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Keywords:

  • horse;
  • narcotic;
  • opioid;
  • pethidine;
  • analgesic

Summary

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Authors' declaration of interests
  8. Ethical animal research
  9. Sources of funding
  10. Acknowledgements
  11. Authorship
  12. References

Reasons for performing study

There are no peer reviewed, blinded controlled studies regarding the skeletal analgesic efficacy of intramuscularly administered meperidine in horses.

Objectives

Using an adjustable heart bar shoe model of equine foot pain, the objective of this study was to test the hypothesis that meperidine (pethidine) administered intramuscularly would prove more efficacious in alleviating lameness than a saline placebo.

Study design

Crossover pharmacodynamic experiment.

Methods

Eight healthy adult Thoroughbred horses randomly underwent weekly i.m. treatments 1 h after lameness induction: saline placebo (1 ml/45 kg bwt) or meperidine hydrochloride (1 mg/kg bwt i.m.). Heart rate (HR) and lameness score (LS) responses were assessed by a blinded observer every 20 min for 5 h after lameness induction and then hourly through 12 h after treatment. Jugular venous blood samples were obtained at -1, 0, 0:05, 1, 2, 4, 6, 8, 10 and 12 h and were subsequently analysed for drug concentrations (lower limit of detection, 1 ng/ml). Repeated measures ANOVA and post hoc Tukey's test were used to identify analgesic effects at a significance level of P<0.05.

Results

Mean (± s.e.) HR were lower in meperidine trials at 2.3, 3.3 and 3.7 h post administration (P<0.05). Mean LS were lower in meperidine trials at 2.0, 2.3 and 3.3 h post administration (P<0.05). Mean plasma (meperidine) peaked at 227 ± 52 ng/ml at 1 h post administration and decreased to 2.7 ± 0.3 ng/ml at 12 h post administration. In 3 of 8 subjects, plasma (meperidine) was below the lower limit of detection at 12 h after administration.

Conclusions

Intramuscular meperidine was more effective than the saline placebo but only for 2.0–3.7 h post administration compared with the 8–12 h durations of efficacy reported previously using this same model when horses were treated with nonsteroidal anti-inflammatory drugs (NSAIDs). Meperidine may be a suitable nonNSAID alternative analgesic for acute foot pain with efficacy lasting from 2–3 h after a single i.m. dose.


Introduction

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Authors' declaration of interests
  8. Ethical animal research
  9. Sources of funding
  10. Acknowledgements
  11. Authorship
  12. References

Acute foot pain in horses is a common ailment often requiring analgesic therapy. In particular, laminitis can be a devastating foot problem in horses. Laminitis has been observed secondary to a number of conditions in the horse including gastrointestinal disturbances, systemic illnesses such as viraemia or bacteraemia, pneumonia, pleuritis and metritis; exercise-related diseases such as myositis and hard-footing and numerous other disease conditions [1]. Analgesia is indicated in acute cases of laminitis or in acute exacerbations of chronic laminitis [2]. Conventionally, nonsteroidal anti-inflammatory drugs (NSAIDs), such as phenylbutazone or flunixin meglumine, are recommended for their analgesic and anti-inflammatory effects [2], but sometimes NSAIDs are insufficient to provide adequate levels of analgesia in acute laminitis or other conditions of acute foot pain. Furthermore, prolonged use of NSAIDs has been associated with toxicities, such as gastric or colonic ulcers, renal cortical necrosis, hypoproteinaemia and hypoalbuminaemia [3-9]. The toxicity of NSAIDs has been shown previously to be drug, dosage and duration dependent [3-9]. As a result, nonNSAID therapies are sought and welcome if they provide analgesic efficacy without potential NSAID toxicity.

Narcotic or opioid analgesics provide a logical alternative for replacement or adjunctive therapy in the treatment of foot pain associated with equine laminitis or other conditions. Meperidine hydrochloride (HCl, pethidine outside the USA) is one such narcotic. Previous reports of meperidine use in horses are limited mainly to visceral analgesia studies [10-13] and often are limited to i.v. rather than i.m. injection as the route of administration. However, i.v. narcotic administration in horses has been associated with moderate to excessive neurological stimulation manifested as agitation and increased locomotion [14-22]. The 2 commonly accepted methods of overcoming that stimulation are to administer a narcotic i.v. to a horse only after prior successful sedation [17, 23, 24], or to administer the narcotic intramuscularly [22]. We chose to administer the narcotic intramuscularly without prior sedation in this experiment because we did not want to confound potential measurements of analgesic efficacy with a sedative effect.

The objective of this experiment was to investigate the efficacy of an intramuscularly administered narcotic when used for skeletal pain relief by comparing the efficacy of meperidine HCl and the time course of that meperidine efficacy with the efficacy of an isotonic saline placebo (SAL). Our hypothesis was that meperidine HCl administered intramuscularly would prove more efficacious in alleviating lameness than would a saline placebo using an adjustable heart bar shoe model of equine foot pain. Variables monitored by a blinded observer included heart rate (HR) and lameness score (LS).

