• 1

    Boston SE, Moens NM, Kruth SA, et al. Endoscopic evaluation of the gastroduodenal mucosa to determine the safety of shortterm concurrent administration of meloxicam and dexamethasone in healthy dogs. Am J Vet Res 2003;64:13691375.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 2

    Jones CJ, Budsberg SC. Physiologic characteristics and clinical importance of the cyclooxygenase isoforms in dogs and cats. J Am Vet Med Assoc 2000;217:721729.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 3

    Lees P, May SA, McKellar QA. Pharmacology and therapeutics of non-steroidal anti-inflammatory drugs in the dog and cat: 1 general pharmacology. J Small Anim Pract 1991;32:183193.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 4

    Lascelles BDX, Butterworth SJ, Waterman AE. Postoperative analgesic and sedative effects of carprofen and pethidine in dogs. Vet Rec 1994;19:187191.

    • Search Google Scholar
    • Export Citation
  • 5

    Slingsby LS, Waterman-Pearson AE. Analgesic effects in dogs of carprofen and pethidine together compared with the effects of either drug alone. Vet Rec 2001;148:441444.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 6

    Borer LR, Peel JE, Seewald W, et al. Effect of carprofen, etodolac, meloxicam, or butorphanol in dogs with induced acute synovitis. Am J Vet Res 2003;64:14291437.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 7

    Caulkett N, Read M, Fowler D, et al. A comparison of the analgesic effects of butorphanol with those of meloxicam after elective ovariohysterectomy in dogs. Can Vet J 2003;44:565570.

    • Search Google Scholar
    • Export Citation
  • 8

    Lascelles BDX, Cripps P, Mirchandani S, et al. Carprofen as an analgesic for postoperative pain in cats: dose titration and assessment of efficacy in comparison to pethidine hydrochloride. J Small Anim Pract 1995;12:535541.

    • Search Google Scholar
    • Export Citation
  • 9

    Papich MG. Principles of analgesic drug therapy. Semin Vet Med Surg (Small Anim) 1997;12:8093.

  • 10

    Martin TJ, Eisenach JC. Pharmacology of opioid and nonopioid analgesics in chronic pain states. J Pharmacol Exp Ther 2001;299:811817.

  • 11

    Mathews KA. Nonsteroidal anti-inflammatory analgesics in pain management in dogs and cats. Can Vet J 1996;37:539545.

  • 12

    Amadio P Jr, Cummings DM, Amadio PB. NSAIDs revisited. Selection, monitoring, and safe use. Postgrad Med 1997;101:257271.

  • 13

    Budsberg S. Nonsteroidal antiinflammatory drugs. In:Gaynor JS, Muir WW, ed.Handbook of veterinary pain management. Philadelphia: Mosby Inc, 2002;184198.

    • Search Google Scholar
    • Export Citation
  • 14

    Nolan AM. Pharmacology of analgesic drugs. In:Flecknell P, Waterman-Pearson A, ed.Pain management in animals. London: WB Saunders Co, 2001;2152.

    • Search Google Scholar
    • Export Citation
  • 15

    Dow SW, Rosychuk RA, McChesney AE, et al. Effects of flunixin and flunixin plus prednisone on the gastro-intestinal tract of dogs. Am J Vet Res 1990;51:11311138.

    • Search Google Scholar
    • Export Citation
  • 16

    Vonderhaar MA, Salisbury SK. Gastroduodenal ulceration associated with flunixin meglumine administration in three dogs. J Am Vet Med Assoc 1993;203:9295.

    • Search Google Scholar
    • Export Citation
  • 17

    Alencar MMA, Pinto MT, Oliveira DM, et al. Margin of safety of meloxicam in dogs: deleterious effects on blood cells and gastrointestinal tract. Ciênc Rural 2003;33:525532.

    • Search Google Scholar
    • Export Citation
  • 18

    Elwood C, Boswood A, Simpson K, et al. Renal failure after flunixin meglumine administration. Vet Rec 1992;27:582583.

  • 19

    Mathews KA, Doherty T, Dyson DH, et al. Nephrotoxicity in dogs associated with methoxyflurane anesthesia and flunixin meglumine analgesia. Can Vet J 1990;31:766771.

    • Search Google Scholar
    • Export Citation
  • 20

    Vasseur PB, Johnson AL, Budsberg SC, et al. Randomized, controlled trial of the efficacy of carprofen, a nonsteroidal anti-inflammatory drug, in the treatment of osteoarthritis in dogs. J Am Vet Med Assoc 1995;206:807811.

    • Search Google Scholar
    • Export Citation
  • 21

    Nolan R, Reid J. Comparison of the postoperative analgesic and sedative effects of carprofen and papaveratum in dogs. Vet Rec 1993;133:240242.

  • 22

    Grisneaux E, Pibarot P, Dupuis J, et al. Comparison of ketoprofen and carprofen administered prior to orthopedic surgery for control of postoperative pain in dogs. J Am Vet Med Assoc 1999;215:11051110.

    • Search Google Scholar
    • Export Citation
  • 23

    Mathews KA, Paley DM, Foster RA, et al. A comparison of ketorolac with flunixin, butorphanol, and oxymorphone in controlling postoperative pain in dogs. Can Vet J 1996;37:557567.

    • Search Google Scholar
    • Export Citation
  • 24

    Fox SM, Johnston SA. Use of carprofen for the treatment of pain and inflammation in dogs. J Am Vet Med Assoc 1997;210:14931498.

  • 25

    Beaver WT. Ketoprofen: a new nonsteroidal anti-inflammatory analgesic. J Clin Pharmacol 1988;28 (suppl 12):S1.

  • 26

    Kay-Mugford P, Benn SJ, LaMarre J, et al. In vitro effects of nonsteroidal anti-inflammatory drugs on cyclooxygenase activity in dogs. Am J Vet Res 2000;61:802810.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 27

    Taha AS, McLaughlin S, Holland PJ, et al. Effect on gastric and duodenal mucosal prostaglandins of repeated intake of therapeutic doses of naproxen and etodolac in rheumatoid arthritis. Ann Rheum Dis 1990;49:354358.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 28

    Budsberg SC, Johnston SA, Schwarz PD, et al. Efficacy of etodolac for the treatment of osteoarthritis of the hip joints in dogs. J Am Vet Med Assoc 1999;214:206210.

