Saturday, September 20, 2014

Wandering Withdrawal-Times and the Racing Medication and Testing Consortium Model Rules: Time for the RMTC to get days

Clara Fenger, DVM, PhD, DACVIM; Andy Roberts, DVM; Jim Casey, DVM, MS

The ARCI Controlled Therapeutic Medication Rules have gone into effect in a number of new states, coming on line rapidly in the last few months.  The regulatory authorities have promised that providing a stringent and well defined set of uniform medication rules would make racing cleaner and safer for all participants.  Gone would be the days of supposed rampant cheating and we could all compete on a level playing field.  In fact, we have known for some time that operating outside the lines of legal and ethical competition in horse racing is extremely rare…representing only 0.015%  of horses passing through the test barn (1).  Clearly, the playing field has been quite level and well regulated for some time.  Nonetheless, it is human nature to suspect “that guy (or gal)” who is winning at a 40% clip must be using something, so we ought to all welcome the ever increasing oversight by our regulatory bodies.  Besides, even the horsemen agree that uniform rules would make racing across state lines easier.

Enter RMTC.  In an effort to produce National uniform medication rules, the RMTC has come up with a plan.  First, limit the number of medications that can be used therapeutically in race horses, and regulate them.  Have uniform National thresholds based on scientific studies which provide valid and realistic withdrawal time guidelines for trainers and veterinarians.  The Executive Director of the RMTC has suggested that adopting these rules actually reduces positive tests(2).  However, recent issues cropping up across the country seem to dramatically refute that claim.

The first uniform medication rule to be implemented across the country was to drop the acceptable phenylbutazone level from 5 µg/mL to 2 µg/mL.  Even though all of the pain relieving effect
of phenylbutazone is eliminated at the 5 µg/mL level(3), racing commissions in various jurisdictions felt that this threshold allowed levels at the time of the pre-race exam that interfered with their ability to determine if a horse was sound.  Nonetheless, at the time the change was made, the recommended withdrawal in many jurisdictions remained 2 g IV at 24 hours(4).  This, despite having data collected at the University of Florida showing that only 95% of the horses that received the original 2 g IV dose were below the regulatory threshold(5).  Which is akin to routinely giving a speeding ticket to one in 20 cars going 55 mph in a 55 mph zone.  Although the 24 hour 2g dose recommendation was continued in several states after the threshold change, the RMTC changed the dose to 9 cc (1.8 g) IV at 24 hours for the model rule, and state recommendations vary from the model rule recommendation to 1 g IV at 24 hours (KY)(6), 2 g IV at 28 (VA) or even 2 g IV at 36 hours (WV)(4).  You have no way of knowing for sure until you get back a positive test.  So much for uniformity.

Flunixin (aka Banamine®) is another example where the RMTC has been flat wrong in their withdrawal recommendations.  The manufacturer’s recommended dose is 500mg, or 10 cc to a 1,000 pound horse.  Originally the RMTC recommended that this dose be administered no closer than 24 hours pre-race(4).  Somehow, the decision was made that the cutoff for a positive test was going to be 20 ng/ml in blood(5).  This, despite the unhappy fact that when you actually read the studies, the science indicates that many 24 h post-race samples will exceed the 20 ng/ml threshold(7).  When post-race samples came up positive in droves, confirming this already-known detail, the RMTC backtracked.  In their meeting this spring at Gulfstream Park, they heard the “positives” message; their solution was to leave the sacred 20 ng/ml threshold in place but to move the withdrawal time out to 32 hours(8).

The RMTC doesn’t seem to be any more clued in with Ketoprofen.  When they set the original 10 ng/ml level, they had minimal “positives.”  So, since they couldn’t believe NO ONE was “cheating” (because there were no positive tests) with this drug, at the same Gulfstream Meeting, the RMTC reduced the threshold to 2 ng/ml(8).  Still no problem with cheating (no positive tests), so surely a further reduction is coming.  Seems like every five minutes, the RMTC and subsequently various regulators are changing a rule or a recommendation, all without real, publicly reviewable substantive scientific evidence to support their “new” position.  If you can’t dazzle the horsemen with brilliant science, baffle them with confusing and ever-changing …well you know.  Somehow, the idea of getting the facts straight with scientifically sound research before implementing rules that profoundly affect the lives of the people and horses you regulate has escaped them.

