Drugs and race-horse performance

TIPS - March 1985

far no e v i d e n c e that such a factor exists in targets of s y m p a t h e t i c neu rones .

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Clear examples of changes of t r ansmi t t e r type in a s ingle neu r - one are rare and v e r y diff icul t to d e m o n s t r a t e in vivo. The neona ta l s u p e r i o r cervical gang l ion cou ld be desc r ibed as ef fec t ively de te r - m i n e d in vivo as no change in its p h e n o t y p e has b e e n so far d e m o n - s t ra ted in spi te of m a n y m a n i p u l a - t ions. It is clear f rom cul ture expe r imen t s , h o w e v e r , that these n e u r o n e s do re ta in s o m e deg ree of p las t ic i ty d u r i n g the i r ear ly deve l - o p m e n t a l stages. N e u r o n e s chang- ing f rom ad rene rg i c to cho l ine rg ic pass t h r o u g h a p e r i o d w h e r e they are clearly of dua l func t ion , and it is u n k n o w n if th is dual func t ion pers is ts . S y m p a t h e t i c n e u r o n e s in vivo m a y be pure ly ad rene rg i c or cho l ine rg ic or m a y be dual func- t ion w i t h one t r ansmi t t e r pre- d o m i n a n t . In o the r sys tems , the e v i d e n c e that s ingle n e u r o n e s

con ta in m o r e than one t r ansmi t t e r c a n d i d a t e a l lows the poss ib i l i t y of n e u r o n a l plast ic i ty , e i the r d u r i n g d e v e l o p m e n t or d u r i n g evo lu t ion . T h e s e n e u r o n e s m a y a p p e a r to be of a f ixed na tu re w h e n v i e w e d in one e n v i r o n m e n t at a s ingle t ime point . It is no t un t i l the appro - pr ia te n e u r o n e is e x a m i n e d ove r the correct pe r iod , as w i t h the rat swea t g land, that plas t ic i ty in a small p o p u l a t i o n of n e u r o n e s can be demons t r a t ed . W i t h the tech- no logy that is cur ren t ly avai lable , dual na tu re neu rones , or n e u r o n e s u n d e r g o i n g plast ic changes , can be sough t and this m a y a l low us to r e - e x a m i n e ou r ef fec t ive ly deter - m i n e d ideas w h i c h m a y also n e e d to u n d e r g o plast ic changes .

R e f e r e n c e s

1 Burnstock, G. (1976) Neuroscience 1, 239-248

2 Purves, R.D., Hill, C.E., Chamley, J. H., Mark, G. E., Fry, D. M. and Bum- stock, G. (1974) Pflug. Arch. 350, 1-7

3 Yamauchi, A., Lever, J. D. and Kemp, K. W. (1973) J. Anat. 114, 271-282

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40'Lague, P. H., Obata, K., Claude, P., Furshpan, E. J. and Potter, D. D. (1974) Proc. Natl Acad. Sci. USA 71, 3602-3606

5 Patterson, P.H., Reichardt, L.F. and Chun, L. L. Y. (1976) Cold Spring Harbor Syrup. Quant. Biol. 40, 389-397

6 Weber, M.J. (1981) J. Biol. Chem. 256, 3447-3453

7 Furshpan, E.J., MacLeish, P.R., O'Lague, P. H. and Potter, D. R. (1976) Proc. Natl Acad. Sci. USA 73, 4225-4229

8 Hill, C.E. and Hendry, I.A. (1977) Neuroscience 2, 741-749

9 Reichardt, L.F. and Patterson, P.H. (1977) Nature (London) 270, 147-161

10 Iacovitti, L., Joh, T. H., Park, D. H. and Bunge, R. P. (1981) Neuroscience 1, 685- 690

11 Landis, S. C. (1983) Fed. Proc. 42, 1633- 1638

12 Landis, S. C. and Keefe, D. (1983) Dev. Biol. 98, 349-372

13 Edgar, D., Barde, Y.-A. and Thoenen, H. (1981) Nature (London) 284, 294-295

14 Walicke, P.A., Campenot, R.B. and Patterson, P. H. (1977) Proc. Natl Acad. Sci. USA 74, 5767-5771

15 Hill, C.E. and Hendry, I.A. (1979) Neurosci. Lett. 13, 133-139

16 McLennan, I. S., Hill, C. E. and Hendry, I. A. (1980) Nature (London) 283, 206-207

17 McLennan, I. S., Hill, C. E. and Hendry, I. A. (1984) Aust. J. Exp. Biol. Med. Sci. 62, 627~34

18 Bird, M. M. and James, D. W. (1975) J. Neurocytol. 4, 633~36

Drugs and race-horse performance Thomas Tobin, Steven G. Kamerling and R. L. Anderson

Since 1900, stimulant drugs have been used illegally to improve the performance of racing horses. Classic performance trials with small numbers of horses have failed to detect drug effects on maximal performance. Careful characterization of the responses of horses to illegal drugs, followed by studies in large numbers of racing horses are required to demonstrate performance effects of drugs in horses. In an article which contains no TiPs tips, Thomas Tob in and his colleagues describe and analyse the various 'dope tests" that have been used and discuss their impact on the racing world.