Materials and methods

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Authors' declaration of interests
  8. Ethical animal research
  9. Sources of funding
  10. Acknowledgements
  11. Authorship
  12. References

All materials and methods used for this study were performed under the approval and authority of the University of Illinois Institutional Animal Care and Use Committee.

Subjects

Eight Thoroughbred horses (mean ± s.e. age 4.6 ± 0.6 years, median 4 years, range 3–7 years; 6 castrated males, 2 females) weighing 443.2–511.4 kg (mean ± s.e. 473.4 ± 8.7 kg, median 476.5 kg) were studied for 2 weeks. Complete physical and lameness examinations were performed before shoeing to ensure that each subject was normal before experiments commenced. Each subject's left front foot had an adjustable heart bar shoe applied [25-31]. The right front foot had a simple keg shoe of a similar weight applied for balance. A minimum of 7 days of stall rest were allowed after shoeing and before any drug trials were commenced.

Lameness model

A set screw was placed in the heart bar shoe [25] to induce lameness 1 h prior to administration of treatment. A hexagonal screw was tightened into a threaded centre hole in the stationary midfoot bar [25], thereby causing the heart bar to apply painful pressure to the frog of the foot [26-31]. The same screw was reused on each trial day for each individual horse. The number of turns of the screw was standardised for each horse each week to ensure that the same degree of lameness was created on each trial day. Previous studies in our laboratory have shown that degree of HR elevation is a valid indicator of severity of lameness in horses in experimentally-induced [26] and naturally occurring lameness [32]. Given that HR is a primary variable of interest in this model [26-31], movement or exercise outside the stall confounds the use of HR measurement as an objective quantifiable determinant of lameness or response to medication. All lameness grading in this model therefore occurred in the individual box stall without jogging any horse and without walking any individual horse, other than observing spontaneous walking and turning movements within the stall [27-31].

Lameness grades

Lameness was scored using a previously described continuous decimal grading system [27-31]. Lameness grades were based originally on the American Association of Equine Practitioners (AAEP) Lameness Scale [26], but were modified for use solely in the stall, more like the Obel laminitis scale. Lameness grades were: grade 0.0 (sound or undetectable lameness), grade 1.0 (barely detectable lameness; horse rarely looked lame at a walk in the stall, mainly when turning, and/or pointed the lame toe forward intermittently and rarely), grade 2.0 (mild lameness; horse was more consistently lame at a walk in the stall, had a mild head bob when walking or turning in the stall and pointed its toe more consistently), grade 3.0 (moderate lameness but not nonweightbearing; horse had more obvious head bob at a walk, toe pointing more frequently), grade 4.0 (nonweightbearing 50% of the time, severe head bob, toe pointing whenever not walking but not always 3-legged lame at a walk) and grade 5.0 (nonweightbearing 100% of the time). The toe point refers specifically to the tendency of these horses, when lameness has been induced, to spend variable amounts of time in an ‘anterior point’ at rest, with the toe touching the floor of the stall but with the horse bearing less than full weight on the entire foot. This posture, and the frequency of this posture, changes with the degree of lameness and contributes to the continuous nature of the grading system, since different horses under different treatment conditions tend to spend varying amounts of time bearing full weight at rest in the stall. Lameness which did not meet all the expressed criteria for a given grade were judged to be between 2 major points on the scale (e.g. a lameness might have been graded as grade 3.3 rather than grade 3 or 4 as the only possibilities for that horse at that point in time), thus rendering the scale continuous rather than a 6-point ordinal scale.

An initial grade 5.0 lameness (nonweightbearing 100% of the time) was achieved by titration-to-effect in each subject. This lameness was achieved at the beginning of the first day of the experiment by one investigator tightening the shoe until the horse was felt by the investigator to partially withdraw the limb (as a horse might do when testing superficially for the efficacy of a peripheral nerve block). The limb was then released and the horse was observed. If a nonweightbearing lameness was achieved, then the screw was not tightened further. If the investigator felt that the horse was not yet nonweightbearing, then the screw was tightened further until the investigator judged that a nonweightbearing grade 5.0 lameness had been achieved. In the following week, the same degree of lameness was achieved for each horse by using its individualised screw turned the same number of times as had been used the previous week.

Treatments

Meperidine was administered intramuscularly to avoid the common side effect of hyperexcitability that occurs in horses given narcotics intravenously without prior sedation [13-21]. Two treatments were studied in a switchback design. Meperidine hydrochloride USP (Demerol 50 mg/ml)a 1 mg/kg bwt i.m. was administered 1 h after lameness induction to 4 horses. This dosage of meperidine has been previously reported [10, 12, 13] and was at the higher end of the range commonly used in our hospital (0.5–1.0 mg/kg bwt i.m. or i.v. only after prior sedation). The remaining 4 horses received isotonic saline as a negative control (1 ml/45 kg bwt i.m.: 0.9% sodium chloride solution USP, 1000 ml)b 1 h after lameness induction. Treatments were administered by a coinvestigator (RR) who had no input on HR and LS determinations. Seven days later, treatment assignments were reversed and the experiment repeated.