Next, Methocarbamol:  Robaxin is a mainstay of the prevention of muscle cramps (i.e. “tying up”) in training, a painful condition that plagues many racehorses and mostly fillies.  It is an important therapeutic medication to have available to horses in training.  And a rash of methocarbamol positives at Delaware Park(9) has further underscored the problems with both the RMTC studies and the implementation of changes in regulatory procedures.  Firstly, the studies were performed on only 20 horses(10), and when the results are applied across thousands of racehorses with varied management, different metabolism and under a myriad of different specific circumstances across the country, the outcomes are not so clean.  Secondly, medication interactions were apparently not taken into consideration.  The RMTC Executive Director has recently explained in great detail(11) that methocarbamol and phenylbutazone are metabolized by the same pathway in the horse and phenylbutazone is preferentially eliminated, slowing the metabolism of methocarbamol, and thereby resulting in the positive tests.   Except there is no published scientific data to support that statement(8).  And if there were, the RMTC should have been aware and done the studies to provide guidelines for the practitioners and horsemen.  Dr. Rick Sams, Director of LGC Sports Science, the lab that runs the Delaware post-race tests responded:  “While the guidelines that are in place were well thought out and researched, there will, I’m sure, be adjustments made as time goes on.(11)”  Sounds like the horsemen are guinea pigs in a high stakes game of chicken:  let’s figure out the rules as we go, and if you try to adhere to the rules and guess wrong, the penalty is harsh.  This is no way for an industry to act.  The stakes are too high for all concerned, including the horse and rider, to base medication regulations on questionable science.  

“There will, I’m sure, be adjustments made…:” not surprising when one considers the history of the RMTC threshold for Methocarbamol, which goes like this: First, RMTC commissioned a study at University of Florida using their 20 exercised horse herd and a 15 mg/kg methocarbamol dose(10)…a typically used dose(12). This study came up with a 20 ng/ml threshold and a 24 hour withdrawal time.  Unfortunately, Pennsylvania already had in place a 1 ng/ml threshold, based on studies with a REALLY low, below any clinical effect, 2.2 mg/kg dose of methocarbamol(5,12).  What to do??  Simple! Just leave the cutoff for a positive test at 1 ng/ml but arbitrarily, and without performing the necessary scientific study to back it up, move the withdrawal time out to 48 hours, and trust that it works.  If it doesn’t work out, come up with something convenient to blame, in this case apparently phenylbutazone.  At the same time tell horsemen that THEY have to move the withdrawal time out again.  The only problem is those pesky horsemen who actually got Methocarbamol positives during this “educate the regulators” “adjustment making” period.

In deflecting the blame towards a heretofore unidentified drug interaction with phenylbutazone, the RMTC is also directing attention away from the simple fact that Methocarbamol has long been known to show dose dependent kinetics.  In other words, as the dose increases, Methocarbamol is eliminated more slowly and tends to accumulate, increasing the likelihood of a positive(13).  Both the RMTC and the University of Pennsylvania studies were single IV dose studies.  We would therefore be not in the least surprised if it turns out that many of the numerous recent positives reported for Methocarbamol are more closely associated with a normal multi-dose therapeutic schedule of Methocarbamol than just with the concomitant administration of phenylbutazone.  The end result of the confusing withdrawal guidelines is to make a safe and effective therapeutic medication, Robaxin, essentially illegal and out of reach for those horses that may get muscle cramps.  

