Clenbuterol and drug regulation in American racing
The drug Clenbuterol is a β2 agonist with some structural and pharmacological similarities to epinephrine (adrenaline). Therapeutically, clenbuterol is a fantastic bronchodilator and has been approved by the FDA for use in horses for the management of airway obstruction. If a horse has mucus in the throat there is nothing better on the market that can clean it up and help the horse get to the racetrack.
That is the good.
Clenbuterol is also the drug that cyclist Alberto Contador of Spain was banned for two years from professional cycling after testing positive for at the 2010 Tour de France. It is the drug that former New York Mets clubhouse employee Kirk Radomski admitted in his plea deal to distributing to dozens of current and former Major League Baseball players and associates. This is the same drug that San Francisco Giants pitcher Guillermo Mota received a 50-game suspension (in 2006) and 100 games (in 2012) due a positive test for and it is the same drug that Mexican boxer Erik Morales was suspended for 2 years after testing positive for earlier this year.
In humans it causes an increase in aerobic capacity and oxygen transportation and it increases the rate at which body fat is metabolized while increasing the body's resting metabolic rate. It’s a straight out performance enhancer. In racehorses, it has a wide range of effects:
Kearns et, al (2001) found that chronic administration of clenbuterol has a repartitioning or steroidal effect. It was noteworthy that they found that chronic clenbuterol administration causes significant repartitioning in the horse, even when administered in therapeutic doses. Thus if you give the recommended dose, but use it frequently, you get a steroidal effect.
McKeever et, al (2002) found that therapeutic levels of clenbuterol and training actually decrease aerobic performance and that the resultant reduction in plasma volume may also affect improvements in cardiovascular function during recovery normally seen with exercise training.
McKeever, et al (2002) found in standardbreds that chronic clenbuterol administration may negatively alter cardiac function by altering the internal diameter, thickening the septal wall and increasing aortic root dimensions.
Nolen-Walston, et al (2012) found that clenbuterol initially reduced airway sensitivity to inhaled histamine, but that prolonged administration of clenbuterol likely results in a reduction in its bronchodilatory effects. That is, if you abuse it, the horses system gets used to it and the drug is less effective in treating what it was meant to treat. Importantly in an interview on the paper Nolen-Walston added, "Our study shows that after about two weeks of use, it quits working and actually makes the horses breathe a little bit worse. The clinical significance is that clenbuterol should be used for no more than 14 days consecutively without a break."
Finally McConnico, et al (2012) found in Quarter horses that clenbuterol doses ≥ 10 2μg/kg (4.5 μg/lb), in excess of those normally prescribed, may cause sustained tachycardia, muscle tremors, hyperglycemia, and cardiac and skeletal muscle necrosis.
Therein lies the problem.
As good a drug as it is, when it is abused its efficacy to treat what it is there to treat (airway obstruction) is diminished and steroidal and other negative effects emerge.
So why is clenbuterol regulation important?
In the last ten years there have been a number of cases where non-FDA approved compounded clenbuterol had resulted in horse deaths including six in Louisiana in 2006 and there had been for a considerable time horsemen's belief that the drug was being abused beyond its therapeutic use for steroidal effect even before steroids were officially banned from racing in 2008/09. At a California Horse Racing Board meeting in 2007, equine medical director Dr Rick Arthur said that "recent blood tests the CHRB has been performing on horses racing in California indicate that only 14% of the horses showed any measurable levels of clenbuterol."
Back in 2007 just 14% testing positive seemed to be par for the course. Forward just five years and in 2012, there was a rash of positives for excess clenbuterol in California. Blood samples analyzed at the University of California-Davis equine testing facility through its out-of-competition and total carbon dioxide tests found that 53 of 98 horse sampled between March 15-30 2012 had the presence of clenbuterol. As Dr Arthur said at the time, "I think that having more than 50% of horses testing positive for clenbuterol is stretching the limits of credibility". That could be the understatement of the year.
