THERAPEUTICS USE IN EQUINE MUSCULOSKELETAL DISEASE

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1 Vet Times The website for the veterinary profession THERAPEUTICS USE IN EQUINE MUSCULOSKELETAL DISEASE Author : JUSTINE KANE-SMYTH Categories : Vets Date : October 20, 2014 JUSTINE KANE-SMYTH BVM&S, MRCVS sums up the treatments available and advocates a holistic approach to ensure the optimum outcome for horses affected by these disorders THE plague of any athlete is musculoskeletal disease and the vast majority of our equine patients, in all their shapes and sizes, are athletes; from the leading rein show pony, right across the board to the national hunt racing thoroughbred. In its myriad forms, musculoskeletal disease most commonly manifests as lameness, but we also recognise its more subtle presentations of poor performance or behavioural problems. In 1888, Alexandre Liautard claimed the idea of a good horse with poor legs is a misnomer, the legs are the essence of the horse and every other part of the equine machine is of only subservient and tributary importance. While the statement was rather bold, it may still hold a grain of truth, as musculoskeletal disease and injury remain the most prevalent cause of horse wastage. Despite the explosive advancement in the quality and array of diagnostics and therapeutics now available to the clinician, a certain reliance on the art of veterinary medicine remains where equine orthopaedics is concerned. A holistic approach is necessary to achieve the optimum outcome in every case, incorporating valid therapeutics, appropriate alterations in management, exercise and farriery as well as employing any suitable complementary therapies. Therein lies the art of orthopaedics. 1 / 12

2 This article is a brief résumé of the equine clinician s medicine bag, the therapeutics we directly administer and prescribe most commonly. NSAIDs The COX inhibitors remain a stalwart in the management of both acute and chronic musculoskeletal pain and inflammation. Clinically, phenylbutazone is suggested to be the most effective. Trials have proven its effectiveness in reducing articular pain; however, little evidence exists to prove any superior efficacy over other NSAIDs. Due to severe adverse effects in humans (specifically aplastic anaemia), licensing has been withheld in some countries. Evidence is increasing regarding the drug s potential for chondrotoxicity and its inability to modulate articular inflammation. Previous suggestions of any synergistic activity with flunixin have been disproven, while combining the drugs substantially increases the risk of toxicity. The safety margin for phenylbutazone is notably narrower than most other NSAIDs, with severe toxicity encountered in vulnerable animals (geriatrics and foals), as well as horses with vascular, hepatic or renal compromise. It is highly irritant and perivascular injection can have major consequences (for example, laryngeal hemiplegia). Despite all this, phenylbutazone and its pro-drug suxibuzone, arguably remains the most costeffective and convenient analgesic anti-inflammatory in practice. In practice, flunixin is typically reserved for soft tissue and visceral pain, despite having efficacy equal to phenylbutazone in the alleviation of lameness, and a greater duration of activity. Many practitioners will administer flunixin in cases of acute, severe soft tissue injury or pain, such as tendonitis or lymphangitis. In vitro studies have suggested the drug s potential adverse influence on synovial membrane homeostasis. The well-recognised gastrointestinal and renal side effects associated with prostaglandin inhibition have led to much interest in selective inhibition of the inducible and inflammatory-mediating COX-2, therefore sparing the constitutively expressed COX-1. Some confusion exists regarding the actual specificity of the COX sparing drugs. Using the current standard assays for determining specificity (where selective COX-2 inhibitors should inhibit prostacyclin but preserve thromboxane B2), phenylbutazone, flunixin, carprofen, ketoprofen and aspirin all equally inhibit COX-1 and COX-2. Meloxicam demonstrates the most selective COX-2 inhibition, which is suggested to explain the reduced potential for side effects in foals. Its potent analgesic and anti-inflammatory effects have been proven; most interestingly, however, is the drug s reported ability to ameliorate the catabolic effects of acute synovitis on cartilage. While the data is very promising, its use is sometimes prohibited by the relative costs. 2 / 12

