(From the October 13, 2004 issue of The Blood-Horse)
A new product for preventing gastric ulcers in horses is due for release by the end of this year, when Ulcergard joins GastroGard as the second product approved by the federal Food and Drug Administration for ulcer management in the horse. On the more distant horizon, new developments in musculoskeletal pain management that are gentle on the stomach might one day arrive on the equine market, and that too could help prevent ulcers in racehorses. A spectrum of factors goes into the making of an equine gastric ulcer. Some of the joint pain medications we routinely give horses--and the regularity with which those medications are given--are one contributing factor, same as some human arthritis medications can cause ulcers in people. Insights into the mechanism of joint pain medications, as they relate to the health of the stomach, will be reported in this article. Ulcers are painful erosions of the stomach lining caused by churning stomach acid. They can vary in severity. Not all horses get ulcers, and in some cases ulcers can be mild enough that the horse does not show clinical signs. But in many cases, ulcers have kept horses from reaching their full potential. Ulcers can be healed, and ulcers can recur after they have healed. Symptoms can be alleviated well enough for the horse to perform adequately. The challenge is to prevent ulcers from ever occurring. What causes stomach acid to burn a hole in the stomach lining? Same as with people, gastric ulcers in horses are caused by a high-stress lifestyle. Racehorses, more than most other horses, are prone to stress in the unnatural environment we create for them. A heavily stressed horse is exercising hard, stabled most of the day, and deprived of free access to pasture. They are fed high phosphorous diets and sometimes ship long distances or ship frequently. Many are routinely given non-steroidal, anti-inflammatory drugs--a group commonly abbreviated to NSAIDs--to reduce musculoskeletal soreness and swelling brought on by their intense exercise program. For Thoroughbreds, stress factors associated with gastric ulcers are inherent in weaning, sales prep, training, and racing. Three-meter endoscopes--an endoscope long enough to reach down the horse's esophagus so that we can peer into the stomach--have come increasingly into use among equine practitioners since the introduction of GastroGard in March 1999. Since then, endoscope exams have confirmed that many racehorses actually do have ulcers--something that had long been suspected. One recent veterinary journal reported that ulcers are "evident endoscopically in 80% of Thoroughbred and Standardbred horses in training." Cost of a stomach endoscope exam (gastroscopy) at most racetracks ranges from $100 to $300. The procedure involves taking the horse off feed for at least eight hours, something many horsemen are reluctant to do with a horse in training. Some horsemen forego the endoscope exam and guess by the outward signs that a horse has ulcers. Signs can include poor appetite, poor condition, weight loss, mild colic, and balking at exercise. Some horses get sour--they pin their ears and bare their teeth when anyone comes near. The major red flag and reason to seek treatment in the athletic horse is poor performance. But these signs are nonspecific, meaning the same signs can indicate other illnesses or diseases. Treatment without proper diagnosis sometimes can relieve the symptoms, but it can also mean time lost in addressing the real problem. Gastroscopy is the gold standard for diagnosing ulcers. The veterinarian can grade the ulcer for severity and treat the horse accordingly. Different products to manage the equine stomach will be reviewed later. Where the future holds an intriguing prospect for prevention is with the adaptation of a new class of NSAIDs. In the past decade, the human medical community has learned a lot about the mechanism of how the older NSAIDs work, and a new category of drug has come into existence. These are the COX-2 inhibitors, also hailed as COX-2 selective inhibitors, selective NSAIDs, and gastrointestinal-safe NSAIDs, because they are GI-safe. This new class of NSAID has been hugely successful for people who suffer from arthritis, and one COX-2 inhibitor has already been developed for dogs. But before we go there, let's review the phase of digestion that occurs in the stomach.