Just prior to this the state of New Mexico decided to suspend the use of clenbuterol completely from racing for a year. This was again based on the belief that it was being abused and that compounded clenbuterol, or so called Mex-Clen, was being used giving significantly different therapeutic results and testing levels. Also around that time the CHRB confiscated brands of clenbuterol not approved by the U.S. Food and Drug Administration at Los Alamitos, which led CHRB regulators to understand that two things were happening:
The clenbuterol was being abused for its muscle building properties in horses rather than simply to treat breathing problems. Basically when steroids were made illegal nationally in 2008/2009, this was being used as a proxy for it more so than ever.
The type of clenbuterol being used was “off market” compounding, not the regulated ventipulmin. This meant that the dose that the horse was being given was unknown and varied considerably making its effect varied also.
Wiser to the outcome of the milkshaking test earlier (they randomly started testing TCO2 levels and found an extraordinarily high percentage of horses were positives), in 2012 the CHRB instituted a 21 day withdrawal period for the drug but gave horsemen a two month period to adjust their medication regimen. The previous withdrawal period for clenbuterol had been just 96 hours. At the time of the CHRB change, Dr. Craig Shoemaker, a veterinarian for pharmaceutical manufacturer Boehringer-Ingelheim, urged the CHRB to wait until UC-Davis completed a study on the effects of clenbuterol before taking action. He felt that the 21-day withdrawal period could lead to trainers running horses "that would be racing in a compromised state."
Earlier this year the Thoroughbred Owners of California announced that they would join regulators from eight states in the Mid-Atlantic and Northeast by committing to implement the Mid-Atlantic Uniform Medication Program starting the 1st of January 2014. For the TOC and the CHRB it was a rather easy sell as the regulations that they had in place were very similar to the recommendations, and in fact the 14 day clenbuterol withholding period is less than what is currently in place. For the Thoroughbred Horsemen’s Association (THA) and the Racetrack Testing and Medication Consortium (RMTC), this was momentum building.
For the past decade or more Alan Foreman, Chairman of the Thoroughbred Horsemen’s Association and more recently Ed Martin of the Racing Commissioners International (RCI), have been working away at creating uniformity of drug rules across America. Starting in the Mid-Atlantic region Foreman has gathered the states to agree on what theraputic drugs are allowed, a responsible threshold level for each of these drugs based on their standard therapeutic use, standardized testing via accredited labs (particularly important as for example the testing requirement in Florida uses 1980's technology that is not effective at all) and a penalty system that applies across state lines (so if you get a positive in one state, other states consider it when looking at any further positives). The RMTC has set a January 1st 2014 implementation for the new protocol. The proposal is that come this date, the states in the Mid-Atlantic compact and California will all have standard thresholds for 24 approved drugs and standard testing procedures for these drugs.
The major racing jurisdictions that are "holdouts" to this at the moment are Kentucky, Louisiana and Florida (Arkansas and Indiana are two others) and the closer that we reach the January 1st 2014 implementation, the more noise is being heard from elements within the National Horsemen's Benevolent and Protective Association (HBPA), especially from those states who have yet to indicate that they are going to move on the protocol. With momentum on the side of the RMTC, the various HPBA members from these states are protesting and producing alternatives that merely water down the protocol to either allow abuse to return or make it less painful for trainers to cheat. Many believe that Kentucky, who was one of the last states to ban and test for milkshaking will adopt the proposal before the 1st of January 2014 as it already has the best testing laboratory in the country which is already accredited for RMTC testing making the process a lot easier although Kentucky HBPA rep Rick Hiles recently said that he was going to fight parts of the regulation when it came up for debate. Kentucky would also need to switch from testing in plasma, which is pretty much a waste of time with Clenbuterol, to urine. The criticisms coming out of Florida and Louisiana are unsurprising as these two states have what is widely considered to be the most woefully inadequate drug testing on the planet. They are going to have to do more than anyone else to change.
On July 13 the scientific and regulatory advisers to the HBPA expressed concerns over the proposed withdrawal time and testing level for clenbuterol, and they warned horsemen of "potential pitfalls" should the regulations be adopted. Leading the charge for them was Dr Steven Barker, a chemist for the Louisiana State Racing Commission. Dr Barker was quoted as saying that the proposed 14-day cutoff for administration, threshold of 140 picograms per milliliter in urine, and "limit of detection" in plasma are "potential minefields" for horsemen. Barker said scientific research has shown clenbuterol can be detected at 14 days—even 30 days in some cases—in horses, or not be detected within three days of administration in other horses. He was also critical of the RMTC for not allowing the data that they developed their recommendations on be seen without a confidentiality agreement being signed.
