EQUINE JOINT THERAPIES
Intra-articular Medications (joint injections)
The administration of medications directly into a joint has evolved into an essential procedure that nearly any equine veterinarian is expected to perform. This procedure is now an invaluable tool for the diagnosis, treatment and maintenance of joint health in horses used for any type of exercise, pleasure riding, and/or competition. The ever- increasing demands on performance horses has produced a boon in our research and understanding of the pathophysiology of joint disorders in horses. As a result, we have seen significant improvement in the specificity of therapy, and an increasing focus on joint health maintenance with Disease Modifiying Osteoarthritis Drugs (DMOAD), systemic medications and complementary therapies. The utilization of intra-articular injection and therapy is an essential component of management used in order to continue to offer these athletes the ability to exercise, train and compete in comfort and to their athletic potential, while also reducing the rapidity of the progression of joint pathology. Given these benefits however, there is also a potential for inappropriate use and over-utilization of these techniques. It is therefore important for the veterinarian and the owner/trainer/rider to consider the potential overuse of intra-articular administration within the context of the medications used, the need to enter a joint and the relative impact on the welfare and benefit to the horse.
"Maintenance" Joint Injections
The above discussion raises another point I frequently encounter in performance horses. There is a perception by some that it is necessary to perform joint injections regularly for "maintenance". I've encountered this frequently in Quarterhorse owners and trainers- especially as it pertains to injecting the hocks. In my opinion, for the reasons stated above and discussed below, this perception is misguided and potentially detrimental to your horse. In my practice, I must have a good reason and justification to enter a joint for any reason. Injecting any joint regularly by justifiying it as "maintenance" is destructive and dangerous to the horse. It is, in my opinion, irresponsible for anyone to suggest that this is necessary in any horse without appropriate verification of joint inflammation and/or pathology.
Joint Inflammation and Ostoearthritis There is increasing interest in intervening in joint disorders earlier than by the time osteoarthritis has become apparent. A single traumatic event, such as a chip fracture, can produce an acute form of joint inflammation or irritation. If acute traumatic events are not managed acutely and intensively (e.g. fragment removal), many of these acute traumas will lead to chronic and possibly severe osteoarthritis. Once the acute joint trauma is initially managed, continued long-term management is often necessary to facilitate joint health and to control the progression of osteoarthritis. However, most horses probably develop a chronic form of osteoarthritis as a result of repetitive mild joint trauma from years of exercise, training and athletic competition. This chronic form is slow in onset, beginning with capsulitis and synovitis (joint capsule and inner surface inflammation), progressing to overt osteoarthritis if untreated. Although poor conformation is likely to be a predisposing factor, horses with excellent conformation also develop capsulitis and synovitis from rigorous training and competition schedules. Capsulitis and synovitis are believed to result in a release of a cascade of inflammatory mediators that can lead to the further release of numerous enzymes associated with cartilage degeneration. This enzymatic degradation is the major factor that leads to development of advanced osteoarthritis. The results are articular cartilage damage, synovial membrane thickening, and joint capsule fibrosis. Osteoarthritis is a byproduct of the wear and tear and daily trauma- beginning with enzymatic release, followed by cartilage degradation, leaching of proteoglycan and unwinding of the collagen due to the activity of inflammatory mediators. Collagen molecules then appear to stimulate more inflammation, and a vicious cycle is initiated. Because of this, some of the most promising techniques to control and manage osteoarthritis is directed at early intervention at the capsulitis and synovitis stages via the utilization of chondroprotective or disease-modifying osteoarthritic drugs (DMOADs). We are becoming increasingly convinced of the role of synovitis and the enzymatic degradation that occurs in the joint as precursors to the development of osteoarthritis for horses with the more common chronic, repetitive trauma-induced joint problems. Subchondral bone injury can occur as a result of a single episode or from repetitive overuseage. Such injuries often appear identical to more prototypical joint injury, despite the fact that the primary injury is not at the joint surface. Osteoarthritis as a result of “joint instability” is often overlooked as an underlying cause of joint pathology. Joints rely upon soft-tissue structures integrity for stability. Examples of these soft tissues include; collateral ligaments, tendons, meniscus, muscle groups as well as the joint capsule. If the joint is not stable, abnormal joint motion may result. Secondary inflammation occurs as the joint is challenged and an abnormal range of motion is manifest. This may result in nonspecific symptoms of joint- inflammation such as swelling, heat, effusion, pain etc. If such a joint is injected, it will likely experience profound temporary improvement. However, the instability/ mechanical motion of the joint also needs to be addressed in order to return normal joint stability and range of motion, and thus curtail the perpetuation of the return of joint inflammation.