    • Search Google Scholar
    • Export Citation
  • 29

    Reimer ME, Johnston SA, Leib MS, et al. The gastroduodenal effects of buffered aspirin, carprofen, and etodolac in healthy dogs. J Vet Intern Med 1999;13:472477.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 30

    Nishihara K, Kikuchi H, Kanno T, et al. Comparison of the upper gastrointestinal effects of etodolac and aspirin in healthy dogs. J Vet Med Sci 2001;63:11311133.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 31

    Distel M, Mueller C, Bluhmki E, et al. Safety of meloxicam: a global analysis of clinical trials. Br J Rheumatol 1996;35 (suppl 1):6877.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 32

    Feldman BF, Carrol EJ, Jain NC. Coagulation and its disorders. In:Jain NC, ed.Schalm's veterinary hematology. 4th ed.Philadelphia: Lea & Febiger, 1986;388430.

    • Search Google Scholar
    • Export Citation
  • 33

    Forsyth SF, Guilford WG, Haslett SJ, et al. Endoscopy of the gastroduodenal mucosa after carprofen, meloxicam and ketoprofen administration in dogs. J Small Anim Pract 1998;39:421424.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 34

    Murphy KF, German AJ, Ruaux CG, et al. Fecal alpha1-proteinase inhibitor concentration in dogs receiving long-term nonsteroidal anti-inflammatory drug therapy. Vet Clin Pathol 2003;32:136139.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 35

    Hazewinkel HA, Van den Brom WE, Theijse LF, et al. Reduced dosage of ketoprofen for the short-term and long-term treatment of joint pain in dogs. Vet Rec 2003;152:1114.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 36

    Nell T, Bergman J, Hoeijmakers M, et al. Comparison of vedaprofen and meloxicam in dogs with musculoskeletal pain and inflammation. J Small Anim Pract 2002;43:208212.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 37

    Sessions JK, Reynolds LR, Budsberg SC. In vivo effects of carprofen, deracoxib, and etodolac on prostanoid production in blood, gastric mucosa, and synovial fluid in dogs with chronic osteoarthritis. Am J Vet Res 2005;66:812817.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 38

    MacPhail CM, Lappin MR, Meyer DJ, et al. Hepatocellular toxicosis associated with administration of carprofen in 21 dogs. J Am Vet Med Assoc 1998;212:18951901.

    • Search Google Scholar
    • Export Citation
  • 39

    Forsyth SF, Guilford WG, Pfeiffer DU. Effect of NSAID administration on creatinine clearance in healthy dogs undergoing anaesthesia and surgery. J Small Anim Pract 2000;41:547550.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 40

    Hodge TM, Wahlstrom T. Three years (1997–1999) of U.S. clinical experience with Rymadil (carprofen). Pfizer Animal Health Technical Bulletin 2000;110.

    • Search Google Scholar
    • Export Citation
  • 41

    Raekallio MR, Hielm-Bjorkman AK, Kejonen J, et al. Evaluation of adverse effects of long-term orally administered carprofen in dogs. J Am Vet Med Assoc 2006;228:876880.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 42

    Ko JC, Miyabiyashi T, Mandsager RE, et al. Renal effects of carprofen administered to healthy dogs anesthetized with propofol and isoflurane. J Am Vet Med Assoc 2000;217:346349.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 43

    Bostrom IM, Nyman GC, Lord PE, et al. Effects of carprofen on renal function and results of serum biochemical and hematologic analyses in anesthetized dogs that had low blood pressure during anesthesia. Am J Vet Res 2002;63:712721.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 44

    Bostrom IM, Nyman G, Hoppe A, et al. Effects of meloxicam on renal function in dogs with hypotension during anesthesia. Vet Anaesth Analg 2006;33:6269.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 45

    Lobetti RG, Joubert KE. Effect of administration of nonsteroidal anti-inflammatory drugs before surgery on renal function in clinically normal dogs. Am J Vet Res 2000;61:15011507.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 46

    McNeil PE. Acute tubulo-interstitial nephritis in a dog after halothane anaesthesia and administration of flunixin meglumine and trimethoprim-sulphadiazine. Vet Rec 1992;15:148151.

    • Search Google Scholar
    • Export Citation
  • 47

    Dodds WJ. Hemostasis. In:Kaneko JJ, Harvey JW, Bruss ML, ed.Clinical biochemistry of domestic animals. San Diego: Academic Press Inc, 1997;241283.

    • Search Google Scholar
    • Export Citation
  • 48

    Mathews KA, Pettifer G, Foster R, et al. Safety and efficacy of preoperative administration of meloxicam, compared with that of ketoprofen and butorphanol in dogs undergoing abdominal surgery. Am J Vet Res 2001;62:882888.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 49

    Hickford FH, Barr SC, Erb HN. Effect of carprofen on hemostatic variables in dogs. Am J Vet Res 2001;62:16421646.

  • 50

    Lemke KA, Runyon CL, Horney BS. Effects of preoperative administration of ketoprofen on whole blood platelet aggregation, buccal mucosal bleeding time, and hematologic indices in dogs undergoing elective ovariohysterectomy. J Am Vet Med Assoc 2002;220:18181822.

    • Crossref
    • Search Google Scholar
    • Export Citation

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Evaluation of adverse effects of long-term oral administration of carprofen, etodolac, flunixin meglumine, ketoprofen, and meloxicam in dogs

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  • 1 Department of Veterinary Surgery and Anesthesiology, School of Veterinary Medicine and Animal Science, São Paulo State University, Botucatu-SP, 18618-000, Brazil.
  • | 2 Department of Veterinary Surgery and Anesthesiology, School of Veterinary Medicine and Animal Science, São Paulo State University, Botucatu-SP, 18618-000, Brazil.
  • | 3 Department of Veterinary Surgery and Anesthesiology, School of Veterinary Medicine and Animal Science, São Paulo State University, Botucatu-SP, 18618-000, Brazil.
  • | 4 Department of Veterinary Surgery and Anesthesiology, School of Veterinary Medicine and Animal Science, São Paulo State University, Botucatu-SP, 18618-000, Brazil.
  • | 5 Department of Veterinary Surgery and Anesthesiology, School of Veterinary Medicine and Animal Science, São Paulo State University, Botucatu-SP, 18618-000, Brazil.
  • | 6 Department of Veterinary Surgery and Anesthesiology, School of Veterinary Medicine and Animal Science, São Paulo State University, Botucatu-SP, 18618-000, Brazil.
  • | 7 Department of Veterinary Surgery and Anesthesiology, School of Veterinary Medicine and Animal Science, São Paulo State University, Botucatu-SP, 18618-000, Brazil.

Abstract

Objective—To evaluate adverse effects of long-term oral administration of carprofen, etodolac, flunixin meglumine, ketoprofen, and meloxicam in dogs.

Animals—36 adult dogs.

