• View in gallery
    Figure 1—

    Difference in mPVF from baseline values (obtained before first treatment), normalized to percentage body weight, in horses with navicular syndrome that were administered etodolac twice daily (23 mg/kg, PO, q 12 h for 3 days; n = 7; dark gray bars), etodolac once daily (23 mg/kg, PO, q 24 h for 3 days; 8; light gray bars), or corn syrup alone (20 mL, PO, q 24 h for 3 days; 7; white bars) at 6, 12, 24, and 36 hours after the final treatment. For a given time point, mean values with the same letter are not significantly different (α = 0.05) as determined by use of protected pairwise ttests. Error bars represent SE.

  • View in gallery
    Figure 2—

    Difference in mPVF from baseline values (obtained before first treatment), normalized to percentage body weight, in horses with navicular syndrome that received etodolac twice daily (23 mg/kg, PO, q 12 h for 3 days; n = 7), etodolac once daily (23 mg/kg, PO, q 24 h for 3 days; 8), or corn syrup alone (20 mL, PO, q 24 h for 3 days; 7) at 6 (black bars), 12 (dark gray bars), 24 (light gray bars), and 36 hours (white bars) after the final treatment. For any given treatment group, mean values with the same letter are not significantly different (α = 0.05) as determined by use of protected pairwise ttest. Error bars represent SE.

  • 1

    USDA. APHIS info sheet: national economic cost of equine lameness, colic, and equine protozoal myeloencephalitis (EPM) in the United States. Washington, DC: USDA, Animal and Plant Health Inspection Service, 2001.

    • Search Google Scholar
    • Export Citation
  • 2

    McIlwraith CW, Frisbie DD, Kawcak CE. Nonsteroidal antiinflammatory drugs, in Proceedings. 47th Annu Meet Am Assoc Equine Pract 2001; 182187.

    • Search Google Scholar
    • Export Citation
  • 3

    Collins LG, Tyler DE. Phenylbutazone toxicosis in the horse: a clinical study. J Am Vet Med Assoc 1984; 184: 699703.

  • 4

    MacAllister CG, Morgan SJ, Borne AT, et al. Comparison of adverse effects of phenylbutazone, flunixin meglumine, and ketoprofen in horses. J Am Vet Med Assoc 1993; 202: 7177.

    • Search Google Scholar
    • Export Citation
  • 5

    Johnston SA, Fox SM. Mechanisms of action of anti-inflammatory medications used for the treatment of osteoarthritis. J Am Vet Med Assoc 1997; 210: 14861492.

    • Search Google Scholar
    • Export Citation
  • 6

    Tomlinson JE, Blikslager AT. Role of nonsteroidal antiinflammatory drugs in gastrointestinal tract injury and repair. J Am Vet Med Assoc 2003; 222: 946951.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 7

    Schnitzer TJ, Constantine G. Etodolac (lodine) in the treatment of osteoarthritis: recent studies. J Rheumatol Suppl 1997; 47: 2331.

    • Search Google Scholar
    • Export Citation
  • 8

    Johnston SA, Budsberg SC. Nonsteroidal anti-inflammatory drugs and corticosteroids for the management of canine osteoarthritis. Vet Clin North Am Small Anim Pract 1997; 27: 841862.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 9

    Glaser K, Sung ML, O'Neill K, et al. Etodolac selectively inhibits human prostaglandin G/H synthase 2 (PGHS-2) versus human PGHS-1. Eur J Pharmacol 1995; 281: 107111.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 10

    Wilson JE, Chandrasekharan NV, Westover KD, et al. Determination of expression of cyclooxygenase-1 and -2 isozymes in canine tissues and their differential sensitivity to nonsteroidal antiinflammatory drugs. Am J Vet Res 2004; 65: 810818.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 11

    Campbell NB, Blikslager AT. The role of cyclooxygenase inhibitors in repair of ischaemic-injured jejunal mucosa in the horse. Equine Vet J Suppl 2000; 32: 5964.

    • Search Google Scholar
    • Export Citation
  • 12

    Campbell NB, Jones SL, Blikslager AT. The effects of cyclooxygenase inhibitors on bile-injured and normal equine colon. Equine Vet J 2002; 34: 493498.

    • Search Google Scholar
    • Export Citation
  • 13

    Van Hoogmoed LM, Snyder JR, Harmon FA. In vitro investigation of the effects of cyclooxygenase-2 inhibitors on contractile activity of the equine dorsal and ventral colon. Am J Vet Res 2002; 63: 14961500.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 14

    Morton AJ, Campbell NB, Gayle JM, et al. Preferential and non-selective cyclooxygenase inhibitors reduce inflammation during lipopolysaccharide-induced synovitis. Res Vet Sci 2005; 78: 189192.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 15

    Stashak T. Navicular syndrome (navicular disease).. In: White NA, Moore JN, eds. Current techniques in equine surgery and lameness. 2nd ed. Philadelphia: WB Saunders Co, 1998; 537544.

    • Search Google Scholar
    • Export Citation
  • 16

    Keegan KG, Wilson DA, Wilson DJ, et al. Evaluation of mild lameness in horses trotting on a treadmill by clinicians and interns or residents and correlation of their assessments with kinematic gait analysis. Am J Vet Res 1998; 59: 13701377.

