perforation has occurred, a broad-spectrum antibiotic is begun prior to exploratory laparotomy. All nephrotoxic drugs are discontinued, and fluids are administered to support circulating volume and help prevent renal failure. Additional supportive therapy such as sucralfatec (0.5 to 1.0 g per os [PO] q 6 to 8 hours), an H2-receptor antagonist (e.g., ranitidined 2.5 mg/kg intravenously [IV] q 12 hours or famotidinee 0.5 to 1 mg/kg IV or PO q 12 hours), or a proton pump inhibitor (e.g., misoprostolf 0.7 to 5.0 μg/kg PO q 8 hours) may also be considered.50
In the case of aspirin toxicosis, clinical signs may include hyperpnea, respiratory alkalosis, hyperthermia, hemorrhagic gastritis, toxic hepatitis, and depression.10,27 Recovery may be hastened by alkalinizing the urine, because salicylate is a weak acid.4
Individual NSAIDs
Aspirin
A dose of aspirin (10 to 20 mg/kg PO q 48 hours) has been established for treating osteoarthritis in cats, but vomiting and gastric erosions are common problems with aspirin administration.37,51 Aspirin may also be used as an antiplatelet agent in cats, because aspirin acetylates COX by binding it covalently.30 The bond is irreversible and persists for the life of the platelet.4,6 In cats, the elimination half-life of aspirin is dose-dependent and ranges from 26.8 hours (for a dose of 2.5 mg/kg PO) to 44.6 hours (for a dose of 44.6 mg/kg PO).30 Extreme care should be taken to ensure that aspirin is not mixed with other toxic NSAIDs, such as acetaminophen.
Carprofen
Carprofen,g a propionic acid-derived NSAID, is approved for use in cats in the United Kingdom, France, Germany, Netherlands, Italy, Belgium, Australia, and New Zealand at 4 mg/kg SC and IV. Carprofen is a racemic mixture, with both R(−) and S(+) enantiomers included in a 50:50 mixture. The S(+) enantiomer is believed to be most active.14 The elimination half-life of the racemic mixture of carprofen has been reported to be 19.4 hours when given at 4 mg/kg IV, and 20.1±16.6 hours (range 9 to 49 hours) when given as 4 mg/kg SC, IV.37,52 A dose-determination study conducted by Lascelles et al. found that 4 mg/kg SC provided effective perioperative analgesia.24
In clinical studies, carprofen given at induction of anesthesia provided better analgesia than butorphanol (0.4 mg/kg SC) given at extubation, when interactive scores were used to assess pain after ovariohysterectomy.53 When comparing carprofen to pethidine, studies found that cats treated with preoperative carprofen had lower mean pain scores for 4 to 24 hours after ovariohysterectomy and at 18 to 24 hours after castration.54 When administered preoperatively, carprofen provided good analgesia without side effects for 2 to 20 hours in cats undergoing ovariohysterectomy.24 In an orthopedic model, carprofen performed well when compared to two opioids (i.e., buprenorphine 0.01 mg/kg SC q 8 hours; levomethadone 0.3 mg/kg SC q 8 hours) administered at extubation, but some cats in the early postoperative period showed signs of insufficient analgesia in all treatment groups.26
Carprofen has been administered preoperatively, but postoperative administration may be preferred in order to guard against potential deleterious effects that might arise from unexpected hypotension or volume depletion during anesthesia and surgery. Fluids should be administered to support circulating volume if carprofen is given preoperatively. At high plasma concentrations, carprofen causes some suppression of platelet COX, but the maximal suppression of TXB2 is only about 50%, which is much less than in other species.52 Greater suppression in cats has been shown with other NSAIDS, including flunixin.52 The hepatic toxicosis that has occurred in dogs with carprofen use has not been reported in cats.57
Ketoprofen