His comment was a propagation of misinformation and distraction.
Earlier in this post I mentioned that back in 2012 Dr. Craig Shoemaker had urged the CHRB to wait until UC-Davis completed a study on the effects of clenbuterol with the questions that the 21-day withdrawal period could lead to trainers running horses "that would be racing in a compromised state." That study was released about a month ago, well before the HBPA board of directors meeting last week (from where Dr Barker's statement came). In that study based on 22 fit racing thoroughbreds, following low dose administration of regulated clenbuterol as per the recommendations of the supplier (0.8 ug/kg), the clenbuterol urine concentrations fell below detectable levels (i.e close to zero) between 21 to 28 days post administration compared to 7 days in plasma. At 13.5 days the measurement of a low dose of regulated clenbuterol had an average pg/mL in urine of just 41.1 with a maximal value of 67.3. This is well below the threshold of 140 picograms per milliliter in urine that the RMTC is suggesting to implement.
Barker's comment about the variation in absorption rate between horses most likely refers to the paper by Thompson, et al (2012) where a larger dose (1.6 ug/kg to 3.2 ug/kg compared to the recommended 0.8 ug/kg) elicited higher plasma concentrations of clenbuterol than those found in the UC-Davis study when it used similar doses. The purpose of the Thompson paper wasn't to look at absorption rates so they didn't have sufficient plasma profiles of the horses to make a definitive comparison between this study and the UC-Davis study so actually working out the reasons behind this one paper coming up with such variation isn't possible. Additionally, the variation in absorption rate was elicited by using a much heavier dose than recommended for normal treatment.
Based on the science available, Clenbuterol regulation based on the RMTC guidelines is not going to be a minefield for trainers if you use the drug for the purpose that it is made for – cleaning up mucus from airways and the dose that is recommended. Yes, Clenbuterol can be detected at 14 days post use, and it can also be detected at 30 days, but if its used normally and with the FDA approved version of it, it is not going to be detected at 140 picograms per milliliter in urine at either 14 or 30 days, it will be a fraction of that 140. If you are using a non-approved compound, aka Mex-Clen, and/or hammering the horse with massive doses of clenbuterol to get a steroidal effect then you are going to get a positive.
Dr Barker, who has been critical of the RMTC in the past, suggested that there was some type of conspiracy in that the RMTC were holding back the data that allowed them to come to these thresholds for political purposes. For a guy that has a PhD, I am surprised that this actually came out of his mouth. He would have to know that the RMTC don't own the data, the scientist that did the research does, and it is standard practice within the scientific community to withhold all data from public consumption until a paper has been released. For anyone to see the data other than those that reviewed the paper (it is peer-reviewed after all so at least three people have reviewed the data) beforehand it would require a confidentiality agreement and as the RMTC don't own the data, they would have to have this in place. The whole "data conspiracy" theory promoted by Dr Barker and furthered by Dr Tobin (a national HBPA advisor from the Gluck Research center in Kentucky) was a "look over here at this shining object' moment. At any rate, the paper is published now so getting the data shouldn't be an issue.
The next big hurdle for the RMTC protocol is the Association of Racing Commissioners International which is due to meet July 30-31 in Saratoga to consider the model rule in particular the multiple violation penalties for trainers. Coming out of that meeting and moving towards the end of the year, expect to hear a lot more noise from various HBPA groups, moreso from Louisiana and Florida who have to make the largest changes to adopt the regulations. It is going to be interesting to see this play out and for a man like Alan Foreman who has literally been spending decades on this, it will be interesting to see if it finally comes together. Who knows, maybe in 2014 we will actually have a Triple Crown where the playing field is level and the drug testing uniform. One can only hope.
One last thought, should the drug model rules be adopted nationwide one of the winners out of this is going to be Boehringer-Ingelheim, the manufacturer of Ventipulmin, the only FDA approved clenbuterol on the market. If the RMTC regulations go nationwide trainers and veterinarians will almost be compelled to use Ventipulmin to treat airways. The UC-Davis study was funded by Boehringer-Ingelheim. I'll let you make of that what you will.