Xylazine: Redistribution of Reputation

On an unseasonably warm day in October 2012, overcast skies cast a shadow over the Charm City, and a handful of scientists and chemists stepped out into the grey day.  The most experienced and brightest minds involved in drug testing in horse racing in America had been summoned for a conference to hash over the final details of a ground breaking new idea in the regulation of horse racing.  The culmination of over 10 years of hard work was the goal.  A list of medications, therapeutic in nature, had been hashed over in meeting after meeting, conference call after conference call, with this group of storied professionals assembling in Baltimore for this final meeting to produce the coup-de-grace:  the Controlled Therapeutic Medication Schedule (CTMS).

The lofty and noble purpose of the CTMS was to permit the rational use of therapeutic medications for the benefit of the health and welfare of the equine racing athlete, while preventing any undue influence on the horse at the time of the race.  This goal is shared almost uniformly among the stakeholders in the realm of horse racing, and this collection of men and women were tasked with making it a reality.

The details of the infamous Baltimore meeting will likely forever remain obscured in the shadow of the clouds that overlooked the city that morning.  The meeting was neither a Racing Medication and Testing Consortium (RMTC) nor an Association of Racing Commissioners International (ARCI) meeting, and therefore this meeting, out of which critical thresholds were adopted, had no minutes, no open records, no transparency.  Just a potpourri of clouded and disparate memories of the participants, no clear record of the details of what transpired on the day.  A lost day, and yet possibly the most important day in the history of the regulation of horse racing in America.

What we understand from this meeting is that, along with other substances, a threshold for xylazine emerged.  At the American Association of Equine Practitioners (AAEP) meeting in 2015, Dr. Rick Arthur, Equine Medical Director of California and the Oak Tree representative on the RMTC, reported to the racing committee in an open meeting that xylazine was among the thresholds determined at that meeting.  His point was that the responsibility for this threshold lay not at the feet of the RMTC, but the attendees at the meeting in Baltimore.  We know from the original version of the CTMS that no scientific basis could be produced for either the threshold of 10 pg/mL, nor the 48 h withdrawal.  But, as we go over the details which have leaked out of that clandestine meeting, we might be able to piece together what happened.

Xylazine is an ultra-short acting tranquilizer which has been used in horses since 1969.  At tranquilizer doses, it produces sedation which is profound, but very short lived, with a return to normal of the horse within 90 minutes.  The most common use of this tranquilizer is for short procedures which cause discomfort to the horse, such as dental procedures, clipping and trimming the mane and ears, and shoeing.  However, in relatively low doses, xylazine has muscle relaxing effects and is very effective to prevent muscle cramping or tying up, one of the most difficult conditions of horses to control, especially with the strict drug restrictions which accompany horse racing. 

A 48 hour withdrawal is an appropriate time frame for the withdrawal of a medication like xylazine.  It permits the use of this short acting tranquilizer for necessary procedures, and the prevention of muscle cramping.  With its effects wearing off within a few hours, 48 hours is not consistent with any possible effect on the horse at the time of the race.  It would seem, on the surface, that the RMTC actually got this one right:  a threshold with a 48 hour withdrawal.  Unfortunately, when thresholds are not based on legitimate science, the outcome of the regulation is anything but right.

At the Baltimore meeting, according to Dr. Arthur, an assemblage of veteran scientists and chemists settled on 10 pg/mL for a 48 h threshold for xylazine.  The xylazine scientific data which was presented to these researchers was a xylazine study in which samples were collected from research horses up to 2 hours after xylazine administration.  The threshold was apparently determined by the extrapolation of these 2 hour data out to 48 hours.  However, the details of the decision making process will forever remain under the clouds in Baltimore, because neither the RMTC nor the ARCI can produce minutes of the meeting.

What were the consequences of the arbitrary decision made on that winter’s day on the Inner Harbor?  There have been at least 21 xylazine infractions reported to ARCI between April 2013, when the ARCI first implemented the RMTC’s CTMS (including the ill-fated 10 pg/mL threshold for xylazine) and December 2015.  Horsemen have paid at least a combined $20,000 in fines, served a cumulative 330 days and owners have paid back $168,537 in purses.  The question remains, how can such a steep collection of penalties have been accumulated for a threshold apparently pulled out of thin air in Baltimore on that gray October day?  Or could it be that the threshold was not so arbitrary and capricious as it appears?  Perhaps there was more substantive evidence presented at the Baltimore meeting than we think.  Except that, since the meeting was neither an RMTC nor an ARCI meeting, no minutes were kept, no transparency, only the conflicting accounts of what was clearly a contentious meeting enshrouded in secrecy.

There are methods to determine the legitimacy of a threshold which can be used as independent double-checks on the primary science.  One such method is the Irrelevant Plasma Concentration (IPC), as proposed in 2002, by the internationally renowned Chemist, Dr. Pierre Toutain.  The IPC is defined as the “plasma…concentrations which guarantees the absence of any relevant drug effect and for which there [should] be no regulatory action.”  Using a simple calculation, the IPC can be calculated for xylazine using the very conservative time of 12 h (even though the effects wear off after 90 minutes), and it comes to 300 pg/mL…or 30 times the randomly chosen RMTC threshold of 10 pg/mL.  So, even in January of 2013, the tools to “check” the threshold were in existence and should have given the members of the RMTC and RCI pause before implementing a threshold and a penalty which has cost trainers and owners in the six figures.

The Washington State Racing Commission took such a pause when the first xylazine violation came up after the adoption of the CTMS in the Emerald State.  On July 29, 2014, a violation over seven times the threshold of 10 pg/mL was found, triggering an investigation by the WSRC.  The medical records reflected a conservative dose of xylazine (200 mg or 2 mL) was administered at 52 hours before post for the purpose of a routine dental procedure.  This violation created consternation among horsemen and regulators alike.  Could this violation be the result of a rogue horseman or is something else afoot in the regulation of horse racing?  This should be simple.  Go to the minutes of the Baltimore meeting and investigate the basis for the threshold.  After all, if the science is solid, it will hold up to transparency and scrutiny.  Except that the cursed October clouds refuse to give up the secrets of the meeting in Baltimore.

Only months after the first violation in Washington, the answer would start to become clear.  First, the regulators on the WSRC reviewed the Toutain IPC calculation and its recommendation of 300 pg/mL, as proposed by Dr. Tom Tobin.  Second, at the International Conference of Racing Analysts and Veterinarians (ICRAV) held in Mauritius in September of 2014, Dr. Glenys Noble of Charles Sturt University in Australia presented the first paper which actually investigated xylazine, not from a safety and effectiveness perspective like all the previously published studies, but from a regulator’s viewpoint.  She followed the elimination curve of xylazine out to 12 hours post administration, and had a startling finding, in light of the RMTC’s threshold:  In the first few hours, the elimination curve was fairly steep, with a slope which predicts a level below 10 pg/mL if extrapolated from 2 hours to 48 hours.  However, after the first few hours, the curve takes a turn, and the terminal elimination becomes flat, essentially remaining unchanged for hours.  When this flat slope of the curve is extrapolated, the new threshold for 48 hours is closer to 200 pg/mL.  The WSRC took heed and revised their threshold to 200 pg/mL. 