SO MUCH TO DIGEST
The equine stomach is a remarkably small part of the horse's digestive tract. The stomach is unevenly divided into two distinct parts by a narrow, raised border called the margo plicatus. Most gastric ulcers occur just above, or along, the margo plicatus. Below the margo plicatus is the glandular region. The glands produce four types of secretions--hydrochloric acid and pepsin begin food digestion, and bicarbonate and mucus protect the stomach lining from the hydrochloric acid. We have known of these secretions for a while, and now, recent research has turned up an enzyme that also helps protect the stomach and GI tract. That enzyme is COX-1. The top of the stomach is the non-glandular region. It is scaly in texture, and serves as a reservoir for undigested food. In their natural habitat, horses graze continuously, and a steady intake of grass enters their stomach. Simply having grass in it helps buffer the stomach from its own hydrochloric acid. Hydrochloric acid is produced almost continuously in the horse's stomach, whether the horse is eating or not, so when food is not there, the stomach lining is exposed to the acid. In addition, grass triggers production of saliva, which is high in bicarbonate, the stomach's natural antacid, so to speak. The grass, the bicarbonate, and the mucus help buffer the top region from the hydrochloric acid. Horses that are kept stabled have limited access to grass. Grain and hay are fed in portions at regular intervals during the day. For most stabled horses, the top part of the stomach is exposed to acid splashing up into it during stretches of the day when there is limited or zero access to food.
FRYING PANS & FIRE
Routine use of NSAIDs to manage joint pain brings to mind the cliché "out of the frying pan and into the fire." NSAIDs help one set of problems, but for some horses, it comes at the expense of another. Phenylbutazone, also known as Butazolidin, or "Bute," is the most commonly used NSAID. It is given for musculoskeletal pain, fever reduction, and as a general anti-inflammatory. Many trainers give horses Bute as freely as some people take aspirin for aches and pains. As a matter of fact, aspirin (also an NSAID) is also occasionally given to horses to manage pain. Other NSAIDs frequently used in racing stables to alleviate musculoskeletal pain include ketoprofen, meclofenamic acid, and naproxen. Flunixin meglumine (the most common brand of this is Banamine) is another NSAID, but it is usually given for abdominal pain. Corticosteroids are another type of drug commonly given to racehorses for their anti-inflammatory properties, often in conjunction with NSAIDs. For racehorses, the risks of developing an ulcer or having an existing ulcer worsen in severity increase whenever NSAIDs are used in combination with corticosteroids. Turning now to human medicine, many people suffer from arthritis, for which they take NSAID painkillers. Anyone who has ever had an ulcer, or knows someone suffering from one, is familiar with the risk in routine NSAID use. Medical doctors advise caution in taking aspirin and NSAIDs to people who are prone to ulcers. Enter the COX-2 inhibitors. When the COX-2 inhibitor Celebrex was introduced to the market a few years ago, it immediately became the fastest selling prescription drug of all time. Vioxx, another COX-2 inhibitor for people, followed but has since been taken off the market. Deramaxx, a COX-2 inhibitor for arthritic dogs, has since entered the veterinary market. Dr. Anthony Blikslager, an associate professor of equine surgery at North Carolina State College of Veterinary Medicine, has done extensive research and written papers on the toxic effects of NSAID use in horses. NSAIDs inhibit a group of enzymes called cyclo-oxygenase, which is shortened to the term COX, Blikslager explained. There are several of these enzymes in different parts of the body and they tend to be associated with different functions. All of them produce prostaglandins. COX-1 functions on a daily basis to produce prostaglandins that protect the GI tract and other organs. COX-2 is not normally present, unless the body has had some sort of injury, and then it is involved in inflammation. "COX-2 is involved in a lot of the inflammation in knees and ankles, the two joints that racehorse trainers would most commonly treat with NSAIDs," Blikslager said. NSAIDs, such as Bute, shut down COX-2 and the inflammatory pathway. "The trouble is, it also hits COX-1, an entirely unintended target," Blikslager said. When the protective COX-1 enzyme shuts down, ulcers are the result. COX-2 inhibitors solely shut down COX-2, the inflammatory enzyme, and leave alone COX-1, which helps protect the stomach. "What they have shown with human arthritic patients that are given COX-2 inhibitors is that they have far fewer problems with gastric ulcers," Blikslager said. Blikslager noted a few reasons why the horse industry has not yet jumped on a COX-2 bandwagon. "One of the big factors is expense and availability," Blikslager said, noting it costs pharmaceutical makers money to get a drug approved for a new species, and the existing COX-2 inhibitor drugs are designed for people or dogs. "Second of all, they're not in a form where you can inject them. They're all oral so far. "Part of the reason it's been sluggish to catch on is because Bute is effective, and it's readily available," Blikslager said. Racing stables everywhere have been using Bute for a long time. It can be administered orally or by intravenous injection, and it acts quickly. To switch over, horsemen will need conclusive results that show the new GI-safe NSAIDs are effective in controlling lameness without damaging the stomach. "That's where I think it's heading," Blikslager said. FIGHTING FIRE
