Abstract
Objective
To evaluate the effect of IA injections of botulinum toxin type A (BoNT-A) in horses with chronic, naturally occurring distal tarsal osteoarthritis.
Methods
9 horses were selected after physical and radiographic assessments. Horses also underwent an objective lameness examination and were included if they had a hindlimb impact lameness (Pmin ≥ 3 mm), which positively responded (≥ 50%) to the tarsometatarsal and centrodistal joints’ anesthetic block. Horses randomly received an intra-articular injection of BoNT-A or an equivalent volume of saline solution. Horses were reevaluated at postinjection days (PIDs) 1, 7, 15, 30, 60, 90, 120, 150, and 180. Success criteria included a decrease in Pmin (≤ 3 mm) or an abolishment of lameness on the baseline lame limb with lameness shifting to the contralateral limb. A percentage of lameness improvement was calculated for all horses at all timepoints.
Results
5 horses were included in the BoNT-A group, whereas 4 individuals were allocated in the placebo group. A significant improvement (P < .05) was observed in horses from the BoNT-A group when compared to placebo at PIDs 90, 120, 150, and 180. Two of 5 horses (40%) from the BoNT-A group had an absolute improvement (100%) in lameness at all the timepoints. Higher percentages of lameness improvement were observed at PID 60.
Conclusions
The results of this study suggest that the intra-articular injection with 50 U of BoNT-A was effective in reducing lameness in horses with distal tarsal osteoarthritis, mainly 90 days after injection.
Clinical Relevance
Botulinum toxin type A can be considered as an option for managing horses with chronic osteoarthritis.
The past decades have witnessed unparalleled advances in the management of equine osteoarthritis. Joint pain is a hallmark and a leading cause of lameness attributable to the disease, directly impacting both performance and animal welfare. Thus, in a complex mechanism, pain stimuli can be generated by both direct damage to joint tissues and chemical stimuli resulting from tissue inflammation.1 These stimuli are detected and forwarded by a variety of receptors, mechanoreceptors, and nociceptors located in different joint tissues. Finally, the signal is carried to the dorsal horn of the spinal cord, where neuromodulators and neurotransmitters send the signal to the brain, where it is processed, modulated, and perceived.2
Some medications have been addressed to reduce the compromising effects of pain and inflammation in such cases, including systemic NSAIDs and intra-articular injections with corticosteroids. Overall, despite being effective, several studies3–5 have reported the side effects promoted by abusive use of systemic NSAIDs and deleterious effects produced by repeated injections of corticosteroids, including chondrocyte necrosis and inhibition of proteoglycan synthesis.6,7 Added to that, some patients can be refractory to their use, needing complementary therapies to achieve a good clinical response. This information raises questions on the need for therapeutic alternatives to control joint pain that target nociceptive pathways rather than traditional medications that target inflammatory pathways.
Nowadays, botulinum toxin type A (BoNT-A) has emerged as one of the most versatile therapeutic agents, which has been used to treat several painful conditions affecting both humans and animals.8,9 Botulinum toxin type A inhibits the release of acetylcholine into the synaptic cleft in cholinergic nerve terminals, producing muscle paralysis.10 Thus, this property of blocking motor nerves has been explored in human medicine to treat disorders characterized by constant painful overactivity.11–15 Additionally, some evidence from studies in rodent models demonstrated that botulinum toxin types inhibit the release of neurotransmitters secreted upon nociceptive stimulation, such as substance P,16 glutamate,17 and calcitonin gene-related peptide.18 Then, a few studies19–23 in people were carried out to investigate the intra-articular use of BoNT-A to treat joint pain, which reported promising results and minimal side effects. Growing clinical interest in BoNT-A in human medicine motivated its use also as a therapeutic agent in veterinary medicine. In this scenario, 2 clinical studies24,25 investigated the intra-articular injection of BoNT-A in dogs with osteoarthritis, showing a consistent improvement in lameness. In equine medicine, however, only 1 small pilot study25 investigated the intra-articular effects of BoNT-A in 4 healthy horses subjected to an experimentally induced synovitis model, which suggested that BoNT-A can attenuate lameness. More recently, a study26 was published suggesting BoNT-A as a safe drug for intra-articular use in horses, producing neither local nor systemic adverse effects. In another study,27 BoNT-A did not show chondroprotective effects on challenged articular cartilage explants nor detrimental effects on cartilage homeostasis.
Thus, the aim of this study was to evaluate the effect of a single intra-articular injection of BoNT-A in horses with naturally occurring chronic distal tarsal osteoarthritis. We hypothesized that a BoNT-A injection would alleviate pain arising from the injected diseased joints.
Methods
Animals and clinical trial enrollment
The Ethics Committee on Animal Research Use at the Federal University of Santa Maria approved all experimental procedures (protocol No. CEUA 3627290920).