Several RMTC members were in attendance at that ICRAV meeting in Mauritius, and yet they returned home with no recommendation for a change to the American threshold of 10 pg/mL.  More than a year and at least 21 violations would pass before this issue would be brought up again.  At a meeting of the Racing Committee of the American Association of Equine Practitioners (AAEP) in December of 2015, the question of the xylazine threshold was brought up by the practitioners, and the RMTC members on the Committee simply referred back to the Baltimore meeting:  It was not an RMTC meeting, and therefore, the RMTC is not responsible.  A lot of responsibility falls on the unrecorded meeting.  For the record, despite their protestations to the contrary, the RMTC has had the xylazine threshold of 10 pg/mL listed on their website from April 2013 until February 2016.

In February of 2016, the RMTC held a meeting near Gulfstream Park, in which they recommended a change in the xylazine threshold from 10 pg/mL to 200 pg/mL.  The horsemen who had been robbed of six figures, accompanied by losses of reputation, business and many nights of slumber hailed the change and simultaneously cried foul.  How many of the CTMS thresholds are similarly in error?  How many other substances are horsemen using in appropriate ways for the health and welfare of their precious horses, and being inappropriately penalized?  The thresholds for xylazine, omeprazole and detomidine that were changed in the February 2016 meeting represent the 5^th, 6^th and 7^th thresholds changed since the original version of the CTMS was released in April of 2013.  How many more are wrong?  The RMTC response is that the CTMS is a “living document” crafted with the best available science and then modified when science changes.  News Flash:  there is no such thing as “best available science.”  We are not seeking a nebulous goal, like curing cancer.  A threshold is what it is.  There is either science available or there is none.  There is no “living document.”  There is only right and wrong.  The RMTC and RCI got this one wrong.

Racing commissions and Boards need to follow the lead of Washington State.  It is critical that Racing jurisdictions do their due diligence and review the details of the recommendations of the RMTC.  In a rush for uniform regulations, the details have been sloppy and do not hold up to the light of day.  Thresholds determined by a rough consensus are arbitrary and capricious, and science hidden by the clouds is not science only innuendo.  The fans of the sport deserve to know that the most appropriate science and medicine is being utilized to keep the stars of the sport happy and healthy and the best version of each horse is brought to paddock every raceday.  The horsemen deserve to know where the boundaries on the uses of therapeutic medication are drawn, without fear of inadvertent positive tests from which there is no protection.  Most importantly, the horses themselves deserve to receive state of the art medical care, without undue influence at the time of the actual race.

Tying Up in Racehorses: Navigating the complicated medication waters

Clara Fenger, DVM, PhD, DACVIM, Pete Sacopulos, Esq

The National Uniform Medication Program which now includes the Controlled Therapeutic Medication Schedule (CTMS) has ushered in a new and complicated era in our sport.  Typically, maintaining optimal health in horses, including race horses, follows reasonably predictable courses, with veterinarians starting their treatment plans in the usual black bag.  This bag consists of more than 26 therapeutic medications, but still a relatively small group of tried and true medications.  However, not all disease conditions follow the usual path in every patient, which has previously led the human physicians to think out of the box, looking to new concepts and ideas borrowed from the medical scientific literature to solve difficult clinical conundrums.  The process is no different between human physicians and equine veterinarians.  The current regulatory environment is turning this standard practice of the “healing art” upside down, making the solving of therapeutic and prophylactic dilemmas for the equine athlete more complicated than ever.

Clinical Signs of Tying Up

As horsemen, we know the signs.  A nervous filly was sent to the track, often the day after walking, but in some fillies it occurs every day.  She may have galloped well, and then started to get “stiff” walking back from the oval.  Back in the barn, she is short-strided with shallow rapid respirations, sweating, often in obvious distress.  Tying Up, technically, Recurrent Exertional Rhabdomyolysis (RER), in Thoroughbreds is exercise-associated muscle cramping which may range from mild “stiffness” to severe inability to move, muscle damage and kidney damage.  In rare cases, it can be fatal.  Typically, RER occurs after training and not after working/breezing or racing, and it affects nervous fillies more commonly than other groups of horses.  RER is considered to run in families, although the gene has not been identified.  It is passed from parent to offspring in an autosomal dominant manner:  this means that a horse carrying either a single or double copy of the gene is affected.

Legendary horsemen lore from many years ago assigned the cause of muscle cramping in racehorses to be the result of lactic acid buildup in the exercising muscles.  This was the basic premise for the common practice of adding baking soda or other buffering agents to feed or water in order to prevent this painful lactic acidosis.  While many horsemen swear by the effectiveness of bicarbonate for tying up, research has failed to show any difference in muscle enzymes, lactic acid or the incidence of RER events when horses are supplemented with bicarbonate.  More importantly, the regulation of bicarbonate administration in horses has made this practice obsolete with respect to actual racing events.

If RER is not caused by lactic acid buildup, then what is the underlying cause?  At the muscle cell level, RER may be associated with the abnormal movement of calcium within the cell. This seems to confer a performance advantage in Standardbreds, but not been proven in Thoroughbreds.  Pain seems to be the result of muscle contracting, but then not relaxing normally, resulting in painful muscle cramping.   Many of the preventative therapies for RER are considered to specifically treat the underlying defective calcium channel.   Dantrolene (Dantrium ®, AHP Pharmaceuticals, Rochester, MI), a blocker of the calcium pump, is very effective, used at doses of 2-4 mg/kg (900 – 1800 mg) in the morning before training.   A natural calcium ion channel blocker, Magnesium, is commonly used intravenously before training to prevent RER, and is effective at a dose of 10 g IV from 30 min to 6 hours before training.   Cobalt, a naturally occurring mineral which has recently been made illegal by the ARCI, is also a calcium channel blocker, and its efficacy in the prevention of RER has been suggested to be the source of its alleged performance impacting effect. 

Management of RER

There are a number of management practices which reduce the impact of RER in susceptible horses.  RER typically does not become evident in susceptible horses until they have been in training for at least three weeks.  At any point after this critical time period, susceptible horses can be identified by testing muscle enzymes (CK, AST) before exercise and again 4 hours after exercise.  Affected horses will have a marked increase in muscle enzymes, even in the absence of overt clinical signs.  This exercise challenge test is very useful in determining which horses in a training barn may require special management going forward.

Management includes exercise and dietary management.  Dietary management usually involves use of one of a number of high fat feeds on the market which have starch, also called non-structured carbohydrates (NSC), comprising less than 20% of Digestible Energy (DE), and at least 13% DE from fats.  Typically, these fats will be in the form of rice bran.  These diets have been demonstrated to reduce the incidence of RER, but the mechanism has not been worked out. While use of these high fat feeds can be helpful, in the case of race horses, when the diet is restricted to these special feeds, it may be difficult to ensure intake of sufficient calories to maintain appetite, weight and level of training.  The high fat content affects the palatability of the feed and many race horses simply back out of the feed tub. 

Exercise management is directed at limiting time off.  Most RER susceptible horses are easier to manage if they do not get days off walking.  Some horses can actually be trained out of a paddock, although whether this practice is advisable depends upon both the temperament of the horse and the availability of turn out at typical race horse stabling areas.  Unfortunately, in some RER horses, exercise and dietary management are insufficient to prevent RER and the associated painful muscle cramping.

