This presentation reviews the issues of drug use in performance horses, compares the rules of different horse sport organizations, gives an overview of the “state of the art” of drug detection methods and outlines what you as a competitor can do to avoid drug rule violations.

altDr. Patricia Dowling, DVM

Patricia Dowling is board certified in large animal internal medicine and veterinary clinical pharmacology and is a professor of veterinary pharmacology at the Western College of Veterinary Medicine. In addition, she is an avid competitor in endurance racing and has been a member of the Canadian Equestrian Team at three Pan American Endurance Championships and was an alternate to the Canadian team for the 2010 World Equestrian Games. She is a member of the Equine Medications Committee of Equine Canada, the Equine Federal Drug Advisory Committee for the Canadian Pari-Mutuel Agency, the veterinary committee of the American Endurance Ride Conference and serves as an advisor to the Ontario Racing Commission.

To protect the health and welfare of horses, veterinarians must legitimately use therapeutic medications. Therapeutic medications have been defined by the American Association of Equine Practitioners.(1) While these drugs are commonly and appropriately used to treat various disease conditions of horses, many of them have the ability to affect athletic performance and/or leave residues in horses that enter the food supply. For performance horses, the primary reason to have drug rules is to ensure fair competition and to protect the welfare of the horses. In Canada, humane slaughter is still a viable option for horses with chronic conditions that render them unfit for service. When medications are administered to horses, it is the responsibility of the veterinarian to ensure that violative drug residues do not occur. However, the sensitivity of drug testing allows for laboratory detection of very small quantities of drug that may even be pharmacologically insignificant for performance horses or of concern in human food. This makes it extremely difficult for veterinarians to advise owners and riders about long a treated horse must wait before being entered in a competition or sent to slaughter. Clearly, if horses are to receive proper veterinary care, suitable information on drug detection times and withdrawal times must be available to equine practitioners.

 

Drug Rules and Performance Horses

Equine competitions may be regulated by a local or discipline-specific group, state or provincial agency, national federation or agency, or international federation. Drug rules vary enormously between sport organizations, but there are 4 basic types of medication rules for competitive horses.(2) The first is the “no drug “ rule, which stipulates that no trace of any drug can be found in any body fluid. This is also known as the “oats, hay and water” rule. The second type of drug rule is the time rule, where the period of time before a competition during which drugs cannot be administered is defined. The third type of rule is no rule at all. Virtually all equine sport organizations have drugs whose use they disregard, as they have no influence on performance (eg, dewormers, vitamins, antibiotics, fly spray). The fourth rule is the “tolerance level” rule, where acceptable concentrations of drug are established and horses are only penalized if this concentration is exceeded at the time of competition.  Many equine sport organizations have “therapeutic substance provisions” and permit the detection of small concentrations of drugs, such as nonsteroidal anti-inflammatory drugs, without penalty.       

Equestrian competitions such as Federation Equestre International (FEI) sanctioned competitions and long distance riding competitions tend to have “no drug” rules. Horses are required to compete entirely on their natural abilities without being influenced by any drug, medication or veterinary treatment. When competing horses are tested, the “no drug” rule means that any trace of a drug or drug metabolite is called as a positive test. Simple confirmation of the presence of any drug is evidence that the rule has been broken (primae facia evidence).(3) While this is a simple and straightforward policy and appeals to those concerned about horse welfare, drug testing methods are now advanced enough to detect very small amounts of drugs for long periods of time after they have been administered, at concentrations that have no effect on performance.(4) This also puts the sport’s drug rule solely into the hands of the analytical chemist. As they develop a more and more sensitive tests, drug violations are called for insignificant traces of drugs, causing unfair penalties to competitors and preventing veterinarians from administering valid therapeutics to horses out of fear of causing positive tests.

