SEARCH

SEARCH BY CITATION

Keywords:

  • horse;
  • exercise;
  • heart rate;
  • nonsteroidal anti-inflammatory drug;
  • NSAID

Summary

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Conflicts of interest
  9. Manufacturers' addresses
  10. References

Reasons for performing study: Objective blinded efficacy data during exercise are lacking on the use of single-dose i.v. nonsteroidal anti-inflammatory drugs (NSAIDs) before, during and after exercise.

Hypothesis: Single i.v. doses of either phenylbutazone (PBZ) or flunixin meglumine (FM) would prove more efficacious than negative saline control (SAL) before, during and after exercise in a reversible model of foot lameness.

Methods: Six Quarter Horse mares had lameness induced by tightening a set screw against a heart bar shoe 1 h prior to treatment. Randomised blinded treatments included PBZ (4.4 mg/kg bwt i.v.), FM (1.1 mg/kg bwt i.v.), and SAL (1 ml/45 kg i.v.). Heart rate and lameness score (LS) were recorded at rest; every 20 min after lameness induction for 5 h and at the end of 2 min treadmill workloads of 2 and 4 m/s. Heart rate was also recorded from 0.5–60 min post exercise. Results were compared using RM ANOVA and Student-Newman-Keul's test (HR) and Wilcoxon signed rank test (%ΔLS) with significance set at P<0.05.

Results: Pre-exercise mean HR was decreased for both NSAIDs compared to SAL from 1:20–4 h post treatment (P<0.05). Pre-exercise mean %ΔLS was decreased for PBZ (1:20–4 h) and FM (1–4 h) compared to SAL (P<0.01). With exercise, there were no HR differences between treatments (P>0.05), but mean %ΔLS was decreased for both NSAIDs compared to SAL (P<0.01). Mean recovery HR was decreased for PBZ and FM from 1–60 min compared to SAL (P<0.05).

Conclusions: PBZ and FM demonstrated definitive clinical efficacy after single i.v. doses before, during and after exercise. Use of single i.v. doses during competition may mask lameness and may affect the ability of judges in determining the soundness of horses in competition.


Introduction

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Conflicts of interest
  9. Manufacturers' addresses
  10. References

Governing jurisdictions for equestrian competitions have widely varying rules and regulations regarding the use of nonsteroidal anti-inflammatory drugs (NSAIDs) before, or on the day of competition, yet objective blinded efficacy data during exercise are lacking after single i.v. NSAID doses. Since 1992, the Fédération Equestre Internationale (FEI) has had a zero tolerance policy for the detectable presence of any NSAID on competition day. A recently-recommended FEI rule change may permit the use of half-doses of single NSAIDs no closer than 12 h prior to competition, beginning possibly in late 2010. Some Thoroughbred and Standardbred racing states allow the presence of one NSAID (most often phenylbutazone) on race day, usually only when present below certain approved maximum allowable plasma limits. Other racing jurisdictions have allowed the use of more than one NSAID on race day, sometimes in any plasma concentration on race day (Dirikolu et al. 2009).

Previous studies have demonstrated NSAID efficacy in horses but nearly all have used oral, not i.v. doses, and nearly all have used multiple, not single doses, more often with phenylbutazone (PBZ) (Owens et al. 1995, 1996; Erkert et al. 2005; Hu et al. 2005; Schoonover et al. 2005; Doucet et al. 2008; Keegan et al. 2008; Sebatéet al. 2009) and rarely with flunixin meglumine (FM) (Hamm et al. 1997; Kallings et al. 1999; Erkert et al. 2005; Keegan et al. 2008). The objective of this experiment was to compare the clinical efficacy of a single i.v. dose of PBZ, FM or isotonic saline (SAL) before, during and after exercise. The hypothesis was that a single i.v. dose of either NSAID would prove more efficacious than the SAL negative control before, during and after exercise in a reversible model of foot lameness.