Dietary Supplements

Tying up is such a frustrating, painful and debilitating disease in horses that many alternative therapies have been tried.  Just because bicarbonate administration is not useful, or practical in light of the regulation of its use, does not mean that other supplements may not provide a benefit.  Some forms of tying up may be caused by electrolyte or mineral imbalances or deficiencies.  A survey of the NAARV practitioners shows that selenium supplementation, by adding to the feed with or without supplemental injections, is recommended in most RER horses, because selenium deficiency is common in many regions.  Salt, balanced electrolytes, magnesium and chromium have all been recommended for horses that tie up.

Recent research has shown that the amino acid L-carnitine decreases serum muscle enzymes and incidence of tying up in Thoroughbreds.  Supplements such as FullBucket Medical Muscle, Animed Tie By, and Animed Muscle Up Max Recovery contain L-carnitine with other ingredients, and many other supplement companies produce pure L-carnitine supplements.  Doses of 5 g to 50 g daily are sufficient to increase blood levels in horses. 

Branched chain amino acids, Leucine, Isoleucine and valine, have been shown to reduce muscle damage during exercise in humans, although the type of muscle damage observed in humans is unlikely to be the same kind of damage as is seen in racehorses.  Several branched chain amino acid supplements are available for use in horses, although no studies have been done in horses.

Polyphenols, including bioflavonoids, quercetin and resveratrol, are potent natural anti-oxidants which may also benefit some RER horses.  Many bioflavonoids are available for equine supplementation with Vitamins C and K for bleeding (Hesperidin C and K), resveratrol (Resvantage Equine, Advantagen Biosciences, Newport Beach, CA), or non-specific polyphenols (Biovigor, Global Organics, Goodyear, AZ).  No research has been done on the specific polyphenols for prevention of muscle cramping in RER horses.

Medical Treatment

Nutritional management by feeding high fat feeds and various supplements is valuable in prevention of RER, but does not prevent every case of RER.  Additionally, many of the feed supplements lack adequate scientific research, leaving us questioning whether or not they are just modern day snake oil.  Further, as the regulatory thresholds for both bicarbonate and cobalt should prove to us, “natural remedy” hardly prevents regulators from pushing such substances out of reach for therapeutic uses in horses. 

Modern sports medicine has made great strides in medical treatments which can be employed to prevent RER.  Methocarbamol is a centrally acting muscle relaxer which is highly effective in the treatment of horses after an episode of RER, and is used commonly at a dose of 25 mg/kg for the prevention of daily events of RER.  Acepromazine, a tranquilizer and vasodilator, is commonly used as a daily treatment in the prevention of RER.  Some trainers have also used other tranquilizers, such as romifidine, xylazine or detomidine at very low doses for the same effect.  Prior to the ban on anabolic steroids, low therapeutic doses of testosterone were used in fillies to prevent severe episodes of RER, a therapy which is now out of reach.  The use of pharmaceutical intervention for the prevention of RER is becoming increasingly complicated, as a result of the recently introduced regulatory restrictions on the use of these products close to racing.

Anti-inflammatory medications including non-steroidals like phenylbutazone and banamine and corticosteroids like dexamethasone and the valuable anti-oxidant, DMSO, are commonly used to treat RER episodes, but can also be used to prevent such episodes.  Daily administration of such anti-inflammatory drugs cannot be recommended because they can interfere with the body’s normal adaptation to exercise, as well as masking the presence of other injuries.  However, many trainers and veterinarians have relied on these substances coming into a race for particularly recidivist cases of RER.  Because the doses used are relatively large, dantrolene and methocarbamol are associated with prolonged withdrawal times before racing, leading some trainers and veterinarians to use a complicated program for withdrawal, withdrawing methocarbamol well in advance of the CTMS, then relying on either unproven supplements, or other medications permissible on the CTMS.  While these prescriptions fall well within the withdrawal recommendations of the CTMS, it puts the trainer at risk for a positive test, as some of these very withdrawals have resulted in methocarbamol, xylazine, flunixin or bute overages.  Honest attempts to prevent a debilitating and painful condition in horses has now taken on overtones of medication abuse, when the fact is simple:  the rules intended to permit the therapeutic use of medications have failed to account for this cohort of horses with severe muscle cramping.

Regulatory Control of RER Drugs

The earnest effort on the part of horsemen and vets to manage the debilitating muscle condition which is RER with therapeutic medications and alternatives has resulted in an interesting and sobering history of drug positives. A review of the ARCI Coded Ruling Reports of two therapeutics, Xylazine and Dantrolene, utilized in the prevention and treatment of RER is illustrative.

Xylazine is an analgesic and sedative, often used in very low doses during training to permit an RER horse to train without an RER event. On the CTMS, there is no research to support the recommended withdrawal of 48 hours and threshold of 10 pg/mL.  Research presented at the International Conference of Racing Analysts and Veterinarians (ICRAV) in September 2014, over a year after the CTMS version 1.0 was initially published by the RCI, demonstrated that xylazine has a long, flat elimination curve, essentially persisting in the horse indefinitely at a very low level. 

Pursuant to the Uniform Classification Guidelines for Foreign Substances and Recommended Penalties, Xylazine is a Class 3 therapeutic medication. A positive drug test result for Xylazine carries a corresponding recommended category “B” penalty.  Despite the new research presented at ICRAV, the RMTC nor RCI made any adjustments in the threshold day suspension, and the recommended penalty for a first time overage, absent mitigating factors, is a 15 together with a$500.00 fine and redistribution of all purse money.

The erroneous science that accompanies the xylazine threshold is reflected by a review of the ARCI Coded Ruling Reports, which details dozens of positives from Arapahoe Park to Wyoming Downs. In most cases involving a positive drug test for Xylazine, the sanction closely follows the guidelines and recommended penalties. For example, in July of last year (2015) an Indiana trainer started a horse at Indiana Grand that finished second and tested positive for Xylazine.  The subject horse tested positive at 21 pg/ml, more than double the threshold of 10 pg/mL and the resulting penalty was $500.00 fine, 15 day suspension and redistribution of purse money. The penalties for Xylazine drug positives were largely consistent in Minnesota, North Dakota and other jurisdictions. In all, the ARCI Coded Ruling Report for Xylazine reflects nearly 50 cases of drug positives for this therapeutic medication for the period of 2005 to 2015 occurring at nearly 30 different tracks across the country.  The problems associated with this threshold have been recognized by one jurisdiction:  Washington has raised their threshold to 200 pg/mL.

In stark contrast to xylazine, an alternative therapeutic choice for the prevention of RER is Dantrolene. Dantrolene is a calcium channel blocking skeletal muscle relaxant that has been shown to prevent RER. In contrast to Xylazine, Dantrolene is a Class 4 therapeutic medication. Dantrolene, pursuant to the ARCI Uniform Classification Guidelines of Foreign Substances, carries a corresponding category “C” recommended penalty.  As such, a trainer who starts a horse that tests positive for Dantrolene, would be subject to a recommended penalty, absent mitigating circumstances, of a $500.00 monetary fine only for the first offense and a redistribution of all purse money. The CTMS lists a research paper by Knych as the basis for the threshold and withdrawal.  In this paper, the researchers use a dose below the recommended dose, and only eight horses are used in the investigation.  However, at least there is some basis for the threshold and withdrawal.

