UNRAVELING SOME OF THE MYSTERY OF "NSAIDS"

Scientific research and common knowledge don't always agree on the uses and misuses of the show world's favorite medications.

Erin Harty

Once upon a time, many thousands and thousands of years ago, a very brave caveman (or, perhaps, cavewoman) first hatched the idea of sitting astride a horse. He probably wasn't so sure it was a good idea at first, as the horse swiftly bucked him into a prehistoric bush.

But our Neanderthal friend-- let's call him Grog--persevered, and after a few bumps and bruises, a beautiful new partnership was born. Grog and his horse could now gallop across the plains as one, and a whole new world of possibilities opened up. Soon all the members of Grog's tribe had horses of their own. They could travel farther and faster than ever before, were more efficient hunters, and more imposing to their enemies. All seemed well in the cave-dwellers' world.

But soon there were problems. Crude bridles and harnesses rubbed the horses raw. Galloping across the rocky plains with the added weight of an unsteady rider injured many of the horses. And the animals' backs grew sore from carrying such heavy loads.

Grog and his tribe realized that the horses weren't designed to pull or carry weight upon their backs, and that by asking them to perform these tasks, the humans were responsible for their injuries.

In the millennia since, horsemen have sought to balance their use of horses for pleasure and profit with their responsibility for maintaining the animals' health. It's a battle that still roils on today--domestic horses certainly enjoy a much more pleasant life than their predecessors, but in exchange for their servitude, they also suffer bowed tendons, arthritic hocks, navicular disease, colic, and any number of other various maladies.

Advances in veterinary care and horse management have made it much easier to maintain the health of our equine partners, but they have created new problems of their own. There's a fine line between helping a horse deal with the aches and pains that accompany a competitive lifestyle, and killing the pain caused by an injury that truly calls for rest.

In an effort to draw a line in this gray area, the Drugs And Medications Committee of the American Horse Shows Association proposed an extraordinary rule change at the 1998 convention regulating five of the most widely used medications for competitive horses--the non-steroidal anti-inflammatory drugs, or "NSAIDs." (Two NSAIDs--Butazolidin and Banamine--had been regulated since 1989.) After vigorous debate, the committee decided to table the major points of the rule change until the 1999 convention, and spend the meantime studying these drugs in more detail, and educating horsemen about their uses.

The Answer Is In The Acronym

When you have a headache, you know that taking some aspirin (or Advil, or Aleve) will probably help. You don't particularly care how it works--you just know that it does. But when the situation involves medicating a highly trained and often highly stressed equine athlete, it behooves horsemen to know about the drugs they're giving their charges. Even though NSAIDs are among the most popular drugs in the horse world, few who use them fully understand their side effects and limitations.

The key to how NSAIDs work is in the name--non-steroidal anti-inflammatory drugs. The body produces its own drugs, called corticosteroids, which help to promote healing and reduce pain by reducing inflammation at the site of an injury. NSAIDs aren't steroids, but they work in much the same way.

"[NSAIDs] do not mimic cortisone or naturally occurring cortisol-like compounds. However, they do mimic their function to some extent," said Dr. Richard Mitchell, former chairman of the AHSA Veterinary Committee and a practicing horse show veterinarian. NSAIDs' most significant effect is on inflammation, and for the most part, that effect is how the drugs relieve pain.

Inflammation is the body's natural response to injury, and the first step in the healing process. It's accompanied by a variety of signs all too familiar to competitive horse owners--heat, pain, swelling, redness and impaired function. When a horse comes in from the pasture with a puffy knee that he's reluctant to move and is hot to the touch, and he flinches when you examine it, inflammation is the culprit.

These outward signs are the work of natural chemicals in the horse's body known as prostaglandins. Remove the prostaglandins, and you remove the source of the inflammation--this, in essence, is what NSAIDs do. They bind to another chemical (cyclooxygenase) in the body that is necessary to produce prostaglandins, taking them out of the equation.

In simpler terms, it's like trying to take a hot shower after you've done three loads of laundry--there simply isn't any more hot water available. When NSAIDs "use up" cyclooxygenase by binding to it, there's less cyclooxygenase available to produce prostaglandins, and therefore less inflammation.

The pain-killing (or "analgesic") effect of NSAIDs is primarily through this process--they reduce the pain by removing the source.

"[NSAIDs are] inhibiting pain by reducing inflammation, and I think that's very important for people to understand," said Mitchell. "It's not like giving them opiates--morphine or heavy sedatives--that work [pri- marily] on the central nervous system. [NSAIDs] work peripherally, reduce inflammation peripherally, and by virtue of that, they reduce the pain because they've reduced the source of the pain."

