Corticosteroids: Short- and Long-Term Effects
Of the medications available in the arsenal of anti-inflammatory therapies, there is one type that has caused considerable debate. This is the class of drugs known as corticosteroids.
Present naturally to some degree in all animals, corticosteroids are normally produced by the adrenal glands. Their natural actions protect the body against a variety of internal and environmental stressors, and they help the animal adapt to changes in its environment for improved survival. As medications, steroids have diverse effects, some of which are beneficial in the short term, yet longer use might exert less desirable results. When used judiciously and appropriately, corticosteroid medications can be of great benefit to limit many disease processes in the horse. When used unwisely, they can injure or kill.
What are Corticosteroids?
Corticosteroids, commonly referred to as "steroids," occur in different forms with various physiologic actions. The glucocorticoids most notably affect the metabolism of carbohydrate, fat, and protein, while also possessing distinctive anti-inflammatory properties. Another class of corticosteroids, the mineralocorticoids, control water and sodium retention by the kidneys.
The adrenal glands generate a third group of corticosteroids, the sex hormones. Anabolic steroids are derivatives of the sex hormone testosterone, and they are recognized for their ability to promote body growth, protein synthesis, and increased muscle mass.
This discussion will focus only on synthetically produced glucocorticoid drugs because of their potent use in targeting inflammation and their extensive use in horses.
It is not uncommon for an athletic horse to be afflicted with degenerative joint disease, known also as osteoarthritis. The degree to which an arthritic joint will affect performance depends on which joint is affected, the degree of damage, the athletic pursuit and demand required, and how stoic an individual horse is to withstand persistent pain. Intra-articular (IA) joint therapy is a common strategy used to combat the discomfort felt by an equine athlete in performing his job. Some of the mainstay medications used in joint injections are glucocorticoids because of their notable ability to reduce inflammation.
David Frisbie, DVM, PhD, Dipl. ACVS, of the Equine Orthopaedic Center at Colorado State University, specializing in research and treatment of equine joint disease, and Stuart Shoemaker, DVM, Dipl. ACVS, of Idaho Equine Center in Nampa, Idaho, have a wealth of knowledge to share about the use of corticosteroids in athletic horses.
Corticosteroids, as mentioned, are potent anti-inflammatory agents. "One well-established mechanism of action of corticosteroids is inhibition of enzymes (mediators) that create inflammation," says Frisbie. "This inhibitory action by corticosteroids occurs closer to their origin along the biochemical pathway as compared to traditional non-steroidal anti- inflammatory drugs (NSAIDs), thereby providing a broader anti-inflammatory effect. Recent research has demonstrated that corticosteroids specifically block the particularly damaging COX-2 inflammatory mediators, whereas available NSAIDs do not."
Shoemaker explains that chemical mediators of inflammation are produced by the soft tissues surrounding the joint. The inflammation creates the pain and swelling seen clinically with arthritis. If allowed to persist, eventually there will be progressive degeneration of joint tissues.
"Some corticosteroids are effective at abating this process," notes Frisbie. "In addition to inhibiting effects on enzymes, corticosteroids also play a role in repair of damaged cell membranes." With suppression of inflammation, pain is alleviated.
"Duration of pain relief is related to the degree of damage in the joint at the time of treatment as well as the particular medication used," adds Frisbie.
A short-acting corticosteroid that is commonly used is betamethasone. A corticosteroid that gives moderate duration relief is triamcinolone (TA). Methylprednisolone (MPA) provides the longest duration of action.
Frisbie says any of these products injected into a mildly inflamed joint affected with inflammation of the synovial membrane (synovitis)--and without other significant problems--can decrease pain unless further damage occurs.
Shoemaker stresses that managing joint inflammation in performance horses prolongs the life of the cartilage by reducing potentially harmful chemical byproducts in the joint. "Conversely, in a joint with moderate arthritis where articular cartilage damage has occurred, this process is believed to be irreversible," says Frisbie. At that point, treatment is aimed at decreasing the progression and inflammation rather than expecting a cure.
Both practitioners prefer TA for joint treatment. "Because research favors protective effects of TA on joint tissues while potentially negative effects are seen with MPA, I routinely use TA in all joints," says Frisbie. "I will use MPA in a low-motion joint if an owner's priority is duration of action. TA has been shown to decrease inflammation and damage to articular cartilage, and it promotes increased metabolic activity of the chondrocytes (cartilage cells) when administered into a damaged joint. Similar effects have not been observed with the other corticosteroids."