In the early 1900s, G e o r g e L a m b t o n , a l ead ing Engl i sh race- horse t ra iner , pub l ic ly a n n o u n c e d that he was ' d o p i n g ' horses w i t h newly avai lable A m e r i c a n ' dopes ' . His p u r p o s e was to d e m o n s t r a t e to the Engl i sh Jockey Club w h a t s t imu lan t m e d i c a t i o n s could do for rac ing horses . W h a t the per- fo rmance effects of these treat- men t s w e r e is not recorded , bu t the regu la to ry effects of his ex- p e r i m e n t s are still w i t h us. Based

Thomas Tobin is a Professor engaged on the Kentucky Equine Drug Research Program, Department of Veterinary Science, College of Agriculture, University of Kentucky, Lexing- ton, KY40546-0076, USA.

on L a m b t o n ' s work , the Jockey Club b a n n e d the use of d rugs in rac ing horses , and m a d e the pen - alty for v io la t ion ' ru l ing off '1. S ince then, v i r tua l ly all rac ing ju r i sd ic t ions have b a n n e d the use of s t imu lan t med ica t i ons in racing horses , and enforce the ban by chemica l tes t ing. Whi l e we still do no t k n o w h o w effect ive these m e d i c a t i o n s are in rac ing horses , a n u m b e r of inves t iga to rs have t r ied to a n s w e r this ques t ion . Unfor tuna te ly , this is a diff icult q u e s t i o n to a n s w e r and the ex- p e r i m e n t a l approaches to th is p r o b l e m are mos t conven i en t l y d i v i d e d into four ca tegor ies (Table I).

T h e m a x i m a l o u t p u t p e r f o r m a n c e e x p e r i m e n t

The s imples t app roach to this p r o b l e m is in the max ima l ou tpu t pe r fo rmance or H o r s e m a n ' s Ex- p e r i m e n t 2, so-cal led because these are the peop le w h o usua l ly suggest it. In this expe r imen t , one runs abou t six horses , w i t h or w i t h o u t the drug, for abou t a mi le at top speed. The d i s t i n g u i s h i n g character is t ic of this e x p e r i m e n t is that the control horses are run at max ima l ou tpu t , and the d rug is b e i n g asked to p roduce a supra- max ima l pe r fo rmance . Drugs s tud ied in this type of expe r imen t inc lude a m p h e t a m i n e , f u r o s e m i d e and the anabol ic s te ro ids 3~. Per- haps , no t unexpec ted ly , such a

TABLE I. Experimental approaches to the effects of drugs on equine performance

1 'Maximal output experiment': run horses +_ drug at top speed for one mile

2 'Sub-maximal output experiment': trot or canter horses + drug for short distances

3 'Pharmacologist's experiment': study the effects of drugs on simple behavioral models

4 'Statistician's experiment': retrospective study of times + drug in large numbers of horses

© 1985, Elsevier Science Publishers B.V. Amsterdam 0165 6!47/85/$02 00

130 T I P S - M a r c h 1985

TABLE II. Results of maximum output performance tests

Test- % Drug Control Test Control n Change Conclusion

Furosemide 3 136.33 136.00 -0.33_+ 1.59 5 -0 .24 no sig. diff. Furosemide 4 146.7 145.2 - 1 . 5 6 -1 .02 no sig. diff. Amphetamine s 3 +2.4 no sig. diff. Nandrolone 6 72.8_+ 1.8 75.8_+ 1.76 3.0 _+ 2.5 6 4.1 no sig. diff.

Only Ref. 3 presents actual performance times for each horse. Report no. 4 provides mean and range, with the notation that the effect is non-significant. Report no. 5 provides only maximum, minimum and mean percent changes. In study no. 6, a cross-over study, the investigator simply notes that his second period times were 4.1% slower than his first period times. Based on the data of Ref. 3, testing at the 5% level and desiring a significant result 80% of the time, furosemide would have to produce an increment in performance of 5.08 seconds or of 3.75%.

drug- induced supra-maximal performance effect has yet to be demonstra ted .

