zacharyfarms
Well-Known Member
Bute: How Much is Too Much?
The Horse
January 2006
Phenylbutazone (PBZ), commonly known as Bute, can be the horse owner's (and horse's) best friend. This popular and economical non-steroidal anti-inflammatory (NSAID) blocks pain, reduces swelling and inflammation, and lowers fever, making it an effective choice for treating injuries, infections, and musculoskeletal disorders such as laminitis, navicular disease, arthritis, and degenerative joint disease. Plus, Bute can deliver the goods for more than 24 hours.
But there is a downside: Generally a safe product when used as directed for most horses, Bute does have a narrow safety margin and, in certain individuals, can cause serious and even fatal side effects, warns Patricia Dowling, DVM, MS, Dipl. ACVIM, ACVP (pharmacology), professor of veterinary clinical pharmacology at the Western College of Veterinary Medicine (University of Saskatchewan) and director of Western Centre Canadian GFARAD (Global Food Animal Residue Avoidance Databank).
Although underlying causes of Bute sensitivity in some individuals go undetermined or undiagnosed, horses at most risk are foals, performance horses that travel, ponies, aged horses, dehydrated horses, and those with hypoproteinemia (low protein blood levels), liver or kidney disorders, or rhabdomyolysis (tying-up).
The most common side effects of Bute toxicity, Dowling says, are oral ulcers (open sores or lesions in the mouth) and right dorsal colitis (a life-threatening, ulcerative inflammatory condition of the colon). Bute toxicity can also cause ulcers or hemorrhages in the esophagus and gastrointestinal tract, diarrhea, low white blood cell count, anemia, and intestinal, kidney, and liver disease. "The kidney effects are usually clinically silent, unless you look for it with ultrasound," Dowling says. "With high doses of Bute in really dehydrated horses, you can see outright kidney failure."
The incidence of Bute toxicity is unknown, but it might be fairly common, says Rebecca S. McConnico, DVM, PhD, Dipl. ACVIM, assistant professor of equine medicine in Louisiana State University's Equine Health Studies Program. "Here at our teaching hospital, we may see one or two horses a month where there is concern that the horse is presented with signs consistent with Bute (or other NSAID) toxicity," she says. "Furthermore, there are likely many unidentified (subclinical) cases of Bute toxicity."
How Bute Works
Phenylbutazone is absorbed well from the stomach, but most of the dose of Bute remains in the blood and does not cross biological membranes well, Dowling explains. "The highest concentrations are in the liver, heart, kidney, lungs, and plasma, with low levels in normal tissues and joint fluid," she says. However, when tissues or joints are damaged, increased blood flow and the leaking of blood fluids from damaged blood vessels allow Bute levels to increase to therapeutic levels at these damaged sites.
"Phenylbutazone is converted by the liver to oxyphenbutazone (OPBZ), a metabolite with the same action as Bute, but that is removed slower from the body than Bute, so the therapeutic effect of Bute lasts for more than 24 hours," Dowling continues. "Less than 2% of the original dose of Bute is excreted in the urine as an unchanged drug, so liver function is very important in the elimination of this drug; the capacity of the liver to process Bute becomes overwhelmed at relatively low drug doses. Therefore, increasing doses of Bute can easily result in toxicity."
Bute is available in many intravenous and oral formulations (powder, paste, gel, tablets). "The injectable formulation must be given by careful intravenous injection, otherwise it causes severe tissue damage if given intramuscularly or subcutaneously," Dowling states. "Orally administered Bute is well absorbed, but the time it takes to reach peak blood levels is delayed by feeding the horse, as the Bute sticks to feed particles in the horse's gut."
Dosage varies somewhat depending on severity of pain or inflammation. "Routine lame horses (average horse weighing about 1,000 pounds or 450 kilograms) usually receive a dose of about 1 gram twice a day (2.2 mg/kg) initially over a five- to 10-day period," McConnico says. "However, it is not unusual for a horse to receive twice that daily dose. In fact, many veterinary textbooks and acceptable dosage recommendations are as high as 4.4 mg/kg twice a day, which is 4 grams a day."
While Bute is labeled for use at up to 4 grams per 1,000 pounds of body weight per day (for which many give 2 grams every 12 hours), Dowling recommends once daily dosing of 2 grams/1,000 pounds to allow as much Bute and OPBZ as possible to be eliminated before giving more. "As soon as possible, I get them on every-other-day therapy. For chronic use, I try to give it every three or four days," she says. "If the horse's condition is so painful that a higher dose would be needed, then I recommend using a different NSAID with a higher safety margin."