Previous research in our laboratory has shown heart rate (HR) to be elevated with lameness before, during and after exercise when compared to negative controls in both laboratory models (Foreman and Lawrence 1987; Foreman et al. 1994, 2008; Seino et al. 2003) and field training settings (Foreman et al. 1990). These HR elevations increase with increasing degrees of lameness in our model, where lameness is induced by tightening an adjustable heart bar shoe (Goetz and Comstock 1985), thereby applying temporary painful pressure to the frog of the foot (Foreman and Lawrence 1987; Foreman et al. 1994, 2008; Seino et al. 2003). Using this model, we measured HR and lameness score (LS) as primary variables in evaluating the response of reversibly lame horses to single i.v. doses of PBZ or FM compared to a negative control before, during and after exercise.

Materials and methods

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Conflicts of interest
  9. Manufacturers' addresses
  10. References

Subjects

All procedures regarding the care and control of these subjects were approved by the University of Illinois Institutional Animal Care and Use Committee. Six Quarter Horse mares (aged 15–18 years and weighing 500–615 kg) with previous treadmill laboratory experience were studied for 3 weeks. Complete physical and lameness examinations were performed before experiments were begun to ensure that each subject was normal. One mare had had a previous heel lameness problem that had necessitated a palmar digital neurectomy in the left front foot; otherwise, it was sound in the opposite (right) foot and sound in the left foot after the neurectomy.

Heart bar shoe model

Five subjects' left front feet had adjustable heart bar shoes applied. The right front feet had a midfoot bar shoe of a similar weight applied for balance. The shoes were reversed in position (heart bar on the right, balanced bar shoe on the left) in the one horse with a palmar digital neurectomy on the left front foot. A minimum of 7 days of stall rest was allowed after shoeing and before any lameness trials were begun. Lameness was induced by tightening a set screw against the adjustable heart bar 1 h prior to administration of treatment.

Treatments

Single i.v. treatments administered in a randomised blinded manner included PBZ1 (4.4 mg/kg bwt i.v.), FM (Banamine2, 1.1 mg/kg bwt i.v.) and SAL (1 ml/45 kg bwt i.v.). The doses used for the NSAIDs were standard label doses commonly-used clinically for lameness problems in veterinary practice; the saline dose was designed to be similar in volume to the doses of the NSAIDs. Treatments were administered by one investigator (T.L.G.) in a randomised fashion, so that all treatment order permutations were represented. Treatment periods were at least 7 days apart to ensure washout of the previously administered treatment. The investigator administering treatments was responsible for protecting the secrecy of the order of treatment assignments to ensure that the investigator measuring HR and LS (J.H.F.) remained blinded throughout the experiment.

Lameness induction

A set screw was placed in the heart bar shoe to induce lameness 1 h prior to administration of treatment. Lameness was scored using a previously-described decimal grading system (Foreman and Lawrence 1987; Foreman et al. 1990, 1994, 2008; Seino et al. 2003). All lameness grading prior to treadmill exercise was performed in the individual box stall without jogging any horse and without walking any horse other than observing spontaneous walking movement within the stall. To perform a more thorough lameness examination was logistically impossible on an every 20 min basis on 6 horses simultaneously. Furthermore, given the importance of HR in monitoring lameness in our model, additional movements outside the stalls for frequent lameness examinations with trotting probably would have compromised the use of HR as an objective quantifiable primary variable to measure physiological response to NSAID administration.

Lameness score grades at rest in the stall were 0.0 (sound or undetectable lameness), 1.0 (barely-detectable lameness; horse intermittently looks lame at a walk in the stall and/or points the lame toe forward intermittently and rarely), 2.0 (mild lameness; horse is more consistently lame at a walk in the stall, has a slight head bob when walking in the stall and points its toe more consistently), 3.0 (moderate lameness but not nonweightbearing; horse has mild head bob at a walk in the stall, toe pointing more frequently; this grade causes a typical obvious head-bobbing lameness when horses are trotted, similar to an AAEP Lameness Scale grade 3[Foreman and Lawrence 1987; Foreman et al. 1990]), 4.0 (nonweightbearing 50% of the time, severe head bob, toe pointing whenever not walking but not always 3-legged lame at a walk in the stall, similar to AAEP Lameness Scale grade 4) and 5.0 (nonweightbearing 100% of the time, similar to AAEP Lameness Scale grade 5). A LS of 3.0 was achieved initially in each subject.