The fact that some research, however lacking, is the basis for the threshold is reflected in the number of positive tests.  The ARCI Coded Ruling Report for Dantrolene reflects fewer reported positive drug tests for Dantrolene. The penalties do follow and track the ARCI recommended penalties. The ARCI Coded Ruling Report does reflect multiple drug positives for Dantrolene at multiple tracks. An example of a drug positive for Dantrolene and corresponding penalty is seen in the case of a Dantrolene positive test result for a thoroughbred in 2014 at Golden Gate Field. The horse, Naturaliste, tested positive for Hydroxydantrolene, the major component of the drug Dantrolene. The trainer received a monetary fine of $1,000.00 and was required to surrender the purse money for redistribution.

Another skeletal muscle relaxant commonly used to prevent and treat RER is Methocarbamol, a centrally acting muscle relaxant with a CTMS recommended withdrawal time of 48 hours and a threshold of 1 ng/mL. The ARCI Uniform Classification Guidelines lists Methocarbamol as a Class 4 therapeutic medication with a corresponding category “C” recommended penalty.  The study which serves as the basis for the CTMS threshold shows, among other shortcomings, that one of six horses accumulates the drug when given orally, suggesting that repeated dosing, like the manner in which methocarbamol is typically used would exceed the threshold.  A review of the ARCI Coded Ruling Reports yields a whopping 325 positive reports from 2010 to the present.  Almost all of the positive tests in which a drug concentration is listed are below 20 ng/mL, an alternative level which has been suggested as a more appropriate threshold.  More interesting is the finding that where the science for the threshold is in question, such as for xylazine and methocarbamol, the number of positive tests are off the charts.

In addition to drugs, minerals such as selenium, magnesium and cobalt have been used to prevent RER.  Indiana was the first U.S. jurisdiction to regulate and implement a Cobalt rule. Indiana’s rule established a threshold of 25 ppb and was implemented by way of an emergency rule and that became effective in October of 2014 for in competition testing and January 1st of last year for out of competition testing. Initially, Indiana’s rule made a positive drug test for Cobalt a category “A” penalty. Such a penalty, absent mitigating circumstances, carries a one year suspension together with a $10,000.00 fine and a redistribution of purse money.

Indiana has since “relaxed” its rule regulating Cobalt providing for leniency for drug positive tests between 25 ppb and 50 ppb and re-categorizing Cobalt as a category “B” penalty. In April of last year the California Horse Racing Board voted 6-0 to regulate Cobalt. The California Horse Racing Board followed Indiana’s lead establishing a threshold level of 25 ppb in blood serum. Between 25-50 ppb the trainer is subject to a fine or warning for a first offense and if the concentration exceeds 50 ppb trainers face both a fine and suspension pursuant to an ARCI Guideline Penalty Class “B” violation. Likewise, the Minnesota Racing Commission and the Maryland Racing Commission, in 2015, began regulating Cobalt establishing a threshold of 25 ppb consistent with both the Indiana and California rules. The Minnesota Racing Commission in its RAHP Medication Related Racing Rules Violation, dated December 5, 2015, reported a Cobalt positive test occurred in July of last year involving a standardbred. While the science, to date, is clear that Cobalt has little, if any, performance enhancing effect, there are pending Cobalt positives in multiple jurisdictions. The outcome of these pending positives will likely be challenged on the basis of a lack of scientific evidence to support such regulation as well as the wildly inconsistent test results regarding Cobalt/Cobalt positives. 

One example of such inconsistencies is the results from different laboratories. Test results from various laboratories resulted in variations as high as 82% for testing of blood serum for Cobalt and 23% in urine samples. What is clear is that regulation of Cobalt will continue and likely become more universal.

The Tying Up Solution

With the ever-tightening restrictions on the pre-race use of both medications and naturally occurring substances for the prevention of RER in racehorses, horsemen must choose their preventative protocols carefully.   Many racehorses back out of the feed tub when the grains are decreased and the fat is increased, but to the extent possible, a high fat feeding program should be used.  Bicarbonate and cobalt have clearly been placed out of reach for use against RER, but other supplements may be of benefit. The consensus among Track Vets across the country is that regular supplementation with Vitamin E and selenium is important for these horses.  In this survey of racetrack practitioners, both the vitamin supplement, AzoturX ® (Finishline Products) and the polyphenol supplement BioVigor ® (Global Organics, Goodyear, AZ) emerged as the top choices for nutritional supplements used close to racing to prevent tying up.   With no scientific studies to guide us, if one natural substance doesn’t work for a particular horse, there is no shortage of others to try. 

   

Among the science based medications, some are better choices than others because of the risk of positive tests.  The published withdrawal for methocarbamol is 48 hours, but if used orally and repeatedly, as is standard practice, the drug may not drop below the threshold for more than a week.  Methocarbamol positives across the country have resulted from its use, which has rendered this very effective preventative unusable.  It is imperative to know the rules in your jurisdiction.  If you are racing in a jurisdiction which penalizes a methocarbamol overage with fines, suspensions, points and redistribution of purse, then you simply cannot use a moderate daily dose to prevent tying up.  Acepromazine at a low dose, IV only, can be safely used up to 7 days from racing, but oral administration and especially repeated oral administration may significantly prolong the withdrawal time.  A low dose of Dexamethasone up to 72 hours seems like overkill for such a purpose, but, unfortunately, or perhaps fortunately, the current regulatory environment permits this.  DMSO at 48 hours likely has little impact on the race itself, but can certainly prevent tying up during training the day before the race.  Your veterinarian should be able to provide guidance about the risk and benefit associated with each medication option in your jurisdiction.

In human sports, the regulation of medications provides for Therapeutic Use Exemptions [TUEs], and in this way, human athletes can benefit from modern medicine, while still competing on a fair and level playing field.  It is unconscionable to deprive the athlete of appropriate treatment laid out by his personal physician, and horses are no different.  When the Food, Drug and Cosmetic Act of 1938 was passed, it underwent several years of debate in the legislature, with the primary conflict about striking a balance between the regulation of food and drugs without interference with or regulation of “the healing art”.  Through amendments to the FDCA in 1951 and 1972, the medical practitioner was specifically protected from regulation, because the medical practitioner alone carries the responsibility that such substances would be properly used.  These principles have been abandoned in the oversight of horse racing in recent years, and the pendulum needs to swing back for the health and welfare of the equine athlete.

Suggested Reading:

http://cvm.msu.edu/research/faculty-research/valberg-laboratory/recurrent-exertional-rhabdomyolysis

Thyroid Hormone Supplementation: Performance enabling or enhancing?

Supplementation with thyroxine (thyroid hormone) is commonplace among racehorse trainers, and recently this practice has been accompanied by a swirl of confusion.  Like so many other typical racetrack practices, the supplementation with thyroxine has been demonized in some corners, from being used to “cover up” cobalt abuse to being responsible for sudden deaths on the track.  Like so many other typical racetrack practices, thyroxine supplementation is defended by its proponents as making the horses “feel better and do better,” with no real explanation of how it might work. 

So, let’s start this discussion by reviewing what thyroxine actually does.  Thyroxine is normally produced in the thyroid gland, a paired gland on either side of the neck, just behind the head.  Thyroxine affects every cell in an animal’s body, affecting everything from normal growth to normal muscle development in response to exercise.  You can consider that thyroxine is the hormone that permits everything else in the body to function properly.  The basic metabolic rate, including heart rate and temperature are determined by thyroxine.  In fact, veterinarians recommend that horses which suffer from metabolic syndrome, a disease not dissimilar to type 2 diabetes in humans, be supplemented with thyroxine to increase their metabolism for the purpose of weight loss, which requires a dose 3 – 6 times the typical amount supplemented to the average racehorse.  Remarkably, these horses don’t seem to have a higher than average risk of sudden death and unquestionably have had no out of the ordinary exposure to cobalt, despite this large dose of thyroxine.  Most have minimal, transient signs or no signs at all of thyrotoxicosis (dangerously high levels of thyroxine in the blood).

