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Home , Detomidine, Haloperidol, Nalmefene, Spiradoline

Pharmacologic Treatment of Equine Self-Mutilation Syndrome

Nicholas H. Dodman, BVMS, DACVBa Louis Shuster, PhDa,b Gary J. Patronek, VMD, PhDa Linda Kinney, BSa aTufts University School of Veterinary Medicine, Departments of Clinical Sciences and Center for Animals and Public Policy, 200 Westboro Road, North Grafton, MA 01536 bTufts University School of Medicine, Department of , 136 Harrison Avenue, Boston, MA 02111

KEY WORDS: horse self-mutilation, sero- -receptor antagonist and tonin, , opioid, , the . These find- flank-biting, Tourette’s syndrome ings provide new information on the neuro- physiological basis of ESMS and suggest ABSTRACT further parallels with Tourette’s syndrome. The effects of drugs that either stimulate or inhibit central opioid, dopamine, norepi- INTRODUCTION nephrine, and serotonin neurotransmitter First described as self-directed ,1,2 systems were examined in horses demon- equine self-mutilation syndrome (ESMS) or strating signs of equine self-mutilation syn- flank-biting has been further delineated as drome (ESMS), a condition similar to an equine equivalent of Tourette’s syndrome Tourette’s syndrome in humans. Eight flank- (TS).3 The prevalence of ESMS in the biting horses with ESMS were recruited for equine population is unknown; however, the study. A series of drugs selected for their 0.7% of and 1.9% of stallions from activity on the aforementioned neurotrans- a survey of more than 700 horses in Canada mitter systems were administered to the were reported to be affected (U. A. Leuscher horses in a saline-controlled behavioral and D. B. McKeown, unpublished data). study. Specific behaviors associated with the Behavioral parallels between ESMS and TS syndrome were videotaped for 4 hours fol- include head and neck motor tics, hemibal- lowing administration of drug or saline. lismus (constant, undirected, purposeless Behaviors recorded hourly during each striking out with either a forelimb or phase of the study were compared with hindlimb), preoccupation with environmen- those of a composite saline control baseline tal boundaries, and occasional bizarre vocal- to determine whether there were significant izations. Other similarities include juvenile differences among the treatments. onset, male predilection, familial tendency, , a dopamine blocker, pro- an unrelenting course, exacerbation by duced a significant reduction in the primary stress, amelioration by absorbing activities, ESMS behaviors of self-mutilative attempts unimpaired performance, and occasional and . , an α-2 precipitation by trauma.4–7 antagonist, also produced a significant (P < .05) reduction in these behaviors, as did the Endorphins and have been Funding for this study was provided by a grant from the Tourette suggested as the predominant group of opi- Syndrome Association, Bayside, NY. oids involved in the pathophysiology of the