For many months preceding the adoption of the RMTC Model Rules regarding uniform medication, racing officials went around the country and were quoted in the press about the new rules regarding joint injections.  Low grade joint inflammation is an extremely common outcome of strenuous exercise, and joint injections are a useful and widely used therapeutic approach to handling this concern.  Modern human sports medicine has included the use of therapeutic joint injections for years, and studies have shown no long term ill effect from repeated injections(14).  Which fits very well with the experiences of racetrack practitioners:  Judicious joint injections are therapeutic and preserve the long term health of the athlete, not just for its racing career, but for the career that follows.  Nonetheless, the racing officials and proponents of the RMTC “driven” Uniform National Model Rule have, perhaps less than logically, insisted that veterinarians should have sufficient time after a joint injection to assess response to therapy.  They argued that horses should not be raced within 7 days of injection with a relatively quick acting corticosteroid like triamcinolone (Vetalog) or betamethasone, or 14 days of injection with a long acting corticosteroid like methylprednisolone (Depo-Medrol).  Veterinarians and horsemen have long agreed that assessing response to therapy should be part of any therapeutic intervention, but felt that the time periods set forth in the Model Rules were well beyond the time frame necessary.  Nonetheless, we were prepared to go along with it.  Unfortunately, we and other practitioners were not prepared for the outcome of the first few weeks of the new medication policy which have resulted in numerous alleged positives in at least 2 jurisdictions (IN,WV).

The uniform medication rules have put in place a 100 pg/mL blood threshold level of methylprednisolone (Depo-Medrol®), and a withdrawal of 7 days, nominally based on an RMTC sponsored report, where 100 mg was injected into a single knee(15).  And yet in the Controlled Therapeutic Medication Schedule recommendations(16), right next to the recommended 7 day withdrawal, it states that the withdrawal for 100 mg (2.5 cc) Depo-Medrol is actually 21 days…so which is it?  7 days or 21 days?  Given this uncertainty in the published guidelines, the states have varied from 10 days (IN) to 21 days (WV) for recommended withdrawal times linked to this threshold.  Faced with these ambiguities, practitioners, in an abundance of caution, have adhered doggedly to the recommended withdrawals.  And, despite this care, “cloudy” or possible positives have been coming up at a frightening rate in the first few weeks of the new rules, such as has been seen in WV(17).  It turns out, if you put the Depo-Medrol in a stifle, the clearance time is one thing.  If you put it in a hock, it is something else.  God forbid the horse moves while you inject it, because then all bets are off.   A racing official stated, off the record, that the purpose of the Depo rule was to discourage the use of Depo at all…hey wait, what happened to “so you could assess the response to therapy”?  A little deceptive to say the least.  And another, safe and effective, FDA approved therapeutic medication relegated to being essentially illegal.

To further complicate matters, Veterinarians, trainers and owners are anxiously awaiting the results of their post-race tests, which are taking an inordinate amount of time [a month or more] as a result of a laboratory backlog.  The new Uniform Model Rules mandate that a Depo Medrol positive requires purse redistribution and a fine(18).  All while the racing officials cannot even provide useful practical guidelines for withdrawal times.  As this article goes to press, even the racing commissions are unsure of their own final decision(17).  We all remember Brass Hat’s impressive effort to finish second in the 2006 Dubai World Cup.  The trainer and veterinarian tried to contact the appropriate authorities to identify the withdrawal time for methylprednisolone, and then added 5 days in order to inject the horse’s hocks well outside of those guidelines.  When the horse was disqualified for the positive test, the trainer and veterinarian protested, but to no avail.  After the trainer and veterinarian did everything possible, there was nothing that could be done: surely this can’t happen in America.