Bute Gone Wrong
NSAIDs like Bute reduce pain and inflammation by blocking chemicals known as prostaglandins that are released by damaged tissues. While controlling these inflammatory prostaglandins is a beneficial effect, unfortunately there are other prostaglandins that are produced by normal tissues. These "good" prostaglandins have normal housekeeping functions in the body: They regulate blood flow to the kidneys and lining of the gastrointestinal tract, and mucus production in the stomach. Toxicity from Bute and other NSAIDs occurs when these "good" prostaglandins are blocked along with the inflammatory prostaglandins.
"Bute is more toxic than other NSAIDs because most of the drug stays in the blood after administration," Dowling explains. "Therefore, it easily blocks the 'good' prostaglandins, resulting in reduced blood flow to the kidneys and GI tract and decreased mucus production in the stomach. This causes the kidney damage and the ulcers throughout the GI tract.
"Dehydration makes the toxicity problem worse," she adds. "As most of the Bute is in the bloodstream, when the horse is dehydrated, the Bute concentration will be higher. So a 'normal' dose to a dehydrated horse can be a 'toxic' dose."
The severity of gastrointestinal ulcers appears to be dose-dependent, and some horses might have an increased sensitivity to standard dosing, reports McConnico. "The incidence of right dorsal colitis subsequent to NSAID treatment is unknown, but probably occurs in varying degrees in most horses treated for longer than 48 hours (intravenous route) or 72 hours (oral route) at a dose of 8.8 mg/kg per day."
High doses of Bute can be directly toxic to the liver, and the liver damage can further decrease the horse's ability to metabolize and eliminate Bute and OPBZ, compounding the systemic toxicity.
Side effects from Bute toxicity can show up as early as a couple of days after starting therapy, or signs might not become apparent for several days to several weeks. "The onset of signs may be slow, then a sudden onset of diarrhea, weight loss, or colic may occur," McConnico says. Other clinical signs include inappetence, lethargy, and pitting edema (fluid swelling) on the underside of the abdomen. "Side effects may be long-lasting," McConnico continues. "Probably the most common long-term side effect is chronic colic due to chronic colonic ulceration, intestinal scarring (stricture formation), or adhesions."
What To Do?
If a horse shows adverse side effects after going on Bute, discontinue the Bute and consult with a veterinarian immediately. "The horse should be examined (including blood work) to determine if toxicity is a possibility," McConnico states.
Treatment will most likely include supportive care in the form of intravenous fluids with additional therapies based on how the Bute toxicity manifests itself.
"Treatment of NSAID gastrointestinal toxicity is intensive and mainly symptomatic," says Dowling. "The hypoproteinemia that results from loss of plasma proteins into the ulcerated gastrointestinal tract can be corrected with intravenous infusions of plasma. The fluid and electrolyte losses that accompany diarrhea are managed with commercially available intravenous fluids. Broad-spectrum antibiotics are indicated when there is evidence of bacterial septicemia."
"Since gastric ulceration is commonly associated with Bute toxicity, appropriate oral anti-ulcer medication is indicated," McConnico says. "The most effective medication for treatment is omeprazole (GastroGard from Merial, 4.4 mg/kg once daily). A lower dose of omeprazole has been recommended for preventative therapy."
"Surgical removal of damaged sections of stomach or the right dorsal colon may be necessary in some cases," notes Dowling. "Recovery is usually slow, and in severe cases the prognosis is guarded."
If pain management is needed, another form of analgesia such as butorphanol (an opioid) or xylazine (Rompun, a tranquilizer with some analgesic effects) will be necessary, McConnico states. More NSAIDs should not be given because, comprising the same drug class as Bute, they could irritate rather than alleviate toxicity reactions.
Dietary management is also important for recovery from Bute toxicity. Dowling recommends a diet high in alfalfa and corn oil. Studies show that the calcium content in alfalfa hays acts like a buffer and helps raise the stomach's pH (making it less acidic), while corn oil contains anti-ulcer properties.
A horse that has a Bute reaction once could have an adverse reaction again, if all the contributing factors are in place again, Dowling says. Therefore, future administration of Bute and other NSAIDs should be closely monitored in horses that have had problems with Bute.
Avoid Problems
To minimize the risk of a Bute reaction, have your horse examined by a veterinarian prior to using the drug, suggests McConnico, so the normal appearance, heart rate, temperature, and breathing rate of the horse is known. Monitor the horse's attitude, appetite, manure production, and overall appearance daily when you start administration; if you notice any changes, don't delay in notifying your veterinarian. Horses treated long-term with Bute (or another NSAID) should receive a veterinary exam every seven to 14 days with blood samples drawn for albumin, total plasma protein, and renal (kidney) function, McConnico says.