The problem with this experiment is that the drug effect is likely to be small, while the noise or background var iabi l i ty found in the controls may be large. We are aware of four such s tudies in racing horses, and all have y ie lded negat ive results (Table II).

More recently, we analysed the data from these exper iments to determine the potent ial for these tests to produce statistically s igni- ficant results (Table II). Unfortun- ately, no other workers have presented ind iv idua l data points or a mean and a statistical es t imate of the variance encountered in their performance trials. However , on the basis of the variance repor ted in t ime trial work from our labora- tory, one would need a performance improvement about 3.75% on top of an already maximal performance in control animals for statistical significance (Table II). This is a large increment in performance to expect of any medication, and is unl ikely to be observ- ed in the small number of animals tested in maximal output performance exper iments to date.

The sub-maximal performance experiment

A modif icat ion of the maximal performance exper iment is to run the horses at less than maximal output wi th and wi thout the drug. Because the horses are not be ing tested at maximal output , there is a bet ter chance of obta in ing statistically significant results. Using this approach, which I call the 'Quas i Horseman ' s ' experiment , a number of workers have repor ted statistically significant effects of drugs in horses. However , the problem with this exper iment is that one cannot know whether the

effect obta ined is a behavioral or a performance effect. Therefore, while this exper iment will yield statistically significant data, it cannot answer the fundamental quest ion be ing asked, which is whether or not the drug be ing tested will actually improve racing performance.

This exper imental approach has been taken by Sanford in England and by Fujii in Japan z. Some of Sanford 's data, which are typical of the data generated by this approach, are presented in Table III. With this type of experiment , Sanford repor ted statistically significant effects of drugs in gallop tests, but how these data may relate to effects of drugs on maximal or near maximal performance is not clear.

The pharmacologist's experiment A much more effective way of

asking quest ions about the effects of drugs in horses is to test their actions in s imple behavioral models 7. For example, narcotic analgesics in the horse produce a

wel l -def ined locomotor response which can be accurately measured by s imply count ing steps that the animal takes wi th its left front leg (Fig. 1). Using this model , one can generate classic dose and t ime response data for these drugs in the horse (Fig. 2) and demonst ra te the l ikel ihood of performance effects. These models produce data similar qual i ta t ively to that obta ined wi th the sub-maximal output performance experiment , bu t which are far more detai led and informative. For example, these exper iments can ident i fy dosage rates and t imes pos t -dosing at which one may expect to obta in peak drug effects. They can also show that some drugs do not produce consistent behavioral effects in the horse, and that the effective doses of some drugs can vary up to 100-fold be tween in- d iv idua l horses 7. For these reasons, s imple behavioral experiments are useful, if not necessary, before performance exper iments of any k ind can be a t tempted in horses.

The necessi ty of careful character izat ion of the pharmacological actions of drugs in horses was brought home to us by our experiments wi th fentanyl. Fentanyl is a h ighly l ip id-soluble narcotic anal- gesic, about 80 t imes more potent than morphine , which was repor tedly wide ly used in racing horses in America dur ing the 1970s. When we started our performance work on this drug, we used the dose and routes of ad- minis t ra t ion (0.25 mg horse -1, 30 min. before race time) report-

TABLE III. Gallop test 2 x 200 m. Compounds increasing speed significantly P < 0.05

Dose Number Compound (mg kg -1) Route tested

Methylamphetamine 0.1 i.m. 3 0.2 i.m. 1

Methylphenidate 0.25 s.c. 4 0.5 s.c. 4

Pemoline 4.0 oral 4 8.0 oral 4

Caffeine 2.0 oral 3 4.0 oral 3

Phenylbutazone 8.0 oral 1 6.6 i.m.* 4

* Injection made 23 h before test. In these gallop tests, horses were run singly over a 200- metre course from a flying start. After an interval of about 5 min, d0ring which period the horse returned to the start at a trot or slow canter, this gallop was repeated. No data on the dosing times, the actual performance times, or the variability in the performance times on which these conclusions were drawn were presented. Source: Sanford, Symposium on Large Animal Therapeutics, University of Surrey, Guildford, Surrey, 1978. Courtesy of Blackwell Scientific Publications. Cited in Tobin, T., 'Drugs and the Performance Horse', 1981.

