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.