A Sound Plan: <i>Focus on equine joint health</i>

(From November 6, 2004 issue of The Blood-Horse)
New joint product development is being driven by an increased awareness of the need to treat joints without hurting the stomach--that is, without causing gastric ulcers. In June 2004, a product that delivers the strength of a non-steroidal anti-inflammatory drug (NSAID) in a topical cream formulation was approved by the federal Food and Drug Administration (FDA) for treating joint pain and inflammation in horses. Its name is Surpass Topical Anti-Inflammatory Cream. This new product and others for treating equine joints will be covered here.

SYSTEMIC NSAIDs
Systemic NSAIDs can by administered orally or by intravenous (IV) or intramuscular (IM) injection. By contrast, a topical preparation is applied directly onto the area being treated.

Phenylbutazone, also known as Butazolidin or Bute, the most commonly used NSAID among racing stables, can be administered orally, or by IV injection. Orally, it is available in tablet, paste, and gel formulations. Flunixin meglumine is well absorbed orally, and can be administered by IV or IM injection. Of other NSAIDs, ketoprofen is IV injectable, and meclofenamic acid and naproxen are administered orally.

These systemic NSAIDs have been widely used in racing since the 1970s. In the past five or so years since the equine ulcer treatment drug GastroGard was approved by the FDA in March 1999, veterinary examinations with stomach endoscopes have revealed that the majority of racehorses in training have some degree of stomach ulcer.

Ulcers limit a racehorse from performing to its full potential, and treatment can be expensive. Equine ulcers were covered in the Oct. 23 issue of The Blood-Horse (page 5806). To review from that article, NSAIDs inhibit a group of enzymes called cyclo-oxygenase, which is shortened to the term COX. COX-1 is normally present and produces prostaglandins that protect the gastrointestinal tract and other organs. COX-2 is not normally present, but when an injury occurs, it is involved in inflammation. COX-2 is frequently involved in inflammation in the knees and ankles, two joints that are commonly treated with NSAIDs.

The NSAIDs that have always been available for horses shut down COX-2, the inflammatory enzyme, as well as COX-1, the protective enzyme and an unintended target. When COX-1 shuts down, ulcers can result.

Dr. Anthony Blikslager, an associate professor of equine surgery at North Carolina State College of Veterinary Medicine, has researched the toxic effects of NSAID use in horses, and spoke to The Blood-Horse for the article on ulcers. Blikslager added the following:

"Studies have shown that NSAIDs definitely cause ulcers and a syndrome called right dorsal colitis. Although a number of these studies have used excessive doses of NSAIDs, clinical cases of ulcers or right dorsal colitis have been documented in horses receiving normal doses. However, it is somewhat unpredictable--some horses appear to be more prone to problems than others, so just because NSAIDs are being used does not mean a horse will get an ulcer. The most sensible approach right now is to pay close attention to the dosage, and to get horses down to the lowest possible dose needed. It's also a good idea not to "stack" NSAIDs--meaning, give more than one at a time--to reduce chances of ulceration."

Other drugs used for managing equine joint pain include corticosteroids, hyaluronic acid (HA), and a related drug, polysulfated glucosaminoglycan (PSGAG). Corticosteroids deliver immediate benefits, but their overuse contributes to degradation of the joint capsule and further unsoundness. When systemic NSAIDs and corticosteroids are used together, the risk of gastric ulcers increases.

HA and PSGAG are milder than corticosteroids and NSAIDs, and they have no effect on the stomach. These milder drugs have not eliminated the use of NSAIDs and corticosteroids, but they provide a greater range of treatment options and more judicious use of other drugs.

TOPICAL NSAID
Surpass Topical Anti-Inflammatory Cream was approved for the control of pain and inflammation associated with osteoarthritis in the hock, knee, fetlock, and pastern joints in horses. The active ingredient is diclofenac sodium, an NSAID that is used in human medicine.

Surpass was developed as a topical cream, rather than a systemic product, to address the issue of gastric ulcers in the horse and to deliver the medication potently to the area it is needed. The cream is rubbed directly onto the affected joint, and thus bypasses the GI tract. The dosage is much lower than a systemic NSAID, also making it safer for the stomach.

Surpass is a pinkish-white cream, resembling toothpaste. It is squeezed out of the tube in a quarter-inch-wide band. The person applying it would wear rubber gloves for protection, squeeze out a five-inch ribbon onto their gloved hand, and thoroughly rub it in through the hair and the skin for a minute or two, until it vanishes.