                                                                                                             

What are the signs of thyrotoxicosis in horses?  There are no published reports…actually there are only a few published reports about thyroid hormone in horses at all.  This leaves us with a large hole in the scientific literature to assess whether our horses need extra thyroxine at all.  Thyrotoxicosis in other species is associated with increased heart rates, increased body temperatures, weight loss and diarrhea.  In fact, most veterinarians will tell you that nervousness and diarrhea accompany excessive thyroxine use, and can be seen occasionally in the first few days after starting the very high dose used in metabolic disease (Type 2 Diabetes-like) horses with high doses of thyroxine.  In humans, extremely high levels of thyroxine, such as those seen with thyroid gland tumors, are associated with cardiac arrhythmias and death, which is clearly the far-reaching source of the supposition made by racing officials when they posited a correlation between extra thyroxine and racetrack deaths.  Based on the fact that many racehorses are supplemented with thyroxine, and the spikes of sudden death were only observed in one jurisdiction, suggestions that there is a relationship between thyroxine supplementation and sudden death is irresponsible at best.

So, the next question is, why do so many trainers supplement racehorses with thyroxine, and is it a legitimate practice?  In actuality, while the scientific literature is sparse on the subject in horses, the only studies that exist clearly demonstrate that racehorses tend to be low in thyroxine^1,2.  These old studies are likely the original source of the idea.  Luckily, there is a lot of good scientific evidence in other species.  Like the Thoroughbred racehorses in those two early studies, humans undergoing intense exercise can experience a low thyroxine³, which significantly impairs the individual’s ability to perform⁴.  Additionally, there is a lot of good scientific evidence in people⁵ and some limited data in horses⁶ that low thyroxine is associated with rhabdomyolysis (tying up).

Are there other causes besides intensive exercise that can cause low thyroxine in a race horse?  The test for thyroxine in horses measures both active (free) and inactive (protein bound) forms of thyroxine, and many exogenously administered substances, including estrogens and antibiotics can displace thyroxine from its protein binding sites, causing a falsely low thyroxine reading, without actually affecting the thyroid function in the horse.  Other exogenously administered substances can actually drop both the active and inactive forms of thyroxine in the blood.  For example, 5 days in a row of bute causes a profound drop in both forms of thyroxine⁷, which lasts 2 days for the active form and 10 days for the inactive form. 

Cobalt chloride also interferes with normal thyroid function.  While a critical and necessary mineral in trace amounts, cobalt has been used in higher than normal quantities for a variety of reasons in horses.  At levels exceeding daily requirements, especially many orders of magnitude above required amounts, cobalt activates and upregulates over 300 genes, of which a number might influence performance.  At modest amounts cobalt has been administered to racehorses to counteract low red blood cell counts, although there is no evidence that it works for this purpose, and has been used as a preventative for rhabdomyolysis⁸.  Very high persistent levels of cobalt in the blood interfere with the iodine uptake by the thyroid gland resulting in hypothyroidism, which is clearly the source of the rumored association between the two.  However, in addition to dropping the thyroxine level, injudicious use of cobalt causes heart and liver damage⁹.  Simple thyroxine supplementation does not counteract these adverse effects.  Additionally, the implementation of regulations limiting cobalt levels renders the exogenous administration of cobalt obsolete.

The veterinary community has not invested a lot of research on thyroxine in racehorses, but clearly the scientific data that do exist support limited use of this therapeutic substance in racehorses.  At the dosages typically used in racehorses, toxicity is unlikely, but the best method to determine if your horse needs supplementation is to have a baseline thyroxine test, and only supplement if your horse actually has a low thyroxine.  The best method to determine a reproducible level of thyroxine is to have the blood test drawn in the morning before training, when the horse has not received other medications within 10 days.

Conclusions?  The use of thyroxine supplementation is clearly an appropriate therapeutic treatment for horses, but it is critical to test for a low blood thyroid before starting on therapy, rather than indiscriminately treating all horses.  Has overuse of thyroxine been responsible for sudden deaths among racehorses?  Highly unlikely.  Is it good to investigate all possible variables when there is an unexpected number of deaths or other incidents involving animals?  Absolutely.  Is it irresponsible to suggest a cause without solid scientific evidence?  Yes.  Both regulators and horsemen are under pressure to have an answer whenever injuries or deaths occur, but kneejerk responses without science to back it up doesn’t get us any closer to solving the problems in our industry.  At the same time, it is critically important that we understand every therapy we institute in our athletes and apply each of them appropriately.

1.       1.      Bayly W, Andrea R, Smith B, Stensislie J, Bergsma G. Thyroid hormone concentrations in racing Thoroughbreds. Pferdeheilkunde; 12, 1996, pg 534-538.2.     Blackmore DJ, Greenwood RES, Johnson C. Observations on thyroid hormones in the blood of Thoroughbreds. Res Vet Sci; 25, 1978, pg 294-297.
3.     Pakarinen A, Häkkinen K, Alen M.  Serum thyroid hormones, thyrotropin and thyroxine binding globulin in elite athletes during very intense strength training of one week.  J Sports Med Phys Fitness. 1991 Jun;31(2):142-6.
4.     Werneck FZ1, Coelho EF, de Lima JR, Laterza MC, Barral MM, Teixeira PD, Vaisman M. Pulmonary Oxygen Uptake Kinetics During Exercise in Subclinical Hypothyroidism.  Thyroid. 2014 Mar 21. [Epub ahead of print]
5.     Lochmüller H, Reimers CD, Fischer P, Heuss D, Müller-Höcker J, Pongratz DE.  Exercise-induced myalgia in hypothyroidism.  Clin Investig. 1993 Dec;71(12):999-1001.
6.     Harris P, Marlin D, Gray J.  Equine thyroid function tests: a preliminary investigation.  Br Vet J. 1992 Jan-Feb;148(1), pg 71-80.
7.     Ramirez S, Wolfsheimer KJ, Moore RM, Mora F, Bueno AC, Mirza T. Duration of Effects of Phenylbutazone on Serum Total Thyroxine and Free Thyroxine Concentrations in Horses. J Vet Int Med 1997 11: 371–374.
8.     Fenger CK, Sacapolus, P.  2015.  What is Cobalt?  Horseman’s Journal Winter 2015.
9.     Ebert B, Jelkmann W. Intolerability of cobalt salt as erythropoietic agent. Drug Test Anal 2014 Mar;6(3):185-9.

Trace Environmental Substances Showing up as Post-Race “Positives” : What every horseman needs to know about being wrongly accused.

by Clara Fenger, DVM, PhD, DACVIM; Steven Barker, PhD; Keith Soring, DVM; Lee Shalgos, Esq.; Thomas Tobin, MRCVS, PhD, DABT.