    • Search Google Scholar
    • Export Citation
  • 17

    Barr ARS, Dow SM, Goodship AE. Parameters of forelimb ground reaction force in 48 normal ponies. Vet Rec 1995; 136: 283286.

  • 18

    McLaughlin RM, Gaughan EM, Roush JK, et al. Effects of subject velocity on ground reaction force measurements and stance times in clinically normal horses at the walk and trot. Am J Vet Res 1996; 57: 711.

    • Search Google Scholar
    • Export Citation
  • 19

    Merkens HW, Schamhardt HC. Evaluation of equine locomotion during different degrees of experimentally induced lameness. I: lameness model and quantification of ground reaction force patterns of the limbs. Equine Vet J Suppl 1988; 6: 99106.

    • Search Google Scholar
    • Export Citation
  • 20

    Merkens HW, Schamhardt HC. Evaluation of equine locomotion during different degrees of experimentally induced lameness. II: Distribution of ground reaction force patterns of concurrently loaded limbs. Equine Vet J Suppl 1988; 6: 107112.

    • Search Google Scholar
    • Export Citation
  • 21

    Merkens HW, Schamhardt HC, van Osch GJVM, et al. Ground reaction force patterns of Dutch Warmblood horses at normal trot. Equine Vet J 1993; 25: 134137.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 22

    Merkens HW, Schamhardt HC, van Osch GJVM, et al. Ground reaction force patterns of Dutch Warmbloods at the canter. Am J Vet Res 1993; 54: 670674.

    • Search Google Scholar
    • Export Citation
  • 23

    Morris EA, Seeherman HJ. Redistribution of ground reaction forces in experimentally induced equine carpal lameness. Equine Exerc Physiol 1987; 2: 553563.

    • Search Google Scholar
    • Export Citation
  • 24

    Schamhardt HC, Merkens HW. Quantification of equine ground reaction force patterns. J Biomech 1987; 20: 443446.

  • 25

    Erkert RS, MacAllister CG, Payton ME, et al. Use of force plate analysis to compare the analgesic effects of intravenous administration of phenylbutazone and flunixin meglumine in horses with navicular syndrome. Am J Vet Res 2005; 66: 284288.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 26

    Hu HH, MacAllister CG, Payton ME, et al. Evaluation of the analgesic effects of phenylbutazone administered at a high or low dosage in horses with chronic lameness. J Am Vet Med Assoc 2005; 226: 414417.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 27

    MacAllister CG. Force plate analysis for the evaluation of NSAIDs in chronically lame horses, in Proceedings. 21st Annu Forum Am Coll Vet Intern Med 2003; 162163.

    • Search Google Scholar
    • Export Citation
  • 28

    Blikslager AT, Campbell NB, Morton AJ. Alternative COX-2 inhibitors for management of pain in horses, in Proceedings. 20th Annu Forum Am Coll Vet Intern Med 2002; 214216.

    • Search Google Scholar
    • Export Citation
  • 29

    American Association of Equine Practitioners. Definition and classification of lameness.. In: Guide for veterinary service and judging of equestrian events. 4th ed. Lexington, Ky: American Association of Equine Practitioners, 1991; 19.

    • Search Google Scholar
    • Export Citation
  • 30

    Lees P, Higgins AJ. Flunixin inhibits prostaglandin E2 production in equine inflammation. Res Vet Sci 1984; 37: 347349.

  • 31

    Lees P, Taylor JB, Maitho TE, et al. Metabolism, excretion, pharmacokinetics and tissue residues of phenylbutazone in the horse. Cornell Vet 1987; 77: 192211.

    • Search Google Scholar
    • Export Citation
  • 32

    Toutain PL, Autefage A, Legrand C, et al. Plasma concentrations and therapeutic efficacy of phenylbutazone and flunixin meglumine in the horse: pharmacokinetic/pharmacodynamic modeling. J Vet Pharmacol Ther 1994; 17: 459469.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 33

    Giuliano F, Ferraz JG, Pereira R, et al. Cyclooxygenase selectivity of non-steroid anti-inflammatory drugs in humans: ex vivo evaluation. Eur J Pharmacol 2001; 426: 95103.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 34

    Ricketts AP, Lundy KM, Seibel SB. Evaluation of selective inhibition of canine cyclooxygenase 1 and 2 by carprofen and other nonsteroidal anti-inflammatory drugs. Am J Vet Res 1998; 59: 14411446.

    • Search Google Scholar
    • Export Citation
  • 35

    Koupai-Abyazani MR, Esaw B, Laviolette B. Etodolac in equine urine and serum: determination by high-performance liquid chromatography with ultraviolet detection, confirmation, and metabolite identification by atmospheric pressure ionization mass spectrometry. J Anal Toxicol 1999; 23: 200209.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 36

    Tomlinson JE, Wilder BO, Young KM, et al. Effects of flunixin meglumine or etodolac treatment on mucosal recovery of equine jejunum after ischemia. Am J Vet Res 2004; 65: 761769.

    • Crossref
    • Search Google Scholar
    • Export Citation

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Use of force plate analysis to assess the analgesic effects of etodolac in horses with navicular syndrome

Kelly D. SymondsDepartment of Veterinary Clinical Sciences, Center for Veterinary Health Sciences, Oklahoma State University, Stillwater, OK 74078.