Procedures—Values for CBC, urinalysis, serum biochemical urinalyses, and occult blood in feces were investigated before and 7, 30, 60, and 90 days after daily oral administration (n = 6 dogs/group) of lactose (1 mg/kg, control treatment), etodolac (15 mg/kg), meloxicam (0.1 mg/kg), carprofen (4 mg/kg), and ketoprofen (2 mg/kg for 4 days, followed by 1 mg/kg daily thereafter) or flunixin (1 mg/kg for 3 days, with 4-day intervals). Gastroscopy was performed before and after the end of treatment.

Results—For serum γ-glutamyltransferase activity, values were significantly increased at day 30 in dogs treated with lactose, etodolac, and meloxicam within groups. Bleeding time was significantly increased in dogs treated with carprofen at 30 and 90 days, compared with baseline. At 7 days, bleeding time was significantly longer in dogs treated with meloxicam, ketoprofen, and flunixin, compared with control dogs. Clotting time increased significantly in all groups except those treated with etodolac. At day 90, clotting time was significantly shorter in flunixin-treated dogs, compared with lactose-treated dogs. Gastric lesions were detected in all dogs treated with etodolac, ketoprofen, and flunixin, and 1 of 6 treated with carprofen.

Conclusions and Clinical Relevance—Carprofen induced the lowest frequency of gastrointestinal adverse effects, followed by meloxicam. Monitoring for adverse effects should be considered when nonsteroidal anti-inflammatory drugs are used to treat dogs with chronic pain.

Abstract

Objective—To evaluate adverse effects of long-term oral administration of carprofen, etodolac, flunixin meglumine, ketoprofen, and meloxicam in dogs.

Animals—36 adult dogs.

Procedures—Values for CBC, urinalysis, serum biochemical urinalyses, and occult blood in feces were investigated before and 7, 30, 60, and 90 days after daily oral administration (n = 6 dogs/group) of lactose (1 mg/kg, control treatment), etodolac (15 mg/kg), meloxicam (0.1 mg/kg), carprofen (4 mg/kg), and ketoprofen (2 mg/kg for 4 days, followed by 1 mg/kg daily thereafter) or flunixin (1 mg/kg for 3 days, with 4-day intervals). Gastroscopy was performed before and after the end of treatment.

Results—For serum γ-glutamyltransferase activity, values were significantly increased at day 30 in dogs treated with lactose, etodolac, and meloxicam within groups. Bleeding time was significantly increased in dogs treated with carprofen at 30 and 90 days, compared with baseline. At 7 days, bleeding time was significantly longer in dogs treated with meloxicam, ketoprofen, and flunixin, compared with control dogs. Clotting time increased significantly in all groups except those treated with etodolac. At day 90, clotting time was significantly shorter in flunixin-treated dogs, compared with lactose-treated dogs. Gastric lesions were detected in all dogs treated with etodolac, ketoprofen, and flunixin, and 1 of 6 treated with carprofen.

Conclusions and Clinical Relevance—Carprofen induced the lowest frequency of gastrointestinal adverse effects, followed by meloxicam. Monitoring for adverse effects should be considered when nonsteroidal anti-inflammatory drugs are used to treat dogs with chronic pain.

Nonsteroidal anti-inflammatory drugs are one of the best classes of drug to prevent and treat postoperative pain. They induce potent analgesic and anti-inflammatory effects,1 inhibit spinal nociceptive transmission,2 and are indicated for situations of potential edema and inflammation, mainly in cases of musculo-skeletal disorders.3

Results of several studies indicate that NSAIDs are sometimes more effective than opioids in treating postoperative pain in dogs1,4–7 and cats.8 These drugs are the World Health Organization's first choice for treating mild to moderate chronic pain.9 Their prolonged use is preferable, compared with pure agonist opioids, because they are nonaddictive, have a long-lasting effect, do not cause sedation or respiratory depression, and have no narcotic control issues.9,10 The NSAIDs reduce inflammation by inhibiting the action of cyclooxygenase, which converts arachdonic acid into prostanoids (PGG2 and H2 and prostacyclines). Prostaglandin H2 is converted into various eicosanoids, such as PGD2, PGE2, PGF, PGI, and thromboxane A2, which are inflammation mediators and amplify nociceptive input and transmission to the spinal cord.2,3,11 Nonsteroidal anti-inflammatory drugs limit the formation of PGs and the effects on peripheral sensory receptors of inflammatory mediators such as histamine, bradykinin, and other kinins.12 Central antinociceptive effects have also been suggested because NSAIDs may act on excitable membranes, on second messenger systems, or in the expression of inflammatory mediators.13

Results of several studies indicate that NSAIDs have good analgesic properties in dogs; however, there is concern about their adverse effects, particularly after long-term use. These include gastric ulcers; development of protein-losing enteropathy; nephrotoxicosis11,14; and coagulation disorders, such as inhibition of platelet cyclooxygenase, reduced formation of proaggregatory eicosanoid thromboxane A2, and prevention of platelet aggregation.3

Advances in developing more specific drugs that reduce these adverse effects have been made. More recently developed drugs predominantly inhibit inductive cyclooxygenase-2 that is released by damaged or inflamed tissue, which is responsible for pain and hyperalgesia after injury, while at the same time maintaining as much of the constitutive cyclooxygenase-1 effect as possible, which modulates renal and gastrointestinal blood flow and coagulation. However, even more specific recent cyclooxy-genase-2 inhibitor NSAIDS are not free of adverse effects, which are intensified when they are used for long periods to treat chronic pain.15–17

Flunixin is a potent anti-inflammatory and analgesic drug,15 which preferentially inhibits cyclooxygenase-1 and is indicated for acute and surgical pain. However, acute renal failure,18 increased serum alanine amino-transferase activity,19 and gastroduodenal ulcers15,16 have been reported in dogs treated with flunixin. Carprofen is classified as a preferential cyclooxygenase-2 inhibitor and is available as a racemic mixture.20 Its mode of action is not fully understood, and the low prevalence of adverse effects caused by clinical doses may be attributed to its weak inhibition of cyclooxygenases.14 Carprofen is an effective analgesic for dogs with induced acute synovitis, orthopedic problems, or osteoarthritis, and after soft tissue surgery.6,20–22

Ketoprofen is an arylpropionic acid and potent cyclooxygenase inhibitor with no cyclooxygenase-2 selectivity in dogs. It is different from other NSAIDs in that it also inhibits lipoxygenase and the leukotriene inflammatory pathway and promotes proteoglycan synthesis, creating a double blockade of arachidonic acid metabolism.2,23,24 Ketoprofen induces a 30% rate of adverse effects, including gastrointestinal changes, dizziness, headache, and nephritis in humans.25

Etodolac is a pyranocarboxylic acid and one of the most commonly used NSAIDs for treating arthritis. In vitro data suggest that it has low cyclooxygenase-2 selectivity.13,26 It does not appear to interfere with PG synthesis in the gastrointestinal mucosa, as do other NSAIDs, and thus preserves the beneficial effects of local PGs.2,9,27 It is well tolerated by dogs with minimal adverse effects when used for 8 days.28 However, when used for 28 days in dogs, minor gastric lesions are observed, similar to carprofen.29,30

Meloxicam has been used in dogs for medium- to long-term treatment of musculoskeletal pain and inflammation. It has selectivity against cyclooxygenase-2 versus cyclooxygenase-1 and appears to be safe for the gastrointestinal tract in humans.31

Several studies have been performed to investigate acute adverse effects from NSAIDs, but only a few report long-term adverse effects. The purpose of the study reported here was to evaluate the safety of administration of carprofen, etodolac, meloxicam, flunixin, or ketoprofen for 90 days in dogs.