The unveiling of the National Uniform Medication Program (NUMP) has come about with much fanfare and publicity; many states, such as the Mid-Atlantic States, signed on quickly while others have been more reticent to come on board.  The scientific basis for the thresholds which are supposed to permit appropriate use of the somewhat restricted list [27] of therapeutic medications while preventing unnecessary and excessive overmedication have hardly been forthcoming, and many hold-out states recognize these problems.  Despite the hurdles which NUMP faces from states unwilling to adopt such restrictive plans and from the internal deficiencies with the “Uniform Program”, such as insufficient scientific evidence, the over-regulation of therapeutic medications is not the only drug related obstacle which racing must face.

Substances used by humans, such as caffeine, cocaine and methamphetamine, commonly prescribed medications  for humans, such as tramadol and anti-anxiety drugs, and even over the counter medications like Aleve and ibuprofen have all come up as trace level “positives” in post-race samples in horse racing.  The biggest question surrounding these “positives” is:  Are these inadvertent environmental exposure, which horses picked up from eating contaminated hay, perhaps the result of a groom relieving himself innocently in a stall, or are they evidence of nefarious activity, forensic evidence of an attempt to steal a horse race?

In the early 1990’s, as the use of crack cocaine rose to a crescendo in the human population, there was a simultaneous rise in the general exposure of the population to trace levels of cocaine.  In fact, there are estimates that 90% of the paper currency in circulation is contaminated with measurable levels of the illegal substance.  People have even been wrongly accused of drug charges as a result of drug sniffing dog detection when they were only guilty of carrying large amounts of paper currency.  Our paper currency is so contaminated with drug residues that a confirmatory level of the major urinary cocaine metabolite, benzoylecgonine (BZE) at 100 ng/mL in urine is considered by the federal government to be a “negative” in that it is a forensically insignificant test.  Not everyone who handles money will test approaching this level:  this is one of the key points of environmental contamination related “positives”:  they strike randomly, and a number of important factors must align, including exposure to a source, individual metabolism and timing of the sample collection.   

The need for regulatory “cut-offs” for a number of environmental substances has been recognized by a number of states, which have put such cut-offs in place.  For example, in Ohio, there is a level for BZE (150 ng/mL in urine) and morphine (50 ng/mL in urine), the BZE “cut-off” being similar to the earlier  thresholds adopted by the federal government for BZE  as environmental contamination, as detailed in the 2012 National HBPA book on World Rules for Equine Drug Testing and Therapeutic Medication Regulation.

The potential for environmental residues of therapeutic substances to give rise to equine “positives” has been demonstrated repeatedly in the scientific literature.  When naproxen (Aleve ®) was administered to horses for 10 days, they continued to show measureable urine levels for over 45 days.  These researchers interpreted this prolonged elimination time  as being  due to stall contamination  with the medication and, consistent with this interpretation, when a horse which received no naproxen was placed in the stall of a naproxen treated horse, this horse  subsequently showed “positive” for urinary levels of naproxen for three days.  This occurred despite the fact that the stall and manger of the stall had been “thoroughly” cleaned.  Similar findings have been reported with flunixin (Banamine ®).  When untreated horses were placed in stalls of horses which had been treated with flunixin for 14 days, the untreated horses tested positive for 2 of the following 14 days.  Similar to what has been identified with BZE in humans, the appearance of an environmental contamination positive can clearly be associated with exposure to environmental residues.  In another study, isoxsuprine could be identified from the floor, walls manger, and even the cobwebs in the rafters of a stall of a horse which had received a therapeutic regimen of the substance, which was then discontinued for three weeks pre-race. A number of other studies have found similar results for a variety of drugs.

Key Factors Influencing a “Positive” from an environmental exposure

What are the key reasons that some substances can remain in the environment and therefore pose a risk for inadvertent environmental exposure to the competitive equine athlete?  There are three key criteria which must be met in order for a substance to represent a high risk.  The first criterion is that the substance, like isoxsuprine, must be chemically stable in the environment.  Once it is introduced into a stall it remains there, and hangs around waiting throughout the stall, including apparently in the cobwebs.  For an environmental contaminant be a significant problem, it first needs to be chemically stable and therefore persist in the environment.

The second point is that the contaminant must be easily absorbed, which usually means orally absorbed.  For an environmental substance to give rise to drug testing problems, it must be able to get into the horse from the environment.  Oral absorption is likely route number one, and we know that isoxsuprine is well absorbed orally.  This is more problematic than the aforementioned incidental exposure of humans to cocaine tainted currency:  horses, especially intact males, are well known to seek out urine in stalls, smelling and tasting the waste from any previous occupants to identify who may have been in that stall before them.  This is an animal behavior unparalleled by humans.

Next comes a very interesting point; although isoxsuprine is well absorbed orally, effective blood levels of isoxsuprine after oral administration are difficult to achieve.  Orally absorbed Isoxsuprine is so rapidly and effectively metabolized/glucuronidated on its first pass through the liver that it fails to rise to effective plasma concentrations after oral administration.  Orally absorbed isoxsuprine is essentially immediately glucuronidated, or changed into an inactive metabolite, while passing through the liver, and it is then shipped as the metabolite to the kidney for excretion.  This feature of isoxsuprine yields the highest known concentrations of any equine drug metabolite, peaking at 700,000 ng/mL.; given that about a 700 mg IV dose of isoxsuprine produced this urinary level of isoxsuprine in urine, a 1 mg dose could produce a 700ng/ml urinary concentration, readily explaining the ability of minute amounts of environmental isoxsuprine to produce low nanogram/ml urinary isoxsuprine glucuronide “positives” . 

To summarize, isoxsuprine is chemically stable in the environment, it is well absorbed orally and is, for all practical purposes, immediately converted into its glucuronide metabolite and excreted at very high concentrations in equine urine.  Take home message:  very small environmental traces of isoxsuprine passed in the urine of one horse, and lingering in its stall will result in sufficient isoxsuprine glucuronide in the urine to trigger a “positive” call for isoxsuprine in any untreated horse which subsequently inhabits the stall.

So the rules for a problem environmental substance are:  (1) it must be chemically stable in the environment; (2) it should be well absorbed orally; (3) it should be excreted in relatively high concentrations in the urine.  Any substance with these chemical/biological characteristics has the potential to be an environmental substance “positive” problem in equine drug testing, as we will see.

Tramadol

Substances  that become widely used in humans for foodstuff [caffeine] recreational [cocaine methamphetamine] or medical use [Ritalin], or as prescription pain medications, such as Tramadol, may well spill over into the equine world as trace environmental substances and  show up, usually at trace levels,  in racehorses.   In contrast to its therapeutic effectiveness as a painkiller in both humans and small animals, Tramadol in the horse has failed to show any significant analgesic effects in horses at similar doses.  At very high doses, exceeding 10 times the effective dose in humans, by weight, Tramadol can induce analgesic effects that may last for less than three hours.  This lack of efficacy in equines appears to stem from the rapid inactivation of the active primary metabolite, 4OH-tramadol, by glucuronidation, a unique feature in this species.  Nonetheless, this inactivated metabolite is detectable in the horse’s system for a long time after the last administration.

Tramadol is clearly stable in the environment; one environmental study looked into the fate and potential impacts of Tramadol after its introduction into water.  It was found that neither tramadol, nor its derivatives formed from exposure to light were significantly biodegradable according to standard test guidelines.  They simply remain in the water forever.  In Europe, Tramadol was #3 on the list of pharmaceuticals found in wastewater, ranked by median concentration, with the highest wastewater concentration reported being 1166 ng/L or 1.166 ng/ml.  Similar to flunixin and isoxsuprine, tramadol is highly persistent in the environment, and could readily serve as a substance of incidental environmental exposure in the horse.

