Naturally occurring corticosteroids are 21-carbon molecules with varying glucocorticoid and mineralocorticoid activity. Synthetic corticosteroids are modifications of the parent molecule, in an attempt to improve anti-inflammatory activity and reduce mineralocorticoid activity. The modifications to the parent corticosteroid alter the water-solubility of the drug, which is thought to be associated with the duration of action. In general, corticosteroids with succinate and phosphate esters are water-soluble, have a short duration of action, and are good for parenteral use. Corticosteroids with acetate and acetonide esters are more lipid-soluble, have a longer duration of action, and are good for intra-articular use.

Intra-articular (IA) corticosteroids are commonly used to treat joint problems in horses. Although a variety of corticosteroid preparations may be used intra-articularly, the 3 most commonly used drugs are methylprednisolone acetate (MPA)^a, triamcinolone acetate (TA)^b, and betamethasone acetate and sodium phosphate (BAP)^c. The obvious clinical questions regarding IA corticosteroid use in horses are: 1) when to use which drug in what joint, 2) what is the most appropriate dose to use in different joints, 3) how can the detrimental effects of corticosteroids be minimized, and 4) how long will each drug provide clinical benefits to the horse. These and other questions regarding the clinical use of corticosteroids in horses will be addressed.

Mechanism and Duration of Action

Corticosteroids work through an interaction with steroid-specific receptors in the cytoplasm of cells. They are potent anti-inflammatory agents, and inhibit the inflammatory process at nearly all levels. Corticosteroids are thought to inhibit the movement of inflammatory cells into the site of inflammation, and inhibit neutrophil function by impairing the release of lysosomal enzymes and neutrophil phagocytosis. Corticosteroids also inhibit prostaglandin production primarily through the inhibition of phospholipase A2 by the steroid-inducible group of proteins known as lipocortins. Inhibition of phospholipase A2 prevents the breakdown of membrane phospholipids to fatty acids, which are subsequently oxygenated by the cyclooxygenase and lipoxygenase pathways to inflammatory eicosanoids. In contrast to nonsteroidal anti-inflammatory drugs (NSAIDs) which only inhibit the cyclooxygenase pathway, corticosteroids inhibit both eicosanoid pathways, and are therefore, more effective anti-inflammatory agents than NSAIDs. Other less well-defined anti-inflammatory actions of corticosteroids include inhibition of metalloproteinases, inhibition of monocyte-macrophage complexes at the site of inflammation, inhibition of chemotaxis and adherence of neutrophils to the vascular endothelium, and inhibition of plasminogen activator activity.

Estimating the duration of action and the relative potency of IA corticosteroids is very difficult and can be misleading. It has been assumed that the duration of action is directly related to the lipid solubility of the corticosteroid. However, the duration of action is not necessarily determined by the continued presence of the drug in the joint fluid. Concentrations of MPA and TA can only be detected in synovial fluid for a short period of time following injection, but the clinical anti-inflammatory effects are thought to last much longer. In 2 recent in vivo studies, reduced synovial membrane inflammatory scores were still present in joints treated with MPA or TA 45 days previously. Additionally, corticosteroids are prodrugs and must be hydrolyzed into their active forms. The rate of hydrolysis within a joint may affect both the onset and duration of action, and the potency of the drug. However, the rate of drug hydrolysis may not be that important since most corticosteroids are rapidly converted to their active forms within synovial fluid. Although there are many caveats in determining duration of action and potency of IA corticosteroids, it is generally considered that MPA and BAP have an intermediate to long duration of action and TA has an intermediate duration of action. Regarding potency, it has been estimated that BAP is more potent than TA, which is more potent than MPA. However, this is controversial and some veterinarians feel that TA is the most potent IA corticosteroid.

IA Corticosteroids

Methylprednisolone acetate (MPA)

Much of the research on IA corticosteroids in horses has concentrated on this drug. This is presumably because it is the most common corticosteroid used intra-articularly. Several studies have documented detrimental effects of multiple doses of MPA on cartilage metabolism, function, and repair in high motion joints (carpus, fetlock, tarsocrural, etc.). However, a recent study found that a single injection of 120 mg of MPA into the tarsocrural joints of horses inhibited the repair of osteochondral defects at 42 days, but had no detrimental effects on the quality of repair tissue at 180 days. Additionally, MPA appeared to incite synovial membrane inflammation compared to saline treated controls that was still evident 180 days after injection. This is in contrast to previous studies, which have demonstrated anti-inflammatory effects of MPA within joint tissues. The recommended dose of MPA in the package insert is 120 mg for large joints with a range from 40–240 mg. It also states that the duration of action averages 3–4 weeks and that intra-articular injections may occasionally cause a local inflammatory response (joint flare). However, lower doses of MPA (40–60 mg/joint) appear to be clinically effective and possibly less detrimental to the articular cartilage, although this assumption has not been substantiated. Because of the reported detrimental effects on articular cartilage, the author rarely uses MPA in high motion joints, and primarily uses MPA in the distal tarsal joints at doses of 40–60 mg/joint