It is actually rare in equine sports for a positive drug test to mean that someone intentionally tried to alter the outcome of the competition. Violations of the drug rules are usually due to carelessness or inattention to dose or dosage form, misunderstanding of the directions or using a therapeutic medication for a medically indicated reason, and not waiting a suitable “withdrawal time” before entering a horse in a competition, or cross-contamination from people or the environment picked up by ultra-sensitive testing methods. In some equine competitions such as flat racing, unscrupulous persons may deliberately administer drugs to horses with the goal of altering performance. With parimutual betting, large sums of money can be involved in “fixing” of racehorses, with some being drugged to win and some being drugged to lose (“nobbling”).

While there are literally tens of thousands of chemicals and drugs available for administration, most of violations are caused by only a few drugs such as procaine, isoxuprine, nonsteroidal anti-inflammatory drugs, bronchodilators, corticosteroids, antihistamines, phenothiazines and methocarbamol. While there is no acceptable excuse for finding narcotics, amphetamines or mood-altering drugs only approved for humans in the blood of competing horses, the occasional detection of trace levels of antihistamines, bronchodilators or nonsteroidal anti-inflammatory drugs is much more understandable. Because of the variability in doses and elimination rates of drugs, horse to horse variation in drug elimination, and the variation in drug testing methods between different laboratories, it is very difficult for veterinarians to give advice to owners, riders or trainers as to when it is safe to compete their horse after it has been given a drug for an appropriate medical reason.(5) A drug testing laboratory may arbitrarily and without notice introduce a more sensitive test, so that a previously followed withdrawal time suddenly results in “positive” drug tests.

Under the rules of most competitive organizations, a “positive” drug test result is an unarguable fact and penalties are imposed, but there is no uniformity between organizations on the penalties imposed. The Association of Racing Commissioners International, Inc. (ARCI) classifies over 700 drugs into five classes in decreasing order of their potential to affect a horse’s athletic performance.(1) With this system, lay persons with little knowledge of drugs can understand the performance altering potential of a detected drug and determine appropriate penalties for infractions. According to the ARCI system, Class I drugs have no recognized therapeutic use in equine medicine, stimulate or depress the central nervous system, or have a history of abuse in humans or horses. Examples include opiates and amphetamines. Class II drugs include therapeutic agents that have a high potential to affect performance. They include phenothiazines (except acepromazine and promazine), benzodiazepines, barbiturates, opioid agonist-antagonists and local anesthetics (except procaine). Class 3 drugs may have generally accepted uses in horses and less potential for altering performance than Class 2 drugs. It includes bronchodilators, vasodilators, potent diuretics affecting renal function and body fluid composition, antihistamines, and local anesthetics with minimal potential for use in nerve blocking or which have a high potential for detection in urine, such as procaine. Positive tests for procaine result primarily from the use of procaine penicillin G, as procaine can easily be detected for weeks after chronic administration.(6) Class 4 drugs are therapeutic medications with some potential for altering performance. It includes antiarrhythmics and cardiac glycosides, gastrointestinal antispasmodics, nonsteroidal anti-inflammatory drugs, corticosteroids, mineralocorticoids, and skeletal muscle relaxants. Class 5 drugs are therapeutic drugs of only minor regulatory interest and include anti-ulcer medications such as cimetidine and omeprazole. Non-classified drugs are considered to be of no interest to regulatory authorities and include antimicrobials, sulfonamides, anthelmintics and vitamins. In 1995, the ARCI resolved to address “trace” level detection of the most commonly detected drugs, to prevent sporting organizations from penalizing owners, riders and trainers for pharmacologically insignificant traces of drugs and preventing the appropriate veterinary care of performance horses for fear of positive drug tests.(1) Their goal is to identify “no effect points”, which are precisely defined drug concentrations at or below which the drug is pharmacologically insignificant and there has been a number of research projects carried out to determine these points for therapeutic drugs.