Individual horses from a retired mounted police herd were selected after a complete physical examination, including visual appraisal at rest, limb palpation, objective lameness evaluation at motion, joint flexion tests, diagnostic anesthesia, and radiographic examination of the tarsi. Only horses that met the 3 following criteria were included in the study: (1) If they had a primary hindlimb impact lameness based upon the objective lameness evaluation using an inertial sensor–based system (Lameness Locator; Equinosis). In brief, for the collection of sensor data, horses were trotted in a straight line on a concrete surface for at least 25 strides. The sensor program recorded the Pmin and Pmax variables, which are measures, respectively, of the minimum (Pmin) and maximum (Pmax) pelvic height difference between the left and right sides of a horse’s body during each stride. Thus, horses were considered eligible (2) if Pmin (impact component) was ≥ 3 mm, if there was a positive response to upper hindlimb joint flexion, and if intra-articular anesthesia of the tarsometatarsal (TMT) and centrodistal (CD) joints with lidocaine hydrochloride 2% (2 mL/joint) gave a lameness improvement of 50% or more based on the descriptive analysis provided by the system when evaluated 5 minutes after the anesthetic block. Thus, before being selected to the study, all horses received anesthetic blocks to both TMT and CD joints. To rule out any possibility of the pain having arisen from a more distal part of the limb, a high plantar nerve (high 6-point) block followed by the deep branch of the lateral plantar nerve block were performed in all horses immediately before blocking the TMT and CD joints. All perineural blocks were performed using a standard technique, and lameness was reevaluated 10 minutes after each block. Thus, only horses that did not respond positively to those blocks were considered eligible for the study. All horses also underwent a complete radiographic assessment of the tarsus, including the lateromedial, dorsolateral-plantaromedial, dorsoplantar, and dorsomedial-plantarolateral views obtained by standard radiographic techniques.28 Radiographic signs of osteoarthritis in each joint were observed in a blinded fashion and included the presence of irregular and sclerotic subchondral bone, narrowed joint space, the presence of osteophytes, and subchondral bone lysis. Finally, (3) horses that showed 1 or more of these radiographic signs were included in the study. Horses were excluded from the experimental protocol if they had received any intra-articular medication in the previous 6 months or they had received systemic NSAIDs in the previous 7 days. Additionally, some horses that presented lameness in both hindlimbs, which presented resolution of lameness after the block of TMT and CD joints, were considered bilaterally affected by the condition.
Study design and definition of outcome
The study was designed as a randomized, placebo-controlled clinical trial. Affected joints were injected with treatment or placebo at postinjection day (PID) 0. Thus, at least 2 days after enrollment, horses that met the inclusion criteria were randomly assigned by coin toss to receive an injection of 50 U of BoNT-A/joint (Botulift; Laboratório Bergamo), a previously described dose,25,26 or an equivalent volume (3 mL/joint) of saline solution in the TMT and CD joints. For joint injections, individuals were sedated with an IV injection of xylazine hydrochloride (0.3 mg/kg), and after aseptic preparation, drug study or placebo was injected into the TMT and CD joints. When injecting the TMT joint, a 23-gauge X 1-inch needle was placed at its caudolateral aspect in a small depression proximal to the head of the fourth metatarsal bone and directed slightly dorsal and distomedially.29 The CD joint was injected medially by placing a 24-gauge X 1-inch needle in a small palpable depression between the distal tubercle of the talus and second and third metatarsal bones at their proximal limits, immediately distal to the cunean tendon.27 Horses that had bilateral lameness received either treatment or a placebo injection on the more severely affected limb. Enrolled horses were reevaluated by objective lameness examination at PIDs 1, 7, 15, 30, 60, 90, 120, 150, and 180.
Treatment was considered successful if the horses had complete lameness abolishment on the injected limb as assessed by the objective assessment (Pmin ≤ 3 mm) or if the lameness shifted to the contralateral untreated limb (in cases of bilateral lameness). Also, a percentual of lameness improvement was calculated by the formula (Pmin before injection – Pmin after injection)/Pmin before injection (100) for all horses at all evaluated timepoints in order to verify absolute or partial lameness improvement. To verify possible adverse effects, both treated and untreated limbs were monitored by a blind evaluator at the same PIDs for swelling at the injection site and painful reactions to limb palpation and passive flexion.
Statistical analysis
Data were examined by the use of a D’Agostino-Pearson omnibus test for normality. To compare the variable Pmin before and after treatment, data were examined by ANOVA with repeated measures adjusted for comparisons with the post hoc Bonferroni test. In horses with bilateral lameness, Pmin values were multiplied by −1 before statistical analysis, indicating a change of lameness to the contralateral limb. All results were considered significant if P ≤ .05 (Prism, version 5.0; GraphPad Software Inc).