Lameness at rest

Lameness was induced 1 h prior to administration of treatment (designated as time point ‘Lame’ in Figs 1, 2). Heart rate (determined via indirect auscultation with a stethoscope) and LS were recorded at rest (designated as time point ‘Rest’ in Fig 1) and every 20 min for 5 h after lameness induction prior to the incremental standardised exercise test (SET). These monitoring techniques have been used successfully previously in our laboratory using this model (Foreman and Lawrence 1987; Foreman et al. 1994, 2008; Seino et al. 2003). Randomised blinded treatments were administered after 1 h of lameness and 4 h prior to the SET (designated as time point ‘Drug’ in Figs 1, 2). The 4 h effectiveness window was selected based on previous work in our laboratory with this model where PBZ was shown to achieve peak clinical effect at 4 h post administration at the same single i.v. dose used in this experiment (Foreman et al. 2008).

image

Figure 1. Mean±s.e. pre-exercise heart rate (HR: beats/min) vs. time (h). Rest designates pre-lameness HR at -1 h. Lameness was induced at Hour 0 (designated by Lame). Drug or placebo was administered at 1 h (designated by Drug). Lameness-induced HR elevation decreased for both phenylbutazone (PBZ) and flunixin meglumine (FM) from 1:20–4 h post treatment (asterisks: P<0.05) when compared to saline (SAL) control. HR was not different between NSAID treatments before exercise (P>0.05).

Download figure to PowerPoint

image

Figure 2. Mean±s.e. pre-exercise percentage change in lameness score (%ΔLS) vs. time. Lameness was induced at 0 h (designated by Lame). Drug or placebo was administered at 1 h (designated by Drug). %ΔLS decreased from 1:20–4 h (phenylbutazone, PBZ) and 1–4 h (flunixin meglumine, FM) post treatment (asterisks: P<0.05) when compared to saline (SAL) control. %ΔLS was not different between NSAID treatments pre-exercise (P>0.05), although PBZ LS was decreased (P<0.05) slightly earlier than that for FM.

Download figure to PowerPoint

Standardised exercise test

Four hours after administration of treatment (designated as time point ‘SET’ in Figs 1, 2), each subject underwent a noninclined SET on a high-speed treadmill (Sato I)3. The SET consisted of 2 steps in 2 min increments at 2 (designated as ‘Walk’ in Fig 3) and 4 (‘Trot’ in Fig 3) m/s. A 2 min canter at 6 m/s was planned initially but was abandoned when it was judged that some horses (presumably negative control horses) were too lame to exercise humanely at that velocity. During and after exercise, HR was measured by a heart rate computer (EqB HR/8a)4 with the electrodes held in place by an elastic surcingle in the saddle area. This HR monitor has been shown in previous studies in our laboratory to be accurate when compared to ECG-derived HRs (Foreman and Rabin 1984). Heart rate was recorded at the end of both exercise steps and while standing quietly on the treadmill during recovery at 0.5, 1, 2, 3, 4, 5, 10, 20, 30, 40, 50 and 60 min post exercise. Lameness at a walk and trot on the treadmill were graded with the same grading scale but more complete and extensive observations of movement could be made since horses were then moving freely on the treadmill. Horses were not walked during the 60 min recovery period when they stood quietly in a restricted manner on the treadmill, so lameness was not graded during the recovery period. Heart bar tension was released after the 60 min recovery period was concluded. Each subject was examined at walk and trot for any adverse effects of the induced lameness and none were observed.

image

Figure 3. Mean±s.e. heart rate (HR: beats/min) vs. time (min) during and after exercise. Lameness-induced HR elevation was lower throughout the entire 60 min recovery period for both phenylbutazone (PBZ) and flunixin meglumine (FM) when compared to saline (SAL) control (asterisks: P<0.05). HR was not different between NSAID treatments after exercise, nor was it different between all treatments during exercise (P>0.05).