Triamcinolone acetonide (TA)

A recent in vivo study demonstrated favorable effects of TA on degree of clinically detectable lameness, and on synovial fluid, synovial membrane, and articular cartilage morphological parameters compared to placebo treatment. This is in contrast to the detrimental effects on articular cartilage that were found with MPA using the same experimental model. However, in an in vitro dose titration study using IL-1 conditioned cartilage explants (unpublished data), TA at all doses was more detrimental to cartilage metabolism than was MPA. Granted, the in vitro study does not simulate the joint environment, but the conflicting results of these studies makes one question whether TA is truly not detrimental to articular cartilage. However, because TA may be less damaging to other joint tissues, TA is the author’s corticosteroid of choice to treat high motion joints (carpus, fetlock, stifle, coffin, tarsocrural, etc). The recommended dose of TA in the package insert is 6–18 mg/joint (1–3 ml). I usually do not exceed 12 mg/joint or 18–24 mg total dose. The package insert on TA also states that cases of laminitis have been reported following administration of TA, and that IA injection of TA may produce osseous metaplasia. The development of laminitis following the use of TA in horses appears to be more likely than with the other IA corticosteroids for reasons that are poorly understood.

Betamethasone acetate and sodium phosphate (BAP)

This corticosteroid combines a water-soluble form (phosphate) for a more rapid short-acting effect together with a more lipid-soluble form (acetate) for a more prolonged effect. Celestone is marketed for use in people and the doses listed in the package insert are intended for humans. There is a wide range depending on the size of the joint but most are between 0.5–2 ml of the 6–mg/ml solution (3–12 mg/joint). I usually use 6–18 mg/joint depending on the estimated joint volume. Similarly to TA, very little research has been done evaluating the effects of BAP on joint tissues. However, an in vivo study using a similar experimental model as was used to evaluate the effects both TA and MPA, found minimal detrimental effects of BAP on joint tissues in both rested and exercised horses. For these reasons, I use BAP primarily in high motion joints similar to TA. Additionally, there is thought to be less risk of a joint flare associated with BAP than the other IA corticosteroids, and the package insert states that it may be safely combined with local anesthetics. I rarely combine IA corticosteroids with lidocaine or carbocaine primarily because I nearly always use hyaluronan together with corticosteroids to treat most joints.

Clinical Use of IA Corticosteroids

The rationale of using IA corticosteroids to treat traumatic arthritis and other joint problems in horses is based on their potent anti-inflammatory effects. Clinical signs of joint disease such as lameness, synovial effusion, heat and pain on joint flexion can usually be reduced more quickly when IA corticosteroids or other IA medications are used as part of the therapeutic regimen. A randomized double blind clinical trial found a clinical benefit (reduced lameness, decreased time to soundness, and prevalence of sound horses) of treating traumatic joint problems in horses with hyaluronan and polysulfated glycosaminoglycans (PSGAG) compared to placebo treatment with saline. Although, a few clinical trials using IA corticosteroids have been performed in years past, a current well-controlled clinical study evaluating IA corticosteroids has not been performed. However, corticosteroids are potent anti-inflammatory agents and it is likely that there would be a clinical benefit of using these drugs similarly to what has been found for hyaluronan and PSGAG. In fact, IA corticosteroids will most likely reduce the clinical signs of joint disease more effectively and for a longer duration than other forms of IA medications based on their potent anti-inflammatory effects. However, the known benefit of using these drugs must be balanced with the potential detrimental effects that they may have on joint tissues.