In summary, osteoarthritis is a disease process. In its mild (early) form, osteoarthritis occurs as a physiologic process involving the initiating conditions such as capsulitis and synovitis. Over time, the physiologic process of a chronic unhealthy synovial environment can lead to structural and even mechanical issues, (loss of joint capsule elasticity and radiographic changes associated with arthritis such as joint bone spurs.
Approaches to the Control of Joint Inflammation It is inescapable that horses that are in prolonged regular training, competition or other exercise will develop some form of joint pathology. Recognizing the early signs of joint inflammation is important in reducing long-term effects and the development of osteoarthritis. Early intervention to control joint inflammation is important to facilitate joint health and the duration of ability to perform at the desired level. Control of joint inflammation is not restricted to joint injections. Extra-articular ( therapies outside of the joint) are often utilized before intra-articular therapy is instituted, or these interventions may be used in conjunction with intra-articular (in the joint) therapies to help manage and control joint inflammation and the progression to osteoarthritis. Rest, cooling therapy and controlled exercise are probably comonly utilized strategies for lameness in horses. However, once arthritis is in its later stages, rest may actually worsen the clinical signs associated with joint pain such as overt lameness.
Although these strategies are used both alone and in conjunction with other therapies, their importance in management of lameness cannot be overstated. Intravenous, intramuscular and oral joint therapies are widely available and appear to have a definite place in management of joint inflammation and control of the progression of osteoarthritis. Judicious anti-inflammatory therapy is a powerful tool to control joint inflammation. Anti-inflammatory therapies may be administered by systemic administration (oral, IM and IV), topical or by intra-articular (joint injection) approaches. Appropriate utilization of these therapies is associated with excellent clinical results and greatly facilitates the control of the progression of joint disease.
Corticosteroids The Steroid Stigma
Corticosteroids, as a class of drugs, have received alot of negative attention in the past two decades. This attention has severely jaded many owners, trainers, riders and some veterinarians towards steroid use. Many performance/ sport horse veterinarians have encountered the situation in which they recommend the to utilization of steroid therapy in order to alleviate joint inflammation to facilitate joint disease modification and control, and to achieve the clinical result the owner/trainer/rider seek. Yet, these same clients may concurrently demand that steroids not be used. These are difficult situations and often are influenced by the jaded impression of steroid use and unfortunately may severely hamper the veterinarian in his/her therapeutic and joint-supportive approach. In such instances, it may become necessary to attempt other, potentially less effective and significantly more expensive therapy, such as IRAP. Corticosteroids have been blamed for complications related to their use in racehorses with arthritis, that sustained injury of the treated joint following their use. Unfortunately, it was not the drug class that was responsible for this occurrence, but rather a potentially inappropriate selection of the clinical situation in which they were utilized. Adding to the already damaged image of corticosteroid use in the horse, a body of research was produced that suggested that the use of corticosteroids in joints was associated with cartilaginous damage. An association of corticosteroid use with laminitis has also become common. These factors are now understood to be misleading and have fueled the apprehension of intra-articular corticosteroid use in the horse. They are discussed below.
The realities of appropriate intra-articular corticosteroid use are dramatically different than these perceptions. In the referenced research studies, the damage created by steroid injection was primarily in horses with end-stage osteoarthritis, where the disease progresses in the face of any treatment. Substantiation for a direct link between corticosteroid administration and arthritis remains unproven by numerous investigations. Recent studies have indicated no difference in cartilage lesions of horses that had surgery and corticosteroid injections when compared to their controls. A conclusion reached and perpetuated by some researchers, clinicians and practitioners was that intra-articular corticosteroids may potentially aggravate existing cartilage lesions in horses involved in intense exercise. However, this occurrence is less prevalent than previously believed by researchers, and vastly less than what public perception suggests. The majority of the problems associated with intra-articular corticosteroid administration can be attributed to poor injection technique (infection), poor case selection and inappropriate use of corticosteroid doses and products. Despite these findings, today's equine veterinarians approach intra-articular steroid use carefully and avoid exceptionally high doses and/or frequent and repetitive injections of the same joint. Many performance veterinarians also utilize various extra-articular (outside the joint) therapies to help manage joint health and to significantly extend the time between the need for intra-articular corticosteroid administration. Equine veterinarians view the need to intervene with repetitive intra-articular corticosteroid therapy as a strong indication for further diagnostic evaluation, for the consideration of other possible complicating problems of the affected joint, or the presence of advanced disease. In our practice, at least a six-month window between intra-articular treatments is considered to be prudent. A need for more frequent injections may indicated advanced disease or an undiagnosed problem.