But the drugs do also have a direct effect on pain. "NSAIDs actually do work on the central nervous system. It's true, they alleviate local inflammation and pain associated with local inflammation. But they are known to work on the central nervous system and have a pain-killing effect," said Dr. John Lengel, administrator of the AHSA's drugs and medications program.

The pain-killing and anti-inflammatory effects are intertwined--a variety of factors determine which effect is more prevalent, but both are evident. They're better described as a spectrum or a continuum of effects, not two separate entities, said Lengel.

"Ibuprofen, for example, is a non-steroidal anti-inflammatory. But it works real well for headaches," said Mitchell. "There are analgesic qualities as well as anti-inflammatory qualities. It's very, very difficult to separate where one stops and the other begins because they go hand in hand."

How Soon Is Now?

Because NSAIDs reduce inflammation indirectly by stopping the production of prostaglandins, their effect isn't usually immediate. The drugs must first be taken into the body and absorbed, and the rate varies with each horse. The creation of new prostaglandins then slows, thanks to the binding of NSAIDs to cyclooxygenase. Only then, as the amount of available prostaglandins decreases, can inflammation begin to subside.

The rate at which the drug is absorbed depends on a myriad of factors. Butazolidin (phenylbutazone), for example, is absorbed more slowly if it is given after feeding hay. The age and breed of the horse are also factors, as is the method in which the drug is administered--drugs may take effect more quickly when they're given intravenously than when they're given orally. Even the time of day when the drug is given can produce variations in how quickly it is absorbed.

But it's not just rate of absorption that determines when NSAIDs will take effect. These drugs are peculiar in that their presence in the bloodstream doesn't necessarily correlate to the strength of their effect. Studies have found that Banamine (flunixin) begins to take effect in as little as two hours, while Arquel (meclofenamic acid) can take 36 to 96 hours to produce clinical effects, even though its concentration in the horse's blood plasma peaks between 30 minutes and four hours after administration.

Examining the amount of prostaglandin and other related chemicals in the fluid (or "inflammatory exudate") around an injury shows that NSAIDs' effects persist long after the drugs have started to disappear from the blood plasma. This may be because of the somewhat indirect way that NSAIDs work. It may take a while for prostaglandins to return to normal levels, even longer than the drug remains in the horse's blood plasma in significant amounts.

Another explanation is that some NSAIDs seem to accumulate in the area of an injury. Studies have shown that flunixin and phenylbutazone are found at higher concentrations in the fluid surrounding injured tissues than they are in the blood plasma. Ketofen (ketoprofen) has also been found to accumulate in injured joints, which may explain why it has a longer-lasting effect than would be expected by its quick elimination from blood plasma.

The peak effectiveness of NSAIDs seems to vary, depending on the drug and the injury for which it is being used. Most NSAIDs seem to produce noticeable effects about three hours after administration, peaking between six and nine hours, and starting to decrease by 12 hours, according to Dr. Steven Kamerling, professor at Louisiana State University.

Some NSAIDs peak later--the manufacturers' guidelines for Ketofen suggest that the drug's greatest effect in flexion tests is at 12 hours after dosing. And in some cases, NSAIDs produce extremely rapid effects. Flunixin has been shown to relieve pain from colic in as little as 15 minutes in some horses.

Colic, while different from a lameness, is also an inflammatory response. Chemicals called endotoxins, produced by the natural bacteria in the horse's intestinal tract, can be released when the intestinal barrier begins to leak. Endotoxins cause prostaglandins to be released, which causes inflammation. So NSAIDs can provide relief in the same manner as with other injuries. But no one knows why the onset of relief seems to be so much faster for colic than with lameness.

Deciding The Dose

How fast and how long NSAIDs work are two questions that are at the heart of the debate over the AHSA's proposed rule change. Of the five legal NSAIDs--Butazolidin, Banamine, Ketofen, Arquel and Equiproxen--AHSA officials recommend that only Butazolidin can safely be given in the 12 hours before competition, and then only at half the maximum daily dose to avoid exceeding recommended plasma levels.

"[The proponents of the drug rule change] are concerned that horses should not be running with deadened pain" from a substantial dose of NSAIDs, said Kamerling. "The 12-hour restriction is allowing horses to compete with a modest level of analgesic on board that will not mask pain. There's enough analgesic and anti-inflammatory effect present between nine and 12 hours to provide an adequate degree of relief."

The primary concern of the drug rule proponents, according to Dr. Kent Allen, practicing veterinarian and chairman of the AHSA Veterinary Committee, is that a too-liberal policy on NSAIDs could allow some trainers, whether inadvertently or on purpose, to hide the subtle signs of more serious injuries.

