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]).
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
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
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).
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
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
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 |
Etodolac, Fort Dodge Animal Health, Fort Dodge, Iowa.
Griffin's Crystal White corn syrup, Griffin Food Co, Muskogee, Okla.
Multicomponent force plate (model 9287BA), Kistler Instrument Corp, Amherst, NY.
Phototiming switch system (model 49-551A), Radioshack, Fort Worth, Tex.
Bioware 3.0, Kistler Instrument Corp, Amherst, NY.
PC SAS, version 8.2, SAS Institute Inc, Cary, NC.
PROC MIXED in PC SAS, version 8.2, SAS Institute Inc, Cary, NC.
SLICE option in an LSMEANS statement, in PC SAS, version 8.2, SAS Institute Inc, Cary, NC.
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