On July 11th 2013 at Hoosier Park Indiana the Harness horse “Justice Jet” yielded a positive for “Tramadol”.  We assume that the actual chemical nature of the analyte was O-desmethyltramadol and the concentration identified was not available to us at the time of writing.  At the time of the identification Tramadol was classified by ARCI as a Class 2, Penalty Class A substance.  However, the trainer involved was apparently highly regarded, with a reportedly 30 year unblemished medication violation record.  Additionally, the trainer was unaware of any risk factors such as individuals prescribed Tramadol in the environment of or close to the horse in question.  Given the circumstances of this case and the apparently complete innocence of the trainer, a review of the ARCI penalty classification for Tramadol was requested by the Indiana Racing Authorities.  While Tramadol is still listed as an ARCI Class 2, penalty class A substance, the Indiana authorities chose to penalize the trainer involved with a relatively “modest” 15 day penalty and a $500.00 fine, a much less severe penalty than the in place ARCI penalty guidelines would have suggested.  It would also be fair to say that in absence of an identified prescription for Tramadol in the racing environment of the horse, this case becomes a simple generic environmental exposure case, with no specifically identified source for the detected Tramadol.  

In a December 4th 2013 case before the New Zealand Judicial Control Authority for Racing, human use of Tramadol was considered to account for “exposure” of a horse to Tramadol, i.e., a reported identification in a Standardbred racehorse.  The trainer/ person responsible for the horse had been prescribed Tramadol by her doctor for back pain, and the Tramadol metabolite O-desmethyltramadol was found in a post-race sample taken from the horse.  Under the New Zealand Rules of Harness Racing, the presence of Tramadol or its metabolites is prohibited. The person responsible admitted to taking 50 mg Tramadol capsules on race nights, and the most likely cause of exposure to the horse was considered to be through contamination of her hands after taking the medication and bridling the horse.  The concentration of tramadol identified in the sample was extremely low, 100 pg/mL (0.1 ng/ml), much lower than the LOD (limit of detection) in the recently published Knych et al. (2013) report.   It is also noted that this very low Tramadol concentration was not identified in the primary New Zealand testing laboratory, but was only identified upon additional and apparently Tramadol-unrelated high sensitivity retesting of the sample by the Hong Kong Jockey Club laboratory.  The trainer in question was fined $3,300 and to our knowledge was not suspended.

In this matter the New Zealand judicial authority appears to have accepted the likelihood of inadvertent exposure of the horse to very small and pharmacologically insignificant amounts of Tramadol associated with Tramadol being prescribed for medical purposes to the trainer in question. 

Similarly, in one California Tramadol positive in a racehorse, the trainer was prescribed Tramadol for chronic back pain associated with a training accident.  This trainer’s horse had tested “clean” only ten days earlier, which underscores the random nature of the environmental positive.

Cathinone

Cathinone, a component of the synthetic amphetamine “bath salts,” has been identified in trace amounts in racehorses in Iowa.  Bath salts hit the streets in the US in 2009 as a drug of human abuse, reaching epidemic proportions by 2011 and started to show up in racehorses in Iowa in 2011.  Further complicating the interpretation of the test, cathinone can be found in urine in some testing systems after the administration of the common antihistamine, Pyrilamine (TriHist®, Anihist®), ephedrine (Sudafed®), or propanolamine.  The AniAaaaAAThe first racehorse positive was in 2011 at a level of 3 ng/mL  in urine, too low to reflect any pharmacologic effect on the animal, and consistent with other drugs of human abuse:  environmental exposure at low levels.  The trainer was summarily suspended and even handcuffed and removed from the grounds in a squad car.  Shortly thereafter, other positive tests for cathinone started to trickle in, and over the course of 70 days, there were 16 trainers involved, encompassing 51% of the barns and 5 different veterinary practices.  The sheer number of “positives”, and the low level of the drug in the animals suggested that  it was likely that this was an environmental exposure (Kind et al., 2012).

A survey was conducted to identify any commonality among the positive identifications of cathinone, and none could be identified.  Hay and several species of broad leaf plants from local farms were analyzed without success and the source of the contamination could not be identified.   Human drug testing was inconclusive as well.   However, based on the levels found in the positive tests, an environmental contamination “cut-off” was determined to be 10 ng/mL, which was adopted by the Iowa Racing Commission as a new regulatory threshold. 

The cathinone positives have slowed down in Iowa after this initial spike, but regulators remain convinced that these positives resulted from some exposure in the environment, possibly of plant origin, although simple contamination from human recreational use cannot be ruled out. 

Methamphetamine

            Another emerging substance of inadvertent environmental exposure in horses is methamphetamine.  Like many of the other substances of concern, methamphetamine has become a widespread drug of human abuse.  A recent case involving a cluster of trace concentration methamphetamine positives in Canada provides a classic example.  These events started when a Michigan trainer purchased a large used horse trailer shortly before shipping her Quarter horses to Toronto to race at Ajax downs. The three horses that shipped in this trailer raced within two days of shipping, and all three tested positive for picogram urinary concentrations of methamphetamine, while another horse, which shipped in a different trailer, also raced but tested negative.  This circumstance presents a classic "cluster" of very low, picogram concentration methamphetamine positives, two occurring on day one and one the second day post shipping, with a horse not shipped in the suspect trailer testing negative.

The Ontario investigators interviewed the trainer and as part of their review tested a number of samples from the trainer's equipment, including a sample from the manger area of the trailer.  This trailer sample turned up “positive” for methamphetamine at 22 ng/milligram, providing a clear-cut environmental source for the methamphetamine identified in the horses shipped in this trailer. The most likely interpretation of these events is that this trailer, at some time in its previous life, had housed an illicit methamphetamine laboratory, and that traces of methamphetamine remained in the newly purchased trailer and transferred to the horses during shipping to Toronto. Similar environmental related methamphetamine contamination of humans working in or around methamphetamine synthesis facilities are well understood.  What is interesting, however, is that this is the first clear-cut link between an environmental source of methamphetamine and a classic "cluster" of low concentration environmentally driven equine methamphetamine identifications.

As with isoxsuprine, we can also estimate the dose of methamphetamine required to give rise to these reported identifications.  Work by Ohio State University researchers performed in the early 1970s shows that administration of a 150 mg dose of methamphetamine (a comparable dose to the effective dose in people) to a horse will yield a peak urinary methamphetamine concentration in the region of 7,000 ng per ml.  Simple arithmetic shows that 1 µg of methamphetamine, or 1/150,000^th of the effective dose investigated by the researchers in Ohio, is all that is required to yield urinary concentration of 47 pg per ML, a concentration very close to the lowest urinary methamphetamine concentration reported in this Toronto cluster, which was 56 pg per ML, or parts per trillion in urine.  Methamphetamine adheres to thhe three key factors of an inadvertent environmental exposure:  (1) it is a chemically stable substance that is (2) orally absorbed from the environment of a horse and (3) can appear in urine at extremely low concentrations, but such findings are indicative of nothing more than totally minuscule exposure of the animal to the substance in question.  Further, the pervasiveness with which methamphetamine is used as a substance of human abuse greatly increases the likelihood that it will overlap with an unsuspecting population of horses.