Ketoprofen,h a propionic acid-derived NSAID, is approved for use in cats in Europe and Canada.25 Reduction of TXB2 concentrations indicates ketoprofen is a potent inhibitor of COX-1 for 24 hours after PO and IV administration and for up to 72 hours after IV administration.55 Ketoprofen may also provide some LOX inhibition in some species.3,25,40,41 The elimination half-life for the R(−) enantiomer of ketoprofen is 0.56 hours, and the elimination half-life for the S(+) enantiomer is 1.52 hours after racemic ketoprofen administration (2 mg/kg IV).55 Even with such a short half-life, its analgesic duration is about 24 hours.3
When intramuscular (IM) administration of ketoprofen (2 mg/kg IM) was compared to buprenorphine (0.01 mg/kg IM) and oxymorphone (0.05 mg/kg IM) after onychectomy or onychectomy and surgical neutering, buprenorphine was the most efficacious, followed by ketoprofen and then oxymorphone.56 However, when ketoprofen (2 mg/kg SC) was compared to a lower dose of buprenorphine (0.006 mg/kg IM) after ovariohysterectomy, ketoprofen performed better.57
As an antipyretic, ketoprofen (2 mg/kg SC once on day 1, followed by 1 mg/kg PO q 24 hours for days 2 through 5) was effective for 8 to 24 hours.58 Return to function (e.g., appetite, attitude, and condition) was also more rapid (i.e., 3 days) for cats receiving ketoprofen and an antibiotic than for cats receiving only an antibiotic (i.e., 5 days).58 Ketoprofen is generally administered at 2 mg/kg SC, followed by 1 mg/kg PO q 24 hours for 2 to 3 days; treatment should be limited to 5 days.30 The parenteral form may be given for 3 days.59 Ketoprofen should only be given postoperatively because of its platelet effects.12,30
Meloxicam
Meloxicami is an enolic acid NSAID with potent antiinflammatory activity (in animal models), low gastrointestinal and renal toxicity, and a long half-life.60 Meloxicam is approved as a single injection (0.3 mg/kg SC) in cats in the United Kingdom, Australia, New Zealand, and the United States. Additionally, meloxicam has antiarthritic, analgesic, and antipyretic activities, and it may be cartilage-sparing.4,60,61 In cats, the half-life is 11 to 21 hours following parenteral and oral administration.62 Meloxicam appears to be a well-tolerated and effective analgesic when administered for 5 days at 0.3 mg/kg SC, PO once, followed by 0.1 mg/kg PO q 24 hours.63,64
Postoperative meloxicam (0.2 mg/kg SC) has been used successfully for analgesia in cats undergoing ovariohysterectomy.13 The label dose of meloxicami (0.3 mg/kg SC) when administered prior to anesthesia for onychectomy or for onychectomy and castration or ovariohysterectomy provided better analgesia than butorphanol.65 Over 24 hours, meloxicam-treated cats had a greater decrease in lameness and pain and a higher pain threshold as measured by subjective scoring and response to palpometry, respectively.65 Consistent with the findings in dogs, no changes were detected in buccal bleeding times.65,66 Meloxicam is thought to have minimal anti-TX activity in both species.
Although not approved for repeated administration, meloxicam has been used extra-label for extended time periods after surgery or to treat lameness in cats.23 The lowest effective dose should always be used. Dosage recommendations vary, but 0.1 to 0.2 mg/kg once after surgery, then 0.05 to 0.1 mg/kg SC, IM, or PO q 24 hours for up to 3 to 5 days have been recommended.23,37 Other doses for chronic administration have also been reported (i.e., 0.2 mg/kg PO followed by 0.1 mg/kg PO q 24 hours for 3 to 4 days, followed by 0.025 mg/kg or 0.1 mg per cat PO two to three times weekly).67
For perioperative use, the label dose (0.3 mg/kg SC) is intended for a one-time injection.c If extended use of meloxicam is desired, a lower dose (e.g., 0.1 to 0.2 mg/kg SC, PO once) is given initially and followed by the least amount orally that is effective (e.g., 0.025 to 0.05 mg/kg PO q 24 hours) for 2 to 3 days. For chronic administration, 0.1 mg per cat PO two to three times weekly may be sufficient for maintenance.68 Meloxicam is labeled for preoperative use,c but it may best be used postoperatively. If it is given preoperatively, fluids should be administered to support circulating volume.