Materials and Methods

This study was approved by the Animal Research Ethics Committee of the School of Veterinary Medicine and Animal Science at São Paulo State University. Forty-two crossbreed adult female dogs, 1 to 5 years of age and weighing from 15 to 20 kg, underwent a clinical and preliminary laboratory investigation (urinalysis, CBC, and serum biochemical analyses) to ensure that they were healthy. The dogs were identified with numbered collars; treated against endoparasites and ectoparasites with selamectina and praziquantel, febantel, and pyrantelb; and vaccinated against distemper, leptospirosis, parvovirus, infectious hepatitis, adenovirus type I, parainfluenza, and rabies.c All dogs were spayed and maintained in quarantine for 3 months prior to the study. During this period, they underwent adaptation to housing and feeding conditions and group socialization.

After a 30-day adaptation period, dogs were clinically inspected and a second complete urinalysis and CBC were performed. Urine samples were collected via cystocentesis; specific gravity was measured with a handheld refractometerd; pH and concentrations of proteins, glucose, ketones, and bilirubin, and fecal occult blood were determined by use of multiple-test reagent strips;e and urinary sediment was evaluated with a light microscope.f Blood (10 mL) was withdrawn from a jugular vein by venipuncture; part was put into a glass tube containing EDTAg for CBC and part into a tube without anticoagulanth for serum biochemical analyses.

The CBC and platelet count were determined by use of an automated cell counteri and Hct via the microhematocrit method.32 Differential leukocyte counts were performed with blood on slides stained according to Leishman32 and total plasma protein by refractometry.d Hemoparasites were also investigated.

Clinical biochemical analyses included serum urea and creatinine concentration and serum activity of alanine transaminase, alkaline phosphatase, and γ-glutamyltransferase. Total protein, albumin, and globulin concentrations were determined with standard kitsj and a spectrophotometer.k

Bleeding time was measured by use of the Duke method. Each dog was restrained, and a puncture was performed on the internal surface of the ear with a trifaced lancet. Time until bleeding stopped was recorded by use of a filter paper and stopwatch. Clotting time was determined by the Lee-White method.32

Gross and occult blood in feces were determined from feces collected from the rectum with lubricated gloves. The feces were divided in 2 aliquots, and each was placed in an envelope window of the standard kit,l with 2 drops of reagent. When blood was present in the feces, a halo formed on the paper around the fecal sample. When results were positive, this test was repeated with fresh, naturally passed feces taken from the floor. Results were recorded as positive if blood was present and negative if blood was absent.

After premedication with acepromazinem (0.05 mg/kg, IM), a cephalic vein was aseptically catheterized with a 20-gauge catheter.n Anesthesia was induced approximately 20 minutes after premedication with thiopental sodiumo (10 mg/kg, IV). After endotracheal intubation, anesthesia was maintained with halothanep in oxygen administered though a circular breathing circuit. Gastroscopy was performed in all dogs at least 8 days before the study to ensure gastric integrity. Lactated Ringer's solution was administered IV at a rate of 10 mL/kg/h throughout examination. Stomach lesions were graded according to Forsyth et al33 as grade 0 (no visible hemorrhages, erosions, or ulcers), 1 (1 to 5 punctate erosions, hemorrhages, or both), 2 (6 to 15 punctate erosions, hemorrhages, or both), 3 (16 to 25 punctate erosions, hemorrhages, or both), 4 (> 25 punctate erosions, hemorrhages, or both; 1 to 5 invasive erosions; or both), 5 (> 6 invasive erosions), or 6 (ulcers of any size). All dogs had grade 0 scores before treatment. Erosion was defined as a discontinuation of the mucosa < 3 mm in diameter and an ulcer as > 3 mm with a craterous center. On the same occasion, 10-mL samples of urine were collected via urethral catheter and anesthesia. Urine was examined for density, protein concentration, and pH.

Thirty-six dogs that met the inclusion criteria (values of all measured variables within reference ranges) were equally allocated into 6 collective 4 X 3.5-m isolated boxes with natural ventilation. Dogs were fed commercial dry food, and water was provided ad libitum. On day 0, dogs were weighed and the boxes randomly assigned to the 6 treatment groups. The dogs were treated for a maximum of 90 days with single daily orally administered doses of one of the following: lactose (control treatment; 1 mg/kg), etodolacq (15 mg/kg), meloxicamr (0.1 mg/kg), ketoprofens (2 mg/kg for 4 days, followed by 1 mg/kg/d thereafter), carprofent (4 mg/kg), or flunixin meglumineu (1 mg/kg for 3 days with consecutive 4-day intervals). The FDA only licenses flunixin and ketoprofen for use in horses in the United States, flunixin is licensed for use in dogs in Europe,11 and ketoprofen is licensed for use in dogs and cats in Canada. Carprofen, etodolac, and meloxicam are FDA-approved for dogs at the doses used in this study.

A veterinarian performed a general daily health examination for any evidence of diarrhea, signs of depression, inappetence, or signs of abdominal pain during the course of the study. When a dog had abnormal clinical findings, it underwent a complete clinical and laboratory examination, as described. When those findings were judged by an investigator (unaware of treatment assignment) to be related to a study drug, the dog was excluded from the study and treated appropriately and no further data were recorded for that dog. Regardless of daily examinations, a complete examination including clinical and laboratory tests was performed on all dogs 7, 30, 60, and 90 days after the beginning of treatments. The study terminated on day 90, when the last endoscopy was performed. The veterinarian performing gastroscopies was unaware of the treatments received by the dogs.

Statistical analysis—The number of dogs removed from the study because of drug-related adverse events was recorded. Statistical analysis was performed with software.v Data with a normal distribution were compared by use of ANOVA followed by the Dunnett test to investigate differences over time in each treatment, compared with baseline values, and the Student-Newman-Keuls test to investigate differences among treatments at each time. Nonparametric data were compared by use of ANOVA followed by the Friedman test to investigate differences over time in each treatment, compared with baseline values, and the Kruskal-Wallis test to investigate differences among treatments at each time. Significance was set at P < 0.05.