Shoemaker's strategy is comparable: "In young performance horses, I prefer short-acting steroids, like TA, to rapidly decrease inflammation and to try to protect cartilage at all costs. I combine the use of these with other chondroprotective drugs (such as hyaluronic acid)."
To amplify the action of corticosteroid benefits in joint therapy, both practitioners use a combination of steroid and hyaluronic acid (HA) in the vast number of joints they treat. Shoemaker says, "Hyaluronic acid has a modest anti- inflammatory effect, but has a more profound effect as a boundary lubricant of the joint and binding to synovial cells to stimulate the production of normal synovial fluid."
Frisbie says there is recent objective evidence that the combination of HA and a steroid is beneficial. He points out that corticosteroids provide potent analgesia (pain relief), so care must be taken to protect an unstable joint from excessive use.
The best results with TA, Frisbie stresses, are achieved when a horse is given 24 hours off before strenuous exercise is resumed. His clinical impression is that a slightly longer duration of action is achieved by following corticosteroid treatment with seven to 10 days of rest.
Shoemaker says the drugs must have an opportunity to exert their effects on the joint in order for the joint's metabolism to return to normal.
Lately, there has been a trend for owners to request that their veterinarians inject "normal" joints. "I personally do not believe in injecting normal joints with corticosteroids, and there are no published articles that would support this practice," states Frisbie.
Shoemaker does recognize an occasional reason to inject as a diagnostic tool: "If a trainer has a concern and wants a joint injected to see if there is a change in training, I will use hyaluronic acid and a short-acting steroid. Periodic injections of normal joints with TA are not necessarily protective against arthritis. I believe that a normal joint is hard to improve upon."
For a competitive equine athlete, an owner must be aware of drug testing and regulations within a discipline. Says Frisbie, "Pharmacologic detection varies greatly based on the governing body of competition, the detection assay at the lab, the product used, the dose, and individual horse."
As a general rule, Shoemaker recommends not treating with steroids for at least a week prior to American Quarter Horse Association and U.S. Equestrian Federation events, and at least three weeks prior to a Fédération Equestre Internationale (FEI) event. It is best to confer with a veterinarian familiar with all these aspects to avoid conflicts with drug rules.
Frisbie stresses that many "reports" of irreparable damage created by steroid injections are cases with end-stage osteoarthritis where the disease progresses even in the face of treatment. "A further diagnostic workup should be done if a horse needs re-injection within two months of treatment," urges Frisbie. "I am especially cautious about injection frequency in high-motion joints such as the fetlock and coffin joints, preferring at least a six-month window between treatments. A need for more frequent injections may signal undiagnosed issues."
He stresses that horses with significant pain should not be asked to perform athletic tasks until the degree of damage is completely understood.
In discussing potential side effects, Shoemaker says, "Most joints that are injected are inflamed, so the increase in circulation speeds absorption into the peripheral circulation, thus creating a systemic effect."
What about laminitis associated with intra-articular (into the joint) steroid injection?
"An Australian study (in 2003) reviewed cases that had been injected with TA and followed up with regards to developing laminitis," says Frisbie. "A single horse in 205 cases (about 0.5%) developed laminitis when given a dose that was two to four times greater than that used by most practitioners in the USA. My clinical experience is that laminitis is rarely induced at a standard dose or frequency in a horse that does not have other metabolic problems or a history of laminitis."
For Older Horses
Anti-inflammatory steroid therapy might be useful to improve quality of life for old, arthritic horses; for example, an old horse that has trouble getting up due to painful hock joints. "In older patients with multiple joint issues, systemic steroids can be very beneficial," states Shoemaker. "Systemic corticosteroids are also beneficial in managing the acute inflammation of tendonitis or desmitis (inflammation of a ligament). Steroid injections into--and in the tissues surrounding--tendons and ligaments can cause secondary problems, such as dystrophic (caused by faulty nutrition) calcification and spontaneous rupture of these surrounding structures, which are not seen with systemic administration."
It is important to weigh the benefit of relieving joint pain with steroids versus the potential to develop laminitis if a horse is predisposed by Cushing's disease or equine metabolic syndrome and obesity.