Sampling intervals

Variables were monitored by an investigator who was unaware of treatment assignments (J.H.F.). Heart rate and LS were determined every 20 min for the first 5 h after lameness induction and then hourly through 12 h post treatment. After HR determination, heparinised jugular venous blood samples were obtained via direct venipuncture at rest (time -1), immediately pretreatment (time 0), 0:05 (5 min after time 0; immediately post treatment), 1, 2, 4, 6, 8, 10 and 12 h of lameness. The samples were chilled, separated by centrifugation and frozen for transport and subsequent determination of plasma drug concentrations. Tension on the heart bar was released after 13 h on trial and each subject was examined at a walk and trot for any adverse effects of the induced lameness. These techniques and monitoring intervals have been used successfully and with minimal lasting adverse effects on soundness in previous experiments in Thoroughbred horses undergoing racetrack exercise [32] and in research horses with experimentally induced foot lameness [26-31].

Plasma drug concentrations

Plasma drug concentrations were determined at the University of Florida Racing Laboratory by an analyst who was masked with regard to sample collection times, but not to the identity of the administered drug. The analytical method used in this study to determine plasma drug concentrations was modified from a previously published method [33] and has been described previously [30]. Briefly, the method consisted of liquid/liquid extraction of the plasma sample followed by LC-MS-MS analysis. Ketoprofen was chosen as the internal standard because it is of similar polarity to the analyte of interest, yet it is inert under the extraction and detection conditions, does not coelute with the analyte and is unlikely to be present in these samples collected from research horses in a controlled environment. The intra- and interassay coefficients of variation were less than 5%. The lower limit of detection for meperidine in plasma was 1 ng/ml.

Data analysis

Mean (± s.e.) HR, LS and plasma drug concentrations were determined for each treatment at each sampling interval. Lameness score was treated as a continuous variable since a fractionated, nonordinal, decimal grading scale was used. Significance of differences between treatments was analysed by repeated measures multivariate analysis of variance (SigmaPlot 11.2)c. When repeated measures documented significant differences between treatments over time, Tukey's test was used post hoc to identify those discrete points in time at which a significant effect between specific treatments existed (SigmaPlot 11.2)c. Significance level was set at P<0.05. Based on previous studies, 8 horses were sufficient for this repeated measures design [26-32].

Results

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Authors' declaration of interests
  8. Ethical animal research
  9. Sources of funding
  10. Acknowledgements
  11. Authorship
  12. References

All treatments were administered at 0 h on the x axis (denoted by the arrow in Figs 1-3).

figure

Figure 1. Mean ± s.e. heart rate (HR) in meperidine trials was lower than saline placebo trials at 2.3, 3.3 and 3.7 h post treatment (P<0.05). Lameness was induced at -1 h and treatments administered at 0 h (denoted by arrow) on the x axis.

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figure

Figure 2. Mean ± s.e. lameness score (LS) was lower for meperidine trials than saline placebo trials at 2.0, 2.3 and 3.3 h post treatment (P<0.05). Lameness score for meperidine was higher than saline placebo at 6.00 and 7.00 h post treatment (P<0.05). Lameness was induced at -1 h and treatments administered at 0 h (denoted by arrow) on the x axis.

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figure

Figure 3. Mean ± s.e. plasma meperidine concentration peaked at 227 ± 52 ng/ml at 1 h post administration and decreased to 2.7 ± 0.3 ng/ml by 12 h post administration. In one of 8 subjects plasma [meperidine] was below the limit of detection (1 ng/ml) by 10 h after administration. In 3 of 8 subjects plasma (meperidine) was below the limit of detection by 12 h after administration. Lameness was induced at -1 h and treatments administered at 0 h (denoted by arrow) on the x axis.

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Heart rate (Fig 1)

Mean HR values for both treatments are depicted in Figure 1. Mean resting HR was 33.0 ± 1.5 (SAL) and 35.5 ± 1.4 beats/min (meperidine) and was not different between the treatment groups (P>0.05). Mean HR for 1 h after lameness induction and before treatments were administered ranged from 46.5 ± 2.3–49.0 ± 1.7 beats/min (SAL) and from 42.0 ± 1.1–47.0 ± 2.3 beats/min (meperidine); there were no differences between the 2 treatment groups before treatment was administered (P>0.05). At 2.3, 3.3 and 3.7 h post administration, mean HR was lower for meperidine trials (37.5 ± 1.1–38.0 ± 1.5 beats/min) compared with SAL trials (41.5 ± 1.3–43.5 ± 1.0 beats/min) (P<0.05). At 6 and 7 h post treatment, mean HR for meperidine trials (45.5 ± 1.1–48.5 ± 2.0 beats/min) was higher than for SAL trials (40.5 ± 1.0–42.5 ± 1.1 beats/min) (P<0.05).