So why do veterinarians need to use steroids?? Current research and tremendous amounts of clinical experience have proven that when used correctly, corticosteroids are very effective and relatively inexpensive medications for the intervention and control of joint disease. They are included in the class of medications considered to be “disease modifying” medications. The enzymes that are produced by diseased or inflamed joints are responsible for the damage to normal cartilage. Joints that are inflamed must be treated with anti-inflammatory medication in order to curtail the production and release of these damaging enzymes and to re-establish the production of normal joint fluid. Because inflamed joint tissues will not produce normal, thick, adequately lubricating hyaluronic acid and joint fluid, intra-articular corticosteroids are important for the re-establishment of the ability of the joint to produce healthy hyaluronic acid and to ameliorate the production of destructive enzymes to the cartilage that directly lead to osteoarthritis over time. Clinical signs of joint disease such as lameness, synovial effusion, heat and pain on joint flexion can usually be reduced more quickly and for a longer duration when intra-articular corticosteroids are utilized in comparison to most other intra-articular monotherapies.
Disease Modifying Osteoarthritis Drugs and Symptom Modifying Osteoarthritis Drugs There are two major drug categories that pertain to osteoarthritis treatment and management. These are the symptom-modifying osteoarthritis drugs (SMOADs) and the disease-modifying osteoarthritis drugs (DMOADs). In general, SMOADs alleviate pain and lead to improved clinical signs, such as reduced lameness and less-pronounced response to flexion. DMOADs however actually affect the degenerative process and they slow the progression of joint deterioration. Not all DMOADs exhibit symptom-modifying effects. The most beneficial treatment approach requires the use of a drug or drug combination that exhibits the characteristics of both drug categories. Currently the most common approach tends is intra-articular steroid administration. Triamcinolone exhibits significant disease- and symptom-modifying effects. However, high doses or long-term use of any intra-articular medication may be associated with adverse events. Therefore, non-articular options to symptom-modifying and disease-modifying drug properties drugs are being activley investigated and marketed. Drugs such as intravenous hyaluronic acid and intramuscular polysufated glycosaminoglycan may offer symptom and disease-modifying effects. Other treatment modalities, such as shock-wave therapy, Interleukin 1 Receptor Antagonist Protein (IRAP) and topical diclofenac (Surpass®), among others, have been associated with some disease modifying effects.
Non-steroidal Anti-inflammatory Drugs (NSAIDS) Phenylbutazone, flunixin meglumine, and ketoprofen are the most commonly administered NSAIDs for the control of musculoskeletal pain and inflammation. It is important to recognize that NSAIDs can be associated with significant side-effects including gastrointestinal ulceration and reductions in kidney perfusion. Because of these potential side-effects, systemic NSAID administration is not recommended at high doses or for prolonged periods of time. It is appropriate to consider some preventive therapy for gastrointestinal ulceration anytime an NSAID is administered to a horse. It is important to consider the impact of a condition that may respond more effectively to direct treatment of the underlying problem (such as intra-articular therapies). Nonetheless, it is frequently important to employ the use of NSAIDs for musculoskeletal pain. The NSAIDs used in horses do not exhibit identical pharmacologic properties and toxicological profiles. The NSAIDs commonly used in horses include; aspirin, phenylbutazone, flunixin meglumine, meclofenamic acid and ketoprofen. As a group, NSAIDs are well absorbed from the stomach and high protein binding means that most of the drug remains in the blood. Only low levels of NSAIDs are found in normal tissues and joint fluid and these levels are derived from the much smaller fraction of free NSAID in the blood. NSAID delievery to damaged tissues and joints is however potentiated by increased blood flow and fluid leakage from the vessels due to inflammation. NSAIDs should be administered cautiously to dehydrated horses. Blood concentrations will be greater than normal in the dehydrated horse and are more likely to cause toxicity. Furthermore, renal perfusion is already impaired by hypovolemia and the effects of high doses of NSAIDs will further significantly reduce renal perfusion. In general, any two NSAIDs administered together will be additive in their effect. The NSAIDs block the cyclooxygenase enzyme, interrupting formation of thromboxane, prostacyclin and the prostaglandins from arachidonic acid. This results in antipyretic action (reduces fever), mild pain relief, anti-inflammatory effects and inhibition of platelet clumping.