Drug Testing Methodology

Drug testing laboratories for equine athletes may be privately owned or government run and predominantly deal with samples from race horses, where there are strong economic incentives for “fixing” the outcome of a race. Depending on the jurisdiction, drug testing protocols may require urine or blood samples. Blood samples are ideal in that they are easily collected and the amount of drug in the blood can be correlated with its effect on performance. Because it is an invasive procedure, collection of blood usually must be done by or under the direct supervision of a veterinarian. Urine testing is a better method to simply determine whether or not a horse has been given a drug, since most drugs are eliminated in the urine, it tends to contain higher levels of drugs for a longer period of time than blood samples. Urine collection is not invasive and may be performed by a lay person. However, urine collection is slow and it may be difficult to collect from horses dehydrated from exercise. Urine testing provides a simple “positive” or “negative” result, as drug levels in urine do not determine if a horse had a blood concentration of drug that was therapeutic or performance altering.(5)

One of the major problems with a “no drug” policy is that there is no standardization between testing laboratories as to which testing methodology is used and they can arbitrarily start using a more sensitive test.(1) In effect, the testing laboratory decides how rigorous the “no drug” policy will be when they select the test method. Most of the private laboratories utilize thin layer chromatography (TLC) or enzyme-linked immunoabsorbent assay (ELISA) tests as their drug screening methodology and confirm positive tests using liquid chromatography-mass spectrophotometry (LC-MS) or gas chromatography-mass spectrophotometry (GC-MS).(7,8) Testing done by TLC or ELISA is only used to call a sample “positive” or “negative” for the presence of a drug; GC-MS or LC-MS must be used to quantify the actual amount of the drug present.(8) The ELISA tests used by drug testing laboratories are commercially available kits that use antibodies that test for individual drugs. When ELISA testing methodology is applied to urine samples, extremely small amounts of drug can be detected long after the other methods would give a negative test. An example of this is screening for the presence of flunixin meglumine. By TLC, the detection time of flunixin in urine is 2 days after a typical intravenous dose. If an ELISA test is used, flunixin can be detected in urine for at least 15 days.(9) Unfortunately, veterinarians and competitors are unlikely to know what screening test is being used or may not know that the screening test (and therefore the detection time) has been changed until notified by the sport organization of a drug rule violation.

Interfering and Naturally Occurring Substances

There are some drugs that are not performance-altering, but their presence interferes with some testing methods. The presence of such an interfering substance will cause the some laboratories to call a “positive”. This is not uniform between testing laboratories, but the usual interfering substances are dipyrone, sulfonamide, isoxsuprine, thiamine and benzimidazole dewormers . As stated previously, most of the laboratories are primarily screening for drugs with the potential to alter the outcome of track races, so they use common sense in what they will call as a “positive” and do not concern themselves with dewormers, fly repellents, menthol and most nutritional supplements. Competitors are often concerned regarding supplements containing yucca, which does contain salicylates similar to salicylic acid (better known as aspirin). Salicylates also occur in some grasses and hays and horse urine naturally contains large quantities of salicylates. In the 1980's the official racing laboratory of Agriculture Canada conducted research trials to establish an accepted concentration limit for salicylic acid in blood and urine.(10) These standards have been validated and accepted as international thresholds.(4) When fed as directed, yucca supplements are highly unlikely to add enough salicylate to result in a positive test for aspirin. Competitors should still be cautious with all herbal or nutriceutical products, as they may contain substances not permitted by sports organizations, despite the claims of “will not test” on the label. Manufacturers of such products have no way to determine what substances the drug laboratories can or can not test for.

Drug Detection Times versus Drug Withdrawal Times

A drug “detection time” is the time period after the drug has been administered that the testing laboratory can detect the drug with accuracy and repeatability. This is specific to the laboratory and subject to change as testing methodology changes. Detection times are also typically determined from studies using only small numbers of horses, so the reporting organization typically has clear disclaimers that this information may not be applicable to your horse (eg, the Canadian Pari-Mutuel Agency guidelines have this on every page). A “withdrawal time” is the period of time that the horse is kept from competition to make sure that a positive test does not occur. It must be determined for an individual horse by the treating veterinarian taking into account a number of factors and should always be longer than the organization’s detection time.