Other problems with the Controlled Therapeutic Medication Schedule (April 17, 2014), the cornerstone of the RMTC Model Rules have not yet reared their ugly heads. The recommendations on a common tying up preventative, dantrolene (Dantrium) is 48 hours.  This is based on a study performed with a single dose of 1 mg/kg, which is well below the therapeutic dose of 2-4 mg/kg(12,16).  Xylazine, a common tranquilizer, used to sedate horses for procedures, including dental work, veterinary procedures and some grooming procedures like clipping is listed as permissible at 48 hours with a published threshold level (cutoff for a positive test), but NO recommended dose and NO research paper to explain where the recommendation came from is listed(16).  Can I use the whole bottle?  Mepivacaine (Carbocaine) has a withdrawal recommendation of 72 hours, and represents a class B penalty i.e., a minimum of a 60 day suspension, loss of purse and fines (RMTC website).  And the RMTC recommendations are based on 1.5 mL of Carbocaine in a 1000 pound horse(16).  This is an amount which is below ANY usual therapeutic use of the product, which would be at least 10 mL for a Caslicks procedure or 5 -10 mL for a typical diagnostic nerve block.  So the actual RMTC recommendations appear to be at best a complete lack of understanding of how therapeutic medications are applied and at worst an intentional set up of any trainer or veterinarian who even thinks of using a therapeutically appropriate amount of mepivacaine.

This seems to be a common theme among the “permitted medication” list:  no good faith effort was made to determine how these medications are correctly and appropriately used as therapeutics before the withdrawal studies were performed or recommendations were made.  As a further matter of interest, the mepivacaine threshold is based on confidential data generated by the European Horseracing Scientific Liaison Committee [EHSLC] and therefore subject to EHSLC non-disclosure requirements apparently signed by all members of the RMTC Scientific Advisory Committee(8); so much for industry-wide transparency and independent scientific review.  Further, the cloak of secrecy does not end there:  a number of other US medications rules, such as acepromazine, albuterol, betamethasone, clenbuterol, dexamethasone, firocoxib, furosemide, isoflupredone, lidocaine, omeprazole, prednisolone, procaine penicillin and xylazine are based on secret data that has never
been subjected to independent review, and is currently unavailable to the horsemen or their racetrack vets(19). 

Drugs outside the magic “26” list of therapeutic substances are a no man’s land.  There is only one antibiotic, procaine penicillin, on the list.  States differ from 24 hours to 96 hours4 to “zero tolerance” (infinite in IN?20) on withdrawal for “sulfa drugs,” like Trimethoprim-sulfadiazine, probably the most commonly used antibiotic in horses, which is not even in the magic “26.”  Within the word “race horse” is the word “horse,” and this word is attendant with all the day to day things that might befall any animal.  In addition to scrapes and infections, a horse may get stung by an insect, necessitating an injection with an antihistamine, or scratch his cornea necessitating atropine or other therapeutic medication.  These conditions are not life threatening, but the varied therapeutic medication rules could prevent this otherwise completely healthy horse from competing, depending upon which jurisdiction you are in.  Imagine:  there are likely more than 26 over the counter medications in your bathroom medicine cabinet at home, but the most elite of athletes are prevented from benefitting from modern day sports medicine under the misnomer of “clean racing”. 

In 1900, infant mortality among humans was 30% and life expectancy was less than 50 years 21.   Much of the reason for the improvement in health of humans is the advent of modern medicine.  And yet we want to send our most precious charges, horses who have no voice for themselves, back to the dark ages.  Modern equine sports medicine is NOT a crime.  It has been developed to give the athlete the best possible quality of life and as a result to perform to the best of their abilities.  There are substances which may potentially enhance performance, and these are and should be banned.  Severe penalties should be in place and vigorously enforced.  But, folks, let’s get it right.  The rush to implement the RMTC rules has had a mountain of unintended consequences.  Shouldn’t we first and foremost get the science right, perform studies which reflect real world and appropriate uses of therapeutic medications and then establish dosage, thresholds, and withdrawal times.  Finally we should implement an appropriate phase in period allowing us to identify gaps in our scientific knowledge before imposing strict and onerous penalties.   Appears that it is the RMTC that needs to get “days.”