Aspirin Aspirin has the weakest anti-inflammatory and analgesic (pain relieving) activity of the NSAIDs in horses, so it is uncommonly used in horses for inflammatory conditions. While the action of most of the other NSAIDs on platelet cyclooxygenase is reversible, aspirin irreversibly binds to cyclooxygenase in platelets and has the greatest anti-clotting activity of the NSAIDs. Its anti-clotting action may be useful in treating conditions in the horse that involve damage to blood vessels and clot formation such as; laminitis, thromboembolic colic and other vascular accidents, recurrent uveitis, and endotoxemia. Aspirin is partially converted in the blood and by the liver to salicylic acid, and this is rapidly excreted by the kidneys into the urine.
Phenylbutazone
Phenylbutazone (PBZ) has analgesic, anti-inflammatory, and fever-reducing activity from inhibition of cyclooxygenase. The injectable formulation must be administered exclusively by careful intravenous administration because this formulation causes severe tissue damage if given intramuscularly or subcutaneously. Following oral administration, PBZ is well absorbed, but the time it takes to reach peak blood levels is delayed by feeding. In the blood, greater than 99% of the PBZ is carried bound to blood proteins. Phenylbutazone is converted by the liver to a metabolite with the same action as PBZ. The capacity of the liver to process PBZ becomes overwhelmed at relatively low drug doses. Therefore, increasing doses of PBZ can easily result in toxicity. In the horse, the therapeutic effect of PBZ lasts for more than 24 hours, due to the slow excretion of the oxyphenbutazone metabolite. Phenylbutazone is used extensively in horses for a variety of common musculoskeletal disorders including navicular disease, laminitis, osteoarthritis and degenerative joint disease. The use of PBZ in performance horses is highly regulated by individual performance associations because PBZ may alleviate lameness in horses for several days following its use. THis property makes it important to consider in pre-purchase examinations as well. Phenylbutazone is regarded as having the most potential for toxicity of all of the NSAIDs routinely administered to horses. Due to drug accumulation from the slow excretion of the metabolite, long-term PBZ therapy for chronic conditions should be extended to every other day, with utilization of the lowest effective dose and consideration for ulcer prevention and alternative approaches for pain management. Toxicity to the gastrointestinal tract is the most prominent adverse effect of PBZ therapy in horses, but PBZ may also cause causes kidney dysfunction by inhibiting the prostaglandins that maintain kidney blood flow. Phenylbutazone competes for the same cellular binding sites as thyroid hormone. Treating horses for just 5 days causes a significant decrease in baseline thyroid hormone (T3 and T4) concentrations. Treated horses have a greater than normal response to injection with thyroid stimulating hormone. Caution should be exercised if and when testing thyroid hormone levels in horses that have received phenylbutazone.
Flunixin Meglumine
Flunixin meglumine is a potent inhibitor of cyclooxygenase that is available in injectable, oral paste and oral granule formulations. The onset of anti-inflammatory and analgesic action is within 2 hours of oral administration, and the duration of action may extend to 36 hours. As other NSAIDs, flunixin meglumine is highly protein bound. It is eliminated by the kidneys, and can be measured in urine for 48 hours following a single dose. Flunixin's pain relieving effect appears to last beyond the persistence of significant blood levels. This duration of pain relief may be due to accumulation of the drug within inflamed tissues and due to the interaction of flunixin with opiod receptors in the central nervous system in a manner similar to morphine. Flunixin is used as an anti-inflammatory and analgesic agent in horses for a variety of conditions including; colic and other visceral pain, colitis, exertional rhabdomyolysis, endotoxemia, pleurodynia, ocular inflammation and pain, general surgery, laminitis, and other musculoskeletal disorders. Flunixin exhibits superior anti-endotoxic activity to other NSAIDs. Although not all equine veterinarians agree, extremely high doses of flunixin have been proposed to mask signs of surgical colic pain. Flunixin has similar adverse effects to PBZ, but appears somewhat less toxic than PBZ in horses. High doses can result in loss of appetite, depression, and gastrointestinal tract ulcers. Intramuscular injections of flunixin have been associated with fatal cases of clostridial myositis and should be avoided.