Determining Drug Withdrawal Times

Amount of Drug Given. The amount of a drug given to a horse has a great effect on drug withdrawal time. For some equine medications, the doses are very small yet for others, the amount of drug given is very large. For example, the butorphanol is usually dosed at 500 micrograms to a 1000 lb horse, while the dose of phenylbutazone to the same horse would be 3 grams. This is a six thousand-fold difference in the number of butorphanol molecules injected in to the horse’s body compared to the number of phenylbutazone molecules. Obviously, the more molecules of drug given, the easier it is going to be to detect amounts of the drug in blood or urine.(5)

Drug Elimination Rate. Drug elimination is the removal of the drug from the horse’s body by all routes. Most drugs are eliminated in the urine by the kidneys, but some drugs may also be eliminated in bile and feces through the intestinal tract and through sweat, tears, saliva and other body secretions. The elimination half-life (t½) is defined as the amount of time for the drug’s concentration to decrease by one half. For any drug, this is determined by administering a dose of the drug to a test group of horses then taking repeated blood samples. The concentrations of the drug in the serum or plasma are measured, and when the concentrations are graphed over time, the drug’s elimination half-life can be calculated. This rate of drug elimination stays constant over time until the drug can no longer be measured in the blood. Values for the t½ of many drugs used in horses can be found in veterinary textbooks such as Plumb’s Veterinary Drug Handbook.(11)

The value for t½ depends on the chemical properties of the drug and the horse’s elimination mechanisms. Values of t½ for different drugs can range from minutes for drugs like prostaglandin F2 alpha (Lutalyse®) to hours for phenylbutazone to days for long-acting tranquilizers like reserpine.  From simple mathematics, after 10 t½’s the drug concentration in the horse’s blood will have decreased by 99.9%, but it will take about 70 t½’s to clear all the drug molecules from the body.(5) In general, the detectability of a drug depends on the amount of drug administered and the speed at which the horse eliminates the drug. If the drug is administered in gram amounts, such as phenylbutazone, and it has a long t½, then it will be detectable in blood or urine for a relatively long period of time. On the other hand, if it is administered in milligram or microgram amounts and it has a very short t½, then it is likely to only be detectable for a short period of time.

Biological Variability Between Horses. One of the major reasons for the difficulty in making drug withdrawal time recommendations is the variability of drug elimination between horses. When a group of horses are given a drug and then the drug concentrations are measured in their plasma, the measured drug concentrations are spread out in a peculiarly skewed fashion, with a cluster of levels at the lower end of the distribution, but a longer tail at the higher concentrations.(5) If withdrawal time recommendations are made from studies using small numbers of horses, they will tend to miss the horses that contribute to the high tail of the distribution curve. So veterinarians should be cautious regarding withdrawal time recommendations made from studies using small numbers of horses, such as the Canadian Pari-Mutual Agency’s recommendations.(10) It appears that you have to test at least 50 horses to get an accurate picture of the skewness of the distribution of drug concentrations.(5)

So What’s a Veterinarian or Competitor to Do?

Riders, owners and trainers of equine athletes should always work with their veterinarian to provide the best medical care for their horse. Valid medical therapy should never be withheld out of fear of a positive drug test. Common sense and some understanding of the properties of drugs and the limitations of drug testing will help everyone to avoid drug rule violations. Before giving any drug to a horse during competition season, consider the following:

1) What is the total drug dose? Drugs that are given in small amounts (micrograms) will be less likely to cause positive tests than drugs given in larger amounts (milligrams or grams).

2) What is the route of administration of the drug? Drugs will be cleared most quickly after an intravenous injection. Orally administered drugs in horses may bind to hay in the gastrointestinal tract which tends to slow the absorption rate, thereby slowing the elimination rate. Also, horses may spit pastes or granules out into water or feed buckets and consume the drug at a later time. Cross-contamination from contaminated stalls, handlers’ hands or feeding equipment can occur.(8) Be very careful with drugs that are considered “long-acting”. Drugs like procaine penicillin G, are formulated to be very slowly absorbed to provide long-acting levels of penicillin. However, the slow absorption of the procaine, which is a local anaesthetic, causes it to be very slowly eliminated from the horse’s body. Positive tests for procaine are very common and the testing laboratory can not determine a positive test that results from the use of the antibiotic preparation from an unethical use of procaine to deaden pain and mask a lameness.