Comparisons of NSAIDs
When multiple NSAIDs are compared for perioperative analgesia, there is little difference in efficacy.13,67,69 When compared to opioids, the opioids perform as well or better in the first 4 hours after surgery, and the NSAIDs generally perform better after the immediate postoperative period.3,24,54,57,69 When carprofen (4 mg/kg SC) was compared with meloxicam (0.3 mg/kg SC) administered after flank ovariohysterectomy in cats, no differences were detected in serum chemistries, visual analogue scores for pain and sedation, or the number of cats requiring additional analgesic agents.67 All drugs performed well when analgesia was compared using carprofen (4 mg/kg SC), ketoprofen (2 mg/kg SC), meloxicam (0.2 mg/kg SC), and tolfenamic acid (4 mg/kg SC) administered at extubation after ovariohysterectomy.13 When ketoprofen (2 mg/kg SC postoperatively) and carprofen (4 mg/kg SC after induction) were compared to two opioids (pethidine 5 or 3.3 mg/kg IM or buprenorphine 0.006 mg/kg IM postoperatively), the two NSAIDs provided better analgesia by 4 hours, but the opioids provided better analgesia immediately.69 Ketoprofen (0.1 mg/kg PO q 24 hours for 5 days) was compared to meloxicam (0.3 mg/kg PO followed by 0.1 mg/kg PO q 24 hours for 5 days) in acute and chronic locomotor disorders, and the only difference found was palatability, with meloxicam being more palatable.64
Miscellaneous NSAIDs
Flunixin has been used in the past in cats, but because of potential serious side effects, its usage has decreased. A new look at pharmacokinetics and pharmacodynamics in cats may help guide usage.70–74 Similarly, piroxicam has been used extensively for treating feline tumors (e.g., transitional cell carcinoma, squamous cell carcinoma, mammary gland tumors).75 Single-dose pharmacokinetics have been conducted and may offer insight into the use of piroxicam in cats.75 The elimination half-life of piroxicam in cats is about 11 hours after IV administration, and it may be 100% bioavailable after oral administration because of enterohepatic recirculation.75 Ketorolac has been used in cats, but such use is extra-label and hard to defend, because better choices are currently available.12,41,49 No current indications exist in cats for tepoxalin, etodolac, firocoxib, meclofenamic acid, or deracoxib. In the Netherlands, vedaprofen gel (0.5 mg/kg PO) has been used in cats for postoperative pain following ovariohysterectomy, but detailed information on the drug in cats is lacking.22
Conclusion
Cats are particularly sensitive to many drugs including NSAIDs, and doses/dosing intervals for NSAIDs cannot be extrapolated from other species. The lowest effective dose should be used for any NSAID. Contraindications for the use of NSAIDs in cats include dehydration, renal or hepatic insufficiency, hypotension, congestive heart failure, ascites, thrombocytopenia, blood dyscrasias, gastrointestinal disease, shock, and possibly asthma. The drugs should be discontinued if the cat develops anorexia, vomiting, diarrhea, or lethargy. Once NSAIDs are approved for use in cats, side effects or adverse events may occur after release of the product that were not recognized before its release. The FDA-CVM and the manufacturer should be alerted to any adverse drug events, even if the cause of the event is known.
Carafate; Axcan Scandipharm, Birmingham, AL 35242
Zantac; GlaxoWellcome Inc., Research Triangle Park, NC 27709
Pepcid; Merck Consumer Pharmaceuticals Co., West Point, PA 19486
Cytotec; GD Searle & Co., Skokie, IL 60077
Rimadyl; Pfizer Animal Health, New York, NY 10017
Ketofen; Fort Dodge Laboratories, Fort Dodge, IA 50501-0518
Metacam; Boehringer Ingleheim Vetmedica, St. Joseph, MO 64506
