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Thursday, January 01, 1998

Joint Therapy - Adequan, Legend, etc - Trish Dowling

Submitted by Trish Dowling - dowling@skyway.usask.ca

The following is extracted from my text that I use to teach veterinary students and giving in continuing education lectures to practitioners. Sorry if it`s a little techincal, I`d be happy to explain if there are any questions or provide references. Personally, I use Adequan and Legend in my own horses. I do not use any of the oral nutriceuticals.

Chondroprotective drugs

The chondroprotective drugs are used to prevent or slow the progression of degenerative joint disease (DJD, "arthritis"), rather than simply reduce the clinical signs of pain like the anti-inflammatory drugs. Chondroprotective drugs help the normal activity of chondrocytes (the cells in cartilage) and prevent or reduce damage to the joint cartilage from enzymes and other inflammatory mediators such as prostaglandins.

Hyaluronan

Hyaluronan ("HA")(Hyalovet®20, Hylartil® Vet, Hyonate®, Hy-50® Hylan, Synacid®), formerly known as hyaluronic acid, is a normal component of joint cartilage and fluid. It has been widely used as a treatment for joint diseases of people and horses.

Pharmacology

Hyaluronan is chemically known as a nonsulfated glycosaminoglycan (contains no sulfur molecules). It is produced by the membrane that lines the joint capsule and disperses into the joint fluid and taken up by the joint cartilage. HA provides joint lubrication and protection of the joint cartilage from shear and compressive forces as the horse moves. It also reduces prostaglandin concentrations and scavenges free radicals in inflamed joints. Hyaluronan is primarily used in the treatment of degenerative joint disease of the carpal , fetlock, coffin and hock joints of performance horses. Although cartilage damage is not always directly responsible for the horse`s lameness, it is the limiting factor in rehabilitation of arthritic joints in the horse. It appears that HA concentration in joint fluid is reduced in degenerative joint disease. Injecting additional HA directly into the joint appears to normalize the joint fluid and increase the production of HA by the joint membrane. The actual injected HA remains in the joint for only a few hours, but its effect on the joint appears to last days to months. It does not appear that HA has any direct effect on joint cartilage.

Uses/Indications

Clinical reports generally support the use of hyaluronan in the treatment of equine joint disease for reducing inflammation and lameness. In performance horses, a rapid return to work is a desirable outcome, and the action of HA has been considered a natural treatment without the risk of adverse effects associated with other treatments. Hyaluronan is effective for mild to moderate degenerative joint disease. For horses with severe DJD, HA therapy alone is not adequate return them to athletic function.

The commercially available hyaluronan products for horses vary in the molecular weight of the HA they include. There is considerable scientific controversy over the relationship between the molecular weight of the HA product and the effectiveness of treatment in equine joint disease. While some studies indicate that the high molecular weight products are superior, this has not been completely demonstrated in clinical trials. In addition, the cost of the lower molecular weight products is considerably less than the high molecular weight products.

A formulation of HA for intravenous use has recently been approved in the Unites States (Legend) and Canada (Hyonate®). This formulation provides a more convenient route of administration, allows for treatment of joints following injection of local anaesthetic drugs without delay, and may reduce the adverse effects of intra-articular injections (bacterial infection, mechanical damage, drug-induced inflammatory reaction within the joint). It is not known how intravenously administered HA achieves therapeutic levels in the joint, but in a controlled study, horses treated with intravenously administered HA had a reduced degree of lameness compared to untreated horses.

Intra-articular HA can be used in combination with other intra-articular medications such as corticosteroids. The combination therapy can result in a better and longer lasting improvement in lameness than either product alone.

Polysulfated Glycosaminoglycans

Pharmacology

Adequan®) is polysulfated glycosaminoglycan (PSGAG), made from an extract of cow lung and trachea that is then sulfated. The result is a large, charged molecule composed of galactosamine, glucosamine, and hexuronic acid. After administration, PSGAG binds to cartilage components. The precise mechanism of action of PSGAG in joints is unknown, but there are many studies demonstrating a beneficial effect of this product on damaged joints. Currently, PSGAG is thought to decrease destructive enzymes, act as an anti-inflammatory agent and stimulate the normal production of hyaluronan and glycosaminoglycan.