Results

Three dogs treated with ketoprofen were removed on days 39, 66, and 87, respectively, because of fighting and consequent lesions that could have interfered with results. There were no changes in values of the CBC, hemoglobin, Hct, total plasma protein, platelet count, urea, creatinine, alanine transaminase, alkaline phosphatase, albumin, and globulin between basal values and other measurement times for each group or among groups at each time. Mean and individual values were within reference ranges for dogs.

Serum γ-glutamyltransferase activity was increased significantly at day 7 in dogs treated with lactose and meloxicam, compared with values obtained at baseline. At 30 and 90 days, bleeding time was significantly increased in dogs treated with carprofen, compared with baseline. At 7 days, bleeding time was significantly longer in dogs treated with meloxicam, ketoprofen, and flunixin, compared with dogs treated with lactose (Table 1). Clotting time increased significantly between 30 and 90 days after meloxicam administration, at 60 days after ketoprofen and carprofen administration, and at 90 days after flunixin administration, compared with baseline values. Dogs that received lactose had significantly longer clotting time before treatment, compared with dogs treated with etodolac, carprofen, and flunixin. At day 90, clotting time was significantly shorter in flunixin-treated dogs than those treated with lactose.

Table 1—

Mean ± SD bleeding and clotting times (seconds) in dogs (n = 6/group) reated with lactose, etodolac, meloxicam, ketoprofen, carprofen, or flunixin for 90 day

DrugBaseline 7 days30 days60 days90 days   
Bleeding timeClotting timeBleeding timeBleeding timeClotting timeBleeding timeClotting timeBleeding time 
Lactose40 ± 811 ± 140 ± 1538 ± 811 ± 138 ± 2111 ± 138 ± 31 
Etodolac45 ± 139 ± 145 ± 1945 ± 1210 ± 149 ± 2811 ± 141 ± 23 
Meloxicam60 ± 910 ± 173 ± 1543 ± 1511 ± 1*50 ± 1513 ± 1*40 ± 20 
Ketoprofen53 ± 2110 ± 173 ± 2828 ± 2012 ± 227 ± 1313 ± 2*55 ± 17 
Carprofen35 ± 89 ± 140 ± 1860 ± 30*11 ± 135 ± 1212 ± 1*60 ± 19* 
Flunixin53 ± 89 ± 175 ± 1653 ± 199 ± 145 ± 2710 ± 160 ± 32 

Significant (P < 0.05) difference from baseline value.

Significant (P < 0.05) differences between lactose and other treatments at each time.

Clotting time was not measured at 7 days.

There was no difference within and among groups in urine density, pH, and proteins before treatment versus day 90 of treatment. At the end of the study, various numbers of dogs had positive results of a fecal occult blood test (Table 2). Two dogs treated with flunixin were removed at day 19 and 2 treated with etodolac were removed at day 25 because of melena.

Table 2—

Proportions of dogs with positive results of fecal occult blood test before and during treatment with lactose, etodolac, meloxicam, ketoprofen, carprofen, or flunixin for 90 days.

TreatmentBefore7 days30 days60 days90 days
Lactose0/60/60/60/60/6
Etodolac*0/64/63/42/44/4
Meloxicam0/61/61/63/65/6
Ketoprofen0/61/60/63/53/3
Carprofen0/60/61/61/63/6
Flunixin0/63/60/44/44/4

Two dogs were removed at day 25 because of melena.

Three dogs were removed at days 39, 66, and 87 respectively, because of fighting and consequent lesions that could have interfered with results.

Two dogs were removed at day 19 because of melena.

There were no gastric lesions in lactose-treated dogs at 90 days. Gastric lesions of various grades were seen in dogs in the other groups (Table 3).

Table 3—

Number of dogs removed from the study and distribution of gastric lesion grades in remaining dogs after 90 days of treatment with lactose, etodolac, meloxicam, ketoprofen, carprofen, or flunixin.

TreatmentNo. of dogs removedGrade      
0123456
Lactose06000000
Etodolac20010201
Meloxicam04000200
Ketoprofen30000201
Carprofen050000 0
Flunixin20000121

Discussion

The most common findings from NSAID-induced PG inhibition in the gastrointestinal tract are nausea, vomiting, gastric pain, diarrhea, and blood in feces.2,12,16 Although endoscopy is considered a sensitive method for detecting early NSAID-induced gastric injury in dogs,15 most studies that used gastroscopy did not find any correlation between clinical signs (eg, attitude, appetite, and signs of abdominal pain) and gastrointestinal injury.15 Gatrointestinal biopsies were not performed in the study reported here, although gross endoscopic evaluation of gastric lesions correlates with gross lesions at necropsy and is therefore a reliable method of evaluating ulceration and gastric adverse effects.1,15

Although false-positive results for fecal occult blood may be found in dogs fed meat-based diets,20 this test was apparently reliable in the present study because dogs from the control group yielded negative results even when fed commercial food. Dogs treated with carprofen had the lowest frequencies of occult blood in feces and gastric lesions, compared with the other NSAID-treated groups. These findings are similar to those of a previous study20 in which carprofen induced a low frequency of adverse gastrointestinal effects when used for 2 weeks in dogs. Fecal alpha(1)-proteinase inhibitor, which is a noninvasive marker for protein-losing enteropathy and an indicator of NSAID-induced gastrointestinal damage, was not modified by daily meloxicam or carprofen administration for at least 30 days.34 This was also confirmed in the present study in which only 1 of 6 dogs had fecal occult blood at day 30 of treatment with meloxicam and carprofen. However, at day 60, with the exception of carprofen, fecal occult blood was detected in at least 50% of dogs in all groups.

Gastric lesions were found in 3 of 6 ketoprofen-treated dogs in this study (grade 4 in 2 dogs; grade 6 in 1 dog). In a previous study,33 endoscopy revealed hemorrhage or erosions in 5 of 6 dogs treated with ketoprofen for 28 days. No gastrointestinal or other adverse effects were observed when a lower ketoprofen dosage (0.25 mg/kg/d) was used for 30 days,35 indicating that most adverse effects from administering ketoprofen are probably caused by higher doses. This may be of clinical relevance because a low (0.25 mg/kg) ketoprofen dose improves peak vertical force weight bearing and signs of joint pain in dogs, similar to 0.5 and 0.75 mg/ kg doses.35 The ketoprofen dosage used in the present study was recommended in pain management text-books.13,14 Further studies are necessary to confirm the analgesic effects of lower ketoprofen doses and the possible reduction in gastrointestinal adverse effects when low doses are used over a long period.