Products to manage ulcers fall into two basic categories: 1. Antacids, which are also sold as digestive aids and feed supplements. 2. Proton pump inhibitors. The one drug in this category contained in the products that are FDA-approved for use in horses is omeprazole. A proton pump inhibitor works by stopping the proton pump from producing gastric acid. Omeprazole is the active ingredient in GastroGard and the soon-to-be-released Ulcergard. Both are made by Merial. GastroGard is approved to heal ulcers and prevent their recurrence. Ulcergard is designed only for prevention, and therefore has a prevention label. It does not require a diagnosis by veterinarians. Although GastroGard is proven effective, some horsemen opt to use a less expensive product to relieve ulcer discomfort. GastroGard has been reported as costing $40 per day while the full dose is given, and $20 per day for follow-up half doses. The actual cost of GastroGard to the owner varies. Some veterinarians have reported that GastroGard is effective for many horses when given at a dosage smaller than that recommended by Merial. Some horses respond more quickly to treatment than others, which could be due to other factors, such as whether the horse got a break from training. Antacids/digestive aids/feed supplements are a segment of the industry that is not subject to FDA regulations. These products are designed and marketed to buffer and protect the stomach or to alleviate the signs of ulcers. Relieving the clinical signs of an ulcer does not necessarily mean it was healed; however, many horsemen settle for having the horse feel well enough to perform up to expectations. Active ingredients are nutrients that neutralize the stomach acid and protectants that coat the stomach lining. Neutralizing nutrients often include aluminum, magnesium, and calcium in derivative form. Protectants often include kaolin, cellulose, and gelatin. Products in this category include Neigh-Lox, U-7 Gastric Aid, G.U.T., and U-Gard. These products are the low cost route in equine ulcer management. Neigh-Lox, for example, might be fed for as little as $2.40 per day for a mature horse and one-half that for a weanling, according to the company Web site. Others cost as low as $.50 per day for horses on a maintenance program. Apart from the products mentioned above, some farms make off-label use of the dewormer medication Panacur in weanlings for its reputed secondary benefit of protecting young stomachs from ulcers. Another group of drug requires mention here because veterinarians still use it to treat equine ulcers, despite the availability of the FDA-approved GastroGard. H2 receptor antagonists stop the triggering mechanism for acid production and are the active ingredients in products approved for people (ranitidine in Zantac, cimetidine in Tagamet), but these are not approved for use in horses. A University of Pennsylvania study published in Journal of the American Veterinary Medical Association in August 2003 reported that, "as H2 receptor antagonists appeared to be no more effective than no treatment in the horses in this study, these drugs should no longer be considered an economic alternative to a racehorse with moderate or severe gastric ulceration." LET'S SETTLE THE MATTER
The best ulcer prevention program involves turn out on open pasture and no work load. Admittedly, this runs counter to our agenda for the horse. Weaning and sales prep are stressful for young horses. Training is the most stressful situation of all. One study of horses that were exercised on high-speed treadmills showed even that form of exercise contributes to ulcers. Fortunately, products designed to protect the stomach can be given safely for extended periods. Feed supplements, also called antacids or digestive aids, can be used in maintenance fashion for horses in stressful situations. Ulcergard, due for release from Merial by the end of this year, will offer an FDA-approved route to prevent ulcers from occurring. Review the feeding program. Provide enough hay to fill the intervals between grain meals. Racehorses are fed hay as a substitute for grass. Hay triggers production of about double the amount of saliva as grain. As with grass, the hay itself, bicarbonate from saliva, and mucus help buffer the stomach from hydrochloric acid. Keep grain meals as light as possible, and feed at evenly spaced intervals. Use discretion before combining non-selective NSAIDs and corticosteroids. Blikslager, the equine surgeon and researcher, suggests that routine monitoring of the stomach with a three-meter endoscope once or twice a year could be beneficial. "There are probably horses out there that can tolerate these (widely-used NSAID) drugs quite well," Blikslager said. "There may be others that don't necessarily show that many clinical signs, but nonetheless, perhaps aren't performing up to their full potential. If you took the trouble to scope them, you'd see why."