Dose with the lowest effective amount and longest possible dosing interval, Dowling recommends. "The practice of giving a gram a couple of times a week to the mature horse with arthritis is fine and unlikely to cause toxicity," she says.
Always provide a well-balanced, palatable, easily digestible feed ration since nutritional support of the intestinal lining and the overall health status is critical, says McConnico. Make sure your horse has plenty of water to prevent dehydration.
Don't use Bute in situations where the horse is--or could become--dehydrated, such as during an endurance race, three-day event, long trailer ride, etc., Dowling says. "I ride endurance horses, and they always have a degree of dehydration after a race. I never use Bute after a competition."
Consider other pain relievers. "The other available NSAIDs are all less toxic than Bute and can be used judiciously when the horse has recovered," Dowling says. "Flunixin meglumine (Banamine), ketoprofen (Ketofen), and vedoprofen (Quadrisol 100, available in Canada, but not the U.S.) all stay in the bloodstream a much shorter time than Bute. However, they all accumulate at sites of inflammation, giving you effective therapy for 24 hours for musculoskeletal pain. Because there is less drug in the blood, there is less drug affecting the kidneys and GI tract. They don't accumulate to high levels because of saturation of the elimination mechanisms. The other benefit is that these drugs are all cleared faster and are less likely to result in positive drug tests--very important for someone in a 'no drug' sport."
If overdosed, these other NSAIDs can cause the same toxic reactions as Bute, but one doesn't see many problems with them in routine clinical use.
Take-Home Message
"The only reason to use Bute instead of another NSAID is that it is cheap," concludes Dowling. "Here in Canada, Bute costs 17 cents for a 1-gram tablet, while Banamine costs about $17 a dose. My horses are worth the extra expense for the extra safety margin. The only place I'd use Bute is in chronic conditions like laminitis or navicular disease, where therapy is for months or years; as long as it's low dose and every two or three days, it's very safe. But for serious pain like colic, rhabdomyolysis, etc., it's just not worth it to go cheap and use Bute instead of flunixin, ketoprofen, or vedoprofen."
Whichever NSAID you choose, make sure it is chosen with the input of your veterinarian. And to minimize the long-term effects of NSAID use, work with your veterinarian to quickly recognize and treat any toxicity problems that might arise.
The Horse
January 2006
Phenylbutazone (PBZ), commonly known as Bute, can be the horse owner's (and horse's) best friend. This popular and economical non-steroidal anti-inflammatory (NSAID) blocks pain, reduces swelling and inflammation, and lowers fever, making it an effective choice for treating injuries, infections, and musculoskeletal disorders such as laminitis, navicular disease, arthritis, and degenerative joint disease. Plus, Bute can deliver the goods for more than 24 hours.
But there is a downside: Generally a safe product when used as directed for most horses, Bute does have a narrow safety margin and, in certain individuals, can cause serious and even fatal side effects, warns Patricia Dowling, DVM, MS, Dipl. ACVIM, ACVP (pharmacology), professor of veterinary clinical pharmacology at the Western College of Veterinary Medicine (University of Saskatchewan) and director of Western Centre Canadian GFARAD (Global Food Animal Residue Avoidance Databank).
Although underlying causes of Bute sensitivity in some individuals go undetermined or undiagnosed, horses at most risk are foals, performance horses that travel, ponies, aged horses, dehydrated horses, and those with hypoproteinemia (low protein blood levels), liver or kidney disorders, or rhabdomyolysis (tying-up).
The most common side effects of Bute toxicity, Dowling says, are oral ulcers (open sores or lesions in the mouth) and right dorsal colitis (a life-threatening, ulcerative inflammatory condition of the colon). Bute toxicity can also cause ulcers or hemorrhages in the esophagus and gastrointestinal tract, diarrhea, low white blood cell count, anemia, and intestinal, kidney, and liver disease. "The kidney effects are usually clinically silent, unless you look for it with ultrasound," Dowling says. "With high doses of Bute in really dehydrated horses, you can see outright kidney failure."
The incidence of Bute toxicity is unknown, but it might be fairly common, says Rebecca S. McConnico, DVM, PhD, Dipl. ACVIM, assistant professor of equine medicine in Louisiana State University's Equine Health Studies Program. "Here at our teaching hospital, we may see one or two horses a month where there is concern that the horse is presented with signs consistent with Bute (or other NSAID) toxicity," she says. "Furthermore, there are likely many unidentified (subclinical) cases of Bute toxicity."