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Charles G. MacAllisterDepartment of Veterinary Clinical Sciences, Center for Veterinary Health Sciences, Oklahoma State University, Stillwater, OK 74078.

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Ronald S. ErkertDepartment of Physiological Sciences, Center for Veterinary Health Sciences, Oklahoma State University, Stillwater, OK 74078.

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Mark E. PaytonDepartment of Statistics, College of Arts and Sciences, Oklahoma State University, Stillwater, OK 74078.

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Abstract

Objective—To evaluate the musculoskeletal analgesic effect of etodolac administered PO every 12 or 24 hours in chronically lame horses by use of force plate analysis.

Animals—22 horses with navicular syndrome.

Procedure—Horses received etodolac (23 mg/kg, PO, q 12 h; n = 7), etodolac (23 mg/kg, PO, q 24 h; 8), or corn syrup (20 mL, PO, q 24 h; control treatment; 7) for 3 days. Combined forelimb peak vertical ground reaction force (PVF) was measured via force plate analysis before the first treatment (baseline) and at 6, 12, 24, and 36 hours after the last treatment. Differences in mean PVF (mPVF) between baseline and subsequent measurements were analyzed (repeated-measures ANOVA) and evaluated for treatment and time effects and treatment-time interaction.

Results—Once- or twice-daily administration of etodolac resulted in significant increases in mPVF from baseline at 6, 12, and 24 hours after the last treatment, compared with the control treatment. There were no significant differences in mPVF between the etodolac treatment groups at any time point. In both etodolac treatment groups, there was a significant increase in mPVF from baseline at 6, 12, and 24 hours, compared with that at 36 hours. Etodolac-associated adverse effects were not detected.

Conclusions and Clinical Relevance—In horses with navicular syndrome, once-daily oral administration of 23 mg of etodolac/kg appears to provide effective analgesia for as long as 24 hours. Twice-daily administration of etodolac at this same dose does not appear to provide any additional analgesic efficacy or duration of effect.

Abstract

Objective—To evaluate the musculoskeletal analgesic effect of etodolac administered PO every 12 or 24 hours in chronically lame horses by use of force plate analysis.

Animals—22 horses with navicular syndrome.

Procedure—Horses received etodolac (23 mg/kg, PO, q 12 h; n = 7), etodolac (23 mg/kg, PO, q 24 h; 8), or corn syrup (20 mL, PO, q 24 h; control treatment; 7) for 3 days. Combined forelimb peak vertical ground reaction force (PVF) was measured via force plate analysis before the first treatment (baseline) and at 6, 12, 24, and 36 hours after the last treatment. Differences in mean PVF (mPVF) between baseline and subsequent measurements were analyzed (repeated-measures ANOVA) and evaluated for treatment and time effects and treatment-time interaction.

Results—Once- or twice-daily administration of etodolac resulted in significant increases in mPVF from baseline at 6, 12, and 24 hours after the last treatment, compared with the control treatment. There were no significant differences in mPVF between the etodolac treatment groups at any time point. In both etodolac treatment groups, there was a significant increase in mPVF from baseline at 6, 12, and 24 hours, compared with that at 36 hours. Etodolac-associated adverse effects were not detected.

Conclusions and Clinical Relevance—In horses with navicular syndrome, once-daily oral administration of 23 mg of etodolac/kg appears to provide effective analgesia for as long as 24 hours. Twice-daily administration of etodolac at this same dose does not appear to provide any additional analgesic efficacy or duration of effect.

Lameness is reported to be the most common and costly health problem in horses; the mean duration of lost use per lameness event is 110 days.1 The drugs most commonly used to manage musculoskeletal pain and inflammation that result in lameness in horses are NSAIDs.2 The NSAIDs that are currently used in horses, such as phenylbutazone and flunixin meglumine, are reported to have toxic adverse effects.3,4 Adverse effects associated with phenylbutazone and flunixin include oral and gastrointestinal ulceration, inflammation of the right dorsal colon, hypoproteinemia, and ventrally located edema.3,4 However, to the authors' knowledge, adverse effects associated with etodolac have not been reported.

The mechanism of action of NSAIDs involves inhibition of the COX enzyme system and suppression of prostanoid formation.5 The molecular structure of COX consists of 2 primary isoforms, designated COX-1 and COX-2. Cyclooxygenase-1 is considered the constitutive enzyme and produces prostanoids used in normal physiologic functions; COX-2 is an inducible enzyme that is upregulated by a variety of inflammatory stimuli. However, the line separating the functions of COX-1 and COX-2 is becoming increasingly blurred.