Allen cited tendon and ligament injuries, which are often accompanied by very slight and inconsistent lameness. If a horse is being ridden with a significant level of NSAIDs, those early signs can be missed, along with the opportunity to treat the problem before it becomes serious.

A low- to middle-level dose of one NSAID should be enough to keep old campaigners with muscle soreness or arthritis sound and comfortable in the show ring, said Allen. But "that dosage should not be able to get the horse who is starting to tear up cartilage in its joints back in the ring for the next month and a half," he said.

"[The goal is] to come up with a rational approach to using non-steroidals so they don't mask a lot of pain. We don't want these horses to compete if they're in a lot of pain. They need a diagnosis instead of a drug at that point."

The other concern addressed by the proposed drug rule is the adverse effects that accompany higher doses of NSAIDs. It's a well-established fact that the drugs can cause ulcers and other problems in the digestive tract through their inhibition of prostaglandin production. Prostaglandins also play an essential role in the production of the mucous coating in the stomach and intestines, which protects these organs' linings from caustic digestive juices. So when prostaglandin levels decrease, the protective function of those linings also decreases. In addition, NSAIDs have been shown to cause liver and kidney damage.

"Is it a common problem? No. It is a potential problem if we keep using these drugs in combination and keep piling drugs on top of each other. We're going to find things nobody ever expected," Allen said.

NSAIDs are all similar in their actions, and their effects have been shown to be additive--giving two different drugs, each at half their recommended dose, is probably comparable to giving one at its full recommended dose. NSAIDs all differ in potency, which is why the recommended dosage of Butazolidin is four times that of Banamine. But the effects from 2 grams of Butazolidin and 500 milligrams of Banamine are extremely similar.

"If you give an appropriate dose of Butazolidin, and then you give them the appropriate dose of Banamine, you might as well have given them a double dose of Butazolidin," said Mitchell. "And that's where the danger comes in--if it's done chronically, constantly.

"Look at the drugs in my truck here. I've got lots of Banamine and ketoprofen and Arquel and naproxen and all, and I know who buys them from me. They can stand here and tell you they're not giving them, but I know for a fact there are people who, in a pinch, start using more than one or two, maybe three. And you know those are not good for the horses," Mitchell said.

Most NSAIDs have been shown to cause ulcers at various points in the digestive tract, but "Bute" is by far the greatest culprit. Not only is the drug irritating to the horse's digestive system, it's actually toxic in higher doses. Bute also accumulates in the body, meaning that less of it is needed to produce the same effect if it's given over a period of time.

"You do see horses that can't tolerate even one gram of phenylbutazone two times a day," said Dr. Midge Leitch, a Federation Equestrian International veterinarian with a private practice in Cochranville, Pa. "But the vast majority can tolerate two grams twice a day. If you've got a horse that can't tolerate it, you don't give it."

Researchers believe that because the beneficial effects of NSAIDs are additive--giving smaller doses of two drugs is similar to giving a larger dose of one drug--the negative effects probably are also. So if two NSAIDs are to be used, both can't be given at the maximum allowable level. When the drugs are used in combination, they have to balance each other out. But it's not yet clear whether drugs used in combination have any greater effect than a single drug used alone.

"I think a lot of people who have gone to two medications are not using one to their full advantage," said Mitchell. "They're not using one drug and allowing it to work and do its thing. They just don't give it time. The horse is going to show tomorrow, so they give it two tabs of Bute in the feed, and then they wonder why it's still stiff the next morning."

But some argue that different NSAIDs can work together in com- plementary fashion, because some drugs seem to have better effects on certain types of injuries than others. In some research studies, Bute was found to be better at reducing sy- novitis in joints than Ketofen, and Ketofen seems to work better on chronic hoof pain. But veterinarians disagree on whether results will be the same in the field as they are in the laboratory.

"If you feel your horse goes better on 500 milligrams of Banamine at night and 10 c.c.s of Ketoprofen in the morning, I don't have any problem with that," said Leitch. "I'll leave that in the hands of the people who deal with the specific horse.

"From my own experience, I think Naproxen seemed to work better on horses who had sore backs. But I'm not opposed to saying there are other drugs that would work better. There are plenty of horses who would go just as well on a twice-daily dose of Bute. There are probably a very small percentage of horses that would benefit by a combination as opposed to just a single drug," Leitch added.

In a compromise reached at the AHSA convention, an extraordinary rule change was passed outlawing the use of more than two NSAIDs at once. A proposed rule for 1999 would allow significant levels of only one drug at a time, however.