1. Association of Racing Commissioners International.  Drugs in US Racing – 2010:  the Facts.  2011. 
2. KAEP meeting, February 
3. Hu HH, MacAllister CG, Payton ME, Erkert RS. Evaluation of the analgesic effects of phenylbutazone administered at a high or low dosage in horses with chronic lameness J Am Vet Med Assoc. 2005 Feb 1;226(3):414-7.  4. http://www.rmtcnet.com/withdrawal_show.asp , accessed 8/12/2014
5. Summary of Medication Recommendations: Pennsylvania Horse Racing Commission Updated September 8, 2010. 6. http://www.khrc.ky.gov/Documents/24%20Therapeutic%20Medications-TB.pdf, accessed 8/12/2014
7. Sams, R.  Scientific Rationale for Establishing a Regulatory threshold for flunixin.  College of Veterinary Medicine, The Ohio State University.  2006.
8. Personal communication, Thomas Tobin 9. http://www.theracingbiz.com/2014/07/21/delaware-horsemen-concerned-positive-drug-tests/, accessed 8/12/2014
10. Rumpler MJ, Colahan P, Sams RA.  The pharmacokinetics of methocarbamol and guaifenesin after single intravenous and multiple-dose oral administration of methocarbamol in the horse. 2013 J Vet Pharm Therap 37:25-34. 11. http://www.drf.com/news/drug-combination-sets-rash-positives, accessed 8/12/2014
12. Hagyard Equine Medical Institute Formulary
13. Muir WW, Sams RA, Ashcraft S.  Pharmacologic and pharmacokinetic properties of methocarbamol in the horse. Am J Vet Res. 1984 Nov;45(11):2256-60.
14. Raynauld JP, Buckland-Wright C, Ward R, Choquette D, Haraoui B, Martel-Pelletier J, Uthman I, Khy V, Tremblay JL, Bertrand C, Pelletier JP. Safety and efficacy of long-term intraarticular steroid injections in osteoarthritis of the knee: a randomized, double-blind, placebo-controlled trial.  Arthritis Rheum. 2003 Feb;48(2):370-7.
15. Knych HK, Harrison LM, Casbeer HC, McKemie DS.  Disposition of methylprednisolone acetate in plasma, urine, and synovial fluid following intra-articular administration to exercised thoroughbred horses. 2013  J Vet Pharm Therap  37:125-132.  16. http://www.rmtcnet.com/resources/Controlled%20Therapeutic%20Medications%20April%202014.pdf, accessed 8/12/2014 17. http://www.bloodhorse.com/horse-racing/articles/86515/wv-hires-new-lab-purse-money-still-in-limbo, accessed 8/12/2014 18. http://www.rmtcnet.com/resources/RCI%20Uniform%20Classification%20Guidelines-December%202012.pdf, accessed 8/12/2014
19. http://arcicom.businesscatalyst.com/assets/arci-controlled-therapeutic-medication-schedule---version-2.1.pdf 
20. Joe Gorajec quoted during a meeting with the Indiana Standardbred horsemen on 8/12/2014 regarding the positive tests  21. http://www.cdc.gov/mmwr/preview/mmwrhtml/mm4838a2.htm, accessed 8/12/2014

3 comments:

  1. Superb! Please keep speaking up and other knowledgeable people as well!

    ReplyDelete
    Replies
    1. I am doing my best. I cannot get the Turf Media to pick up my pieces. We have to educate them kicking and screaming, or we stand to lose everything. Tweet the link to this page. Post it on Facebook. Join the blog (upper left hand corner of the page), and keep an eye out for additional articles. Every modern day revolution has been a grassroots social media campaign, and we now need to do the same. This is the greatest sport in the world, with the most incredible athletes God ever made, and nothing short of a revolution will save it.

      Delete
  2. Your blog article is really extremely genuine, that is the reason I cherish your website, in which you have granted your appreciable suggestions about.

    Methocarbamol 500mg | Tizanidine 2mg

    ReplyDelete