Uses/Indications

Adequan® is indicated for the treatment of degenerative joint diseases. For horses, it is available in two formulations, one for intra-articular injection and one for intramuscular injection. When injecting directly into the joint, one 250 mg vial is used once a week for five weeks. When using the intramuscular injection, 500 mg is injected every four days for four weeks. "Maintenance" therapy is not addressed by the manufacturer and has not been investigated in scientific studies, but veterinary practitioners have administered additional doses at intervals of weekly or monthly intervals with success in some horses, dogs and cats.

When performing the intra-articular injection, the area to be injected must be clipped and cleansed as if performing a surgical procedure. Intra-articular injection should not be made where the skin has been blistered or is scurfed. Intramuscular injection of Adequan® can be performed in the same manner as any other intramuscular injection.

Adverse Effects

Inflammatory reactions: severe inflammation after intra-articular injection of Adequan® can occur due to the individual horse`s sensitivity to the drug, traumatic injection technique or from exceeding the recommended dose, frequency or number of injections. This inflammatory reaction can occur within 48 hours of injection, and is characterized by increased lameness, and heat, pain and swelling of the injected joint. This inflammatory reaction can be treated with nonsteroidal anti-inflammatory drugs, cold water therapy and rest, and usually resolves in a few days.

Septic arthritis: the most serious side effect of intra-articular Adequan® injection is joint infection, usually from skin bacteria deposited into the joint from the needle tip. The anti-inflammatory action of PSGAG increases the ability of a few bacteria to successfully infect the joint. Joint infection can be life threatening. Successful treatment of an infected joint requires prompt identification and aggressive antibiotic treatment. Unfortunately, the early signs of an infected joint are indistinguishable from the signs of the non-infections joint inflammation due to Adequan® injection. Giving NSAIDs for joint inflammation will mask the signs of infection and further delay recognition that the joint is infected. Because of the potential for joint inflammation and infection from direct injection of the joint, many veterinary practitioners prefer the intramuscular product.

Chondroitin sulfates/Glucosamines

These chondroprotective products (Cosequin®, Flex Free®, Xtra-Flex®, Glyco-flex®) are sold as nutritional supplements - "nutriceuticals". The classification of nutriceutical means that these products are not considered as "drugs" and do not have to meet the same standards of purity, efficacy and safety that the FDA or the Bureau of Veterinary Drugs would require of a drug for the treatment of degenerative joint disease. The nutriceuticals are promoted as oral supplements supplying the horse with the "building blocks" necessary for repair of damaged cartilage. However, the building blocks for production of joint cartilage are adequately supplied by most normal equine diets. There are many anecdotal reports of improvement in clinical signs of lameness in horses supplemented with nutriceuticals. However, well-designed scientific studies proving that these products are effective have not been published. Some of the nutriceutical manufacturers are sponsoring such studies and results are pending. These products appear to be safe, may improve a lameness condition, but are somewhat expensive for long-term therapy. Because the nutriceuticals are not regulated by government agencies in the same manner as a drug would be, there is considerable variation in the composition and purity of the available products. Therefore, clinical results may vary considerably between the products.

The chondroprotective nutriceuticals 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. Glucosamine also regulates cartilage synthesis of proteoglycans and collagen.

Dimethylglycine (DMG)

Dimethylglycine (DMG) is also a nutriceutical product, that is advocated for daily feeding to horses to improving stamina and endurance by increasing oxygen utilization and improved lactic acid metabolism. Despite favourable anecdotal reports, DMG did not produce any beneficial effects on cardiorespiratory function or lactic acid production in exercising Thoroughbreds.

Methylsulfonylmethane (MSM)

Methylsulfonylmethane (MSM) is also a nutriceutical product, that is promoted as a bioavailable source of sulfur or a dietary derivative of dimethylsulfoxide (DMSO), a known 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, so it is thought to have some benefit in horses with degenerative joint disease. There are no published scientific studies documenting a beneficial effect from feeding MSM to horses.

Cheers, Trisha

Trisha Dowling, DVM, MS, Diplomate ACVIM & ACVCP
Associate Professor, Veterinary Clinical Pharmacology
Western College of Veterinary Medicine
Saskatoon, SK S7N 5B4
306-966-7359/FAX 306-966-7376

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