The potential adverse gastrointestinal effects of prolonged flunixin use have been reported15; however, most adverse effects were caused by incorrect doses and intervals or treatment being maintained despite signs of toxicosis.16 Four dogs treated with flunixin in the present study had gastric lesions ranging from grade 4 to 6, and 2 dogs were removed at day 19 because of occult blood in feces and melena. The remaining flunixin-treated dogs had occult blood in feces after 90 days of treatment. Therefore, flunixin cannot be recommended for chronic use and should be restricted to the postoperative period only.9,14

At the end of treatment, 2 dogs treated with meloxicam had grade 4 gastric lesions and 5 of 6 dogs had occult blood in feces. To the authors' knowledge, this is the first report of administration of meloxicam over such a long period. At day 30, only 1 of 6 dogs had occult blood in feces. Similar findings have been reported in which 12% of dogs treated with meloxicam for up to 39 days had mild transient clinical signs, such as diarrhea, vomiting, dullness, and loss of appetite and treatment was discontinued in 5%.36Also, a larger dose (0.2 mg/kg, PO) of meloxicam administered daily for 16 days caused vomiting and soft feces in 80% of dogs on day 5 of treatment, with hyperemia and gastroduodenal mucosal erosions in 80% and histopathologic signs of gastritis in 60% at necropsy.17 These data suggest that the ideal dosage for meloxicam is 0.1 mg/kg, PO, once daily, as used in the present study.

Long-term use of carprofen and etodolac in this study caused grade 5 gastric lesions in 1 dog and grade 2 to 6 gastric lesions in 4 dogs, respectively. Two dogs treated with etodolac were removed at day 25, 1 because of occult blood in feces and the other because of melena, and the 4 remaining dogs had occult blood in feces after 90 days of treatment with etodolac. Although a previous study37 in which dogs were treated with etodolac for 10 days did not reveal important gastric mucosal lesions during gastroscopy, in the present study, 4 of 6 dogs had occult blood in feces after 7 days of treatment, which indicated that etodolac is apparently not safe even for short-term treatment.

When just considering occult blood in feces, it seemed that the frequency was similar for carprofen, meloxicam, and ketoprofen when used for 30 days, as reported. However, frequency of occult blood was lower with carprofen after 60 and 90 days of treatment, which suggested that carprofen should be used for treatment periods exceeding 30 days. Evaluation of the mechanisms involved in NSAID-induced gastrointestinal tract injury was beyond the scope of this study and is reported elsewhere.9,14,15

Hepatotoxicosis has been associated with the use of carprofen and other NSAIDs in dogs38 and is generally considered an idiosyncratic reaction. Creatinine clearance is significantly lower in dogs receiving a single dose of carprofen and ketoprofen, compared with dogs treated with saline (0.9% NaCl) solution.39 Although clinical and laboratory findings of hepatic and renal lesions have been reported with administration of carprofen in dogs,38 no significant changes were detected in the study reported here. The number of dogs used in this study was too low to draw a firm conclusion, but a retrospective study40 involving a large number of dogs revealed that the frequency of liver dysfunction was < 0.06% in dogs treated with carprofen. Other studies have not detected hepatotoxic effects from the long-term use (60 days) of carprofen41 or renal effects from carprofen in anesthetized dogs,42 even with hypotension.43 The same may be true for meloxicam because serum biochemical values, results of urinalysis, and glomerular filtration rate measured by use of scintigraphy44 were not modified by administration of meloxicam in dogs with hypotension during anesthesia. Although ketoprofen did modify the serum biochemical profile in 1 study,45 it induced transient azotemia in 2 of 10 clinically normal dogs undergoing general anesthesia and decreased urine specific gravity.

The potential risk of renal failure may be intensified when flunixin is combined with inhalation anesthesia because acute interstitial nephritis has been reported in a dog undergoing halothane anesthesia46 and increased urea and creatinine concentrations and tubular necrosis have been reported after 24 hours of anesthesia with methoxiflurane.19 As with the other drugs, flunixin and etodolac did not have any significant renal effects on the clinically normal dogs in the present study.

Although urea and creatinine concentrations may be used to evaluate renal function, they are not sensitive markers of renal failure because they increase only when renal damage is severe and are not reliable for early diagnosis of renal failure.41 For a better assessment of renal function, glomerular filtration rate should be used because it is a good marker of the progress of renal insufficiency and nephropathies, even at early stages.41 Urea and creatinine concentrations were measured in the present study because they are easy to measure under clinical conditions and because there is a possibility that long-term use of NSAIDs may induce alterations in serum biochemical variables associated with renal function.

Bleeding time is the best in vivo test for evaluating primary hemostasis, and several sites may be used for this examination. Skin bleeding time varies from 1 to 5 minutes in healthy dogs.47 Most studies1,7,48 use buccal mucosa bleeding time. In the present study, the internal surface of the ear was used to minimize physical restraint and stress to the dogs. Nonsteroidal anti-inflammatory drugs prevent or reduce the formation of thromboxane A2 in platelets, impairing platelet functions such as adhesion.41 Carprofen was the only NSAID in this study to increase bleeding time significantly, compared with baseline values, and with the exception of etodolac, all other NSAIDs increased clotting time significantly, compared with baseline values, although all values were within reference ranges for dogs. Except for 1 study49 in which carprofen decreased and delayed the onset of platelet aggregation, most studies22,24,41 have revealed that carprofen does not modify hemostatic variables. Also, mucosal bleeding time does not significantly change after a single dose of meloxicam7,48 or ketoprofen in dogs.48 Platelet aggregation is inhibited by preoperative administration of ketoprofen in dogs but not by a single dose of meloxicam.7,22,50

Our findings suggested that all NSAIDs studied induced only minor, clinically unimportant changes in hemostatic and serum biochemical variables in dogs, even after long-term use. Results suggested that carprofen induced the lowest frequency of gastrointestinal adverse effects, followed by meloxicam, etodolac, flunixin, and ketoprofen, when given to dogs for 90 days. Periodically, CBC, serum biochemical analysis, and endoscopy must be performed to monitor adverse effects.

ABBREVIATIONS

NSAID

Nonsteroidal anti-inflammatory drug

PG

Prostaglandin

a.

Revolution 12%, Laboratórios Pfizer LTDA, Guarulhos, Brazil.

b.

Drontal Plus, Bayer SA, São Paulo, Brazil.

c.

Vanguard HTLP 5/CV-L, Laboratórios Pfizer LTDA, Guarulhos, Brazil.

d.