Lameness score (Fig 2)

Mean LS values for both treatments are depicted in Figure 2. Mean pretreatment LS was 5.0 ± 0.0 for both trials and was not different between the 2 treatment groups (P>0.05). At 2.0, 2.3 and 3.3 h post administration, mean LS in meperidine trials was 3.2 ± 0.6–3.5 ± 0.6 and was lower than SAL means of 4.4 ± 0.3–4.8 ± 0.3 (P<0.01–0.05). Otherwise, LS for meperidine and SAL were not different from one another (P>0.05).

Plasma meperidine concentration (Fig 3)

Mean plasma meperidine concentration is depicted in Figure 3. Mean plasma meperidine concentration peaked at 227 ± 52 ng/ml at 1 h post administration and decreased to 2.7 ± 0.3 ng/ml by 12 h post administration. In 1 of 8 subjects plasma (meperidine) was below the lower limit of detection (1 ng/ml) by 10 h after administration. In 3 of 8 subjects plasma (meperidine) was below the lower limit of detection by 12 h after administration. Plasma concentration when meperidine was no longer efficacious (based on HR and LS returns to be no different than SAL values) at 3.7 h post administration was approximately 75 ng/ml of plasma.

Discussion

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Authors' declaration of interests
  8. Ethical animal research
  9. Sources of funding
  10. Acknowledgements
  11. Authorship
  12. References

This study is the first controlled blinded documentation of the efficacy and plasma concentrations of meperidine administered intramuscularly to horses with musculoskeletal pain. Intramuscular administration of meperidine resulted in improvement in HR and LS but only for brief periods of time (2.0–3.67 h) after administration. The 100 min duration of efficacy was longer with i.m. administration compared to descriptions in the literature when meperidine was administered intravenously. Previous studies using the same dosage of meperidine reported a narrow range of results, from minimal visceral analgesia after i.m. injection [10] to visceral analgesia lasting 30–35 min after i.v. injection [12]. One nonrefereed and unreferenced textbook citation states that analgesia (not specified to visceral or skeletal or both) with meperidine (1–2 mg/kg bwt i.m.) lasts 1–2 h [22]. In the current experiment, the peak analgesic effect of meperidine was blunted and the duration of efficacy was shorter when compared with the effects of NSAIDs, such as phenylbutazone and flunixin meglumine, administered intravenously in this same lameness model [28-31]. The horses in the present experiment were the same horses on which we previously reported that phenylbutazone, flunixin meglumine and the combination of phenylbutazone and flunixin meglumine administered simultaneously intravenously resulted in demonstrable efficacy from 2–12 h post administration [30]. Intramuscular injection requires a more gradual absorption of the drug from the injection site before it can be circulated in blood to arrive at μ and κ receptors in the brain and spinal cord to provide central pain relief, resulting typically in a delayed onset of action with a diminished or blunted peak effect.

The analgesic efficacy of NSAIDs and/or narcotics has previously been tested using other models of pain in horses such as dental dolorimetry [17, 34], caecal balloon catheters [10-12, 16, 35, 36] and induction of irreversible arthritis with either chemical or bacterial injection of the joint or cartilage damaged induced by surgical intervention [37-40]. The advantages of the pain model used in this experiment are that it mimics or creates skeletal pain, the model is reversible, each horse can serve as its own control and yet there are no lasting effects of the induced lameness on the subjects [26-31]. As occurs in horses with naturally occurring solar pain, the lameness induced using this model can be eliminated with local subcutaneous mepivacaine anaesthesia of the palmar digital nerves [41]. The lameness induced using this model has been shown previously in several experiments to be responsive to NSAIDs including phenylbutazone and flunixin meglumine [28-31]. Since we first described the use of this model, other shoeing models which also cause increase sole pressure have been described using small bolts tightened into nuts welded eccentrically inside the solar margin of the shoe [42-47].

Another strength of this study is the blinded design by the use of an experienced evaluator who was unaware of treatment assignment. There are reports of a more objective method of quantifying equine lameness using inertial sensor systems [48-53]. Most recently a comparison of one inertial system with the results of examinations performed by 3 experienced lameness clinicians revealed that, despite interindividual variability in the observations of the evaluators, the experienced evaluators were still able to discriminate lame from sound limbs routinely and were at times more discriminating than the lameness quantifier itself, particularly as the sensor system cannot determine effectively when a horse is bilaterally lame either in front or behind [53]. The authors concluded that ‘inertial sensor-based evaluation may augment but not replace subjective lameness examination of horses' [53]. Force plates have also been shown previously to provide similar quantitation of equine lameness, but again require special expensive equipment, repetitive jogging trials to capture sufficient data for meaningful analysis, and extensive post hoc analysis [54]. An inshoe pressure measurement system [55] that allows collection of vertical ground reaction force data might be adaptable to the current model if it could be made compatible with the shoe design. However, those investigators' own observation that they ‘recommend evaluating multiple trials from each horse to improve the accuracy of the data obtained from the sensors' makes one question the rapid repeatability of these measurements in our dynamic model where we make frequent measurements (every 20 min for the first half of the day) of multiple horses (as few as 6, as many as 10) nearly simultaneously as they change quickly in response to various drug therapies. Using the present model, all horses are made lame and treated on the same day, to minimise day-to-day variability and HR serves as the most quantifiable objective variable for monitoring lameness at rest in the box stall. In this system, one experienced investigator evaluates every subject's lameness every 20–60 min according to previously published grading criteria which result in a quantifiable measure of lameness [26-31].