The decision of when to use IA corticosteroids to manage horses with joint disease must be made on a case by case basis. Despite the known clinical benefits of IA corticosteroids, there is a sense of apprehension in using corticosteroids because of their known detrimental effects. Alternative joint therapies are often used initially because they have no known negative effects but may have questionable therapeutic effects as well. However, reaching for the corticosteroid should not be viewed as a last resort to manage horses with joint problems. The author uses IA corticosteroids routinely to manage horses with joint disease, and nearly always combines the corticosteroid with hyaluronan (“white acid”). Exceptions to this would be a horse with severe osteoarthritis of the distal tarsal joints or if a client does not wish to purchase the more expensive hyaluronan. IA medication is preferred over systemic treatment basically because it appears to be more effective at reducing the clinical signs of joint disease. A very simplistic approach in selecting an appropriate corticosteroid is to use TA or BAP in high motion joints (all joints other than the distal tarsal joints) and MPA in low motion joints such as the distal tarsal joints. However, there are exceptions to this generalization. Most joints are clipped prior to the injection, although there should be minimal problems injecting non-clipped joints if they are prepared adequately. I rarely combine antimicrobials (gentamicin or amikacin) with the corticosteroid and hyaluronan unless I feel there is an increased risk of infection associated with medicating a particular joint. A light bandage is place over the injection site, and oral phenylbutazone is given for 5 days to help prevent joint flare. Most horses are not worked for at least 1–2 weeks following injection, although an extended rest is not recommended unless the problem in the joint warrants a period of inactivity. The IA treatment may also be combined with systemic therapies such as IV hyaluronan (Legend), IM PSGAG (Adequan) or nutraceutical compounds depending on the clinical problem and finances of the client.

Negative Effects of IA Corticosteroids

The 2 primary reasons not to utilize IA corticosteroids to treat horses with joint disease are the risk of synovial infection and the potential detrimental effects the drugs may have on articular cartilage and subchondral bone. Although infection is always possible, it is rare if good aseptic technique is used during the injection process. Combining antimicrobials with the injection should further decrease the risk of infection. Additionally, there is some speculation that joints with severe osteoarthritis may be more prone to post-injection infections. Combining antimicrobials with IA medication may be warranted when treating these types of joints. In an attempt to minimize the deleterious effects of IA corticosteroids on joint tissues, lower doses of drugs are being used. This is based on the assumptions that lower doses of corticosteroids will be less harmful to joint tissues, and that lower doses of drug will still reduce the clinical signs of joint inflammation. The recent trend is to utilize the lowest clinically effective dose possible for all IA corticosteroids. Determining this minimally effective dose for each corticosteroid is presently based on clinical experience and empirical use because no in vivo studies comparing different doses of corticosteroids have been performed. Data from in vitro dose titration studies have given conflicting results with some suggesting that lower doses are less detrimental to cartilage metabolism and others indicating that lower doses are equally detrimental to cartilage metabolism and may be less effective at counteracting the inflammatory process. Further work in this area will be needed to determine the minimally effective dose of IA corticosteroids.

Table 1. Proposed characteristics of corticosteroids and guidelines for utilizing IA corticosteroids to treat joint problems in horses.^d (*)

References

1.  Carter BG, Bertone AL, Weisbrode SE, et al. Influence of methylprednisolone acetate on osteochondral healing in exercised tarsocrural joints of horses. Am J Vet Res 1996;57:914-922.

2.  Dechant JE, Baxter GM, Frisbie DD, et al. Effect of methylprednisolone acetate and triamcinolone acetonide on equine articular cartilage explants in vitro. Vet Surg 1999;28:391.

3.  Foland JW, McIlwraith CW, Trotter GW, et al. Effect of betamethasone and exercise on equine carpal joints with osteochondral fragments. Vet Surg 1994;23:369-376.

4.  Frisbie DD, Kawcak CE, Trotter, GW et al. Effects of triamcinolone acetonide on an in vivo equine osteochondral fragment exercise model. Equine Vet J 1997;29:349-359.

5.  Frisbie DD, Kawcak CE, Baxter GM, et al. Effects of 6a-methylprednisolone acetate on an equine osteochondral fragment exercise model. Am J Vet Res 1998;59:1619-1628.

6.  Trotter GW. Intra-articular corticosteroids. In, McIlwraith CW and Trotter GW (eds): Joint Disease in the Horse.Philadelphia,PA, WB Saunders, 1996,pp 237-256.

Footnotes

a. Depo-Medrol, Pharmacia & Upjohn Company, Kalamazoo, MI 49001

b. Vetalog, Fort Dodge Animal Health, Fort Dodge, IA 50501

c. Celestone Soluspan, Schering Corporation, Kenilworth, NJ 07033

d. Recommendations for IA corticosteroid injections are based on combining the drugs with hyaluronan, but not antimicrobials.