Download figure to PowerPoint

Statistical analysis

For data analysis, individual LS values were converted to percentage change in LS (%ΔLS) by the equation: (LS 3.0)/3.0 × 100 (because 3.0 was the original LS for each subject at the beginning of each trial). Mean ± s.e. HR and %ΔLS were determined for each treatment at each sampling interval. Significance of differences between treatments was tested by repeated measures multivariate analysis for HR and by the Wilcoxon signed rank test for %ΔLS. When repeated measures analysis indicated significant time-by-treatment interactions for HR, differences at specific sampling intervals were tested by Student-Newman-Keul's test. A value of P<0.05 was considered significant.

Results

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Conflicts of interest
  9. Manufacturers' addresses
  10. References

All results are presented as mean ± s.e.

Pre-exercise

Pre-exercise mean HR (Fig 1) was decreased (mean ∼10 beats/min lower) for both PBZ and FM compared to SAL from 1:20–4 h post treatment (P<0.05). Pre-exercise mean %ΔLS (Fig 2) was decreased compared to SAL from 1:20–4 h (PBZ) or 1–4 h (FM) post treatment (P<0.05−P<0.001).

Exercise

During exercise there were no mean HR differences between treatments (Fig 3: P>0.05). Lameness Scores were similar at the walk and trot. With exercise, 3 horses were unchanged (still grade 3) and 3 horses were graded worse (2 horses at grade 3.5, one at grade 4) than at the beginning of the lameness period with SAL treatment (mean %ΔLS =+11.1 ± 5.6%). With PBZ at exercise, one horse was graded unchanged (grade 3) and 5 were graded improved or sound (one at grade 2, 2 at grade 1 and one at grade 0); PBZ improved %ΔLS (−61.1 ± 13.8%) compared to SAL trials (P = 0.002). With FM at exercise, one horse was graded unchanged (grade 3) and 5 were graded improved or sound (one at grade 1 and 4 at grade 0); FM improved exercise mean %ΔLS (-77.8 ± 16.5%) compared to SAL trials (P<0.001). There was no difference in mean exercise %ΔLS when the 2 NSAIDs were compared to one another (P>0.05).

Post exercise

Mean recovery HR (Fig 3) was decreased for both NSAIDs (mean 10–15 beats/min lower) from 1–60 min compared to SAL (P<0.05). There were no differences in recovery HR between the 2 NSAID treatments (P>0.05).

Discussion

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Conflicts of interest
  9. Manufacturers' addresses
  10. References

The data in this experiment show objectively that either PBZ or FM in a single typical therapeutic i.v. dose relieves foot pain sufficiently to improve both HR and LS before, during and after mild treadmill exercise. In other experiments using this model in our laboratory, we have shown foot pain induced by this model to be responsive to local blockade with either mepivicaine (Thomas 2002) or topical capsaicin (Seino et al. 2003) and to single i.v. doses at rest of PBZ (Foreman et al. 2008), FM (Foreman et al. 1994) or ketoprofen (Foreman et al. 1994). These new data illustrate clearly the efficacy of single-dose i.v. PBZ and FM before, during and after exercise. Many would consider this efficacy during exercise to be ‘masking’ lameness sufficiently to allow a horse to compete effectively when, without the NSAID medications, its lameness would be readily clinically apparent and would be cause for disqualification by veterinary officials, judges or competition management.

This novel controlled, blinded demonstration of single-dose i.v. efficacy during and after exercise is a critical illustration of the need to regulate the use of NSAIDs before and during competition. Unfortunately, management philosophies continue to vary widely regarding the use of pain medications during competition. Until recently, FEI has had a zero tolerance policy for detectable plasma concentrations of NSAIDs after competition. The United States Equestrian Federation (USEF) permits simultaneous same-day presence of 2 of 7 different NSAIDs (but not PBZ and FM combined) if not given within 12 h of competition (except for within 4–6 h for ketoprofen) and only when detected within proscribed maximum allowable plasma concentrations. A more restrictive USEF rule changes has been approved to begin in December 2011 and will allow the presence of only one NSAID during competition, again only when detected within proscribed maximum allowable plasma concentrations. In Thoroughbred racing, other investigators recently published data where they monitored for the presence of measurable plasma concentrations of NSAIDs in injured vs. noninjured horses (Dirikolu et al. 2009). They concluded that the use of NSAIDs during racing was widespread and that ‘the (HPLC) plasma concentrations of phenylbutazone and flunixin (but not naproxen) were higher in injured horses than in control horses.’

