There’s More To Drug Violations Than Parts Per Million

Mar 11, 2015 - 10:39 AM
Photo by Molly Sorge

As drug tests have evolved over the years, the USEF Drugs and Medications Department has continually upgraded their program to protect the horse and maintain a level playing field.

The U.S. Equestrian Federation Equine Drugs and Medications Program has worked to protect the welfare of equine athletes and ensure the balance of competition for more than 40 years. The safety and welfare of the horse is always our first and foremost concern; concerns about performance enhancement are secondary.

While all horses are relatively similar, what we ask them to do as athletes can be incredibly diverse. It would be unheard of to watch a 10-year-old horse running in a major stakes race, or a 15-year-old horse in a simple claiming race. However, in many of the breeds and disciplines governed by the USEF, older horses are just hitting their stride, so to speak. From the horse performing dressage tests to those in the western pleasure division of the Arabian Nationals, these horses differ greatly from the 2-year-old Thoroughbred racing around a track.

These differences are important to consider when regulating the performance-altering substances used in horses. A substance that creates a significant advantage in racing may be counterproductive in show horses, and a substance that is considered benign in racing could be routinely abused for performance enhancement in the show ring.

In a Jan. 19 Horseman’s Forum in The Chronicle of the Horse, attorney Joel Turner, who has defended his clientele on substance violation charges before the USEF Hearing Committee, argued that modern drug testing has gotten so sensitive that sport horses routinely test positive for trace amounts of a substance that would have no effect on performance.

It’s true that most equine regulatory bodies formerly adopted a “Zero Tolerance” position on drug infractions; the detection of a drug in any quantity was equivalent to a violation.

The advances in drug detection have rapidly grown in the last few decades with the development of more sensitive methods and technology capable of greater specificity in the identification of drugs.

However, along with these advancements, many regulatory bodies have embraced the new philosophy that the mere detection of a drug at any level does not automatically qualify as a violation of the rules. Some drugs are forbidden because they have no or little recognized therapeutic application in the horse, and the only reason for their use is to alter the performance of the horse while avoiding detection. For drugs in this class it’s not about appropriate therapeutic levels but instead whether or not that drug is detected.

But this is a significant distinction as compared to those commonly used therapeutic drugs, which remain detectable at very low levels, well below the amount thought to achieve an effect. For this reason, many regulatory bodies, including the USEF, have adopted levels that are called “Screening Levels” for these types of substances and thresholds for substances naturally produced by the horse (endogenous).

A great deal of work has gone into identifying appropriate limits and implementing them in a prudent and responsible manner. Any detection below the SLs is considered a “negative” finding.

In addition, regulatory bodies, such as the Fédération Equestre Internationale, have created systems that standardize what drug levels laboratories detect independent of the technology used.

Dilution Is Not Always The Solution

But when it comes to looking at the effect a substance has on a horse (or a human for that matter), there are more factors that come into play than mere parts per million.

With plasma levels of drugs, it’s all too common to try to simplify it and describe the “minute” amounts detected as inconsequential. For example, one billionth of a gram is typically referred to as a miniscule or “trace amount,” but every drug is different in its properties when absorbed, distributed throughout the body, metabolized, and eliminated. Some drugs may have a toxic or fatal result when detected at microgram (µg-one millionth of a gram), a nanogram (ng-one billionth of a gram), or even at picogram (one trillionth of a gram) levels.

What is commonly misunderstood is that at picrogram levels and even lower, drugs can remain pharmacologically active. The upper limit of the therapeutic window for digoxin, a drug used in the treatment of heart failure, can be as low as 1.5 ng/ml of blood. This means that toxicity can occur in the “2 billionths” of a gram range.

The drug etorphine, while similar in its make-up to morphine, can be as much as 80,000 times more potent. A 2-4 mg dose will incapacitate a black rhinoceros. A tiny fraction of this dose will kill a human.

Appropriate doses can vary radically between species, so blindly using the plasma level of a drug as an indication of its effectiveness is erroneous. A great example of interspecies differences are the recommended doses of Previcox® (firocoxib) approved for use in dogs and Equioxx® (firocoxib) approved for use in horses. In this example, a horse 10 times the size of a dog should receive 1/5 the dose.

Another problem with focusing on a specific dosage or amount detected is that it doesn’t take into account the number of receptors occupied by the drug, the distribution of receptors, the binding affinity a drug might have for a specific receptor, and the possibility for irreversible binding of a drug to a receptor.

One example is a human anti-psychotic drug called fluphenazine (Prolixin®). It acts by blocking dopamine receptors in the brain. Depending upon the dose, this blockade can lead to reactions where the horse appears to have similar deficits as people with Parkinson’s disease. This drug binds nearly irreversibly to the receptors and is administered by injection in a formulation that prolongs the release of the drug, so that it provides a prolonged period of action. The end of the effect occurs once the last of the drug has been released, and the dopamine receptors have been replaced with new ones. This is a very potent drug in the family of antipsychotics, and a small amount will have a pharmacological effect. In people, this drug has been detected up to six months following an injection. Currently, the USEF recommends a 90-day withdrawal from competition following the injection of fluphenazine into a horse.

