Researchers discover pitfalls of flunixin meglumine (Banamine) in treating cases of colic

by Denise Steffanus

FOR THE past decade, the first-line treatment for colic in horses has been flunixin meglumine (Banamine), a nonsteroidal anti-inflammatory drug (NSAID) that reduces pain, inflammation, and swelling.

For nonsurgical colic, often just one dose of flunixin will ease the horse's symptoms while the episode passes by itself or until routine treatment, such as administration of water and mineral oil via nasogastric tube, can take effect. In cases of severe colic, flunixin often is administered after surgery for its anti-inflammatory action that facilitates recovery while making the horse more comfortable.

Researchers at North Carolina State University have discovered that this same drug may have a detrimental effect on intestinal tissue that actually retards healing after colic.

"It's a little bit of a shock to a lot of equine practitioners that the very drug they've been using to treat horses with colic, Banamine, isn't necessarily helping their intestine to recover," said Anthony Blikslager, D.V.M., Ph.D., associate professor of surgery.

Blikslager, who collaborated with Sam Jones, D.V.M., Ph.D., on the research project, said in cases of severe colic where a twist, a blockage, or an injury diminishes blood flow to a section of intestine that causes it to slough its lining, flunixin will interfere with the repair process.

"If you can get that blood flow back again, the intestine can heal very quickly because it has a lot of cells there that can reproduce quickly," Blikslager explained. "That still happens even when you give Banamine. [The body] will very quickly reseal a defect where the lining has sloughed, but then the cells are quite loosely connected--they produce like a little Band-Aid--and the Banamine prevents the cells from closely adhering to one another."

NSAIDs produce their analgesic effects by reducing prostaglandins, hormones that play a key role in inflammation. Synthesis of prostaglandins in the body begins a chain reaction that results in swelling and edema that stretches the nerve endings, which transmits a pain response to the brain. NSAIDs reduce inflammation by breaking down prostaglandins and blocking their synthesis.

While some prostaglandins cause inflammation and pain, others form a protective lining of the digestive system. When NSAIDs are used to reduce the harmful effects of prostaglandins, they also strip away that protective lining.

"Mostly what we've seen [with reduction of prostaglandins] is a beneficial effect, but there are some things that those prostaglandins do that are actually quite useful, and we've inadvertently taken that out of the picture, too," Blikslager said.

The main problem, according to Blikslager, is that once the colon has been untwisted and the horse is in recovery, veterinarians often administer flunixin.

"Those horses now are in a situation where, even though their lives have been saved, they've got to get their [intestinal] lining back in order," Blikslager said. "That's the time when this effect is probably going to show up. The reason Banamine is used at that time is because it reduces some of the inflammation, but it shuts down gut repair all in one go."

NSAID-induced colitis

Overuse of NSAIDs such as flunixin and phenylbutazone has been linked to a particular type of colitis, or inflammation of the colon, that occurs on the right side of the horse's gut, toward the rear. Blikslager theorized that this particular section of the colon might require more prostaglandins for normal function and repair, so it is the first to show the effects of diminished production of the hormone.

According to Blikslager, it is possible that this type of colitis might result from a combination of damage to the intestine from colic and administration of NSAIDs to reduce the resulting pain and edema.

"If you had a horse that had a large intestinal twist and then untwisted it and kept the horse on Banamine, it could delay the repair to the extent that [the horse] got colitis," Blikslager said. "But, more commonly, you see colitis in horses that have a normal gut and are being treated for a painful condition somewhere else, typically in a joint.

"And what ends up happening is either the horse is very sensitive to the drug or it's overused. Then that normal gut actually becomes damaged for the same sort of reason: The prostaglandins are needed just for normal gut function, and when you take that out of the picture, [the horse's body] can only take it for so long."

Blikslager pointed out that NSAID-induced colitis is a gradually occurring problem, rather than the sudden, acute colitis-X that often causes death. A human drug, misoprostol, can be used to replenish the protective prostaglandins in the gut. "It costs about $40 per day, and you need to treat them for two to three weeks," Blikslager said.

The only drawback of misoprostol, which is a synthetic prostaglandin, is that if it is used to treat a pregnant mare, it may endanger her pregnancy, as it does in humans. (Prostaglandin is the drug administered to mares to short-cycle them back into heat.) But Blikslager said the risk must be assumed if the mare is to be saved.

"We would warn the owner that there was a possibility of losing the pregnancy, but the chances of losing the horse are going to override that concern because you can't save that foal without the mare," he said. "We'd probably put the mare on some additional drugs to try to maintain the pregnancy, and we'd ultrasound her routinely to make sure she wasn't getting into trouble."

Search for new drugs

"The next level is going to be to get a drug that will do the same thing [as Bute and Banamine] but that is safer," Blikslager said. He and Jones are looking at a class of human drugs that includes the recently banned Vioxx and Bextra, which had been used to treat arthritis and other inflammatory conditions.

Cyclooxygenase (COX) is an enzyme responsible for the production of prostaglandins. Vioxx and Bextra are COX-2 inhibitors. They were removed from the market in 2004 because of a link between them and increased incidence of heart attack and stroke. Because horses do not experience the same type of heart disease that afflicts humans, the impact of COX-2 inhibitors on the equine cardiovascular system is not a factor, and the drugs are less likely to cause gastrointestinal insults than other NSAIDs.

Blikslager and Jones continue to study the effects of COX-selective drugs on the horse. "We're looking for more anti-inflammatory action and less damaging effect on the gut," Blikslager said.

Two drugs they have tested, EtoGesic (etodolac) and Deramaxx (deracoxib), had significant drawbacks. EtoGesic did not damage intestinal tissue in the laboratory, but it did not offer gut protection in a live horse. Deramaxx, while promising, is available only in tablet form, and Blikslager does not believe the manufacturer would be inclined to invest in an intravenous formulation just for horses.

Next, Blikslager and Jones will study meloxicam, a COX-2 inhibitor approved for use in large animals in the United Kingdom, Mexico, and Canada but only approved for small-animal use in the United States. One drawback of meloxicam, however, could be its interference with the bleeder medication furosemide (Salix).

"Sooner or later, we'll bump into a drug that inhibits pain and inflammation and will not hurt the gut," Blikslager added.

Interestingly, an old standby, dipyrone, may be just what the doctor ordered. Dipyrone had been a staple in every equine veterinarian's bag for treating colic until 1996 when the U.S. Food and Drug Administration removed it from the market and made its use a felony because it feared off-label use in dairy cattle might contaminate diary products. Dipyrone, which reduces pain, spasm, and inflammation, since has been found to be a COX-3 inhibitor.

"COX-3 is mostly expressed in the central nervous system," Blikslager said. "What it's going to do is get into the central nervous system tissues and inhibit pain at the level of the major nerves in the brain, but it's not going to inhibit [prostaglandins] in the gut. So that might explain why it was so safe."

In Blikslager's native England, Buscopan is the medication of choice for treatment of colic, and that drug has recently been made available in the U.S. Since research into the use of COX-selective drugs in horses is in the early stages, Blikslager recommends that veterinarians continue to treat colic with flunixin, but with the caveat that there are significant dangers associated with its use. He suggests they wean the horse off the drug as soon as possible or get it down to the lowest reasonable dose.