3 Firocoxib is the newest COX-2 specific contender on the UK market, licensed for treatment of osteoarthritis. Similar to meloxicam, the reports of its efficacy and safety profile are encouraging, but the higher costs and its availability only in paste and injectable formulations have limited its use thus far. Carprofen is also reported to have a potentially beneficial influence on articular homeostasis and has been touted as the future NSAID of choice. Only an injectable formulation is available for horses in the UK, limiting its usefulness. Due to the peculiarities of the donkey s metabolism, more frequent administration of some NSAIDs is necessary, except with carprofen, which has a longer duration of action in donkeys than horses. Once-daily dosing is therefore sufficient, making carprofen useful in the hospital setting. Corticosteroids The most potent anti-inflammatories in the equine clinician s armoury are corticosteroids and they are probably still the first-line treatment for arthropathies in many cases. Convenient, effective, cheap and safe or are they? While their efficacy in reducing articular pain is irrefutable, the debate regarding their safety rages. On the one hand, corticosteroids inhibit several inflammatory pathways, with the additional benefits of analgesia and cartilage preservation. On the other hand, higher doses disrupt cartilage matrix synthesis and the analgesic effect permits overuse of diseased joints, both leading to acceleration of cartilage degradation and the much-publicised syndrome corticosteroid arthropathy. On balance it would appear that, used judiciously at conservative doses, corticosteroids are very useful. However, they have the potential to exacerbate existing chondral lesions, most probably when used at higher doses or administered repeatedly, and particularly when strenuous exercise continues. A 24 to 48-hour period of box rest post-administration appears to slow the rate of clearance from the joint, allowing improved penetration and a considerably prolonged duration of effect. Perilesional administration may be beneficial in chronic tendonitis or desmitis, because of corticosteroid inhibition of collagen formation; however, long-term use should be avoided. Corticosteroid choice and dosage remains largely empirical, though recommended maximum doses have been lowered to minimise the laminitis and chondrotoxicity risks ( Table 1 ). Methylprednisolone acetate has the longest duration of activity, but due to its reported deleterious effects on cartilage (at high doses), it is typically reserved for low motion joints. An even more cautious approach has recently been advocated due to the suggestion the drug may affect cartilage in joints other than those directly injected. Using 10mg to 40mg per synovial compartment is lower than the datasheet recommendations (40mg to 120mg), but is safer and probably sufficient. A human preparation of triamcinolone acetonide may be used on the cascade and is the 3 / 12

4 most widely used corticosteroid in equine orthopaedics, with fewer adverse effects reported. Betamethasone acetate has also been used, although not licensed, for competition horses, due to claims of shorter detection times. Disease-modifying drugs Based on the findings of several investigations, the traditional indication (and indeed licensing) for polysulphated glycosaminoglycans (PSGAGs) for pre-existing cartilage lesions can no longer be advocated. A growing body of evidence suggests a role as chondroprotectants in acute synovitis. This provides a rationale for administration to manage acute (traumatic) arthritis or following arthroscopic surgery to treat the inevitable haemarthrosis and synovitis. Originally developed as an articular medication, it will potentiate Staphylococcus aureus synovial infection, although this effect is completely ameliorated when administered with amikacin. Intramuscular administration (every four days for seven injections) has become popular; unfortunately, only weak evidence exists to support its efficacy when given via this route. Articular medication appears to be more effective, but the recommendations are three to five injections weekly, making it expensive and impractical. PSGAGs are also used to treat tendonitis, by either intramuscular or intralesional injection. Reported to inhibit collagenase and metalloproteinase activity, they are probably most useful in the acute phase of repair. Studies have not revealed any significant reduction in reinjury rate, and robust data to validate the suggestion the drug stimulates tenocyte repair is lacking. A component of articular cartilage and synovial fluid, hyaluronan is vital for maintaining synovial environment homeostasis and natural production is increased in response to synovial inflammation. Physically, it contributes to the viscoelasticity of synovial fluid and exerts the effect of steric hindrance, minimising the deleterious effects of inflammatory mediators. It also has receptormediated anti-inflammatory activity with resultant cartilage-sparing effects. Exogenous administration is advocated to treat synovitis (in joints, bursae, sheaths) and tendonitis. There are four licensed preparations ( Table 2 ), each with varying indications, administration routes and different mean molecular weights. Product choice depends on the clinician s opinion regarding the most effective molecular weight. Higher molecular weight products (which tend to be more expensive) are said to have superior influence on synovial fluid viscosity and, therefore, greater chondroprotective effects. Proponents of the lower molecular weight products claim the receptor-mediated effects are more important, and with greater tissue penetration a superior anti-inflammatory effect is achieved. Current opinion favours products with a molecular weight in the range of Daltons to 2 4 / 12

5 10 6 Daltons. Articular medication in combination with a corticosteroid is advised to minimise the risk of synovial flare. It is suggested these drugs act synergistically, resulting in a prolonged clinical effect and allowing administration of lower doses of corticosteroid. While most clinicians rely on a single injection, the data would suggest a series of four to five injections at one to two-week intervals provides optimal results. The cost implications prohibit this in many cases however. Intravenous use is reported to have an anti-inflammatory effect, though less clinical benefit is seen with this route. It does have the advantage of influencing multiple synovial structures simultaneously. Some clinicians will administer by the intrasynovial and intravenous routes at the same time. Derived from beech wood, pentosan polysulphate is suggested to positively influence synoviocyte metabolism, inhibit enzyme-mediated cartilage degradation and increase hyaluronan synthesis. It has gained substantial popularity in osteoarthritis management, but while there is a reasonable body of data substantiating its efficacy in people and dogs, convincing evidence in horses is lacking. Only the (intramuscular) injectable form is available in the UK and it is not licensed for use in horses. Some clinicians advocate intra-articular injection or oral administration, although its bioavailability is very poor. Licensed bisphosphonate tiludronate inhibits osteoclastic bone resorption and may restore equilibrium when there is dysregulation of bone turnover. It has been shown to reduce disuse osteopaenia due to limb immobilisation in horses. One of the seminal studies investigating its effects reported improvement in lameness attributed to navicular disease. These were horses with lameness localised to the foot, without advanced imaging to rule out soft tissue lesions. The drug is now considered to exert anti-inflammatory and analgesic effects on soft tissues. In retrospect, the clinical benefits seen in that study may have been due to an anti-inflammatory effect on unrecognised soft tissue lesions rather than supposed osteolytic lesions. The drug is licensed for spavin in the UK (and navicular disease elsewhere), but has been advocated for numerous other orthopaedic conditions with little but anecdotal evidence to support any claims of efficacy in horses. The most noteworthy of these is the suggestion of a benefit in fracture healing. In the absence of trials, opinion suggests any such interference with the fracture repair mechanism is potentially dangerous and contraindicated. 5 / 12