TIPS - March 1985

120 A .001 mg kg -1 • ] 0 .005 m g k g -I

I~, ,~, ~> .010 mg kg "-I

i o n ~< ~,,,l \ • ".020 mg kg "-I " v i ; ' ", x .040mgkg -1

40 ,, ,

I1%, oo~o- "'~'z'~r'9-~. x • 1

0 r-~T'~ r ° - % ~ _ i __ i -

0 20 40 60

Minutes postfentanyl

Fig. 1. Effect of fentanyl on spontaneous locomotor activity in four horses. Horses were injected with saline or increasing doses of fentanyl L v. The average counts per two- rain pedod following saline injection are shown by the straight line near the bottom of the graph. The response to 0.001 mg kg - I fentanyl is shown by the open triangles ( A - - A); 0.005 mg kg -~ by open circles (0 - - 0); 0.010 mg kg -~ by open diamonds ( ~ - - O); O. 020 mg kg - ~ by solid triangles ( • - - • ) ; and O.040mgkg -~ by crosses ( x - -x ) . At the highest dose tested, aft horses showed a loss of co-ordination resulting in a decrease in locomotion during the first six min. All points are the means of counts determined on four horses and the vertical bars represent S.E.M.s Reproduced with permission from Ref. 1.

edly used illegally on the racetrack. In this work, we saw no behavioral or performance effects due to fentanyl whatsoever .

Later, when we increased the dose of fentanyl for kinetic s tudies, we discovered the characteris- tic behaviora l effects presented in Fig. 1. It then became apparen t to us that the behaviora l effects of fentanyl require a m i n i m u m dose of about 2-3 mg horse -1 and that the drug has to be given i.v. This lesson brought home to us the necessi ty of def in ing carefully the pharmacology of a drug in racing horses before start ing expensive performance experiments .

T h e s t a t i s t i c i a n ' s e x p e r i m e n t The last type of exper iment that

we will discuss is the so-called stat is t ician 's experiment . In this type of exper iment , the data are ob ta ined by a s tudy of the effects of approved medica t ions on actual track t imes of racing horses. This is potent ial ly the most powerful of all the exper imental methods available for answer ing ques t ions about the actions of drugs in racing horses.

This exper iment was first pro-

posed by Mr Carl Larsen of the Kentucky Harness Racing Com- miss ion, who po in ted out that in 1977 the only drug permi t ted in harness racing in Kentucky was furosemide. He sugges ted that we s tudy the differences in track t imes for harness horses racing at the Louisvil le Downs with and wi thou t furosemide. Furosemide pre-race is r ecommended in racing horses for the treatment of exercise- induced pulmonary hemorrhage (epistaxis or 'b leed- ers'). Whether or not it is effective in the t reatment of this condi t ion and whe ther or not it improves the performance of racing horses is unknown. We ident i f ied about 232 t imes for these horses while they were on furosemide, compared wi th 160 t imes for the horses wi thout furosemide. The results of this s tudy (Table III) suggest that the horses treated

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abi l i ty of ob ta in ing statistically signif icant data from maximal output performance exper iments (Table I), these racetrack experiments are much more promising. From the data of Table IV one can calculate that a true mean difference of 0.72 s. (a 0.56% improvement) would be required to produce significant differences from controls at the 0.05 level, assuming that it is des i red to obta in a significant result 80% of the time. These are more at tainable figures than those developed from maximal ou tput performance trials, and suggest that this experimental approach should be pursued.

This approach has been taken a step further by Larry Soma of the Univers i ty of Pennsylvania in s tudies on thoroughbred horses 8. (Soma et al. unpub l i shed observa- tion.) Dr Soma s tudied the effects of furosemide at Keystone Race-

• X &'~ .-

• . . , *~ ,-¢,.p , ,

While narcotic analgesics make man drowsy and want to sleep,

the right dose makes horses want to run.

\

. k . i ~ "

i f , J, ~/

with furosemide were about one- tenth of a second slower after t reatment than before. The numbers are large, the exper iment undoub ted ly relates to the performance si tuation, and statistically the answer is unequivocal . Furosemide t reatment had no effect whatsoever on the performance of s t andardbred horses at this Louisvil le Downs meet.

In contrast wi th the small prob-

track on horses whose t imes had decl ined for three successive races and whose owners had then had them endoscopical ly examined. Those found posi t ive for epistaxis (pulmonary bleeding) were then put on furosemide. The results showed that furosemide restored the performance of the epistaxis- posi t ive horses to the level obser- ved pr ior to their decline in performance. This experiment ,

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160

• 140

120

100

Dose-Response curves for locomotor activity following narcotic analgesics in the horse

i I ] I

O

A---~

V 60 / Fentanyl

!fJ : ' . . . . . . . . . . . . . _

1 I I

.0000l 0001 .001 01

Aporaorphine Az~leridine ~

Methadon~e ~]/

• lO 1.0

Dose mg k~ -]