Meclofenamic Acid (Arquel®)
Meclofenamic acid is a very palatable oral granule used in horses as an analgesic and an anti-inflammatory agent for musculoskeletal conditions. This drug has not been extensively researched in veterinary medicine. Feeding prior to dosing may delay absorption of meclofenamic acid from the horse's stomach. Arquel® is the commercially available product and it is administerd as 20 grams of granules per 1000 lb horse, once a day in the feed. Its anti-inflammatory and analgesic action can take 36-96 hours to develop. Therefore, the drug is often used, when permitted, in anticipation of joint inflammation or in preparation for a competition. Repeated daily dosing does not result in drug accumulation, making it a useful drug for chronic inflammatory conditions such as navicular disease or bone spavin. Many horses can be maintained comfortably with twice weekly dosing without side effects. This drug appears to be relatively less toxic than most of the other NSAIDs. At normal doses, some decrease in blood protein concentrations may be seen. Doses much higher than the label dose appear to be necessary to induce toxicity which may include; mouth ulcers, loss of appetite, depression, edema and weight loss.
Ketoprofen
Ketoprofen is a propionic acid derivative (in the same class as human Advil®). Ketoprofen blocks the production of cyclooxygenase derived mediators of inflammation. Ketoprofen and its active metabolites persist in inflamed tissues at concentrations higher than those obtained in the blood. Therefore, the anti-inflammatory effects of ketoprofen are not necessarly related to its concentration in the blood. Ketoprofen is rapidly eliminated from the blood, therefore kidney-damaging drug accumulation does not occur. The anti-inflammatory effects of ketoprofen peak at 12 hours after a dose and last for about 24 hours. The advantages claimed for the use of ketoprofen in horses include inhibition of bradykinin and inhibition of both cyclooxygenase and lipoxygenase pathways. However, anti-lipoxygenase activity has not been demonstrated in actual studies involving live horses. A purported cartilage-protective effect reported from investigations using cartilage cultures, has also not been demonstrated in horses. Ketoprofen is recommended for musculoskeletal injuries, where a single dose provides pain relief and anti-inflammatory activity for 24 hours. Clinically, ketoprofen does not appear to offer significant benefit over the use of flunixin meglumine, but may be less likely to cause gastrointestinal ulcers than other NSAIDs. In a small toxicity study in horses, ketoprofen produced fewer gastrointestinal lesions than treatment with flunixin meglumine or phenylbutazone.
Firocoxib (Equioxx®) This new NSAID is the first cyclooxygenase-1 (COX-1) sparing drug to be approved by the FDA for use in horses. Laboratory studies have shown Firocoxib to be highly selective for cyclooxygenase-2 (COX-2), which is responsible for the production of inflammatory mediators. It is concurrently very sparing of cyclooxygenase-1 (COX-1) activity, which is argued to be more involved in production of prostaglandins for maintenance of physiologic functions including gastric lining protction, kidney function and normal platelet function. Firocoxib was restricted to use outside competition until the rule allowing its use took effect August 1, 2007. The new rule lists firocoxib as a NSAID with a restrictive quantitative limit and allows for a maximum permitted concentration of 0.240 micrograms per milliliter of blood plasma. The recommendation for appropriate dose and time consideration is consistent with the manufacturer's guidelines for its use at 0.1 milligram per kilogram of body weight once daily. This dose corresponds to a 45.5 milligram dose for a 1000 lb. horse, which should be given no closer than 12 hours prior to competing. Firocoxib can be used for a period of 14 consecutive days. Per manufacturer recommendation, firocoxib should not be used in a horse in the 30 days prior to competing in an Fédération Equestre Internationale event. Some of the COX-2– selective anti-inflammatory agents have been reported to help ease pain in dogs but did not show disease-modifying beneficial effect. It is important to continue to focus on decreasing the progression of disease. At this time, it is unclear if that is a characteristic of the COX-2–selective anti-inflammatory agents.
Topical NSAID (Diclofenac sodium, Surpass®) Diclofenac is a nonsteroidal anti-inflammatory drug (NSAID) with analgesic properties. Diclofenac sodium is a nonselective cyclooxygenase and lipoxygenase inhibitor that is commonly used in human medicine. The safety profile of topical diclofenac has been clearly established in humans. Although there is not a diclofenac product approved for oral, IV or IM administration in horses, a 1% diclofenac liposomal cream formulation (Surpass® [1% diclofenac sodium] Topical Anti- Inflammatory Cream, IDEXX Pharmaceuticals) exists for topical administration to horses for control of joint pain and inflammation associated with osteoarthritis. The drug is recommended for application in the horse by application of a five-inch (5”) ribbon of Surpass® topical cream twice daily over the affected joint for up to ten days. Potential side effects include gastrointestinal and kidney toxicity. Colic and weight loss and jaundice were also listed as potential adverse effects with this medication. Although topical diclofenac has been cited as effective for the control of joint pain and inflammation associated with osteoarthritis, at least one study that investigated the anti-inflammatory efficacy of diclofenac dietilamine, applied topically indicated a lack of pharmacological effect of this compound after such administration. Other studies demonstrated the slow absorption and elimination of 1% liposomal diclofenac cream. After administration of 1×, 2×, and 4× the label dose twice daily for 10 days, the decline in concentrations occurred gradually over the next 3 days.