"One of the things that was suggested was that if a horse went on a second non-steroidal, you have a vet sign off on it," said Mitchell. "It doesn't necessarily require that a vet come and examine the horse, I don't think. If I know somebody's got an old equitation horse, and they want to give him Ketofen on the second and third day of his showing, I'm going to say 'Sure.' And they can put my name on the medication report. It would just provide a little accountability and make it enough trouble for them to think about giving that second drug."

"Everyone wants to see a situation where we have a rational approach to therapeutic medication," Allen emphasized. Supporters and opponents of the proposed rule change may differ on how strict the rules should be, but both groups want the same thing--to protect the horse. What AHSA officials hope to do is prevent owners and trainers who simply don't know better from giving NSAIDs in place of an examination by a veterinarian.

Mitchell's suggestion that competitors have vets sign off on their use of a second NSAID "is exactly what I'm talking about," Allen said. "At least the veterinarian can get his hands on the horse and palpate it and detect an early bow."

The rule's opponents fervently noted at the convention that few scientific studies demonstrate the effects of NSAIDs as they're used in the horse show world. They particularly pointed to lack of information about the benefits and drawbacks to using combinations of drugs.

"It's all up for discussion at this time, but there are no definite plans [for research] yet," said Lengel. "Almost every one of [drug rule opponents'] requests has a price tag on it."

But plans are underway for three educational forums about the uses and dangers of NSAIDs--one in the East, one in the Midwest and one in the West. "Watch Horse Show magazine--it's going to be a lot of good information on what the drug rule really is," Allen said.


What Trainers Actually Use

An informal survey of four top hunter/jumper trainers on the Florida circuits revealed that the use of non-steroidal anti-inflammatories is common and carefully prescribed, depending on a horse's activity and needs.

The trainers asked not to be identified for this survey.

Trainer A, who took more than 25 horses and ponies to the five-week HITS Ocala circuit for her mainly junior and amateur riders, has many older campaigners in her barn and a few young, green horses. She uses Butazolidin or Banamine the night before each horse shows--one tablet "Bute" or 10 c.c.s of Banamine. She selects which NSAID to use depending on the individual horse.

The day of the show, Trainer A gives some, but not all, of her horses 10 c.c.s of Ketofen about six hours before their estimated show time. Others receive Arquel, especially those who are footsore or sensitive to the footing.

"After the fifth week down here in Ocala, I do have some horses who are maybe a little backsore too," said Trainer A. "I may give them a little Robaxin [a muscle relaxant]. But the most I give to any one horse is Bute or Banamine the night before and something else the day they show."

Trainer B, another who specializes in juniors and amateurs, said she usually uses few NSAIDs. "But I use more than I like down here [on the HITS Ocala circuit] in Florida," she said. "With the sand footing and five weeks of showing, they do tend to need a little more to feel comfortable."

Her maximum dosage is Robaxin at night (12 tablets) and 10 c.c.s of Ketofen the day the horse shows.

"I give Ketofen. I don't think it makes them sound, but it makes them comfortable," she said. "It's like after I'm on my feet all day, I want some Advil to help me feel better the next morning. I want to make my horses feel their best too. They work hard down here."

Trainer C has several green horses as well as junior hunters that competed on the Winter Equestrian Festival. She gives her

horses one NSAID (usually Bute or Banamine) the night before they show and then either Ketofen (10 c.c.s), Robaxin or Arquel the day they show.

"It all depends on the individual horse," she said. "If I thought the horse had an easier day or maybe the rider needed to practice, I give the horse a little less or more depending on that.

"But since we don't have specific times we show, like some of the other disciplines do, I usually give a horse a little something in the morning since it may be late afternoon or even after 5 p.m. before they actually get to the ring," she added.

Trainer D was busy with more than 25 horses on the Winter Equestrian Festival, a mixture of ponies, green, amateur and junior hunters as well as jumpers and equitation horses. Like the other trainers, he has each horse on a program and doesn't indiscriminately "dole out" NSAIDs.

He explained that his green horses may get a little more since they usually spend more time being ridden or longed, and his older veterans may get more since they have experienced wear and tear on their joints and may have past injuries. He usually uses Bute (1 gram) and Banamine the evening before his horses show and Ketofen (10 c.c.s) or Robaxin in the morning.

"I'm very careful to plan my medications so that each horse receives the right amount for them to feel comfortable. NSAIDs don't mask lameness, and they don't make a lame horse sound," he said. "These horses are athletes, and I think we need to help them stay comfortable and happy. I have one horse who's 18 and still going strong in the big equitation divisions. He may need two grams of Bute the night before he shows, but he still goes in that ring with his ears pricked. He loves his job, and, I'll tell you, he wouldn't be very happy sitting at home watching all the others getting on the van."

Erin Harty (eharty@geocities.com)