It has been suggested that selected inhibition of the COX-2 enzyme would provide analgesia without inhibiting the protective actions of COX-1, thus decreasing potential toxic effects of NSAIDs.6 Etodolac is an NSAID that is used in humans7 and dogs8 to treat osteoarthritis. It selectively inhibits both the human9 and canine10 COX-2 pathways and also appears to be selective for the equine COX-2 pathway.11–14

Lameness in horses is commonly evaluated subjectively by assigning a clinical score derived from accepted numerical rating scales.15 However, subjective evaluation of lameness is influenced by the experience of the evaluator.16 Use of a force plate provides an objective means of measuring lameness.17–26 In our laboratory, it has been shown that clinically normal horses trotting at speeds of 2.5 to 2.9 m/s strike the plate with their forelimbs at an mPVF of 104.2 ± 1.16% body weight (mean ± SE).27 In lame horses, the mPVF decreases proportionally as the degree of lameness increases.19,20,23,25

Navicular syndrome is one of the most common causes of lameness in horses; although the etiology is incompletely understood, navicular syndrome produces chronic progressive, typically bilateral forelimb lameness.15 In our experience, navicular syndrome results in a stable lameness with no significant interday or interweek variation. Also, the light exercise necessary during force plate evaluation does not affect the mPVF and therefore does not create an unwanted variable during data collection.

Results of a pharmacokinetic study28 in horseshave indicated that etodolac should be administered at a dosage of 23 mg/kg PO every 12 hours. However, one of the authors is aware that many equine practitioners are administering the product once daily and only with anecdotal evidence of efficacy. In addition, etodolac is being used with objective evidence of efficacy. The objective of the study reported here was to evaluate the musculoskeletal analgesic effect of etodolac administered PO every 12 hours or every 24 hours to horses with navicular syndrome by use of force plate analysis.

Materials and Methods

Horses—Twenty-two chronically lame but otherwise healthy horses (21 geldings and 1 mare) were used in this study; the mean ± SD weight of the horses was 551 ± 41 kg, and mean age was 12.5 ± 3.2 years. Navicular syndrome had been previously diagnosed in these horses on the basis of findings of clinical examination, diagnostic nerve blocks, and radiography. Horses were owned by the Oklahoma State University College of Veterinary Medicine and housed in paddocks at the Equine Research Park. They were acclimated to their diet and surroundings for at least 2 weeks prior to the start of the study. Horses were fed grass hay free choice and had free access to fresh water and mineral salt blocks. During the study, horses were observed twice daily for signs of illness. At each time of treatment of each horse, an examination of the oral cavity was performed and heart and respiratory rates and rectal temperatures were assessed. Hooves were trimmed to balance at least 7 days prior to the start of the study. Twelve of the horses had been used in previous studies25,26 that were similar to the one reported here. The Oklahoma State University Institutional Animal Care and Use Committee approved the study protocol.

Inclusion criteria—All horses were required to have a forelimb lameness score of 2 to 4 assigned on the basis of the American Association of Equine Practitioners 5-point lameness grading scale.29 Navicular syndrome was diagnosed on the basis of findings of clinical and lameness examinations, response to hoof testers across the heel and the middle third of the frog, improvement of lameness following a palmar digital or abaxial sesmoidean nerve block, and radiographic evidence of degenerative changes within the navicular bone. Additionally, horses had to strike the force plate with an mPVF < 90% of body weight on at least 1 forelimb prior to beginning treatment. Pretreatment force plate data was used as the baseline values.

Study design—Horses were randomly assigned to 1 of 3 treatment groups; horses received 23 mg of etodolaca/kg administered PO every 12 hours for 3 days, 23 mg of etodolaca/kg administered PO every 24 hours for 3 days, or 20 mL of corn syrupb alone administered PO every 24 hours for 3 days (control group). Etodolac tablets were ground in a coffee grinder and mixed with 20 mL of corn syrup to form a paste. Etodolac and control treatments were administered by use of 30-mL dosing syringes. Prior to administration of any treatment, the horse's mouth was rinsed with water to remove grass and debris. Peak vertical force measurements were recorded from both forelimbs prior to starting treatment (baseline) and at 6, 12, 24, and 36 hours after the last treatment. Personnel collecting force plate data were unaware of which treatment each horse had received.

Force plate data acquisition—A force plate session consisted of 6 valid trials with a handler leading the horse at a trot across a centrally positioned floor-mounted force plate.c Valid trials consisted of the hoof of each forelimb striking squarely on the force plate; constant gait as the horse moved across the force plate; and a velocity of 2.50 to 2.90 m/s. Forward velocity was measured by use of a millisecond timer and 2 photoelectric switchesd spaced 3 m apart. Trials were rejected if the timer failed to trigger, strikes were partial or questionable, strikes were abnormal because of obvious changes in gait, or velocities were outside the established range. For each pass, an observer confirmed proper gait and hoof strike. Valid strikes were analyzed by use of specialized softwaree and all forces normalized to percentage body weight. Body weight was assessed just prior to each force plate evaluation.

Data analysis—Statistical analyses were performed by use of standard statistical software.f The difference in the combined right and left forelimb mPVF between baseline and each of the values at 6, 12, 24, and 36 hours after that last treatment were compared for each treatment group and the control group. Effects of treatments were analyzed via ANOVA techniques with repeated measures by use of an autoregressive covariance structure.g Time by treatment interaction was investigated. Simple effects of treatment with given times and time with given treatments interactions were assessed prior to conducting post hoc multiple comparisons.h Multiple comparisons for time were performed when appropriate. Effects were considered significant at a value of P < 0.05.

