Sunday, May 8, 2016

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.

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