SUR-NE, Atago Co Ltd, Tokyo, Japan.

e.

Combur10testUX, Roche Diagnostics GmbH, Mannheim, Germany.

f.

JENAMED 2, CARL ZEISS Inc, Jena, Germany.

g.

EDTA, Vacutainer, Beckton-Dickinson, Franklin Lakes, NJ.

h.

Vacutainer, Beckton-Dickinson, Franklin Lakes, NJ.

i.

Cell-Dyn 3500R, Abbott Diagnostics, Abbott Park, Ill.

j.

CELM, Cia Equipadora de Laboratórios Modernos, Barueri, Brazil.

k.

SB190, Cia Equipadora de Laboratórios Modernos, Barueri, Brazil.

l.

Propper Manufacturing Co, Long Island City, NY.

m.

Acepran 0.2%, Lab Univet, São Paulo, Brazil.

n.

Angyocath, Beckton-Dickinson, São Paulo, Brazil.

o.

Thiopental, Lab Cristália, Itapira, Brazil.

p.

Tanohalo, Lab Cristália, Itapira, SP, Brazil.

q.

Etogesic tablets, Fort Dodge Animal Health, Madison, NJ.

r.

Metacam suspensión oral, Boehringer Ingelheim Vetmedica, Guadalajara, México.

s.

Ketofen tablets, Rhodia, São Paulo, Brazil.

t.

Rimadyl comprimidos mastigáveis, Laboratórios Pfizer LTDA, Guarulhos, Brazil.

u.

Banamine comprimidos, Schering Plough, São Paulo, Brazil.

v.

GraphPad Prism, GraphPad Software Inc, San Diego, Calif.

References

  • 1

    Boston SE, Moens NM, Kruth SA, et al. Endoscopic evaluation of the gastroduodenal mucosa to determine the safety of shortterm concurrent administration of meloxicam and dexamethasone in healthy dogs. Am J Vet Res 2003;64:13691375.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 2

    Jones CJ, Budsberg SC. Physiologic characteristics and clinical importance of the cyclooxygenase isoforms in dogs and cats. J Am Vet Med Assoc 2000;217:721729.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 3

    Lees P, May SA, McKellar QA. Pharmacology and therapeutics of non-steroidal anti-inflammatory drugs in the dog and cat: 1 general pharmacology. J Small Anim Pract 1991;32:183193.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 4

    Lascelles BDX, Butterworth SJ, Waterman AE. Postoperative analgesic and sedative effects of carprofen and pethidine in dogs. Vet Rec 1994;19:187191.

    • Search Google Scholar
    • Export Citation
  • 5

    Slingsby LS, Waterman-Pearson AE. Analgesic effects in dogs of carprofen and pethidine together compared with the effects of either drug alone. Vet Rec 2001;148:441444.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 6

    Borer LR, Peel JE, Seewald W, et al. Effect of carprofen, etodolac, meloxicam, or butorphanol in dogs with induced acute synovitis. Am J Vet Res 2003;64:14291437.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 7

    Caulkett N, Read M, Fowler D, et al. A comparison of the analgesic effects of butorphanol with those of meloxicam after elective ovariohysterectomy in dogs. Can Vet J 2003;44:565570.

    • Search Google Scholar
    • Export Citation
  • 8

    Lascelles BDX, Cripps P, Mirchandani S, et al. Carprofen as an analgesic for postoperative pain in cats: dose titration and assessment of efficacy in comparison to pethidine hydrochloride. J Small Anim Pract 1995;12:535541.

    • Search Google Scholar
    • Export Citation
  • 9

    Papich MG. Principles of analgesic drug therapy. Semin Vet Med Surg (Small Anim) 1997;12:8093.

  • 10

    Martin TJ, Eisenach JC. Pharmacology of opioid and nonopioid analgesics in chronic pain states. J Pharmacol Exp Ther 2001;299:811817.

  • 11

    Mathews KA. Nonsteroidal anti-inflammatory analgesics in pain management in dogs and cats. Can Vet J 1996;37:539545.

  • 12

    Amadio P Jr, Cummings DM, Amadio PB. NSAIDs revisited. Selection, monitoring, and safe use. Postgrad Med 1997;101:257271.

  • 13

    Budsberg S. Nonsteroidal antiinflammatory drugs. In:Gaynor JS, Muir WW, ed.Handbook of veterinary pain management. Philadelphia: Mosby Inc, 2002;184198.

    • Search Google Scholar
    • Export Citation
  • 14

    Nolan AM. Pharmacology of analgesic drugs. In:Flecknell P, Waterman-Pearson A, ed.Pain management in animals. London: WB Saunders Co, 2001;2152.

    • Search Google Scholar
    • Export Citation
  • 15

    Dow SW, Rosychuk RA, McChesney AE, et al. Effects of flunixin and flunixin plus prednisone on the gastro-intestinal tract of dogs. Am J Vet Res 1990;51:11311138.

    • Search Google Scholar
    • Export Citation
  • 16

    Vonderhaar MA, Salisbury SK. Gastroduodenal ulceration associated with flunixin meglumine administration in three dogs. J Am Vet Med Assoc 1993;203:9295.

    • Search Google Scholar
    • Export Citation
  • 17

    Alencar MMA, Pinto MT, Oliveira DM, et al. Margin of safety of meloxicam in dogs: deleterious effects on blood cells and gastrointestinal tract. Ciênc Rural 2003;33:525532.

    • Search Google Scholar
    • Export Citation
  • 18

    Elwood C, Boswood A, Simpson K, et al. Renal failure after flunixin meglumine administration. Vet Rec 1992;27:582583.

  • 19

    Mathews KA, Doherty T, Dyson DH, et al. Nephrotoxicity in dogs associated with methoxyflurane anesthesia and flunixin meglumine analgesia. Can Vet J 1990;31:766771.

    • Search Google Scholar
    • Export Citation
  • 20

    Vasseur PB, Johnson AL, Budsberg SC, et al. Randomized, controlled trial of the efficacy of carprofen, a nonsteroidal anti-inflammatory drug, in the treatment of osteoarthritis in dogs. J Am Vet Med Assoc 1995;206:807811.

    • Search Google Scholar
    • Export Citation
  • 21

    Nolan R, Reid J. Comparison of the postoperative analgesic and sedative effects of carprofen and papaveratum in dogs. Vet Rec 1993;133:240242.

  • 22

    Grisneaux E, Pibarot P, Dupuis J, et al. Comparison of ketoprofen and carprofen administered prior to orthopedic surgery for control of postoperative pain in dogs. J Am Vet Med Assoc 1999;215:11051110.