Plasma concentrations of meperidine in this study peaked at 227 ± 52 ng/ml at 1 h post administration and decreased to 2.7 ± 0.3 ng/ml by 12 h post administration. In one pharmacokinetic meperidine study using the same 1 mg/kg bwt dosage administered intravenously in horses, plasma concentrations of meperidine peaked at approximately 1370 (preoperatively) and 2750 ng/ml (under anaesthesia intraoperatively) and decreased to approximately 150–200 ng/ml at 3 h post administration [13]; that report did not include 12 h meperidine concentrations. Mean plasma concentration in the present study at the same 3 h time window was approximately 130 ng/ml (Fig 3), a concentration not dissimilar from that of the i.v. pharmacokinetic study [13]. Thus, meperidine is rapidly absorbed from i.m. injection sites. Although i.m. injection of the same dosage results in a lower peak concentration (Fig 3), an expected finding, the decay of plasma concentrations seems to be similar between i.m and i.v. routes within 3 h of administration. This finding is due to the short half-life and rapid elimination of meperidine in horses [13], resulting in the much shorter duration of efficacy of meperidine compared with NSAIDs in the same foot pain model [28-31].

One interesting and unexplained observation in this experiment is the increase in HR in meperidine-treated horses at 6 and 7 h post treatment. This occurred after meperidine efficacy had waned demonstrably, based on a return of both HR and LS to SAL placebo values between 4 and 6 h post administration. A phenomenon of ‘rebound pain’ has been described in man, particularly associated with the management of headaches and migraines [56-58]. Rebound pain is often associated with chronic painful conditions and often seems to result from chronic analgesic use, both physician-prescribed and self-medicated, for those chronic painful conditions. Analgesics implicated in withdrawal rebound pain in man include opioids, ergotamine, NSAIDs, triptans or some combination thereof [58]. Rebound pain is more often, but not always, observed with chronic use of analgesics in man, but there is no reason to believe that it could not occur after initial acute pain control has waned. It cannot be stated definitively that the elevated HR documented here must be due to rebound pain phenomenon after meperidine analgesic efficacy waned, but the observation is intriguing and worthy of further diligent observation in horses treated with analgesics, particularly opioids, for persistently painful conditions such as laminitis. It is also possible that this increase in HR is a random beta error characterised by detecting a difference when one does not truly exist.

Further opioid research is warranted as a result of this experiment. A dose titration study comparing the skeletal analgesic efficacies of meperidine, butorphanol or morphine could be performed using this shoeing model or using a system incorporating a force plate, inertial sensor or in-shoe pressure measurement system. We have previously reported on such a dose titration study with i.v. administered flunixin meglumine [31]; the results in that study discriminated between half and single (standard 0.5 mg/kg bwt i.v.) dosages of flunixin meglumine but also documented that double dose flunixin meglumine was no more efficacious than was single dose flunixin meglumine [31]. Additionally, the use of epidural administration of analgesics, including meperidine, has become popular lately in horses [59-61]. The intent of this delivery method is to administer the drug at potentially lower doses, closer or more locally to the central sites of the μ and κ opioid receptors. Documentation of the efficacy of epidurally administered meperidine or other analgesics in lame, or experimentally lame, horses would provide additional information for equine clinicians to make more informed decisions about skeletal pain management.

It was concluded in this study that i.m. meperidine was more effective than SAL placebo but only for a short period of time (2.0–3.7 h post administration) compared with the previous 8–12 h durations of efficacy in this same model when horses were treated with NSAIDs [28-31]. Meperidine may provide a suitable nonNSAID alternative but may, with further study, require an increased dosage and/or more frequent administration than NSAIDs such as phenylbutazone or flunixin meglumine. However, increased dosage and/or frequency of administration of meperidine may contribute increased agitation and/or to delayed intestinal transit time by increasing intestinal sphincter tonicity. Although beyond the scope of this experiment, it is possible that intermittent use of meperidine between doses of typical NSAIDs may provide greater analgesia than either medication alone. Combined use might also allow use of decreased dosages of NSAIDs and may therefore contribute to minimisation of NSAID-related toxicities.

Ethical animal research

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Authors' declaration of interests
  8. Ethical animal research
  9. Sources of funding
  10. Acknowledgements
  11. Authorship
  12. References

This study was performed under the approval and authority of the University of Illinois Institutional Animal Care and Use Committee.

Sources of funding

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Authors' declaration of interests
  8. Ethical animal research
  9. Sources of funding
  10. Acknowledgements
  11. Authorship
  12. References

Funded by the Maria Caleel Fund for Equine Sports Medicine Research at the University of Illinois. Horses were purchased with funds provided by the Grayson/Jockey Club Foundation, Keeneland Racing Association, Thoroughbred Owners and Breeders Association, Kentucky Thoroughbred Association.