Results
Nine mature crossbred horses (8 mares and 1 gelding; mean ± SE age, 11.9 ± 2.1 years; mean ± SE weight, 494.12 ± 23.45 kg) were included in this study. From the selected population, by randomization, 5 horses were allocated into the BoNT-A group, whereas the remaining 4 individuals were included in the placebo group. Four horses from the BoNT-A group were diagnosed with bilateral distal tarsal pain based on the physical examination and diagnostic blocks. Meanwhile, 2 horses from the placebo group also positively responded to bilateral diagnostic anesthesia, being considered bilaterally affected.
During the experimental protocol, no immediate or delayed signs of swelling or pain were observed after injections of the study drug or placebo on the TMT and CD joints. The BoNT-A injection significantly decreased the Pmin variable at PIDs 90 (P < .05), 120 (P < .001), 150 (P < .001), and 180 (P < .05) when compared to placebo (Figure 1), demonstrating a reduction in severity of lameness at these timepoints. Botulinum toxin type A injection resulted in higher percentages of lameness improvement at PID 60 (95.92 ± 9.13%). In the same group, 4 of 5 bilaterally affected horses shifted lameness to the contralateral untreated limb for at least 1 timepoint. This phenomenon was considered an improvement in lameness due to the shifting lameness to the contralateral limb in a bilateral lameness pattern. Considering individual responses, 2 of 5 horses (40%) showed complete lameness alleviation on the limb treated with BoNT-A (Table 1) at PID 1; meanwhile, 1 horse switched lameness to the contralateral limb. Two of 5 horses (40%) that received a BoNT-A injection demonstrated complete improvement (100%) or switched lameness to the contralateral affected limb at all PID evaluated when compared to the baseline. In the same group, 4 of 5 horses (80%) had complete alleviation in lameness or switched lameness to the contralateral limb for at least 4 timepoints evaluated. No horses from the placebo group had completely improved in terms of lameness at any time after injection (Table 2). Additionally, bilaterally lame placebo horses remained most lame on the same hindlimb throughout the study.
Comparison between Pmin values in the objective lameness evaluation after intra-articular injection of botulinum toxin type A (BoNT-A) or placebo into the tarsometatarsal and centrodistal joints (mean ± SE). A significant improvement (P < .05) in severity of lameness, represented by asterisks, was observed from 90 up to 180 postinjection days in horses from the BoNT-A group when compared to placebo.
Citation: American Journal of Veterinary Research 2025; 10.2460/ajvr.24.10.0294
Percentage of lameness improvement observed after intra-articular injection of botulinum toxin type A (BoNT-A).
| PID | Horse 1 (B) | Horse 2 (B) | Horse 3 (B) | Horse 4 | Horse 5 (B) |
|---|---|---|---|---|---|
| 1 | Switched | 0 | 100* | 40.1 | 100* |
| 7 | 100* | 25.3 | Switched | 25.3 | 18.4 |
| 15 | Switched | 47.7 | Switched | 28.3 | 100* |
| 30 | Switched | 100* | Switched | 41.9 | 42.1 |
| 60 | Switched | 100* | 100* | 79.6 | Switched |
| 90 | Switched | 37.3 | Switched | 67.2 | Switched |
| 120 | 100* | Switched | Switched | 49.3 | 23.6 |
| 150 | Switched | 32.8 | Switched | 59.2 | 43.4 |
| 180 | 100* | 100* | Switched | 72.8 | 57.8 |
Pmin values (mm) observed before (PID 0) and after intra-articular injection of placebo.
| PID | Horse 1 | Horse 2 (B) | Horse 3 | Horse 4 (B) |
|---|---|---|---|---|
| 0 | 15.8 | 9.2 | 13.6 | 10.1 |
| 1 | 14.4 | 8.4 | 11.3 | 8.7 |
| 7 | 10.7 | 6.6 | 12.7 | 5.3 |
| 15 | 7.2 | 6.9 | 9.2 | 8.9 |
| 30 | 15.7 | 8.1 | 12.7 | 8.6 |
| 60 | 23.6 | 6.4 | 21.6 | 7.7 |
| 90 | 26.8 | 9.9 | 28.8 | 9.5 |
| 120 | 40.9 | 11.3 | 42.6 | 12.2 |
| 150 | 55.7 | 8.7 | 48.4 | 9.7 |
| 180 | 28.3 | 9.7 | 38.3 | 10.8 |
The magnitude of lameness presented oscillations over time, and especially horses 1 and 3 from the placebo group, showed worsening of lameness after day 60 (Table 3). In contrast, only 1 individual (horse 4) did not completely improve its lameness following BoNT-A treatment at any PID, demonstrating mean ± SE lameness improvement of 51.53 ± 19.36% during the study. No significant worsening of lameness was observed in horses from the BoNT-A group (Table 3).