Other recent work has suggested that the commercially available form of diclofenac for horses (Surpass®) exhibits disease-modifying effects for osteoarthritis. Further clinical application of this formulation of diclofenac is advocated for horses that have a tendency to have swelling after hard work, especially around the fetlock joints, and for routine topical management of horses with joint inflammation and/or disease. Comparison of diclofenac sodium to phenylbutazone in disease-modifying effect appears to favor diclofenac over phenylbutazone. Fewer side effects are likely to be encountered with topical diclofenac.
Tiludronic acid (Tildren®) ‘Tildren’ is composed of Tiludronic acid, a bisphosphonate, a drug class with activity on bone metabolism. The main activity of Tiludronic acid is to reduce bone resorption by inhibiting osteoclasts. Tiludronic acid acts as a regulator of bone remodeling in any situation involving excessive bone resorption. The drug does not affect bone formation or bone mineralization at the recommended dose. Tilduronic acid exhibits anti-inflammatory effects on arthritis by inhibiting the secretion of enzymes that damage cartilage. Tiludronic acid helps to facilitate the binding of blood calcium to bone. Tiludronic acid limits the release of bone calcium by the inhibition of resorption. Through these mechanisms, Tilduronic acid enhances calcium absorption, increases bone density and acts as a regulator of bone remodeling. As a consequence of these properties, Tiludronic acid has been beneficial in the treatment of lameness where bone pathology is involved, in particular, when radiographs show that osteolysis and sclerosis are features of the pathology
Overall, Tiludronic acid is reported to be helpful in the treatment of lameness associated with navicular syndrome, osteoarthritis, bone spavin and other bone-related causes of lameness. It is reported to be most effective for cases with clinical signs of less than 6 months duration. Although currently unavailable in the United States, a veterinarian can contact the FDA and file paperwork to get the drug imported for specific horses by verifying a clinical indication for the drug in the intended recipient horse. In double-blind, placebo-controlled clinical trials, treatment with intravenous tiludronic acid induced a clear improvement of lameness as demonstrated by long-term reduction in lameness and resumption of athletic activity. Another clinical trial involving the treatment of back pain manifest with bony lesions of the spinal column with tiludronic acid resulted in clear improvement in back flexibility. The anti-arthritic activities of tiludronic acid are supported by its inhibitory effects on the secretion of enzymes that degrade cartilage. Tiludronic acid is recommended at a dose of 0.1mg/ kg bodyweight once daily for 10 days by slow intravenous injection (10mL or 1 vial of reconstituted solution per 500kg bodyweight per day for consecutive 10 days). This drug has also been given as a single bolus intravenously and diluted in at least 1 liter of fluids. Anecdotal experience indicates a higher rate of the side effects, particularly colic, when the entire 10 day dose of the medication is given as a single bolus. This appeared to be particularly common when the drug is not well diluted in IV fluids.
Intramuscular and Intravenous Joint Therapies: Chondroprotective Drugs Hyaluronic acid
Chondroprotective drugs are used to prevent or slow the progression of degenerative joint disease. Their effect on clinical signs of lameness is limited in comparison to that of anti-inflammatory drugs. Instead, chondroprotective drugs are utilized to facilitate chondrocyte and overall joint health and function by preventing and reducing damage to joint cartilage that occurs when there is release of enzymes and inflammatory mediators due to inflammation.