Authorship

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Authors' declaration of interests
  8. Ethical animal research
  9. Sources of funding
  10. Acknowledgements
  11. Authorship
  12. References

Dr Foreman designed and executed the study, analysed the data, prepared the manuscript, and approved of the final manuscript. Dr Ruemmler assisted in the execution of the study and approved the final manuscript.

Manufacturers' addresses
  1. aAbbott Laboratories, North Chicago, Illinois, USA.

  2. bHospira, Inc., Lake Forest, Illinois, USA.

  3. cSystat Software, Inc., San Jose, California, USA.

References

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Authors' declaration of interests
  8. Ethical animal research
  9. Sources of funding
  10. Acknowledgements
  11. Authorship
  12. References
  • 1
    Hood, D.M. (1999) The pathophysiology of developmental and acute laminitis. Vet. Clin. N. Am.: Equine Pract. 15, 321-343.
  • 2
    Stashak, T.S. (1987) Laminitis. In: Adams' Lameness in Horses, Ed: T.S. Stashak , Lea & Febiger, Philadelphia, Pennsylvania. pp 486-499.
  • 3
    Snow, D.H., Bogan, J.A., Douglas, T.A. and Thompson, H. (1979) Phenylbutazone toxicity in ponies. Vet. Rec. 105, 26-30.
  • 4
    Snow, D.H., Douglas, T.A., Thompson, H., Parkins, J.J. and Holmes, P.H. (1980) Phenylbutazone toxicity in ponies. Vet. Rec. 106, 68.
  • 5
    Snow, D.H., Douglas, T.A., Thompson, H., Parkins, J.J. and Holmes, P.H. (1981) Phenylbutazone toxicosis in equidae: a biochemical and pathophysiological study. Am. J. Vet. Res. 42, 1754-1759.
  • 6
    Traub, J.L., Gallina, A.M., Grant, B.D., Reed, S.M., Gavin, P.R. and Paulsen, L.M. (1983) Phenylbutazone toxicosis in the foal. Am. J. Vet. Res. 44, 1410-1418.
  • 7
    Collins, L.G. and Tyler, D.E. (1985) Experimentally induced phenylbutazone toxicosis in ponies: description of the syndrome and its prevention with synthetic prostaglandin E2. Am. J. Vet. Res. 46, 1605-1615.
  • 8
    MacAllister, C.G., Morgan, S.J., Borne, A.T. and Pollet, R.A. (1993) Effects of large doses of phenylbutazone, flunixin meglumine, and ketoprofen in horses. J. Am. Vet. Med. Ass. 202, 71-77.
  • 9
    Reed, S.K., Messer, N.T., Tessman, R.K. and Keegan, K.G. (2006) Effects of phenylbutazone alone or in combination with flunixin meglumine on blood protein concentrations in horses. Am. J. Vet. Res. 67, 398-402.
  • 10
    Lowe, J.E. (1978) Xylazine, pentazocine, meperidine and dipyrone for relief of balloon-induced equine colic: a double blind comparative evaluation. J. Equine Med. Surg. 2, 286-291.
  • 11
    Pippi, N.L. and Lumb, W.V. (1979) Objective tests of analgesic drugs in ponies. Am. J. Vet. Res. 40, 1082-1086.
  • 12
    Muir, W.W. and Robertson, J.T. (1985) Visceral analgesia: effects of xylazine, butorphanol, meperidine, and pentazocine in horses. Am. J. Vet. Res. 46, 2081-2084.
  • 13
    Waterman, A.E. and Amin, A. (1992) The influence of surgery and anaesthesia on the pharmacokinetics of pethidine in the horse. Equine Vet. J. 24, Suppl. 11, 56-58.
  • 14
    Robertson, J.T., Muir, W.W. and Sams, R. (1981) Cardiopulmonary effects of butorphanol tartrate in horses. Am. J. Vet. Res. 42, 41-44.
  • 15
    Tranquilli, W., Thurmon, J.C., Turner, T.A., Benson, G.J. and Lock, T.F. (1983) Butorphanol tartrate as an adjunct to the xylazine-ketamine anesthesia in the horse. Equine Pract. 5, 26-29.
  • 16
    Kalpravidh, M., Lumb, W.V., Wright, M. and Heath, R.B. (1984) Analgesic effects of butorphanol in horses: dose-response studies. Am. J. Vet. Res. 45, 211-216.
  • 17
    Brunson, D.B. and Majors, L.J. (1987) Comparative analgesia of xylazine, xylazine/morphine, xylazine/butorphanol, and xylazine/nalbuphine in the horse using dental dolorimetry. Am. J. Vet. Res. 48, 1087-1091.
  • 18
    Matthews, N.S. and Lindsay, S.L. (1990) Effects of low-dose butorphanol on halothane minimum alveolar concentration in ponies. Equine Vet. J. 22, 325-327.
  • 19
    Pascoe, P.J., Black, W.D., Claxton, J.M. and Sansom, R.E. (1991) The pharmacokinetics and locomotor activity of alfentanil in the horse. J. Vet. Pharmacol. Ther. 14, 317-325.
  • 20