How Bute Works
Phenylbutazone is absorbed well from the stomach, but most of the dose of Bute remains in the blood and does not cross biological membranes well, Dowling explains. "The highest concentrations are in the liver, heart, kidney, lungs, and plasma, with low levels in normal tissues and joint fluid," she says. However, when tissues or joints are damaged, increased blood flow and the leaking of blood fluids from damaged blood vessels allow Bute levels to increase to therapeutic levels at these damaged sites.
"Phenylbutazone is converted by the liver to oxyphenbutazone (OPBZ), a metabolite with the same action as Bute, but that is removed slower from the body than Bute, so the therapeutic effect of Bute lasts for more than 24 hours," Dowling continues. "Less than 2% of the original dose of Bute is excreted in the urine as an unchanged drug, so liver function is very important in the elimination of this drug; the capacity of the liver to process Bute becomes overwhelmed at relatively low drug doses. Therefore, increasing doses of Bute can easily result in toxicity."
Bute is available in many intravenous and oral formulations (powder, paste, gel, tablets). "The injectable formulation must be given by careful intravenous injection, otherwise it causes severe tissue damage if given intramuscularly or subcutaneously," Dowling states. "Orally administered Bute is well absorbed, but the time it takes to reach peak blood levels is delayed by feeding the horse, as the Bute sticks to feed particles in the horse's gut."
Dosage varies somewhat depending on severity of pain or inflammation. "Routine lame horses (average horse weighing about 1,000 pounds or 450 kilograms) usually receive a dose of about 1 gram twice a day (2.2 mg/kg) initially over a five- to 10-day period," McConnico says. "However, it is not unusual for a horse to receive twice that daily dose. In fact, many veterinary textbooks and acceptable dosage recommendations are as high as 4.4 mg/kg twice a day, which is 4 grams a day."
While Bute is labeled for use at up to 4 grams per 1,000 pounds of body weight per day (for which many give 2 grams every 12 hours), Dowling recommends once daily dosing of 2 grams/1,000 pounds to allow as much Bute and OPBZ as possible to be eliminated before giving more. "As soon as possible, I get them on every-other-day therapy. For chronic use, I try to give it every three or four days," she says. "If the horse's condition is so painful that a higher dose would be needed, then I recommend using a different NSAID with a higher safety margin."
Bute Gone Wrong
NSAIDs like Bute reduce pain and inflammation by blocking chemicals known as prostaglandins that are released by damaged tissues. While controlling these inflammatory prostaglandins is a beneficial effect, unfortunately there are other prostaglandins that are produced by normal tissues. These "good" prostaglandins have normal housekeeping functions in the body: They regulate blood flow to the kidneys and lining of the gastrointestinal tract, and mucus production in the stomach. Toxicity from Bute and other NSAIDs occurs when these "good" prostaglandins are blocked along with the inflammatory prostaglandins.
"Bute is more toxic than other NSAIDs because most of the drug stays in the blood after administration," Dowling explains. "Therefore, it easily blocks the 'good' prostaglandins, resulting in reduced blood flow to the kidneys and GI tract and decreased mucus production in the stomach. This causes the kidney damage and the ulcers throughout the GI tract.
"Dehydration makes the toxicity problem worse," she adds. "As most of the Bute is in the bloodstream, when the horse is dehydrated, the Bute concentration will be higher. So a 'normal' dose to a dehydrated horse can be a 'toxic' dose."
The severity of gastrointestinal ulcers appears to be dose-dependent, and some horses might have an increased sensitivity to standard dosing, reports McConnico. "The incidence of right dorsal colitis subsequent to NSAID treatment is unknown, but probably occurs in varying degrees in most horses treated for longer than 48 hours (intravenous route) or 72 hours (oral route) at a dose of 8.8 mg/kg per day."
High doses of Bute can be directly toxic to the liver, and the liver damage can further decrease the horse's ability to metabolize and eliminate Bute and OPBZ, compounding the systemic toxicity.
Side effects from Bute toxicity can show up as early as a couple of days after starting therapy, or signs might not become apparent for several days to several weeks. "The onset of signs may be slow, then a sudden onset of diarrhea, weight loss, or colic may occur," McConnico says. Other clinical signs include inappetence, lethargy, and pitting edema (fluid swelling) on the underside of the abdomen. "Side effects may be long-lasting," McConnico continues. "Probably the most common long-term side effect is chronic colic due to chronic colonic ulceration, intestinal scarring (stricture formation), or adhesions."
What To Do?
If a horse shows adverse side effects after going on Bute, discontinue the Bute and consult with a veterinarian immediately. "The horse should be examined (including blood work) to determine if toxicity is a possibility," McConnico states.