Pmin values (mm) observed before (PID 0) and after intra-articular injection of BoNT-A.
| PID | Horse 1 (B) | Horse 2 (B) | Horse 3 (B) | Horse 4 | Horse 5 (B) |
|---|---|---|---|---|---|
| 0 | 4.6 | 6.7 | 5.9 | 16.2 | 7.6 |
| 1 | 2.5a | 7.5 | 0.4* | 9.7 | 1.8* |
| 7 | 1.2* | 5.0 | 1.2a | 12.1 | 6.2 |
| 15 | 1.4a | 3.5 | 1.1a | 11.6 | 2.3* |
| 30 | 1.2a | 2.4* | 0.9a | 9.4 | 4.4 |
| 60 | 1.1a | 1.5* | 2.1a | 3.3 | 1.1a |
| 90 | 1.0a | 4.2 | 2.3* | 5.3 | 1.4a |
| 120 | 0.5* | 7.6a | 0.5a | 8.2 | 5.8 |
| 150 | 0.5a | 4.5 | 0.1a | 6.6 | 4.3 |
| 180 | 0.6* | 1.4* | 3.6a | 4.3 | 3.2 |
Timepoints in which lameness shifted to the contralateral limb in horses diagnosed with bilateral distal tarsal osteoarthritis.
Discussion
The results of the present study indicated that a single intra-articular injection of 50 U of BoNT-A alleviated pain related to the TMT and CD joints. To the authors’ knowledge, this is the first study evaluating the effect of this neurotoxin as an option for the management of selected cases of naturally occurring osteoarthritis pain in horses. The findings of this clinical trial were interesting, which demonstrated significant long-lasting antinociceptive effects of BoNT-A at PIDs 90, 120, 150, and 180 when compared to placebo. However, early responses to the drug administration were also observed considering that 2 of 5 horses demonstrated lameness abolishment at PID 1, and 1 bilaterally affected horse from the same group shifted lameness to the contralateral limb, demonstrating significant improvement. Also, it must be emphasized that all of these subjects showed no adverse events during the clinical trial, corroborating the findings from a safety study26 recently published.
Distal tarsal osteoarthritis is the major hindlimb musculoskeletal problem observed in middle-aged horses that perform a variety of athletic disciplines,30 the main reason that motivated the choice for including retired horses with this condition in our study. Four horses from the BoNT-A group had bilateral lameness, which is also frequently observed in performance horses.31 In these particular subjects, the predominant lame limb can switch over time depending on the severity of each lameness. This pattern of pain alleviation in the baseline lame limb and lameness shifting to the contralateral limb was attributed by the authors as at least a substantial response to BoNT-A injection.
A pioneering noncontrolled study exploring BoNT-A as a treatment for joint pain was conducted by Mahowald et al,19 in which human patients with chronic arthritis received injections of BoNT-A, obtaining pain relief ranging from 3 to 12 months. In dogs, promising but controversial results were found in different clinical trials.24,32,33 In those studies,24,32 canine patients sustaining elbow, stifle, or hip osteoarthritis showed a significant improvement in lameness after intra-articular deposition of BoNT-A. Further, contrasting these results, a randomized, controlled clinical trial in dogs reported no relevant analgesic effects of BoNT-A.33 Interestingly, results from our study were in accordance with the majority of the clinical studies performed in both human and canine medicine. Horses from our trial demonstrated substantial improvements in lameness, peaking 60 days on average after BoNT-A injection. Moreover, partial or complete lameness improvement was obtained for at least 6 months, depending on individual responses, as observed in people. Otherwise, an increase in lameness severity was observed in 2 individuals from the placebo group (horses 1 and 3), especially after PID 60, which could negatively affect the statistical interpretation of effects between groups. Before entering the study, those horses were involved in athletic activities, had a history of chronic lameness, and then had been retired to pasture, presumably lessening the severity of clinical signs. Once they were accepted into the study and submitted to some level of exercise when trotted for study enrollment and the serial clinical evaluations without any treatment, the authors had them progressively worsen. Although they also experienced prolonged periods of inactivity preceding the study enrollment, horses from the BoNT-A group had the severity of lameness significantly controlled after treatment.