    Mama, K.R., Pascoe, P.J. and Steffey, E.P. (1993) Evaluation of the interaction of μ and κ opioid agonists on locomotor behavior in the horse. Can. J. Vet. Res. 57, 106-109.
  • 21
    Nolan, A.M., Besley, W., Reid, J. and Gray, G. (1994) The effects of butorphanol on locomotor activity in ponies: a preliminary study. J. Vet. Pharmacol. Ther. 17, 323-326.
  • 22
    Dobromylsky, P.A., Flecknell, P.A., Lascelles, B.D., Pascoe, P.J., Taylor, P. and Waterman-Pearson, A. (2000) Management of postoperative and other acute pain. In: Pain Management in Animals, Eds: P. Flecknell and A. Waterman-Pearson , W.B. Saunders, Philadelphia, Pennsylvania. pp 81-145.
  • 23
    Klein, L.V. and Baetjer, C. (1974) Preliminary report: xylazine and morphine sedation in horses. Vet. Anesth. 2, 2-4.
  • 24
    Clarke, K.W. and Paton, B.S. (1988) Combined use of detomidine with opiates in the horse. Equine Vet. J. 20, 331-334.
  • 25
    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.
  • 26
    Foreman, J.H. and Lawrence, L.M. (1987) Lameness and heart rate elevation in the exercising horse. In: Proceedings of the 10th Equine Nutrition and Physiology Symposium, Equine Nutrition and Physiology Society. pp 339-344.
  • 27
    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.
  • 28
    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. Ther. 31, 39-44.
  • 29
    Foreman, J.H., Grubb, T.L., Inoue, O.J., Banner, S.E. and Tyler, K.S. (2010) Efficacy of intravenous phenylbutazone and flunixin meglumine before, during, and after exercise in an experimental reversible model of foot lameness in horses. Equine Vet. J. 42, Suppl. 38, 601-605.
  • 30
    Foreman, J.H. and Ruemmler, R. (2011) Phenylbutazone and flunixin meglumine used singly or in combination in experimental lameness in horses. Equine Vet. J. 43, Suppl. 40, 12-17.
  • 31
    Foreman, J.H., Bergstrom, B.E., Golden, K.S., Roark, J.J., Coren, D.S., Foreman, C.R. and Schumacher, S.A. (2012) Dose titration of the clinical efficacy of intravenously administered flunixin meglumine in a reversible model of equine foot lameness. Equine Vet. J. 44, Suppl. 43, 17-20.
  • 32
    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.
  • 33
    Luo, Y., Rudy, J.A., Cornelius, E.U., Soma, L.R., Guan, F., Enright, J.M. and Tsang, D.S. (2004) Quantification and confirmation of flunixin in equine plasma by liquid chromatography – quadrupole time-of-flight tandem mass spectrometry. J. Chromatogr. B 801, 173-184.
  • 34
    Brunson, D.B., Collier, M.A., Scott, E.A. and Majors, L.J. (1987) Dental dolorimetry for the evaluation of an analgesic agent in the horse. Am. J. Vet. Res. 48, 1082-1086.
  • 35
    Pippi, N.L., Lumb, W.V., Fialho, S.A.G. and Scott, R.J. (1979) A model for evaluating pain in ponies. J. Equine Med. Surg. 3, 430-435.
  • 36
    Kalpravidh, M., Lumb, M.V., Wright, M. and Heath, R.B. (1984) Effect of butorphanol, flunixin, levorphanol, morphine, and xylazine in ponies. Am. J. Vet. Res. 45, 217-223.
  • 37
    McIlwraith, C.W. and Van Sickle, D.C. (1981) Experimentally-induced arthritis of the equine carpus: histologic and histochemical changes in the articular cartilate. Am. J. Vet. Res. 42, 209-217.
  • 38
    Frisbie, D.D., Kawcak, C.E., Werpy, N.M., Park, R.D. and McIlwraith, C.W. (2007) Clinical, biochemical, and histologic effects of intra-articular administration of autologous conditioned serum in horses with experimentally-induced osteoarthritis. Am. J. Vet. Res. 68, 290-296.
  • 39
    Bertone, A.L., Jones, R.L. and McIlwraith, C.W. (1988) Serum and synovial fluid steady-state concentrations of trimethoprim and sulfadiazine in horses with experimentally-induced infectious arthritis. Am. J. Vet. Res. 49, 1681-1687.
  • 40
    Kawcak, C.E., Frisbie, D.D., McIlwraith, C.W., Werpy, N.M. and Park, R.D. (2007) Evaluation of avocado and soybean unsaponifiable extracts for treatment of horses with experimentally-induced osteoarthritis. Am. J. Vet. Res. 68, 598-604.
  • 41
    Thomas, K.K. (2002) Physiological Effects of Perineural Mepivacaine Anesthesia and Topical Perineural Capsaicin in a Reversible Model of Equine Foot Lameness, University of Illinois, Urbana, Illinois.
  • 42