Clearly, the permitted use of NSAIDs during competition may have serious implications for the safety of the horse and therefore the rider or driver. If the prevalence of NSAID use is higher in injured than in noninjured horses, one must be concerned about the probability of creating a new or exacerbating a previous injury in a horse while exercising under the influence of one or more NSAIDs. In their prospective investigation of the results from 5 Kentucky Thoroughbred racetracks for an entire 2 year period, Dirikolu et al. (2009) demonstrated unequivocally that the ‘average apparent plasma concentrations of flunixin and phenylbutazone in injured horses were higher than that in both winning and special horse categories.’ Amazingly, 81% of injured horses, 71% of winners and 55% of specials (horses identified randomly by the racing stewards for drug testing) had plasma FM concentrations >0.1 µg/ml, the concentration considered by the investigators to be the minimal effective plasma concentration for FM (Dirikolu et al. 2009). When examining the prevalence of PBZ use, 27% of the winners and 30% of the injured horses had PBZ plasma concentrations >7 µg/ml after the race (Dirikolu et al. 2009).

A recently-recommended FEI rule change may legalise the use of half-doses of NSAIDs no closer than 12 h prior to competition, only once in each 24 h period and only when administered by a veterinarian. While this current study does not directly address the time interval and half-doses recently being studied by FEI, the data do show that the use of single full i.v. doses affects soundness and accompanying variables such as HR and/or LS before, during and after exercise; thus at these full doses, either single i.v. doses of PBZ or FM can act as lameness masking agents. Further research is necessary to determine if the use of half-doses causes similar masking of lameness signs. Preliminary research in our laboratory with PBZ at full- vs. half-doses has shown that half-doses are effective in masking lameness signs in this model only for brief periods of time (<3 h) (J.H. Foreman, unpublished data). Furthermore, the new proposed FEI NSAID rule requires no dosing for at least 12 h prior to competition. Our recent preliminary data have shown that the analgesic benefits of half-doses wane and are no longer clinically effective for 6–8 h prior to the point 12 h after dosing when competition might become legal after a half-dose of PBZ has been administered under the newly-proposed FEI rule changes (J.H. Foreman, unpublished data).

In conclusion, at the standard, single, full i.v. doses used in this experiment with this model, both PBZ and FM demonstrated definitive clinical efficacy vs. SAL before (HR and LS), during (LS) and after (HR) exercise (P<0.05). There was no difference in efficacy between the 2 NSAIDs compared to one another (P>0.05).

Acknowledgements

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Conflicts of interest
  9. Manufacturers' addresses
  10. References

Supported by the Maria Caleel Fund for Equine Sports Medicine Research. The University of Illinois Equine Treadmill Laboratory was funded in part by the Illinois Department of Agriculture Thoroughbred and Standardbred Breeders' Funds.

Manufacturers' addresses

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Conflicts of interest
  9. Manufacturers' addresses
  10. References