A pilot study25 investigated the potential benefits of intra-articular injections of BoNT-A in horses. Fourteen days after a single injection with 50 U of BoNT-A into the midcarpal joint, 2 clinically healthy horses underwent induction of synovitis with IL-1β. Surprisingly, 1 horse developed lameness, whereas the other remained sound. Two horses used as a control demonstrated changes in baseline evaluation compatible with lameness.25 As observed in other species, despite remaining the mainstay of joint pain therapy in horses, management with NSAIDs or intra-articular corticosteroids could not promote sufficient pain relief and may induce undesirable effects.3–7 The results found in a retrospective study34 regarding intra-articular medication with corticosteroids with or without sodium hyaluronate into the distal tarsal joints reported an improvement for a median 56 days, and there was no significant difference between triamcinolone acetonide and methylprednisolone acetate. Similar results were described by 2 studies35,36 using a carpal osteochondral fragmentation model of synovitis-induction. Injections with both triamcinolone acetonide and methylprednisolone acetate were administered at postsurgical days 14 and 28, and effectiveness was still observed at day 70 after injection. Of note, considering that the majority of horses from our study remained sound at PID 180, the effect of BoNT-A seems to be longer lasting than those obtained with corticosteroids. Therefore, our investigation opened new horizons for the treatment of chronic osteoarthritis, mainly for horses with refractory joint pain.
Conservative management of osteoarthritis also comprises rest, corrective shoeing, and intra-articular injections of glycosaminoglycans, hyaluronic acid, and polyacrylamide hydrogel.37,38 However, available medical treatments are often disappointing on a long-term basis, and lameness may persist in up to 50% of the cases.37 Recent studies39 have also shown that biological therapeutics, including platelet-rich plasma, IL-1 receptor antagonist protein, and mesenchymal stromal cell sources, hold potential regenerative properties for articular tissues. Despite reported satisfactory effects, the lack of homogenous standardization protocols and outcome measurements are the main limitations of these modalities.39 Ankylosis of the distal tarsal joints will ultimately eliminate pain, presumably by improving joint stability. Spontaneous ankylosis can occur, but usually it is slow and unpredictable. Alternatively, ankylosis can be achieved either chemically or surgically. Chemical facilitated ankylosis by neurolysis and/or cartilage destruction can be performed using intra-articular injections of sodium monoiodoacetate or ethyl alcohol with variable success rates and eventual undesirable side effects.40,41 Surgical arthrodesis of the distal tarsal joints by drilling is reserved for chronic cases, returning horses to their intended use, but its disadvantages include expense and a prolonged convalescence period, which may range from 4 to 12 months.42,43 In this scenario, the antinociceptive effects of BoNT-A appear to be an effective and affordable alternative, returning horses to soundness with no convalescence period nor complications related to its use. Thus, BoNT-A may especially help some animal categories such as retired osteoarthritic horses, to improve their quality of life; or even horses with advanced osteoarthritis, which temporarily would not be candidates to undergo an arthrodesis, including stallions and broodmares during the breeding season. It is important to highlight that the intra-articular use of BoNT-A brings ethical concerns. Considering its property of suppressing pain, off-label use of the toxin in athletic horses or racehorses to mask lameness before competitions would predispose them to catastrophic injuries, emphasizing that its application should be reserved only for selected cases.
One of the main difficulties encountered during clinical trials is assessing the response to treatment because of the need for an efficient and consistent method of scoring lameness over time. Subjective lameness evaluation by experienced clinicians is a traditional method for lameness evaluation and has been extensively used in research to define outcomes. However, subjective evaluation is prone to failure, especially in horses with mild lameness, and has poor interobserver agreement.44,45 Thus, the authors opted for using a kinematic gait analysis system to objectively evaluate the effectiveness of treatments in this study. This method has also been used to provide accurate quantification of lameness in equine clinical trials.46
Our study has some important limitations that need to be commented on. First, the main limitation is the small sample size. Although outcome measures were objectively evaluated, we recognize that further studies using a larger number of hoses might benefit the interpretation of BoNT-A effects. Likewise, only responses to the injection of TMT and CD joints were investigated here; therefore, future research must be conducted to investigate the potential benefits of BoNT-A injections into other joints, especially the high-motion ones. Regardless of the technique, many clinicians recognize that arthrocentesis of the CD joint is difficult to perform. The accuracy of arthrocentesis has been increased using radiographic-guided needle positioning in the CD joint.47 The lack of needle placement confirmation within the CD joint of the horses in this study is recognized by the authors as a major limitation. Like any clinical trial using patients with naturally occurring osteoarthritis, misdiagnosis could be possible at the time of study enrollment, leading to the selection of subjects that do not truly have the condition of interest. Regarding the horses of this study, horses were selected only if substantial improvement in lameness severity was seen following diagnostic anesthesia of the distal tarsal joints. Additionally, it is possible that horses with proximal suspensory desmitis associated with lameness arising from distal tarsal joints could have been selected.42 However, horses were only selected after a complete clinical evaluation, ruling out other possible sources of lameness through diagnostic analgesia. The concentration of the toxin tested in the present study was extrapolated from an early pilot study,25 which was further considered safe for intra-articular use in horses.26 Therefore, the results found here should not be extrapolated to other BoNT-A dose regimes. Considering the wide range of commercially available BoNT-A preparations, it is the authors’ opinion that the results of injections with products other than the one used here are likely to be the same. Finally, future studies could be focused on nociceptive biomarkers, which certainly would contribute to elucidating the promising use of BoNT-A for joint pain.