    Merkens, H.W. and Schamhardt, H.C. (1988) 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. 20, Suppl. 6, 99-106.
  • 43
    Merkens, H.W. and Schamhardt, H.C. (1988) Evaluation of equine locomotion during different degrees of experimentally induced lameness II: distribution of ground reaction force patterns of the concurrently loaded limbs. Equine Vet. J. 20, Suppl. 6, 107-112.
  • 44
    Schumacher, J., Steiger, R., Schumacher, J., de Graves, F., Schramme, M., Smith, R. and Coker, M. (2000) Effects of analgesia of the distal interphalangeal joint or palmar digital nerves on lameness caused by solar pain in horses. Vet. Surg. 29, 54-58.
  • 45
    Schumacher, J., Schumacher, J., de Graves, F., Steiger, R., Schramme, M., Smith, R. and Coker, M. (2001) A comparison of the effects of two volumes of local analgesic solution in the distal interphalangeal joint of horses with lameness caused by solar toe or solar heel pain. Equine Vet. J. 33, 265-268.
  • 46
    Schumacher, J., Schumacher, J., de Graves, F., Schramme, M., Smith, R., Coker, M. and Steiger, R. (2001) A comparison of the effects of local analgesic solution in the navicular bursa of horses with lameness caused by solar toe or solar heel pain. Equine Vet. J. 33, 386-389.
  • 47
    Keegan, K.G., Wilson, D.A., Smith, B.K. and Wilson, D.J. (2001) Changes in kinematic variables observed during pressure-induced forelimb lameness in adult horses trotting on a treadmill. Am. J. Vet. Res. 61, 612-619.
  • 48
    Weishaupt, M.A., Schatzman, U. and Staub, R. (1993) Quantification of supportive forelimb lameness by recording movemeents of the horse's head during exercise using an accelerometer. Pferdeheilkunde 3, 375-377.
  • 49
    Barrey, E., Hermerlin, M., Vaudelin, J.L., Poirel, D. and Valette, J.P. (1994) Utilisation of an accelerometric device in equine gait analysis. Equine Vet. J. 26, Suppl. 17, 7-12.
  • 50
    Pfau, T., Robilliard, J., Weller, R., Jespers, K., Elisashar, E. and Wilson, A.M. (2007) Assessment of mild hindlimb lameness during over ground locomotion using linear discriminant analysis of inertial sensor data. Equine Vet. J. 39, 407-413.
  • 51
    Church, E.E., Walker, A.M., Wilson, A.M. and Pfau, T. (2009) Evaluation of discriminant analysis based on dorsoventral symmetry indices to quantify hindlimb lameness during over ground locomotion in the horse. Equine Vet. J. 41, 304-308.
  • 52
    Keegan, K.G., Kramer, J., Yonezawa, Y., Maki, H., Pai, P.F., Dent, E.V., Kellerman, T.E., Wilson, D.A. and Reed, S.K. (2011) Assessment of repeatability of a wireless, inertial sensor-based lameness evaluation system for horses. Am. J. Vet. Res. 72, 1156-1163.
  • 53
    Keegan, K.G., Wilson, D.A., Kramer, J., Reed, S.K., Yonezawa, Y., Maki, H., Pai, P.F. and Lopes, M.A.F. (2013) Comparison of a body-mounted inertial sensor system-based method with subjective evaluation for detection of lameness in horses. Am. J. Vet. Res. 74, 1-24.
  • 54
    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.
  • 55
    Judy, C.E., Galuppo, L.D., Snyder, J.R. and Willits, N.H. (2001) Evaluation of an in-shoe pressure measurement system in horses. Am. J. Vet. Res. 62, 23-28.
  • 56
    Robinson, R.G. (1992) Pain relief for headaches. Is self-medication a problem? Can. Fam. Physician 39, 867-872.
  • 57
    Biondi, D.M. (2006) Is migraine a neuropathic pain syndrome? Curr. Pain Headache Rep. 10, 167-178.
  • 58
    Tepper, S.J. and Tepper, D.E. (2010) Breaking the cycle of medication overuse headache. Cleve. Clin. J. Med. 77, 246-252.
  • 59
    Skarda, R.T. and Muir, W.W. 3rd (2001) Analgesic, hemodynamic, and respiratory effects induced by caudal epidural administration of meperidine hydrochloride in mares. Am. J. Vet. Res. 62, 1001-1007.
  • 60
    DeRossi, R., Medeiros, U. Jr, de Almeida, R.G., Righetto, F.R. and Frazilio, F.O. (2008) Meperidine prolongs lidocaine caudal epidural anaesthesia in the horse. Vet. J. 178, 294-297.
  • 61
    DeRossi, R., Sampaio, B.F.B., Varela, J.V. and Junqueira, A.L. (2004) Perineal analgesia and hemodynamic effects of the epidural administration of meperidine or hyperbaric bupivacaine in conscious horses. Can. Vet. J. 45, 42-47.