6 Biologic therapies Initially heralded as the great panacea for equine musculoskeletal disease, mesenchymal stem cells therapy appears to hold promise, but has yet to reach such expectations. Clinical studies investigating treatment of tendonitis demonstrated a reduced reinjury rate following intralesional transplantation of cultured autologous cells, derived from bone marrow. Implanted pluripotent cells are thought to differentiate into cells capable of producing tendon matrix and growth factors, hence promoting healing and replacement of functional tissue rather than scar tissue. Acute inflammation appears to be detrimental to cell viability, but optimal results are achieved when treatment is performed within a month of injury. Treatment two to three weeks postinjury is therefore recommended. Further understanding of the mechanisms and refinement of the techniques is probably required before the true benefit of this regenerative medicine is realised. Cell harvest and culturing is costly and time consuming, which continues to limit the utilisation of this therapy in practice. Intrasynovial use has also been investigated and the results are promising, although further work is needed. With the advent of a patient-side collection system, intra-lesional injection of non-activated plateletrich plasma (PRP) has gained popularity for treatment of tendon and ligament injuries. This therapy relies on concentrating a sufficient number of autologous platelets (arbitrarily cited as greater than 1, /?l, which are activated by the inflamed tissue upon administration, resulting in clot formation and release of growth factors. There is evidence the clot provides a scaffold and the growth factors enhance cellular repair. Efficacy issues arise due to inconsistencies in the number of platelets harvested and the potential for premature activation of the platelets during processing, ultimately resulting in lower growth factor concentrations delivered to the site of injury. Data to support the claimed clinical benefits should be interpreted with caution as there are inconsistencies in the preparation and administration of PRP between studies. The clinical data to support its use in horses is scarce, but what exists is encouraging. Mostly used for tendinous or ligamentous core lesions, a single intralesional injection (under ultrasound guidance) one to two weeks post-injury usually results in defect filling, but if the ultrasonographic appearance is not substantially improved by four weeks, repeat treatment is advocated. A concurrent strict exercise rehabilitation regimen is of critical, and potentially greater, importance. Most research data on autologous conditioned serum concerns interleukin-1 receptor antagonist protein, an antagonist of interleukin-1, the most prominent inflammatory mediator in osteoarthritis. The product is actually an acellular mélange of growth factors, as well as anti-inflammatory and indeed pro-inflammatory cytokines. The precise mechanisms of activity are therefore not fully understood. Trials suggest modest improvement in signs of early degenerative joint disease in horses, but the anecdotal accounts of its benefits are compelling. 6 / 12

7 Usually administered on three to four occasions at seven-day intervals, clinical improvement is expected after the second injection and resolution of lameness after the final injection. Advocates of the treatment suggest a good response in horses with joint disease refractory to corticosteroid medication and report a clinical effect lasting between three and 12 months, when used in this way. Intralesional administration in cases of tendonitis and desmitis is practised by some, and the benefits attributed to the presence of growth factors (similar to PRP). References Caron J P (2005). Intra-articular injections for joint disease in horses, Vet Clinics Nth Amer 21(3): van Weeren P R and de Grauw J C, (2010). Pain in osteoarthritis, Vet Clinics Nth Amer Eq Prac 26(3): Baxter G M (2011). Adams and Stashak s Lameness in Horses (6th edn), Lippincott Williams and Wilkins, Philadelphia. Ross M and Dyson S (2010). Diagnosis and Management of Lameness in the Horse (2nd edn), Elsevier Saunders, St Louis. A full list of references is available on request from the author. 7 / 12

8 The equine athlete. 8 / 12

9 MRI illustrating a deep digital flexor tendon lesion in the foot. Advances in diagnostics continue to improve the clinician s ability to institute the most appropriate therapeutics. 9 / 12

10 Three different samples of prepared autologous conditioned serum: careful preparation is required to ensure the serum contains the minimum number of cells. 10 / 12

11 Table 1. Commonly used corticosteroids Table 2. The hyaluronan products licensed in the UK, in order of increasing molecular weight 11 / 12

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