A special preparation called liposome technology delivers the medication through the skin and into the deeper tissue. Liposome technology is described as being like an onion that has multiple layers. As the layers peel off, the medication is absorbed into the tissue. This delivery mechanism differs from other topical treatments, such as liniments. Liposome technology makes Surpass a unique product.

"That is the whole product right there, otherwise you'd just be squirting diclofenac on the skin and it would have no effect whatsoever," said Dr. Scott McClure, a veterinary surgeon at Ohio State University who has treated horses with Surpass since the product was introduced to the market. "We know the liposome carries it down into the fluid and the inflamed area, and we know that the diclofenac is effective because it decreases the concentrations of prostaglandin.

"The big thing is, it takes a lot less drug," McClure said. "Rather than having the drug diluted throughout the bloodstream and everywhere else, it's concentrated at the site. We're talking milligrams versus grams of drug."

McClure uses Surpass in addition to other routine therapies. It is especially useful in treating new, acute injuries, and when joints are not responding to other therapies.

"I'm still going to use my routine hyaluronic acid, my corticosteroids, whatever my routine procedures are," he said. "Then, in a horse where I still have some inflammation, I'm going to reach for the Surpass when my routine stuff needs another step. The other time when I reach for it is in acute inflammation, in a horse that's just been out and 24 hours later he's got an ankle that's a little bit warm. I'm going to use my Surpass initially to help control that inflammation, and while I'm doing my cold therapy.

"This drug is not going to replace all of these things," said McClure. But, he added, "This drug gives us another mechanism to control inflammation that can be used in conjunction with other medications and treatments. We can cut way back on our systemic non-steroidals, because we can put a non-steroidal on locally. I still use Bute, as indicated, but I don't need to use near as much, near as long."

A 10-day course of treatment is recommended, based on the FDA approval study. "You don't necessarily have to use it 10 days at a time, but if you're going to use it, it would be indicated to use for at least three or four days," McClure advised. That will allow the drug to get up in concentration in order to work effectively.

Surpass is a veterinary prescription medication and as such, IDEXX sells the product to the veterinarian, who is free to determine the price charged to the client. IDEXX estimates client cost will be in line with other prescription medications and some over-the-counter remedies. A tube is going to cost close to $50, noted McClure, enough to treat twice a day for 10 days. The product ought to save owners money in other ways. "There are not the risks of ulceration and other problems you can have when you use Bute long term," McClure said.

THE CRYSTAL BALL
Where the future holds an intriguing prospect for managing equine joint pain without damaging the GI tract is with the adaptation of a new class of NSAIDs called COX-2 inhibitors. Such products are available for people who suffer from arthritis and are prone to stomach ulcers, and there is already one COX-2 inhibitor for dogs.

"COX-2s are being developed for horses. That's no secret. There are companies working on that," McClure said.

One COX-2 product containing rofecoxib was recalled by its manufacturer on Sept. 30 after a study confirmed it increased the risk of heart attack and stroke in humans. Neither Blikslager nor McClure believe the product recall will alter the COX-2 inhibitor market in animals, because cardiovascular and stroke complications are rare in animals, possibly because of the shorter lifespan, or differences in susceptibility to specific diseases. Blikslager added, "These drugs may be prohibited for use in race and show horses until we have additional information on therapeutic levels."

Both Blikslager and McClure noted that the initial COX-2 inhibitor drugs for horses will be expensive. Meanwhile, the long popular Bute and others from this class of NSAIDs--which potentially harm the stomach--are cheap.

Can we expect COX-2 inhibitors for horses to one day replace Bute?

"Yes!" McClure said. He predicts that 10 years from now, "we'll use Bute occasionally. But within five years, we're going to have some nice COX-2 inhibitors that we're going to reach for like we reach for Bute now. There's no doubt, COX-2 inhibitors are the near-future."

AAEP Focus Topic
Equine joint health was spotlighted in the second annual Focus meeting of the American Association of Equine Practitioners (AAEP) which took place in Louisville, Ky., from July 22-24. Noted equine orthopedic surgeon Dr. Larry Bramlage chaired the three-day seminar, which was attended by about 150 people. Besides chairing the meeting, Bramlage gave a talk on the influence of month of birth on the location of osteochondritis dissecans. Researchers from the United States, England, New Zealand, and Hong Kong also gave talks, on topics such as the effect of exercise on cartilage in young horses, and high-tech diagnostics such as magnetic resonance imaging (MRI), biomarkers, and scintigraphy.

The AAEP Focus meeting was sponsored by Bayer Animal Health, maker of Legend. Legend is used by racetrack veterinarians for managing joint pain and inflammation in Thoroughbreds. Its active ingredient is hyaluronic acid (HA), a natural component of bodily tissue and fluid that increases synovial fluid production and thus improves joint lubrication. HA is used to treat mild to moderate inflammation of the joint capsule, a condition called synovitis. Several companies make an intra-articular HA product. Legend is available as an intra-articular, and as Legend I.V., which is FDA-approved for intravenous (IV) injection.