The intra-articular injection of 50 U of BoNT-A produced a substantial improvement in lameness in horses with naturally occurring distal tarsal osteoarthritis that peaked 60 days after injection. When compared to placebo, significant pain relief was observed at PIDs 90, 120, 150, and 180. Interestingly, no immediate or delayed adverse effects were observed in the patients included in the study. Thus, the apparent antinociceptive properties offered by BoNT-A at the recommended dose appear to alleviate pain for selected cases of osteoarthritis in horses. Future studies must be carried out to better explore the potential role of this neurotoxin as a therapy for this condition.
Acknowledgments
The authors would like to thank the Rio Grande do Sul State Mounted Police for providing horses for this study.
Disclosures
The authors have nothing to disclose. No AI-assisted technologies were used in the composition of this manuscript.
Funding
Funding for this study was provided by Coordination for the Improvement of Higher Education and the Foundation to Support Science and Technology (grant No. 5.03.0046), Brazil.
ORCID
Antônio A. Beck Jr https://orcid.org/0000-0003-0021-0190
References
- 1.↑
Van Weeren PR, de Grauw JC. Pain in osteoarthritis. Vet Clin North Am Equine Pract. 2010;26(3):619–642. doi:10.1016/j.cveq.2010.07.007
- 2.↑
Raffa RB. Mechanism of action of analgesics used to treat osteoarthritis pain. Rheum Dis Clin North Am. 2003;29(4):733–745. doi:10.1016/S0889-857X(03)00058-9
- 3.↑
McCkay RJ, French TW, Nguyen HT, Mayhew IG. Effects of large doses of phenylbutazone administration to horses. Am J Vet Res. 1983;44(5):774–780.
- 4.
Doucet MY, Bertone AL, Hendrickson DA, et al. Comparison of efficacy and safety of paste formulations of firocoxib and phenylbutazone in horses with naturally occurring osteoarthritis. J Am Vet Med Assoc. 1997;232(1):91–97. doi:10.2460/javma.232.1.91
- 5.↑
Knych HK. Nonsteroidal anti-inflammatory drug use in horses. Vet Clin North Am Equine Pract. 2017;33(1):1–15. doi:10.1016/j.cveq.2016.11.001
- 6.↑
Chunekamrai S, Krook LP, Lust G, Maylin GA. Changes in articular cartilage after intra-articular injections of methylprednisolone acetate in horses. Am J Vet Res. 1989;50(10):1733–1741. doi:10.2460/ajvr.1989.50.10.1733
- 7.↑
Fubini SL, Boatwright CE, Todhunter RJ, Lust G. Effect of intramuscularly administered polysulfated glycosaminoglycan on articular cartilage from equine joints injected with methylprednisolone acetate. Am J Vet Res. 1993;54(8):1359–1365. doi:10.2460/ajvr.1993.54.08.1359
- 8.↑
Safarpour D, Jabbari B. Botulinum toxin therapy in medical pain disorders. In: Jabbari B, ed. Botulinum Toxin Treatment in Surgery, Dentistry, and Veterinary Medicine. Springer; 2020:131–156.
- 9.↑
Heikkila H. Botulinum toxin treatment in veterinary medicine. In: Jabbari B, ed. Botulinum Toxin Treatment in Surgery, Dentistry, and Veterinary Medicine. Springer; 2020:337–358.
- 10.↑
Wheeler A, Smith HS. Botulinum toxins: mechanisms of action, antinociception and clinical applications. Toxicology. 2013;306:124–146. doi:10.1016/j.tox.2013.02.006
- 11.↑
Scott AB. Botulinum toxin injection into extraocular muscles as an alternative to strabismus surgery. J Ped Ophthalmol Strabismus. 1980;17(1):21–25. doi:10.3928/0191-3913-19800101-06
- 12.
Simpson DM, Hallett M, Ashman EJ, et al. Practice guideline update summary: botulinum neurotoxin for the treatment of blepharospasm, cervical dystonia, adult spasticity, and headache: report of the Guideline Development Subcommittee of the American Academy of Neurology. Neurology. 2016;86(19):1818–1826. doi:10.1212/WNL.0000000000002560
- 13.
Jankovic J. Dystonia syndromes. In: Jankovic J, Tolosa, E, eds. Parkinson’s Disease and Movement Disorders. 1st ed. Urband and Schwarzenberg; 1988:283–314.
- 14.