There are other relationships that are essential to understanding how drugs work and why some drugs may be quantitated in the microgram range versus the nanogram or the picogram range. Plasma concentrations don’t necessarily correlate to the impact a drug may have on an animal or person. Most assume that the peak effect of a drug is experienced at the same time as the peak plasma concentration, and that’s not typically true; effect usually lags behind plasma concentration. Additionally, depending on the mechanism of action, the effects of some drugs can last long after the drug is no longer detectable, even when using extremely sensitive methods. Some drugs exert their impact through the expression of genes even after the drug is no longer present.

Evaluating Levels And Limits

And then there’s risk assessment.

Take, for example, blood alcohol levels. These vary around the globe as countries attempt to minimize the dangers associated with impairment when driving a vehicle. For example, bus drivers may have lower limits imposed on permitted BAC levels. This restriction reflects the greater risk associated with the bus drivers’ duties, not that bus drivers are more impaired by alcohol. In Sweden the limit is 0.02 and in Switzerland it is 0.05. Does this mean that the Swiss are less impaired by alcohol?

While studies may provide some insight as to the effect that alcohol might have on the average adult drawn from a diverse population, each regulatory body draws upon its own risk assessment to determine the appropriate level for their industry or country.

 The analogy of acceptable BAC levels brings up another question: Are the same regulations used for driving under the influence of alcohol equivalent to those for driving under the influence of cocaine? And should they be? In this situation two very different drugs would have very different acceptable levels. Just as in horses, an acceptable SL for acepromazine, a forbidden substance with therapeutic value well outside of competition, would be completely different than guanabenz, a substance that tranquilizes the horse by slowing the heart and has little or no recognized therapeutic application in the horse.

There has always been a struggle between people trying to break the rules and the laboratories working with the regulatory bodies to enforce the rules. Once the regulatory body discovers the use of new drugs, it must find a method or a machine capable of detecting it. The regulatory body must then consult with other regulatory bodies, such as racing or FEI, to set the SL. USEF will consult with various agencies before making any determination of SLs.

USEF has participated in a “harmonization” project with the FEI for the past 15 years that further standardizes drug testing, so there isn’t a large variation around the world. This project allows the two federations to share information from their laboratories, SLs and pharmacological studies. The sharing of information is important because while FEI medication rules and USEF rules have some significant differences, the equine athletes within the two organizations are actually quite similar.

USEF also goes to great lengths to ensure its committees are made up of a well-educated, balanced group of professionals. For many years, USEF has maintained its own medication advisory group that consists of a treating veterinarian, a regulatory veterinarian, a veterinary pharmacologist/toxicologist, an analytical chemist and a legal consult when necessary. This group regularly consults with FEI and racing authorities as necessary, but all USEF drug rules are directed towards horses that compete in the breeds and disciplines of USEF.

USEF’s approach differs from racing because it specifically addresses the risks posed to our horses, what they are asked to do, and how they are judged in competition. The group routinely reviews new drugs, SLs and new areas of research.

The medication advisory group maintains a working relationship with the USEF Equine Drugs and Medications Committee, which provides oversight of the program and advice from the field, as well as input on the direction of the program. The Drugs and Medications Committee consists of a wide range of professionals from the breeds and disciplines of USEF. Many perspectives are drawn from in determining appropriate regulatory levels, but all drug regulations are directed towards the welfare of the horses.

Frequently the complaint is that the use of certain drugs is rampant and that stricter enforcement is necessary. Individuals may try to use low levels of forbidden drugs or vary the routes of administration to avoid detection and then cry foul when the drug is then detected. These individuals do this in spite of clearly published drug rules and regulations. Some would like you to believe that because of an explosion of technology the USEF is handing out violations left and right due to a “zero tolerance position.” However, the reality is that the positive rate still hovers around 0.5-1 percent, exactly where it was 20 years ago, in spite of the advances in technology.

If the amounts of specific drugs detected were truly so tiny, one would think there should be a lot more acepromazine positives rather than the average of eight/year out of 9,000-11,000 (conservatively, a positive rate of 0.0008 percent) horses tested. The USEF understands that just because a drug can be found does not automatically mean that there has been a violation. But the vast majority of its members compete their horses appropriately, and when it comes to the field of play, they’d rather be beaten by better riders, not better chemists.

A. Kent Allen

A. Kent Allen received his veterinary degree from the University of Missouri in 1979. His practice, Virginia Equine Imaging in Middleburg, Va., focuses on top-level sports medicine, lameness and diagnostic imaging. Allen is certified by the International Society of Equine Locomotor Pathology and serves as its vice president and executive director. He serves as the volunteer chairman of the U.S. Equestrian Federation Veterinary and Drugs and Medications Committees. He has served as USEF team veterinarian in multiple roles in multiple disciplines. He’s also served on the board of directors for USEF and the U.S. Eventing Association. Allen is the national head veterinarian for the Fédération Equestre Internationale for the United States and serves on the FEI Veterinary and List Committees. He’s been the foreign veterinary delegate (veterinary judge and technical delegate) in two Olympic Games, two Pan American Games and served as the veterinary services manager at an Olympic and World Equestrian Games. 

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