Although corticosteroid use in joint therapy has proven invaluable, there are alternatives on the horizon. Shoemaker comments, "I believe the use of IRAP (interleukin-1 receptor antagonist protein) is going to represent a new age of intra-articular therapies. These are immune system mediators designed to turn off joint receptors to control specific inflammatory mediators excreted in joint fluid. As we gain increased knowledge of receptors and their controls, these products will become increasingly effective and hopefully will control joint inflammation with no side effects."
Jennifer MacLeay, DVM, PhD, Dipl. ACVIM, of Colorado State University, has used corticosteroids many times in the clinic at the veterinary teaching hospital. She stresses, "Veterinarians do not take corticosteroid use lightly. We always try to use them in clinical settings where they are absolutely necessary and the benefits outweigh the risks."
Following are some of the ailments that might benefit from corticosteroid use.
Respiratory The capability of systemic corticosteroids to suppress the immune response and limit inflammation makes it a useful drug to manage allergic syndromes--particularly of the respiratory tract or skin--or autoimmune problems. A horse that is afflicted with chronic reactive airway disease (RAD) is greatly helped by corticosteroids in systemic or inhaled aerosol form. Aerosol delivery of steroids localizes the drug at high levels in the lungs with minimal systemic effects. Coughing and breathing difficulty are relieved as steroids decrease airway spasm, reduce inflammation and production of mucus, and indirectly improve dilation of the airways.
"Inhaled steroids are absorbed to a small degree and have some systemic effects, although these effects are far less than if given orally or injected," says MacLeay. "It is the goal of owner and veterinarian to balance the risk of chronic (long-term) inhaled steroids, such as increased risk of respiratory infection, against the pros of their use in controlling RAD. In my experience treating horses with severe RAD, the benefits well outweigh the risks."
Environmental management strategies are essential in successful resolution of RAD, while other medications, such as bronchodilators (i.e., clenbuterol), minimize the necessary dose of steroid to control airway reactivity. Horses given inhaled steroids might test positive at a show, so owners should be aware of this possibility.
Shock One potent application of steroids is in the face of cardiovascular shock related to trauma or blood loss, or to treat endotoxic shock arising from colic or an overwhelming systemic bacterial infection. "Most corticosteroids have a short duration of action," says MacLeay. "They help stabilize membranes and limit the release of inflammatory mediators that would otherwise lead to increased blood vessel permeability and dilation, both of which exacerbate shock."
Yet, their role in suppressing the immune response poses a risk to a horse that is being treated for sepsis or in the face of a concurrent bacterial infection. MacLeay cautions, "If used during an infection in conjunction with an antibiotic, then steroids are helpful to control inflammation and pain. But, long-term use in the face of infection may suppress a horse's ability to fight off that infection."
Situations that preclude use of corticosteroids would be following surgery, in the face of overwhelming systemic sepsis, in a suspect case of a fungal infection, or in a horse experiencing, or prone to, laminitis.
MacLeay also reports that if both corticosteroids and NSAIDs are given for more than a single dose, there is a greater possibility for a horse to develop gastric ulcers. In those cases, concurrent anti-ulcer medications (omeprazole or ranitidine) should be given.
Immunizations Paul Lunn, BVSc, MS, PhD, MRCVS, Dipl. ACVIM, professor and head of the Department of Clinical Sciences at the Colorado State University teaching hospital, comments on the impact of steroid treatment on immunizations: "If your vet is treating with steroids to achieve systemic suppression of a horse's immune response, then we anticipate a high risk of a compromised immune response to a vaccine. So, it would be better to wait at least two to three weeks after steroid treatment ends before vaccines are given.
"On the other hand," continues Lunn, "if a steroid dose is not excessive, and if the steroid administered is an inhaled form with its primary activity local to the respiratory tract, then it is unlikely that vaccine responses would be seriously impacted. The extent of systemic effects vary between different inhaled steroid products, and the degree of immunosuppression is dependent on the dose amount and which type of steroid medication is used."
Lunn says joint injections with steroids are another example of a treatment that should not interfere with vaccination response.
Dean Hendrickson, DVM, MS, Dipl. ACVS, a surgeon and professor at Colorado State's veterinary teaching hospital, is commonly confronted with traumatic wounds. One common use for short-acting, topical steroids is in the control of exuberant granulation tissue, or proud flesh.
"Corticosteroids inhibit the replication of both fibroblasts and epithelial cells, with more effect on the fibroblasts," says Hendrickson. "Steroids are then useful to control buildup of an excessive amount of proud flesh."