Other Drugs of Human and Animal Use

There has also been a recent flurry of low-level “positives” for O-desmethylvenlafaxine, the major metabolite of venlafaxine, better known as the anti-depressant Effexor, in Canada, the USA and recently in India.  As with Tramadol, routes of human contamination of the horses are thought to be the same. In a small study conducted by Canadian authorities, a horse was dosed with venlafaxine and an aliquot of the horse urine used apparently “poured” on hay and the hay placed in a “clean” stable and housing a “clean” horse, rapidly leading to the “clean” horse becoming positive for O-desmethylvenlafaxine.  Indeed, low levels of this metabolite have also been found in supplements. This is similar to the sildenafil or Viagra positives seen several years ago, where a supplement source for the drug was identified in products produced by a compounding pharmacy.

Across the US and Canada there has also been a number of very low level levamisole positives. Levamisole, an “old time” wormer approved by the FDA for use in cattle and commonly used off label for horses was originally categorized as an Association of Racing Commissioners International, ARCI  Class 4 substance, but has been reclassified as a 2 with an A penalty.  It has experienced a resurgence in usage in horses in recent as a result of its immune stimulating properties, and has been widely recommended by researchers in the field of Equine Protozoal Myeloencephalitis.  Additionally, levamisole is very environmentally stable, is routinely used in food animals and can be found in fertilizers made from their excrement.  Experiments are currently underway to determine how much of this compound is taken up into food products such as corn and whether or not this is a potential source for some levamisole positives.  Nonetheless, levamisole can be found in runoff from organic fertilizer treated fields.

The list of such instances could continue and many more cases for low level positives in racing could be cited. This is, in many cases, the result of our ever increasing ability to detect pharmacologically insignificant amounts of drugs commonly used by humans and other animals in equine samples. More and more of the positives being called approach the low picogram (1,000^th of a nanogram)/ml level and are being treated by many Commissions as if they were pharmacologically effective levels normally seen immediately following administration. There is, in such cases, no distinction being made between “trace” and perhaps even “ultra-trace” levels arising from environmental sources and what a true attempt to influence performance actually requires. “Zero Tolerance” or no tolerance for the finding of a substance, regardless of the level, has once again reared its ugly head but is now armed with more sensitive equipment than ever before.

As more therapeutic medications are prescribed to humans and used in food animals, as more enter the environment of the horse by a variety of mechanisms, as more medications and recreational substances  go into our wastewater, our foods, feeds, supplements and even the air, we will eventually reach a point where the sensitivity of our testing and the pervasiveness of these drugs will cause ever greater numbers of positives for the racing industry.  If we fail to address these facts the consequences are an ever increasing suspicion of corruption in racing, from the calling of drug “positives” at irrelevant levels which inevitably erode confidence in the integrity of the industry.  The attempts by several of the controlling associations to subsequently regulate common therapeutics by placing thresholds on useful veterinary products at the same level as may occur from contamination will only add to this problem. It is possible that their attempts will only result in the opposite of what they desired.

Conclusions:

For reasons that are unclear the RMTC is uninterested in setting thresholds/cut-offs for inadvertent environmental exposure, despite the obvious need and at times specific requests for such guidance by regulators and horsemen’s organizations.   It is incumbent upon the regulators that police racing to distinguish between unavoidable trace level environmental exposure with no effect on the animal or the competitive event and no intentional malfeasance.  Innocent and unavoidable environmental sources should be considered in every instance in which low levels of substances are identified in post-race samples.  Identification of trace levels of substances of human abuse should be carefully investigated, and policies should be enacted to prevent the improper penalization of innocent horsemen.  In fact, in New York, the Court of Appeals has ruled that testing laboratories for humans could be held liable for calling positives on drug levels consistent with environmental contamination.

Guidance for Horsemen:

The primary source of environmental contamination positives in racehorses is exposure to humans who have handled or are taking prescription medications or illegal substances.  The best defense is careful oversight of your shed row.  If any grooms are suspected of illegal drug use, drug testing, with hair testing is by far the best option followed, where necessary, by removal from the care of the horses is the best option.  Any grooms taking prescription medications should be warned to wash their hands thoroughly between taking their medications and handling horses.   Tongue ties are of particular importance.  Use only new tongue ties on race-day, and do not allow grooms to carry them in their pockets, where they may be commingled with prescription pill fragments.   Carefully admonish grooms and riders NOT to urinate in the horse’s stalls.  Even over the counter pain medication, like Aleve® have been implicated in positive tests as a result of careless urination by a groom in a horse’s stall.

Horsemen and veterinarians should be cognizant of the source of their medications and supplements.  Positives may result from the use of supplements and compounded materials prepared and sold by less reputable compounding pharmacies, containing unidentified drugs.  Often, claims that sound too good to be true are exactly that. 

As the medication rules become more onerous, horsemen must be ever more proactive in controlling the environment of their charges.  Even when we have controlled everything in our shed rows, there will still be inadvertent environmental contamination positives, because we cannot control the ship-in barn.  Horses live in barns and not maximum security facilities.  We can only hope that the regulatory pendulum swings back towards reason, and our regulators can determine a way to avoid unfair penalizing of innocent horsemen, much like the justice system ultimately did the right thing by the unfairly convicted parolees of the 1990’s.

Suggested additional reading:

http://www.pewtrusts.org/en/research-and-analysis/blogs/stateline/2013/10/17/should-drug-testing-labs-be-liable-for-faulty-results

http://www.drugabuse.gov/publications/drugfacts/synthetic-cathinones-bath-salts

Kind AJ, Soring K, JD, Brewer K , Eisenberg, R., Hughes CG, Hartmann-Fishbach, P and Tobin T (2012) Cathinone and Related "Bath Salt" Substances - Detection in Equine Urine and Potential Sources, In press, The 19th International Conference of Racing Analysts and Veterinarians, University of Pennsylvania, Philadelphia, Pennsylvania, September 2012.

http://www.scientificamerican.com/article/cocaine-contaminates-majority-of-american-currency/

Wennerlund I, Ingvest-Larson C, Kallings P, Fredrickson E, Bondesson U.  2000.  Pharmacokinectics and urinary excretion of naproxen after repeated oral administration in the horse.  In RB Williams, E Houghton, JF Wade (Eds) Proceedings of the 13^th Annual Conference of Racing Analysts and Veterinarians (pp. 195-200).  Cambridge, UK.

Norgren A, Ingvest-Larson C, Kallings P, Fredrickson E, Bondesson U.  2000.  Contamination and urinary excretion of flunixin after repeated administration in the horse.  .  In RB Williams, E Houghton, JF Wade (Eds) Proceedings of the 13^th Annual Conference of Racing Analysts and Veterinarians (pp. 377-380).  Cambridge, UK.

Russell CS, Maynard S.  2000.  Environmental contamination with isoxsuprine.  In RB Williams, E Houghton, JF Wade (Eds) Proceedings of the 13^th Annual Conference of Racing Analysts and Veterinarians (pp. 377-380).  Cambridge, UK.

Knych HK, Corado CR, McKemie DS, et al. 2013. Pharmacokinetics and pharmacodynamics of tramadol in horses following oral administration. J Vet Pharmacol Ther 2013;36:389-398.

Loos R, Carvalho R, Antonio DC, et al. 2013. EU-wide monitoring survey on emerging polar organic contaminants in wastewater treatment plant effluents. Water Res 47:6475-6487.