Hyaluronic acid or hyaluronan (HA), is a normal component of joint cartilage and fluid. It has been widely used as a treatment for joint diseases of horses and is administered by intravenous administration and direct injection into the joint. Chemically, HA is an unsulfated glycosaminoglycan. It is produced by a membrane lining the joint capsule, is released into the joint fluid and is taken up by the cartilage. HA provides joint lubrication and protection of joint cartilage from the shear and compressive forces of joint motion. HA is also shown to reduce joint concentrations of inflammatory mediators and free radicals. HA concentration in inflamed joints is reduced in degenerative joint disease. Intravenous formulations of HA provide a convenient and less invasive route of administration relative to joint injection. Despite the popularity of this mode of administration of HA it is unclear if or how HA administered intravenously actually produces benefit to the joints. Presumably, when HA is given intravenously, it disperses to all the joint capsules in the body. However, it has been reported that intravenously administered HA does not appear to penetrate the joints at all. Its apparent beneficial effects may occur by HA molecule attachment to anti-inflammatory receptors of the joint capsule. By such a mechanism, intravenously administered HA may exhibit more potent anti-inflammatory activity than when it is directly injected into the joint. However, if intravenously administered HA does not enter the joints, there can be no lubrication effect when HA is given intravenously. Studies indicate that horses treated with intravenously administered HA do exhibit a reduced degree of lameness compared to untreated horses. The anti-inflammatory effect of HA when given intravenously is reported to be anywhere from 2 to 7 days. Because it works well for these short periods and is a naturally occurring substance, HA is often used during major USA Equestrian or FEI sanctioned competitions in place of other medications that result in a positive drug tests. Some veterinarians administer this medication frequently during competitive events. However, rules and limitations for the administration of medications should be followed as per the event regulations.
Polysulfated Glycosaminoglycan (Adequan® et al)
Polysulfated glycosaminoglycan (PSGAG) is a joint therapy derived from an extract of cow lung and trachea. Following administration, PSGAG binds to cartilage components. The mechanism of action of PSGAG in joints is unclear, but there are many studies that demonstrate a beneficial effect in damaged joints. PSGAG is believed to exhibit anti-inflammatory effects by decreasing the effect of destructive enzymes associated with joint inflammation and disease, and by stimulation of normal production of hyaluronan and glycosaminoglycan. PSGAG is commonly administered to horses by either intra-articular injection or by intramuscular administration. When using the intramuscular injection, a dose is often administered every four days for four weeks. Some equine practitioners advocate administration of additional doses at weekly or monthly intervals. Because of a potential for joint inflammation and infection from direct injection of a joint, many practitioners prefer the intramuscular product. Commercially available PSGAG (Adequan®) is advocated for preventive or therapeutic intervention of degenerative joint disease. In several studies, intramuscularly administered PSGAG was shown to penetrate and incorporate into newly produced cartilage. PSGAG works to help heal damaged cartilage. The end result is presumably a healthier joint more capable of resisting the wear and tear imposed by athletic performance. There appears to be minimal anti-inflammatory effect of intramuscular PSGAG administration. Therefore, the use of PSGAG is more important for long term joint health and maintenance. Following the initial series, strategic planning of the use of this drug can be helpful to control expense for the client while maximizing benefits.
“Generic” Hyaluronic Acid and Polysufated Glycosaminoglyan Type Drugs (Hycoat, Chondroprotect, Polyglycan, MAP-5, etc) An ever-expanding number of drugs are being produced by many companies in order to compete with Legend® for the market in hyaluronic acid and with Adequan® for the polysulfated glycosaminoglycan market. The vast majority of these “generic” drugs are not labeled for intravascular administration. Instead many are labeled for use in wounds to facilitate wound healing, and/or they have no supportive research in their efficacy for producing the clinical effects perceived with the 2 proprietary products, Legend® and Adequan®. However, there is extensive use of these “generic” products in order to facilitate more economical and more frequent administration of the same or similar compounds to horses in competition. It is imperative to recognize that this constitutes off-label use. Nonetheless, it is clear that many of these products are used extensively in equine practice with a variety of associated anecdotal reports of clinical success. Their use is not substantiated by any research or field investigation, and the response to the drug may depend on the formulation and method of production by the company that markets it.
Pentosan polysulfate Pentosan is a newer drug used now in horses to help manage osteoarthritis. Pentosan is a semi-synthetic polysaccharide polymer based on an extract of the Beechwood plant. It is a sulfated heparinoid with reduced anti-coagulant effects and enhanced anti-inflammatory, fibrinolytic, and tissue trophic effects. It was originally only available from Australia, but now can be compounded in the United States. This drug is not the same as Adequan® or Legend® or oral joint supplements. It is reported to exhibit several potentially beneficial effects in joints including; 1) The stimulation of chondrocytes to produce more proteoglycans to facilitate the building and repair of the cartilage matrix, 2) the stimulation of synovial fibroblasts to produce increased amounts of high molecular weight hyaluronic acid, 3) the inhibition of release of many degradative enzymes which damage cartilage and cause peri-articular inflammation and the induction of release of an enzyme which inhibits these degradative enzymes, 4) the reduction of inflammation via an inhibitory effect on all mediators of the arachidonic acid cascade and lysosomal catabolic enzymes. Leukocyte migration into joints is also reduced. It is administered to horses by intramuscular injection and can be used with hyaluronic acid injectables, PSGAG injectables (Adequan®), and oral joint supplements. Initial research in the horse is yet limited, but does suggest beneficial effects in an equine osteoarthritis model.