Treatment will most likely include supportive care in the form of intravenous fluids with additional therapies based on how the Bute toxicity manifests itself.
"Treatment of NSAID gastrointestinal toxicity is intensive and mainly symptomatic," says Dowling. "The hypoproteinemia that results from loss of plasma proteins into the ulcerated gastrointestinal tract can be corrected with intravenous infusions of plasma. The fluid and electrolyte losses that accompany diarrhea are managed with commercially available intravenous fluids. Broad-spectrum antibiotics are indicated when there is evidence of bacterial septicemia."
"Since gastric ulceration is commonly associated with Bute toxicity, appropriate oral anti-ulcer medication is indicated," McConnico says. "The most effective medication for treatment is omeprazole (GastroGard from Merial, 4.4 mg/kg once daily). A lower dose of omeprazole has been recommended for preventative therapy."
"Surgical removal of damaged sections of stomach or the right dorsal colon may be necessary in some cases," notes Dowling. "Recovery is usually slow, and in severe cases the prognosis is guarded."
If pain management is needed, another form of analgesia such as butorphanol (an opioid) or xylazine (Rompun, a tranquilizer with some analgesic effects) will be necessary, McConnico states. More NSAIDs should not be given because, comprising the same drug class as Bute, they could irritate rather than alleviate toxicity reactions.
Dietary management is also important for recovery from Bute toxicity. Dowling recommends a diet high in alfalfa and corn oil. Studies show that the calcium content in alfalfa hays acts like a buffer and helps raise the stomach's pH (making it less acidic), while corn oil contains anti-ulcer properties.
A horse that has a Bute reaction once could have an adverse reaction again, if all the contributing factors are in place again, Dowling says. Therefore, future administration of Bute and other NSAIDs should be closely monitored in horses that have had problems with Bute.
Avoid Problems
To minimize the risk of a Bute reaction, have your horse examined by a veterinarian prior to using the drug, suggests McConnico, so the normal appearance, heart rate, temperature, and breathing rate of the horse is known. Monitor the horse's attitude, appetite, manure production, and overall appearance daily when you start administration; if you notice any changes, don't delay in notifying your veterinarian. Horses treated long-term with Bute (or another NSAID) should receive a veterinary exam every seven to 14 days with blood samples drawn for albumin, total plasma protein, and renal (kidney) function, McConnico says.
Dose with the lowest effective amount and longest possible dosing interval, Dowling recommends. "The practice of giving a gram a couple of times a week to the mature horse with arthritis is fine and unlikely to cause toxicity," she says.
Always provide a well-balanced, palatable, easily digestible feed ration since nutritional support of the intestinal lining and the overall health status is critical, says McConnico. Make sure your horse has plenty of water to prevent dehydration.
Don't use Bute in situations where the horse is--or could become--dehydrated, such as during an endurance race, three-day event, long trailer ride, etc., Dowling says. "I ride endurance horses, and they always have a degree of dehydration after a race. I never use Bute after a competition."
Consider other pain relievers. "The other available NSAIDs are all less toxic than Bute and can be used judiciously when the horse has recovered," Dowling says. "Flunixin meglumine (Banamine), ketoprofen (Ketofen), and vedoprofen (Quadrisol 100, available in Canada, but not the U.S.) all stay in the bloodstream a much shorter time than Bute. However, they all accumulate at sites of inflammation, giving you effective therapy for 24 hours for musculoskeletal pain. Because there is less drug in the blood, there is less drug affecting the kidneys and GI tract. They don't accumulate to high levels because of saturation of the elimination mechanisms. The other benefit is that these drugs are all cleared faster and are less likely to result in positive drug tests--very important for someone in a 'no drug' sport."
If overdosed, these other NSAIDs can cause the same toxic reactions as Bute, but one doesn't see many problems with them in routine clinical use.
Take-Home Message
"The only reason to use Bute instead of another NSAID is that it is cheap," concludes Dowling. "Here in Canada, Bute costs 17 cents for a 1-gram tablet, while Banamine costs about $17 a dose. My horses are worth the extra expense for the extra safety margin. The only place I'd use Bute is in chronic conditions like laminitis or navicular disease, where therapy is for months or years; as long as it's low dose and every two or three days, it's very safe. But for serious pain like colic, rhabdomyolysis, etc., it's just not worth it to go cheap and use Bute instead of flunixin, ketoprofen, or vedoprofen."
Whichever NSAID you choose, make sure it is chosen with the input of your veterinarian. And to minimize the long-term effects of NSAID use, work with your veterinarian to quickly recognize and treat any toxicity problems that might arise.