Results

For 3 days, 8 horses (all geldings) received etodolac once daily, 7 horses (6 geldings and 1 mare) received etodolac twice daily, and 7 horses (all geldings) received the control treatment once daily. All horses maintained good appetite and remained healthy, other than lameness, throughout the study. In each horse, examinations of the oral cavity at each time of treatment revealed no abnormalities; heart and respiratory rates and rectal temperatures were within reference limits at all examinations. Horses did not develop clinical evidence of NSAID toxicosis.

Force plate data analysis—Results of treatment with respect to time were analyzed (Figure 1). Once-daily treatment with 23 mg of etodolac/kg resulted in a significant increase in mPVF at 6, 12, and 24 hours (P = 0.002, 0.015, and 0.020, respectively) after the last treatment, compared with findings in the control group (horses that received corn syrup alone). Similar results at 6, 12, and 24 hours (P = 0.009, 0.040, and 0.010, respectively) after the last treatment were obtained in horses that received twice-daily treatment with etodolac, compared with findings in the control horses. At 36 hours after the last treatment, there were no significant differences between the control group and either of the etodolac treatment groups (P = 0.307 [once-daily treatment group] and 0.112 [twice-daily treatment group]). At no time point was there a significant difference between the 2 etodolac treatment groups (P = 0.583 [6-hour values], 0.721 [12-hour values], 0.696 [24-hour values], and 0.524 [36-hour values]).

Figure 1—
Figure 1—

Difference in mPVF from baseline values (obtained before first treatment), normalized to percentage body weight, in horses with navicular syndrome that were administered etodolac twice daily (23 mg/kg, PO, q 12 h for 3 days; n = 7; dark gray bars), etodolac once daily (23 mg/kg, PO, q 24 h for 3 days; 8; light gray bars), or corn syrup alone (20 mL, PO, q 24 h for 3 days; 7; white bars) at 6, 12, 24, and 36 hours after the final treatment. For a given time point, mean values with the same letter are not significantly different (α = 0.05) as determined by use of protected pairwise ttests. Error bars represent SE.

Citation: American Journal of Veterinary Research 67, 4; 10.2460/ajvr.67.4.557

Changes in the mPVF over time for individual treatment groups were assessed (Figure 2). The group receiving etodolac twice daily had significant increases in mPVF at 6 and 24 hours, compared with the value at 36 hours (P = 0.036 and 0.014, respectively); however, based on the statistical criterion for significance (P < 0.050) used in our study, there was no significant (P = 0.061) difference in mPVF at the 12- and 36-hour time points. In this group, there was no significant difference between the 6- and 12-hour mPVF values (P = 0.549), the 6- and 24-hour mPVF values (P = 0.702), or the 12- and 24-hour mPVF values (P = 0.911).

Figure 2—
Figure 2—

Difference in mPVF from baseline values (obtained before first treatment), normalized to percentage body weight, in horses with navicular syndrome that received etodolac twice daily (23 mg/kg, PO, q 12 h for 3 days; n = 7), etodolac once daily (23 mg/kg, PO, q 24 h for 3 days; 8), or corn syrup alone (20 mL, PO, q 24 h for 3 days; 7) at 6 (black bars), 12 (dark gray bars), 24 (light gray bars), and 36 hours (white bars) after the final treatment. For any given treatment group, mean values with the same letter are not significantly different (α = 0.05) as determined by use of protected pairwise ttest. Error bars represent SE.

Citation: American Journal of Veterinary Research 67, 4; 10.2460/ajvr.67.4.557

The group receiving etodolac once daily had significant increases in mPVF at 6, 12, and 24 hours, compared with the value at 36 hours (P = 0.0004, 0.001, and 0.003, respectively). In this group, there was no significant difference between the 6- and 12-hour mPVF values (P = 0.339), the 6- and 24-hour mPVF values (P = 0.107), or the 12- and 24-hour mPVF values (P = 0.268).

The control group had no significant increase in mPVF at 6, 12, or 24 hours, compared with the value at 36 hours (P = 0.369, 0.202, and 0.422, respectively). In this group, there was no significant difference between the 6- and 12-hour mPVF values (P = 0.720), the 6- and 24-hour mPVF values (P = 0.711), or the 12- and 24-hour mPVF values (P = 0.408).

Discussion

The results of the present study indicated that the analgesic efficacy of etodolac administered PO once daily at a dose of 23 mg/kg for 3 days was similar to that of the same dose of drug administered PO twice daily for 3 days in horses with navicular syndrome. Compared with findings in the corn-syrup–treated control horses, both the once-daily and twice-daily etodolac treatments provided effective analgesia in chronically lame horses for at least 24 hours, but not exceeding 36 hours. This indicates that, under the conditions of our study, administration of etodolac twice daily had no advantage over once-daily administration despite apparently contradictory pharmacokinetic data. On the basis of the established requirement for significance in the study (P < 0.05), the mPVF values at 12 and 36 hours after the last treatment in the group receiving etodolac twice daily were not significantly (P = 0.061) different. However, if more horses were included in this treatment group or the study design was different (ie, a crossover study), it would be most likely that the values at these 2 time points would be significantly different. This is supported by the significant difference between the 12- and 36-hour mPVF values in the group receiving etodolac once daily.