What About Regulations?
The Association of Racing Commissioners International (RCI) defines corticosteroids and NSAIDs as class four drugs, meaning, they are in the family of drugs which do not have prominent nervous system effects. Regulations differ among racing jurisdictions regarding raceday use, but corticosteroids and NSAIDs can be used within individual state regulatory limits. Hyaluronic acid and polysulfated glucosaminoglycan have not been classified by the RCI; if they were, they would probably be classified in the lowest category, as therapeutic drugs. Though not classified by RCI, their use and administration are subject to state regulations for other medications, specifically, what is referred to as the "Hour Rule," or cutoff time when medication can be administered prior to a race.

Many Options
Liniments and cold therapy are part of the arsenal to keep joints tight. Liniments, poultices, and bandages were covered in the Sept. 25 issue of The Blood-Horse (page 5156). Nutraceuticals are an expansive market which includes the glucosamine and chondroitin sulfate feed supplements, among others, that are designed for maintenance of healthy joints. The research community is still looking at how extracorporeal shock wave therapy (ESWT) could be useful in treating joints in the horse. ESWT, used appropriately, requires a racehorse to be temporarily taken out of training. The reason for so many options in equine joint health--a single product or treatment cannot solve all joint conditions in all horses.

Skill Is Required
Some joint medications are administered by intra-articular injection--directly into the joint. Skill is required by the veterinarian when a joint is injected, because there is a risk of infection if harmful bacteria from the environment are introduced. Joint infections are difficult to treat, and hazardous to the horse. The needle has to go in far enough to deliver the medicine, but not so far that it pierces the articular cartilage. Preparing for joint injection includes cleansing and shaving the area to be injected. It should almost be treated as a surgical site. For veterinarians who are skillful in injecting a joint, the manufacturer's presentation of the syringes and packaging can make a difference in how comfortable the veterinarian feels in using a product.

Less risky to administer are the intravenous (IV) and intramuscular (IM) products, Legend and Adequan. Both are available as intra-articular preparations, and in addition, Legend, a hyaluronic acid (HA) product, is available as an IV preparation, and Adequan, a polysulfated glucosaminoglycan (PSGAG) product, is available as an IM preparation.

Medication Indications
What happens in the joint for it to require treatment? Racing and training are hard on equine joints. Varying degrees of soreness and swelling can occur in a single joint or in several joints at once. When trauma occurs, the resulting inflammation stimulates the release of damaging enzymes, prostaglandins, and cytokines. These attack the basic components of articular cartilage and set in motion a degenerative process that causes lameness. The following three conditions are common in horses:

Synovitis--In a healthy joint, synovial fluid lubricates the joint. Synovitis is mild-to-moderate inflammation of the synovial membrane that lines the joint capsule and produces synovial fluid. Signs of synovitis include loss of flexibility and what is variously described as filling, swelling, or a puffy joint. This is due to an accumulation of synovial fluid.

Capsulitis--The inflammation of the joint capsule, capsulitis often accompanies synovitis.

Osteoarthritis--This condition involves damage to the joint capsule and articular cartilage. It is chronic and can get progressively worse if not adequately treated. It is also called degenerative joint disease. Signs include swelling and pain.

Digital Radiography
A new diagnostic tool taking its place in veterinary medicine is digital radiography (DR), which was adapted from human medicine and provides much higher resolution than conventional film radiography. DR is already being used for diagnosing lameness in racehorses and as a pre-purchase tool. The ability to send DR images via e-mail attachment makes the technology a useful tool for vets to consult other vets for diagnostic purposes.

Machines designed specifically for x-raying horses are being manufactured and sold to veterinary clinics in the United States, and the choices include portable models. Original DR images are stored to a file format called DICOM, an acronym that stands for digital image and communication in medicine. DICOM creates a legal and traceable record of an image that cannot be altered, and ensures correct identification of each horse x-rayed. DICOM files are stored to a highly secure-rated server. The server takes the place of a film library. Required equipment includes the server, a viewing monitor, and of course a radiograph machine.

Although a growing number of veterinary clinics in the U.S. are investing in a DR system, it might take a while before the expensive new technology gets the widespread usage that film radiography currently enjoys. Film radiographs can be viewed on any light box. DR systems made by different manufacturers would need to be compatible. The sales sector of the industry in particular is concerned about investing in an expensive system that can only read images from machines made by one manufacturer.