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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