    • Search Google Scholar
    • Export Citation
  • 23

    Mathews KA, Paley DM, Foster RA, et al. A comparison of ketorolac with flunixin, butorphanol, and oxymorphone in controlling postoperative pain in dogs. Can Vet J 1996;37:557567.

    • Search Google Scholar
    • Export Citation
  • 24

    Fox SM, Johnston SA. Use of carprofen for the treatment of pain and inflammation in dogs. J Am Vet Med Assoc 1997;210:14931498.

  • 25

    Beaver WT. Ketoprofen: a new nonsteroidal anti-inflammatory analgesic. J Clin Pharmacol 1988;28 (suppl 12):S1.

  • 26

    Kay-Mugford P, Benn SJ, LaMarre J, et al. In vitro effects of nonsteroidal anti-inflammatory drugs on cyclooxygenase activity in dogs. Am J Vet Res 2000;61:802810.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 27

    Taha AS, McLaughlin S, Holland PJ, et al. Effect on gastric and duodenal mucosal prostaglandins of repeated intake of therapeutic doses of naproxen and etodolac in rheumatoid arthritis. Ann Rheum Dis 1990;49:354358.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 28

    Budsberg SC, Johnston SA, Schwarz PD, et al. Efficacy of etodolac for the treatment of osteoarthritis of the hip joints in dogs. J Am Vet Med Assoc 1999;214:206210.

    • Search Google Scholar
    • Export Citation
  • 29

    Reimer ME, Johnston SA, Leib MS, et al. The gastroduodenal effects of buffered aspirin, carprofen, and etodolac in healthy dogs. J Vet Intern Med 1999;13:472477.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 30

    Nishihara K, Kikuchi H, Kanno T, et al. Comparison of the upper gastrointestinal effects of etodolac and aspirin in healthy dogs. J Vet Med Sci 2001;63:11311133.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 31

    Distel M, Mueller C, Bluhmki E, et al. Safety of meloxicam: a global analysis of clinical trials. Br J Rheumatol 1996;35 (suppl 1):6877.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 32

    Feldman BF, Carrol EJ, Jain NC. Coagulation and its disorders. In:Jain NC, ed.Schalm's veterinary hematology. 4th ed.Philadelphia: Lea & Febiger, 1986;388430.

    • Search Google Scholar
    • Export Citation
  • 33

    Forsyth SF, Guilford WG, Haslett SJ, et al. Endoscopy of the gastroduodenal mucosa after carprofen, meloxicam and ketoprofen administration in dogs. J Small Anim Pract 1998;39:421424.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 34

    Murphy KF, German AJ, Ruaux CG, et al. Fecal alpha1-proteinase inhibitor concentration in dogs receiving long-term nonsteroidal anti-inflammatory drug therapy. Vet Clin Pathol 2003;32:136139.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 35

    Hazewinkel HA, Van den Brom WE, Theijse LF, et al. Reduced dosage of ketoprofen for the short-term and long-term treatment of joint pain in dogs. Vet Rec 2003;152:1114.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 36

    Nell T, Bergman J, Hoeijmakers M, et al. Comparison of vedaprofen and meloxicam in dogs with musculoskeletal pain and inflammation. J Small Anim Pract 2002;43:208212.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 37

    Sessions JK, Reynolds LR, Budsberg SC. In vivo effects of carprofen, deracoxib, and etodolac on prostanoid production in blood, gastric mucosa, and synovial fluid in dogs with chronic osteoarthritis. Am J Vet Res 2005;66:812817.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 38

    MacPhail CM, Lappin MR, Meyer DJ, et al. Hepatocellular toxicosis associated with administration of carprofen in 21 dogs. J Am Vet Med Assoc 1998;212:18951901.

    • Search Google Scholar
    • Export Citation
  • 39

    Forsyth SF, Guilford WG, Pfeiffer DU. Effect of NSAID administration on creatinine clearance in healthy dogs undergoing anaesthesia and surgery. J Small Anim Pract 2000;41:547550.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 40

    Hodge TM, Wahlstrom T. Three years (1997–1999) of U.S. clinical experience with Rymadil (carprofen). Pfizer Animal Health Technical Bulletin 2000;110.

    • Search Google Scholar
    • Export Citation
  • 41

    Raekallio MR, Hielm-Bjorkman AK, Kejonen J, et al. Evaluation of adverse effects of long-term orally administered carprofen in dogs. J Am Vet Med Assoc 2006;228:876880.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 42

    Ko JC, Miyabiyashi T, Mandsager RE, et al. Renal effects of carprofen administered to healthy dogs anesthetized with propofol and isoflurane. J Am Vet Med Assoc 2000;217:346349.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 43

    Bostrom IM, Nyman GC, Lord PE, et al. Effects of carprofen on renal function and results of serum biochemical and hematologic analyses in anesthetized dogs that had low blood pressure during anesthesia. Am J Vet Res 2002;63:712721.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 44

    Bostrom IM, Nyman G, Hoppe A, et al. Effects of meloxicam on renal function in dogs with hypotension during anesthesia. Vet Anaesth Analg 2006;33:6269.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 45

    Lobetti RG, Joubert KE. Effect of administration of nonsteroidal anti-inflammatory drugs before surgery on renal function in clinically normal dogs. Am J Vet Res 2000;61:15011507.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 46

    McNeil PE. Acute tubulo-interstitial nephritis in a dog after halothane anaesthesia and administration of flunixin meglumine and trimethoprim-sulphadiazine. Vet Rec 1992;15:148151.

    • Search Google Scholar
    • Export Citation
  • 47

    Dodds WJ. Hemostasis. In:Kaneko JJ, Harvey JW, Bruss ML, ed.Clinical biochemistry of domestic animals. San Diego: Academic Press Inc, 1997;241283.

    • Search Google Scholar
    • Export Citation
  • 48

    Mathews KA, Pettifer G, Foster R, et al. Safety and efficacy of preoperative administration of meloxicam, compared with that of ketoprofen and butorphanol in dogs undergoing abdominal surgery. Am J Vet Res 2001;62:882888.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 49

    Hickford FH, Barr SC, Erb HN. Effect of carprofen on hemostatic variables in dogs. Am J Vet Res 2001;62:16421646.

  • 50

    Lemke KA, Runyon CL, Horney BS. Effects of preoperative administration of ketoprofen on whole blood platelet aggregation, buccal mucosal bleeding time, and hematologic indices in dogs undergoing elective ovariohysterectomy. J Am Vet Med Assoc 2002;220:18181822.

    • Crossref
    • Search Google Scholar
    • Export Citation

Contributor Notes

Presented as an abstract at the Association of Veterinary Anaesthetists Spring Meeting, Liverpool, UK, April 2006.

Address correspondence to Dr. Steagall.