Dong Y, Wu T, Hu X, Wang T. Efficacy and safety of botulinum toxin type A for upper limb spasticity after stroke or traumatic brain injury: a systematic review with meta-analysis and trial sequential analysis. Eur J Phys Rehabil Med. 2017;53(2):256–267. doi:10.23736/S1973-9087.16.04329-X
- 15.↑
Nitti VW, Ginsberg D, Sievert KD, et al. Durable efficacy and safety of long-term onabotulinumtoxinA treatment in patients with overactive bladder syndrome: final results of a 3.5-year study. J Urol. 2016;196(3):791–800. doi:10.1016/j.juro.2016.03.146
- 16.↑
Welch MJ, Purkiss JR, Foster KA. Sensitivity of embryonic rat dorsal root ganglia neurons to Clostridium botulinum neurotoxins. Toxicon. 2000;38(2):245–258. doi:10.1016/S0041-0101(99)00153-1
- 17.↑
Cui M, Sid K, Rubino J, Aoki KR. Subcutaneous administration of botulinum toxin A reduces formalin-induced pain. Pain. 2004;107(1–2):125–133. doi:10.1016/j.pain.2003.10.008
- 18.↑
Durham PL, Cady R, Cady R. Regulation of calcitonin gene-related peptide secretion from trigeminal nerve cells by botulinum toxin type A: implications for migraine therapy. Headache. 2004;44(1):35–43. doi:10.1111/j.1526-4610.2004.04007.x
- 19.↑
Mahowald ML, Singh JA, Dykstra DD. Long term effects of intra-articular botulinum toxin A for refractory joint pain. Neurotox Res. 2006;9(2–3):79–88. doi:10.1007/BF03033937
- 20.
Dykstra DD, Stuckey MW, Schimpff SC, Singh JA, Mahowald ML. The effects of intra-articular botulinum toxin on sacroiliac, cervical/lumbar facet and sterno-clavicular joint pain and C-2 root and lumbar disc pain: a case series of 11 patients. Pain Clin. 2007;19(1):29–32. doi:10.1179/016911107X217473
- 21.
Singh JA, Mahowald ML, Kushnaryov A, Goelz E, Dykstra DD. Repeat injections of intra-articular botulinum toxin A for the treatment of chronic arthritis joint pain. J Clin Rheumatol. 2009;15(1):35–38. doi:10.1097/RHU.0b013e3181953b14
- 22.
Boon AJ, Smith J, Dahm DL, et al. Efficacy of intra-articular botulinum toxin type A in painful knee osteoarthritis: a pilot study. PM R. 2010;2(4):268–276. doi:10.1016/j.pmrj.2010.02.011
- 23.↑
Singh JA, Mahowald ML, Noorboloochi S. Intra-articular botulinum toxin A for refractory painful total knee arthroplasty: a randomized controlled trial. J Rheumatol. 2010;37(11):2377–2386. doi:10.3899/jrheum.100336
- 24.↑
Hadley HS, Wheeler JL, Petersen SW. Effects of intra-articular botulinum toxin type A (Botox) in dogs with chronic osteoarthritis. Vet Comp Orthop Traumatol. 2010;23(4):254–258. doi:10.3415/VCOT-09-07-0076
- 25.↑
DePuy T, Howard R, Keegan K, et al. Effects of intra-articular botulinum toxin type A in an equine model of acute synovitis – a pilot study. Am J Phys Med Rehabil. 2007;86(10):777–783. doi:10.1097/PHM.0b013e3181157718
- 26.↑
Beck Júnior AA, Paz LB, Frank MI, et al. Safety and inflammatory response after intra-articular injection of botulinum toxin type A in healthy horses. J Equine Vet Sci. 2022;110:103865. doi:10.1016/j.jevs.2022.103865
- 27.↑
McCarthy MG, Duesterdieck-Zellmer KF, Larson MK. Botulinum neurotoxin type A does not exert concentration-dependent effects on equine articular cartilage in vitro. Am J Vet Res. 2023;84(9):ajvr.23.04.0076. doi:10.2460/ajvr.23.04.0076
- 28.↑
Butler JA, Dyson SJ, Kold SE, Poulos PW. The tarsus. In: Baxter GM, ed. Clinical Radiology of the Horse. 2nd ed. Blackwell Science; 2000:247–284.
- 29.↑
Moyer W, Schumacher J, Schumacher J. Joint injection. In: Moyer W, Schumacher J, Schumacher J, eds. A Guide to Equine Joint Injection and Regional Anesthesia. MediMedia; 2007:49–51.