3) What is the elimination half-life (t½) of the drug? The numerical value for t½ can give a rough estimate of a drug’s withdrawal time, as drug concentrations are reduced by 99.9% in 10 t½’s, but remember to also consider the total amount of drug given as that 0.1% of drug may still be easily measures with sensitive analytical tests. Try to avoid drugs with values of t½ of many hours or days. When there are similar drugs with the same drug action, select the drug with the smallest total dose and the shortest elimination half-life. For example, the dose of phenylbutazone is in grams and the elimination is 8 hours, while the doses for flunixin and ketoprofen are in milligrams and their elimination half-lives are approximately an hour, so detection limits for these drugs are typically shorter than that recommended for phenylbutazone.(10)

 

4) Look for published detection times for drugs. The detection limit information is available in published guides from the Canadian Pari-Mutuel Agency(10), the Australian Equine Veterinary Association(12,13) and the Federation Equestre International.(14) Most of the detection limits have been determined using small numbers of horses, so this information should be used only as a general guide for determining when it is safe to enter a treated horse in a competition. Note the extreme variation in some of the reported drug detection limits. This is mainly due to test methods varying between testing laboratories. The Canadian detection times are shorter than some others because the Canadian Pari-Mutuel Agency has made a deliberate effort to limit the sensitivity of their test methods to levels of drug that are performance altering.(1) The Canadian detection times may not be valid for testing done in the United States or other countries, especially if more sensitive testing methodology, such as ELISA testing is used. A veterinarian should consider the published detection times and the sport organization’s rules as well as his/her knowledge of the particular horse’s physiology to advise a competitor on an appropriate drug withdrawal period prior to a competition.

References

1.         Tobin T, Harkins JD, Sams RA: Testing for therapeutic medications: analytical/pharmacological relationships and limitations on the sensitivity of testing for certain agents. J Vet Pharmacol Therap 22:220-233, 1999

2.         Tobin T: Medication Control: Rules. Equine Veterinary Science 6:191-195, 1986

3.         AERC Veterinary Committee: AERC Drug Rule Policy, 2000

4.         Short CR, Sams RA, Soma LR, Tobin T: The regulation of drugs and medicines in horse racing in the United States. The Association of Racing Commissioners International Uniform Classification of Foreign Substances Guidelines. J Vet Pharmacol Therap 21:144-153, 1998

5.         Tobin T: Uncertainty in the "detection times" for drugs in horses. Equine Veterinary Science 6:124-128, 1986

6.         Stevenson AJ, Weber MP, Todi F, Young L, Beaumier P, Kacew S: Plasma elimination and urinary excretion of procaine after administration of different products to standardbred mares. Equine Vet J 24:118-24, 1992

7.         Blake JW, Tobin T: Testing for drugs in horses. Equine Veterinary Science 6:93-97, 1986

8.         Kollias-Baker C: Residues and considerations for use of pharmaceutics in the performance horse. Vet Clin North Am Equine Pract 17:433-44, 2001

9.         Sams RA, Gerken DF, Ashcraft SM: Detection and identification of flunixin after multiple intravenous and intramuscular doses to horses. J Anal Toxicol 23:372-9, 1999

10.       Canadian Pari-Mutuel Agency Schedule of Drugs. http://www.cpma-acpm.gc.ca/english/cpma.htm, 2006.

11.       Plumb DC: Veterinary Drug Handbook, 5th edition. Ames, Iowa, Iowa State University Press, 2007

12.       Australian Equine Veterinary Association: Detection of therapeutic substances in racing horses. Edited by N Nichols. Ararmon, NSW, Australia, Australian Equine Veterinary Association, 1992, pp 69

13.       Dyke TM: Pharmacokinetics of therapeutic substances in racehorses. Australian Equine Veterinarian 7:1-54, 1989

14.       FEI List of Detection Times. http://www.feicleansport.org/Detection_Times_Lab.pdf