On the basis of pharmacokinetic data, it is recommended that horses be treated with 23 mg of etodolac/kg twice daily.28 However, results of studies25,26,30,31 involving phenylbutazone and flunixin meglumine have indicated a longer duration of analgesic and anti-inflammatory efficacy than would be expected on the basis of pharmacokinetics. The findings of those studies are suggestive of third-space sequestration of the drugs in inflamed tissue. By use of pharmacokinetic-pharmacodynamic models of phenylbutazone and flunixin, the duration of effects associated with administration of these drugs at typical clinical doses of 4.4 mg/kg and 1.1 mg/kg, respectively, should be approximately 16 hours.32 In previous pharmacodynamic studies25,26 involving force plate analyses, a duration of analgesic efficacy of 24 hours was identified for both phenylbutazone and flunixin following once-daily administration of typical clinical doses for 4 days. Similarly, for both these drugs, the period during which eicosanoid concentrations in inflammatory exudate remained decreased was longer than that predicted by pharmacokinetic data.30,31 It is likely that a similar phenomenon is associated with etodolac, which may account for the lack of significant difference in analgesic efficacy between the horses receiving etodolac once daily and twice daily in the present study.

The most commonly used NSAIDs for the treatment of lameness in horses are phenylbutazone and flunixin meglumine.2 The analgesic efficacy of these drugs has been evaluated in studies25,26 involving a model of lameness in horses similar to that used in the present study. In a study25 that evaluated phenylbutazone and flunixin (administered at dosages of 4.4 mg/kg and 1.1 mg/kg, respectively, IV, q 24 h for 4 days), the mean percentage increase in mPVF from baseline ranged from 9% to 13% at 6, 12, and 24 hours after the final treatment, and no significant difference in mPVF between treatments was detected. In another study26 in which 2 dosages of phenylbutazone (4.4 mg/kg and 8.8 mg/kg, IV, q 24 h for 4 days) were evaluated, similar mean percentage increases in mPVF from baseline were identified at 6, 12, and 24 hours after the last treatment, and no significant difference in mPVF between dosages was detected. In contrast, in the study reported here, the mean percentage increase in mPVF from baseline ranged from 5% to 9%. This apparently lesser degree of improvement in lameness after treatment with etodolac may reflect a lower potency for analgesia or indicate that the maximum effective dose was not achieved under the conditions of our study. The latter explanation is less likely because there was no additional improvement in lameness in the group receiving etodolac twice daily, compared with that achieved in the group receiving the drug once daily. Alternatively, because etodolac is considered a preferential COX-2 inhibitor, it may be that contributions of COX-1 to the inflammatory response are not substantially inhibited. Further studies, however, are required to fully evaluate the potential differences in analgesic efficacy among etodolac, phenylbutazone, and flunixin meglumine.

Phenylbutazone and flunixin do not selectively inhibit the COX-2 pathway. In humans, etodolac has been shown in vitro to have a 10-fold preference for COX-2 with a COX-1:COX-2 inhibition ratio of 0.094.9 However, in an ex vivo study,33 high dosage (400 mg, PO, q 12 h [9 doses]), but not low dosage (200 mg, PO, q 12 h [9 doses]), of etodolac caused a significant reduction in the activity of both COX-1 and COX-2 with no significant COX-2 selectivity for either dosages. Results of initial studies34 involving washed platelets from dogs indicated that etodolac was not as selective for COX-2 in dogs as it is in humans; in that study, the COX-1:COX-2 inhibition ratio was 0.517. However, in a more recent in vitro study,10 whole blood samples from dogs were used as a more realistic model of physiologic conditions. Results of that study indicated that etodolac is 7 times as selective (COX-1:COX-2 ratio of 0.16) for COX-2 as it is for COX-1 in dogs. The discrepancy in the findings of these 2 studies was thought most likely to be due to differences in the models used for analysis of COX inhibition.

On the basis of previously reported data,35 a 2-g dose of etodolac administered to horses yields a peak serum concentration of approximately 3.25 μg/mL; this corresponds to a 1.13 × 10−5M concentration, which is similar to the concentration of etodolac used in several in vitro studies.11–13 The results of in vitro studies involving samples of jejunal and colonic mucosa in Ussing chambers appear to support the COX-2 selectivity of etodolac in horses. However, the findings of those previous studies appear to be contradicted by results of a recent ex vivo study36 that used a dose of 7 to 14 g of etodolac/horse, which would correspond to molar concentrations higher than those used in the in vitro studies. Therefore, a third explanation may be that clinical dosages in horses are high enough to inhibit both COX isozymes, as determined in humans.13,33

Although specific tests were not performed to evaluate the horses for NSAID toxicosis in the study reported here, all horses remained healthy throughout the study period. However, overt adverse effects are more commonly associated with long-term NSAID administration and therefore not expected to be detected after only 3 days of treatment. Although treatment with etodolac may have the potential to be safer than treatments with other nonselective NSAIDs, further studies are required to assess potential safety and doserelated COX selectivity.

Regardless of selectivity, etodolac appears to provide good analgesia for at least 24 hours when administered at a dosage of 23 mg/kg PO once daily in horses with navicular syndrome and should be considered as a viable alternative for management of musculoskeletal pain in this species. However, the authors emphasize that precautions should be taken to monitor horses for signs of toxicosis when they are treated with etodolac for extended periods.

