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 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 1/150,000th 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 (1,000th 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:
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.
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 13th 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 13th 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 13th 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.
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