He cautions that corticosteroids should not be used in wounds for an extended period of time as they open the door for infection due to immune system depression. Steroids also can slow the healing process by inhibiting proliferation of epithelial cells.
"The best time to use a topical steroid is following use of dressings that stimulate granulation tissue formation through mild inflammation," says Hendrickson. "Exuberant granulation tissue is best removed with a sharp scalpel, rather than being 'killed back' with steroids. Short-acting, water-soluble steroids applied topically once or twice are also useful prior to skin grafting."
Eye injuries, such as corneal ulcers or penetrating wounds, heal in a manner similar to skin, i.e., by laying down a fresh "skin" of epithelial cells. Corticosteroids inhibit growth of epithelial cells, so an ulcer on the eye could expand rapidly in the presence of topical steroid treatment.
Steve Roberts, DVM, MS, Dipl. ACVO, of the Animal Eye Center in Loveland, Colo., describes this phenomenon: "The exacerbation effect of topical corticosteroids relates to suppression of the normal healing response and the inflammatory response to microbes, and its enhancement of the breakdown of proteins within the collagen of the cornea. Within a few hours of a break in the corneal epithelium (outer layer), white blood cells (neutrophils or PMNs--polymorphonuclear leukocytes) move into the tear film and gain access to the epithelium and underlying corneal connective tissue (stroma). As the PMNs try to stop infection, they begin to remodel the wound area in preparation of healing by epithelial cell migration to form a new layer. If the initial influx of PMNs is reduced by the presence of steroids, then microbes may gain a foothold, making ultimate control difficult even with antibiotics or antifungal medications."
Roberts recommends avoidance of topical corticosteroids when there is a break in the corneal epithelium and during the first few weeks of healing when an ulcer no longer stains with fluorescein dye. Whenever your horse shows pain in his eye, it is always best to have your veterinarian examine the eye to determine the exact nature of the problem before implementing treatment.
In cases of anterior uveitis (inflammation of the uveal tissues that make up the pupil of the eye, also known as moon blindness), Roberts says corticosteroids are immensely helpful in controlling the inflammatory response in the eye to allow resolution of the uveitis.
Yet, he cautions, "Because of the unique attributes of the equine eye being of large size, one must overtreat the body to get the desired tissue levels into the eye."
Topical treatment often doesn't provide a sufficient amount of steroid medication to suppress uveitis inflammation. "An acute uveitis case is likely going to receive less than therapeutic drug levels, possibly reducing inflammation to just below a threshold of clinical detection," says Roberts. "The eye seems to get better, but inflammation remains. Systemic delivery of oral or systemic steroids along with injection of repository steroids within the conjunctiva of the eye provide better penetration to facilitate enough drug reaching uveal tissue. The problem then is to deliver this treatment without causing systemic side effects or dangerous interactions with other systemic delivery of drugs that suppress inflammation, such as other steroids or NSAIDs."
Dosing and Withdrawal
MacLeay explains the invisible effects of long-term (weeks or months) systemic steroid therapy: "Prolonged use of systemically administered steroids downregulates a horse's adrenal response. If medication is stopped abruptly, the horse is left with an insufficient adrenal response, making him less able to adapt to internal or external stressors. Weaning a horse off steroid treatment over a course of several weeks enables the adrenal glands to start working efficiently again.
"Another practical reason to slowly wean a horse off steroids is to enable your veterinarian to identify the lowest effective dose of therapy," she adds. "In that way, we can limit the adverse effects of steroids while maintaining their benefits."
Steroids are useful medications that have gotten a bad rap. When used properly, they have many functions in equine health care. Improper use can result in laminitis, systemic or localized infections, and further injury due to pain-reducing effects of decreased inflammation. Horse owners also need to be aware of the potential for positive drug tests due to steroid use in competition horses.
About the Author
Nancy S. Loving, DVM, owns Loving Equine Clinic in Boulder, Colorado, and has a special interest in managing the care of sport horses. Her book, All Horse Systems Go, is a comprehensive veterinary care and conditioning resource in full color that covers all facets of horse care. She has also authored the books Go the Distance as a resource for endurance horse owners, Conformation and Performance, and First Aid for Horse and Rider in addition to many veterinary articles for both horse owner and professional audiences.
POLL: Complementary Therapies