ABBREVIATIONS

NSAID

Nonsteroidal anti-inflammatory drug

COX

Cyclooxygenase

mPVF

Mean peak vertical force

a.

Etodolac, Fort Dodge Animal Health, Fort Dodge, Iowa.

b.

Griffin's Crystal White corn syrup, Griffin Food Co, Muskogee, Okla.

c.

Multicomponent force plate (model 9287BA), Kistler Instrument Corp, Amherst, NY.

d.

Phototiming switch system (model 49-551A), Radioshack, Fort Worth, Tex.

e.

Bioware 3.0, Kistler Instrument Corp, Amherst, NY.

f.

PC SAS, version 8.2, SAS Institute Inc, Cary, NC.

g.

PROC MIXED in PC SAS, version 8.2, SAS Institute Inc, Cary, NC.

h.

SLICE option in an LSMEANS statement, in PC SAS, version 8.2, SAS Institute Inc, Cary, NC.

  • 1

    USDA. APHIS info sheet: national economic cost of equine lameness, colic, and equine protozoal myeloencephalitis (EPM) in the United States. Washington, DC: USDA, Animal and Plant Health Inspection Service, 2001.

    • Search Google Scholar
    • Export Citation
  • 2

    McIlwraith CW, Frisbie DD, Kawcak CE. Nonsteroidal antiinflammatory drugs, in Proceedings. 47th Annu Meet Am Assoc Equine Pract 2001; 182187.

    • Search Google Scholar
    • Export Citation
  • 3

    Collins LG, Tyler DE. Phenylbutazone toxicosis in the horse: a clinical study. J Am Vet Med Assoc 1984; 184: 699703.

  • 4

    MacAllister CG, Morgan SJ, Borne AT, et al. Comparison of adverse effects of phenylbutazone, flunixin meglumine, and ketoprofen in horses. J Am Vet Med Assoc 1993; 202: 7177.

    • Search Google Scholar
    • Export Citation
  • 5

    Johnston SA, Fox SM. Mechanisms of action of anti-inflammatory medications used for the treatment of osteoarthritis. J Am Vet Med Assoc 1997; 210: 14861492.

    • Search Google Scholar
    • Export Citation
  • 6

    Tomlinson JE, Blikslager AT. Role of nonsteroidal antiinflammatory drugs in gastrointestinal tract injury and repair. J Am Vet Med Assoc 2003; 222: 946951.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 7

    Schnitzer TJ, Constantine G. Etodolac (lodine) in the treatment of osteoarthritis: recent studies. J Rheumatol Suppl 1997; 47: 2331.

    • Search Google Scholar
    • Export Citation
  • 8

    Johnston SA, Budsberg SC. Nonsteroidal anti-inflammatory drugs and corticosteroids for the management of canine osteoarthritis. Vet Clin North Am Small Anim Pract 1997; 27: 841862.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 9

    Glaser K, Sung ML, O'Neill K, et al. Etodolac selectively inhibits human prostaglandin G/H synthase 2 (PGHS-2) versus human PGHS-1. Eur J Pharmacol 1995; 281: 107111.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 10

    Wilson JE, Chandrasekharan NV, Westover KD, et al. Determination of expression of cyclooxygenase-1 and -2 isozymes in canine tissues and their differential sensitivity to nonsteroidal antiinflammatory drugs. Am J Vet Res 2004; 65: 810818.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 11

    Campbell NB, Blikslager AT. The role of cyclooxygenase inhibitors in repair of ischaemic-injured jejunal mucosa in the horse. Equine Vet J Suppl 2000; 32: 5964.

    • Search Google Scholar
    • Export Citation
  • 12

    Campbell NB, Jones SL, Blikslager AT. The effects of cyclooxygenase inhibitors on bile-injured and normal equine colon. Equine Vet J 2002; 34: 493498.

    • Search Google Scholar
    • Export Citation
  • 13

    Van Hoogmoed LM, Snyder JR, Harmon FA. In vitro investigation of the effects of cyclooxygenase-2 inhibitors on contractile activity of the equine dorsal and ventral colon. Am J Vet Res 2002; 63: 14961500.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 14

    Morton AJ, Campbell NB, Gayle JM, et al. Preferential and non-selective cyclooxygenase inhibitors reduce inflammation during lipopolysaccharide-induced synovitis. Res Vet Sci 2005; 78: 189192.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 15

    Stashak T. Navicular syndrome (navicular disease).. In: White NA, Moore JN, eds. Current techniques in equine surgery and lameness. 2nd ed. Philadelphia: WB Saunders Co, 1998; 537544.

    • Search Google Scholar
    • Export Citation
  • 16

    Keegan KG, Wilson DA, Wilson DJ, et al. Evaluation of mild lameness in horses trotting on a treadmill by clinicians and interns or residents and correlation of their assessments with kinematic gait analysis. Am J Vet Res 1998; 59: 13701377.

    • Search Google Scholar
    • Export Citation
  • 17

    Barr ARS, Dow SM, Goodship AE. Parameters of forelimb ground reaction force in 48 normal ponies. Vet Rec 1995; 136: 283286.