- 30.↑
Dabareiner RM, Cohen ND, Carter GK, Nunn S, Moyer W. Lameness and poor performance in horses used for team roping: 118 cases (2000-2003). J Am Vet Med Assoc. 2005;226(10):1694–1699. doi:10.2460/javma.2005.226.1694
- 31.↑
Dabareiner RM, Carter GK, Dyson SJ. The tarsus. In: Ross, MW, Dyson SJ, eds. Diagnosis and Management of Lameness in the Horse. 1st ed. Saunders; 2003:440–449.
- 32.↑
Heikkila HM, Hielm-Bjorkman AK, Morelius M, et al. Intra-articular botulinum toxin A for the treatment of osteoarthritic joint pain dogs: a randomized, double-blinded, placebo-controlled clinical trial. Vet J. 2014;200(1):162–169. doi:10.1016/j.tvjl.2014.01.020
- 33.↑
Nicácio GM, Luna SPL, Cavaleti P, Cassu RN. Intra-articular botulinum toxin type A (BoNT/a) for pain management in dogs with osteoarthritis secondary to hip dysplasia: a randomized controlled clinical trial. J Vet Med Sci. 2019;81(3):411–417. doi:10.1292/jvms.18-0506
- 34.↑
Labens R, Voute LC, Mellor DJ. Retrospective study of the effect of intra-articular treatment of osteoarthritis of the distal tarsal osteoarthritis in 51 horses. Vet Rec. 2007;161(18):611–616. doi:10.1136/vr.161.18.611
- 35.↑
Frisbie DD, Kawcak CE, Trotter GW, Powers BE, Walton RM, McIlwraith CW. Effects of triamcinolone acetonide on an in vivo equine osteochondral fragment exercise model. Equine Vet J. 1997;29(5):349–359. doi:10.1111/j.2042-3306.1997.tb03138.x
- 36.↑
Frisbie DD, Kawcak CE, Baxter GM, et al. Effects of 6alpha-methylprednisolone acetate on an equine osteochondral fragment exercise model. Am J Vet Res. 1998;59(12):1619–1628. doi:10.2460/ajvr.1998.59.12.1619
- 37.↑
Baxter GM, Southwood LL, Dechant JE. Treatment of horses with distal tarsal osteoarthritis. Compend Contin Educ Pract Vet. 2003;25(2):148–156.
- 38.↑
Tnibar A, Schougaard H, Camitz L, et al. An international multi-centre prospective study on the efficacy of an intraarticular polyacrylamide hydrogel in horses with osteoarthritis: a 24 months follow-up. Acta Vet Scand. 2015;57(1):20. doi:10.1186/s13028-015-0110-6
- 39.↑
Mayet A, Zablotski Y, Roth SP, Brehm W, Troillet A. Systematic review and meta-analysis of positive long-term effects after intra-articular administration of orthobiologic therapeutics in horses with naturally occurring osteoarthritis. Front Vet Sci. 2023;10:1125695. doi:10.3389/fvets.2023.1125695
- 40.↑
Sammut EB, Kannegieter NJ. Use of sodium monoiodoacetate to fuse the distal hock joints in horses. Aust Vet J. 1995;72(1):25–28. doi:10.1111/j.1751-0813.1995.tb03471.x
- 41.↑
Carmalt JL, Bell CD, Pazzini L, et al. Alcohol-facilitated ankylosis of the distal intertarsal and tarsometatarsal joints in horses with osteoarthritis. J Am Vet Med Assoc. 2012;240(2):199–204. doi:10.2460/javma.240.2.199
- 42.↑
Barber SM. Arthrodesis of the distal intertarsal and tarsometatarsal joints in the horse. Vet Surg. 1984;13(4):227–235. doi:10.1111/j.1532-950X.1984.tb00798.x
- 43.↑
Adkins AR, Yovich JV, Steel CM. Surgical arthrodesis of distal tarsal joints in 17 horses clinically affected with osteoarthritis. Aust Vet J. 2001;79(1):26–29. doi:10.1111/j.1751-0813.2001.tb10634.x
- 44.↑
Keegan KG, Dent EV, Wilson DA, et al. Repeatability of subjective evaluation of lameness in horses. Equine Vet J. 2010;42(2):92–97. doi:10.2746/042516409X479568
- 45.↑
Fuller CJ, Bladon BM, Driver AJ, Barr ARS. The intra- and inter-assessor reliability of measurement of functional outcome by lameness scoring in horses. Vet J. 2006;171(2):281–286. doi:10.1016/j.tvjl.2004.10.012
- 46.↑
Keegan KG. Mechanisms of objective lameness analysis. In: Proceedings of the 2009 American College of Veterinary Surgeons Veterinary Symposium. American College of Veterinary Surgeons; 2009:109–112.
- 47.↑
Seabaugh KA, Selberg KT, Mueller POE, et al. Clinical study evaluating the accuracy of injecting the distal tarsal joints in the horse. Equine Vet J. 2017;49(5):668–672. doi:10.1111/evj.12667