Morphine

~ P ~ e n t ~ e

J

% / ~ Pethidine

_S _e i

10 100

Fig. 2. Dose-response curves for locomotor activity following narcotic analgesics in the home. Horses were dosed with increasing amounts of the indicated drugs and the average number of steps taken during the peak two-min period were plotted for etorphine, fentanyl and apomorphine. For all other drugs, average counts per two-min period were determined for the 16 min. interval of peak activity. Three to 10 horses were used in the experiments on etorphine, fentanyl, apomorphine, methadone, morphine and pentazocine. One horse was used to determine each dose-response curve for hydromorphone, anileridine and pethidine. The average counts per two-min period for the saline control are shown by the dashed line near the bottom of the graph. Reproduced with permission from Ref. 1.

therefore, suggests that the action of furosemide is to restore 'normal ' performance in racing horses. Whi le there were difficul- t ies wi th the controls avai lable for this exper iment , this work clearly poin ts to the racetrack as the most sat isfactory exper imenta l tool for answer ing ques t ions about drugs and racing performance.

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The classic performance trial or maximal output performance ex-

pe r imen t is expensive, t ime con- suming, and difficult to perform. Fur thermore the information yield from these exper iments has been trivial. If one reduces the output d e m a n d e d of the animals, as in the sub-maximal output performance exper iment , one can produce statistically significant results but these results do not necessarily demonst ra te effects of drugs on performance.

Simple behavioral experiments can be used to de termine the sui tabi l i ty of drugs for perform-

TABLE IV. Effect of medication with furosemide on the performance of horses racing at Louisville Downs, Summer 1977

No. of No. of Mean horses trials times S.E.M.

Prefurosemide 58 160 128.5925 0.2031 F = 0.31 With furosemide 58 232 128.7366 0.1594 (F for

significance should be > 3.0)

At this meet, furosemide was the only permitted medication, and its use was monitored by urinalysis. Horses could elect to go on furosemide at any time throughout the meet, but once on furosemide had to stay on ~t. Performance times for horses pre- and postfurosemide treatment were obtained from the meet programs and compared. Only times on good or fast tracks were taken. For the 58 horses selected, 160 prefurosemide times were available and 232 posffurosemide times. A randomized block design was used where each horse represented a block. After adjusting for blocks (i.e. differences between horsmes), there was no significant difference between treatments (i.e. times on and off furosemide).

T I P S - M a r c h 1985

ance experiments , the optimal dose of a drug and the t ime post- dos ing to test performance. They can also be used to determine the rel iabi l i ty and responsiveness of ind iv idua l horses to drugs. Be- cause of the expense of any performance experiment , it is advis- able to use these experiments to characterize the action of drugs in the horse before any performance exper iments are carried out.

The most satisfactory performance exper iments are those carried out at a racetrack dur ing an actual race. They are l imited to the use of those drugs which are legal for racing horses or which are sanc- t ioned by racing authorit ies. This exper imental approach has yield- ed good results with the diuretic furosemide and should be extend- ed to other drugs.

In the final analysis, however, the impact of any performance exper iment on the way in which society views the use of s t imulant drugs in racing horses is likely to be small. If the drug is found to have a s t imulant effect, regulators will conclude that the ban on s t imulant drugs is proper• On the other hand, negative results are not l ikely to lead to any change in the way society or racing regulators v iew stimulants. For these reasons, research efforts on the performance effects of drugs might be bet ter directed towards drugs for which experimental re- suits will resolve doubts or influ- ence decis ions for regulators or society in general.

R e f e r e n c e s 1 Tobin, T. (1981) Drugs and the Perform-

ance Horse, Charles C. Thomas, Spring- field, Illinois

2 Tobin, T., Kamerling, S. and Nugent, T. E. (1984) in Drugs and Equine Perform- ance: A Review. Equine Exercise Physi- ology (Snow, D. H., Perrson, S. G. B. and Rose, R. T., eds), Granta editions, Cam- bridge

3 Tobin, T., Roberts, B. L., Swerczek, T. W. and Crisman, M. (1978) J. Equine Med. Surg. 2, 216-226

4 Milne, D. W., Gable, A. A., Muir, W. W., Skarda, R. T., Hamlin, R• L. and Pipers, F. S. (1980) Am. J• Vet. Res. 41, 1183-1889

5 Stewart, G. A. (1972) Aust. Vet. J. 48, 544- 547

6 Snow, D. H., Munro, C. D. and Nimmo, M. A. (1982) Equine Vet. J. 14, 224-228

7 Tobin, T. and Combie, J. D. (1982) J. Vet. Pharmacol. 5

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Drugs and race-horse performance