  • 18

    McLaughlin RM, Gaughan EM, Roush JK, et al. Effects of subject velocity on ground reaction force measurements and stance times in clinically normal horses at the walk and trot. Am J Vet Res 1996; 57: 711.

    • Search Google Scholar
    • Export Citation
  • 19

    Merkens HW, Schamhardt HC. Evaluation of equine locomotion during different degrees of experimentally induced lameness. I: lameness model and quantification of ground reaction force patterns of the limbs. Equine Vet J Suppl 1988; 6: 99106.

    • Search Google Scholar
    • Export Citation
  • 20

    Merkens HW, Schamhardt HC. Evaluation of equine locomotion during different degrees of experimentally induced lameness. II: Distribution of ground reaction force patterns of concurrently loaded limbs. Equine Vet J Suppl 1988; 6: 107112.

    • Search Google Scholar
    • Export Citation
  • 21

    Merkens HW, Schamhardt HC, van Osch GJVM, et al. Ground reaction force patterns of Dutch Warmblood horses at normal trot. Equine Vet J 1993; 25: 134137.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 22

    Merkens HW, Schamhardt HC, van Osch GJVM, et al. Ground reaction force patterns of Dutch Warmbloods at the canter. Am J Vet Res 1993; 54: 670674.

    • Search Google Scholar
    • Export Citation
  • 23

    Morris EA, Seeherman HJ. Redistribution of ground reaction forces in experimentally induced equine carpal lameness. Equine Exerc Physiol 1987; 2: 553563.

    • Search Google Scholar
    • Export Citation
  • 24

    Schamhardt HC, Merkens HW. Quantification of equine ground reaction force patterns. J Biomech 1987; 20: 443446.

  • 25

    Erkert RS, MacAllister CG, Payton ME, et al. Use of force plate analysis to compare the analgesic effects of intravenous administration of phenylbutazone and flunixin meglumine in horses with navicular syndrome. Am J Vet Res 2005; 66: 284288.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 26

    Hu HH, MacAllister CG, Payton ME, et al. Evaluation of the analgesic effects of phenylbutazone administered at a high or low dosage in horses with chronic lameness. J Am Vet Med Assoc 2005; 226: 414417.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 27

    MacAllister CG. Force plate analysis for the evaluation of NSAIDs in chronically lame horses, in Proceedings. 21st Annu Forum Am Coll Vet Intern Med 2003; 162163.

    • Search Google Scholar
    • Export Citation
  • 28

    Blikslager AT, Campbell NB, Morton AJ. Alternative COX-2 inhibitors for management of pain in horses, in Proceedings. 20th Annu Forum Am Coll Vet Intern Med 2002; 214216.

    • Search Google Scholar
    • Export Citation
  • 29

    American Association of Equine Practitioners. Definition and classification of lameness.. In: Guide for veterinary service and judging of equestrian events. 4th ed. Lexington, Ky: American Association of Equine Practitioners, 1991; 19.

    • Search Google Scholar
    • Export Citation
  • 30

    Lees P, Higgins AJ. Flunixin inhibits prostaglandin E2 production in equine inflammation. Res Vet Sci 1984; 37: 347349.

  • 31

    Lees P, Taylor JB, Maitho TE, et al. Metabolism, excretion, pharmacokinetics and tissue residues of phenylbutazone in the horse. Cornell Vet 1987; 77: 192211.

    • Search Google Scholar
    • Export Citation
  • 32

    Toutain PL, Autefage A, Legrand C, et al. Plasma concentrations and therapeutic efficacy of phenylbutazone and flunixin meglumine in the horse: pharmacokinetic/pharmacodynamic modeling. J Vet Pharmacol Ther 1994; 17: 459469.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 33

    Giuliano F, Ferraz JG, Pereira R, et al. Cyclooxygenase selectivity of non-steroid anti-inflammatory drugs in humans: ex vivo evaluation. Eur J Pharmacol 2001; 426: 95103.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 34

    Ricketts AP, Lundy KM, Seibel SB. Evaluation of selective inhibition of canine cyclooxygenase 1 and 2 by carprofen and other nonsteroidal anti-inflammatory drugs. Am J Vet Res 1998; 59: 14411446.

    • Search Google Scholar
    • Export Citation
  • 35

    Koupai-Abyazani MR, Esaw B, Laviolette B. Etodolac in equine urine and serum: determination by high-performance liquid chromatography with ultraviolet detection, confirmation, and metabolite identification by atmospheric pressure ionization mass spectrometry. J Anal Toxicol 1999; 23: 200209.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 36

    Tomlinson JE, Wilder BO, Young KM, et al. Effects of flunixin meglumine or etodolac treatment on mucosal recovery of equine jejunum after ischemia. Am J Vet Res 2004; 65: 761769.

    • Crossref
    • Search Google Scholar
    • Export Citation

Contributor Notes

Dr. Symond's present address is 2421 W Mt Comfort Rd, Fayetteville, AR 72704.

Dr. Symonds conducted this study during the 3rd year of her professional program in the College of Veterinary Medicine as part of the NIH summer research training program.

The authors thank Fort Dodge Animal Health for provision of etodolac and Carl Gedon, Clint Stubblefield, Sabrina Cummings, and Amanda Skogen for technical assistance.

Dr. MacAllister.