Oral Supplements: Chondroitin sulfates/Glucosamines
Glucosamine is a precursor to the subunits of the proteoglycans. Studies indicate that glucosamine increases proteoglycan synthesis by chondrocytes and may also exhibit anti-inflammatory activity. Glucosamine appears to be effective in reducing the suppressive effects of some cytokines on cartilage proteoglycan synthesis. Glucosamine has been shown to be protective against proteoglycan loss and to inhibit synthesis and activitity of degradative proteinases in equine cartilage. Chondroitin sulfate is the principal glycosaminoglycan of aggregating proteoglycan (aggrecan). Chondroitin resembles PSGAG in structure and it appears to exhibit mechanisms of action that parallel those of PSGAG. In experiments, the chondroprotective effects of chondroitin sulfate included stimulation of proteoglycan synthesis and inhibition of damaging enzymes. Chondroitin sulfate has shown protective effects on proteoglycan loss in animal models of joint inflammation.
Despite these exciting potential benefits, as an oral product to date, there is no significant evidence to suggest that effective absorption of nutraceuticals from the equine gut occurs in a clinically relevant manner. There has been significant debate about whether horses can absorb oral forms of joint supplementation. Since horses are herbivores and have different GI absorption characteristics, efficacy of oral supplementation is in question until further studies can be done. Furthermore, if these products are absorbed and if the horse is capable of utilizing them, they must be combined into a very complex, large molecule in order to be effective. One cannot assume that, even if these complex molecules are included in the formulation of the nutraceutical, they are absorbed intact by the intestinal tract (without being broken down) and then reassembled into the same molecule, transported to the joints, penetrate the joint capsule and enter the joint environment to be of benefit. As "supplements", nutraceuticals are not required to undergo investigations to prove efficacy or benefit. The Food and Drug Administration does not regulate the formulation of glucosamine and chondroitin sulfate-containing supplements and, therefore, their purity and content are not assured. The use of a nutraceutical product that utilizes certified contents from reputable sources is recommended. Despite these facts, there has been a significant increase in the popularity of using nutritional supplements to treat and prevent osteoarthritis in horses.The condroprotective neutriceuticals usually contain glucosamine salts and/or chondroitin sulfate. Cartilage cells normally synthesize glucosamine from glucose and amino acids, however they can also use externally supplied, preformed glucosamine. Regardless of the source, the cartilage cells use glucosamine to synthesize glycosaminoglycans and hyaluronan for the joint. Glucosamine also regulates cartilage synthesis of proteoglycans and collagen. Glucosamine and chondroitin sulfate are the compounds that have received the most investigation and have shown the greatest potential for benefit. Some advocates of nutraceutical administration claim that the compounds included in their choice formulation not only provide symptomatic relief of arthritis pain, but also help to prevent the continued degeneration of articular cartilage. This remains to be substantiated by controlled studies. There is comparatively few clinical research studies conducted on the effects of these compounds in horses. Most laboratory investigations of glucosamine and chondroitin sulfate do suggest potential favorable effects for the protection cartilage from degradation. Clinical symptomatic relief appears to be limited, particularly in advanced cases. It has been suggested that the benefit of the use of these compounds may be more for the prevention of osteoarthritis than for therapy of existing disease. These products appear to be safe and may help improve a lameness condition, but are somewhat expensive for long-term therapy.
Oral Supplements: Dimethylglyeine (DMG)
Dimethylglycine (DMG) is also a nutriceutical product advocated for daily feeding to improving stamina and endurance by increasing oxygen utilization and improved lactic acid metabolism. Despite favorable anecdotal reports, DMG did not produce any beneficial effects on cardiorespiratory function or lactic acid production in exercising Thoroughbreds.
Oral Supplements: Methylsulfonylmethane (MSM)
Methylsulfonylmethane (MSM) is also a nutriceutical product suggested to be a dietary source of sulphur and a derivative of dimethylsulfoxide (DMSO), a putative anti-inflammatory agent. Sulfur is a necessary component of several amino acids, therefore MSM is promoted as helping to provide the "building blocks" for normal tissues. It is therefore proposed as providing some benefit in horses with degenerative joint disease. There are no published scientific studes specifically documenting a beneficial effect from feeding MSM to horses.