1 Butler Company, Columbus, Ohio, USA.

2 Schering-Plough Corporation, Kenilworth, New Jersey, USA.

3 Sato, Uppsala, Sweden.

4 Equine Biomechanics and Exercise Physiology, Unionville, Pennsylvania, USA.

References

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Conflicts of interest
  9. Manufacturers' addresses
  10. References
  • Dirikolu, L., Woods, W.E., Boyles J., Jr, Lehner, A.F., Harkins, J.D., Fisher, M., Schaeffer, D.J. and Tobin, T. (2009) Nonsteroidal anti-inflammatory agents and musculoskeletal injuries in Thoroughbred racehorses in Kentucky. J. vet. Pharmacol. Therap. 32, 271-279.
  • Doucet, M.Y., Bertone, A.L., Hendrickson, D., Hughes, F., MacAllister, C., McClure, S., Reinemeyer, C., Rossier, Y., Sifferman, R., Vrins, A.A., White, G., Kunkle, B., Alva, R., Romano, D. and Hanson, P.D. (2008) Comparison of efficacy and safety of paste formulations of firocoxib and phenylbutazone in horses with naturally occurring osteoarthritis. J. Am. vet. med. Ass. 232, 91-97.
  • Erkert, R.S., MacAllister, C.G., Payton, M.E. and Clarke, C.R. (2005) 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. 66, 284-288.
  • Foreman, J.H. and Rabin, D. (1984) Determination of accuracy of a digitally displaying equine heart rate meter. J. equine vet. Sci. 4, 161-163.
  • Foreman, J.H. and Lawrence, L.M. (1987) Lameness and heart rate elevation in the exercising horse. Proc. equine Nutr. Physiol. Symp. 10, 345-350.
  • Foreman, J.H., Grubb, T.L. and Inoue, O.J. (1994) Comparison of the effects of flunixin meglumine and ketoprofen on experimentally-induced lameness in the horse. Proc. Am. Ass. equine Practnrs. 40, 51.
  • Foreman, J.H., Bayly, W.M., Grant, B.D. and Gollnick, P.D. (1990) Standardized exercise test and daily heart rate responses of Thoroughbred horses to conventional race training. Am. J. vet. Res. 50, 914-920.
  • Foreman, J.H., Barange, A., Lawrence, L.M. and Hungerford, L.L. (2008) Effects of single-dose intravenous phenylbutazone on experimentally-induced, reversible lameness in the horse. J. vet. Pharmacol. Therap. 31, 39-44.
  • Goetz, T.E. and Comstock, C. (1985) The use of the adjustable heart bar shoe in the treatment of laminitis in horses. Proc. Am. Ass. equine Practnrs. 31, 605-616.
  • Hamm, D., Turchi, P., Johnson, J.C., Lockwood, P.W., Thompson, K.C. and Katz, T. (1997) Determination of an effective dose of eltenac and its comparison with that of flunixin meglumine in horses after experimentally induced carpitis. Am. J. vet. Res. 58, 298-302.
  • Hu, H.H., MacAllister, C.G., Payton, M.E. and Erkert, R.S. (2005) Evaluation of the analgesic effects of phenylbutazone administered at a high or low dosage in horses with chronic lameness. J. Am. vet. med. Ass. 226, 414-417.
  • Kallings, P., Johnston, C. and Drevemo, S. (1999) Effects of flunixin on movement and performance of standardbred trotters on the track. Equine vet. J. 30, 270-273.
  • Keegan, K.G., Messer, N.T., Reed, S.K., Wilson, D.A. and Kramer, J. (2008) Effectiveness of administration of phenylbutazone alone or concurrent administration of phenylbutazone and flunixin meglumine to alleviate lameness in horses. Am. J. vet. Res. 69, 167-173.
  • Owens, J.G., Kammerling, S.G., Stanton, S.R. and Keowen, M.L. (1995) Effects of ketoprofen and phenylbutazone on chronic hoof pain and lameness in horses. Equine vet. J. 27, 296-300.
  • Owens, J.G., Kammerling, S.G., Stanton, S.R., Keowen, M.L. and Prescott-Matthews, J.S. (1996) Effects of pretreatment with ketoprofen and phenylbutazone on experimentally induced synovitis in horses. Am. J. vet. Res. 57, 866-874.
  • Schoonover, M.J., Jann, H.W. and Blaik, M.A. (2005) Quantitative comparison of three commonly used treatments for navicular syndrome in horses. Am. J. vet. Res. 66, 1247-1251.
  • Sebaté, D., Homedes, J., Salichs, M., Sust, M. and Monreal, L. (2009) Multicentre, controlled, randomized and blinded field study comparing efficacy of suxibuzone and phenylbutazone in lame horses. Equine vet. J. 41, 700-705.
  • Seino, K.K., Foreman, J.H., Greene, S.A., Goetz, T.E. and Benson, G.J. (2003) Effects of topical perineural capsaicin in a reversible model of equine foot lameness. J. vet. intern. Med. 17, 563-566.
  • Thomas, K.K. (2002) Physiological Effects of Perineural Mepivacaine Anesthesia and Topical Perineural Capsaicin in a Reversible Model of Equine Foot Lameness. M.S. Thesis, University of Illinois, Urbana.