90 Vol. 2, No. 2, 2004 • Intern J Appl Res Vet Med TS.8 may have dual modulatory Table 1. Identification of Horses Presenting effects on tic expression, although low doses with Equine Self-Mutilation Syndrome of opioid antagonists often reduce tic fre- Horse ID Sex Breed Age (yr) quency.6 Dopamine pathways are also PST Stallion Arabian 7 involved in the pathogenesis of TS, as evi- M Stallion Arabian 15 denced by the palliative effects of both DR Quarter horse 13 dopamine antagonists (e.g., ) and RV Stallion Arabian 12 (e.g., and per- MD Stallion Paint 3 8–11 golide). Additionally,norepinephrine NP Mare Thoroughbred 2 appears to be to be involved in the pathobiol- B Gelding Oldenburg 4 ogy of TS because norepinephrine levels in PB Mare Standardbred 2 cerebrospinal fluid are 55% higher in patients with TS than in healthy controls, and cloni- dine suppresses TS tics.12,13 Finally, the fact examination by rectal palpation), and der- that selective serotonin reuptake inhibitors matologic examination (by direct visual are drugs of choice in TS suggests the inspection and microscopic examination of involvement of mechanisms.7 skin scrapings) to eliminate possible med- The only evidence of a role for any of ical causes for the abnormal behavior. these neurotransmitter systems in ESMS is Additionally, a blood sample was collected from a clinical survey in which two horses by venipuncture from each horse for a com- with ESMS reportedly responded to therapy plete blood count and chemistry profile with a and a case analysis. Finally, at least 48 hours after report describing the suppression of ESMS admission to the clinic, horses were tics with , an .3,4 observed and then videotaped for 4 hours to The present study was conducted to inves- confirm that each was exhibiting behavior tigate neurobiologic similarities between characteristic of ESMS. Two horses (M and ESMS and TS. The effects of drugs that either MD) had to be blanketed at all times to pre- stimulate or inhibit central opioid, dopamine, vent them from injuring themselves during noradrenergic, and serotonin pathways on their intense self-mutilation episodes. One ESMS were studied. Individual drugs were horse (B), a high-intensity cribber, was selected based on familiarity with their use in always equipped with a cribbing collar. horses and their principal . ESMS was diagnosed based on the obser- vation of self-mutilative attempts or actual MATERIALS AND METHODS flank-biting; hemiballismus; excessive head- Horses tossing; bizarre, unsolicited vocalization; pre- Eight horses identified as flank-biters were occupation with the periphery of the stall; admitted to the Large Animal Hospital of and constant sniffing, especially of manure. Tufts University School of Veterinary Sudden explosive bouts of self mutilation or Medicine for clinical evaluation and possi- flank-biting associated with any of other ble enrollment in a behavioral study characteristic signs (and the absence of any approved by the Institutional Animal Care medical explanation for the behavior) was and Use Committee (Table 1). A signed considered diagnostic of ESMS. owner consent was obtained for each horse participating in the study. Each horse was Treatments given a thorough physical evaluation, Drugs evaluated included detomidine, nal- including a general medical examination, trexone, , acepromazine, , gastric endoscopy, retinal examination, apomorphine, , , reproductive assessment (testicular palpation haloperidol, and buspirone. Dosages, routes and measurement or ovarian and uterine of administration, and mechanisms of action

Intern J Appl Res Vet Med • Vol. 2, No. 2, 2004 91 Table 2. Dosages, Routes of Administration, and Mechanisms of Action for Drugs Administered to Horses with Equine Self-Mutilation Syndrome Drug Dosage (mg/kg) Route Neurotransmitter System Targeted Acepromazine 0.02 IV Dopamine antagonist Amphetamine 0.4 IV Increases and noradrenergic activity Apomorphine 0.06 IV Increases dopaminergic activity Buspirone 0.5 (2 hours PO for serotonin receptors prior to taping)

Clomipramine 1Ð2 PO daily Serotonergic enhancement for 3 wk

Cocaine 0.75 IV Increases dopaminergic, noradrenergic, and serotonergic activity Detomidine 0.02 IV Inhibition of norepineprine release Haloperidol 0.5 IV Dopamine antagonist Morphine Escalating doses: IV Opioid agonist 0.05, 0.1, 0.2, 0.4 at 30-min. intervals

Naltrexone 0.5Ð1.0 IV Opioid antagonist of each drug are shown in Table 2. On treat- daily for 3 weeks, and the 4-hour videotap- ment days, one drug was administered via ing was done only at the end of this treat- IV catheter, and behaviors were monitored ment period.14 Horses treated with and recorded in the same manner as for the apomorphine were videotaped for only 2 control periods. Two drugs (buspirone and hours after treatment because apomorphine clomipramine) were administered orally in a has a transitory effect in horses. small quantity of molasses-flavored grain. Based on what is known about each The sequence of treatments is shown in drug’s and pharmacoki- Table 3. netics, at least 24 hours was allowed for Evaluations drugs to clear before each control-period measurement. Four relevant, easily quantifi- The horses were observed in a padded stall able behaviors (self mutilation attempts, equipped with a wall-mounted video camera spontaneous kicks, head tosses, and vocal- wired to a television and videocassette izations) were recorded for each horse dur- recorder. Behavior for each horse was moni- ing each observation period. The results, tored for five 4-hour observation periods expressed as events per hour, were used as following IV of saline at approxi- baseline data. Videotaped behaviors were mately 4- to 5-day intervals during the first always scored by the same observer in this 3 weeks of each horse’s 6-week stay in the open (non-blinded) clinical study. hospital. Control measurements were recorded before and between drug treat- Statistical Analysis ments, with the exception of clomipramine. Data were entered into a commercially In most cases, horses were videotaped available software package (SPSS), and during the 4-hour period immediately fol- descriptive statistics were generated. Each lowing a drug’s administration. Two excep- horse served as its own control. To obtain tions were for clomipramine and the most representative control frequency of apomorphine. Because of its slow onset of ESMS behavior for each horse, the frequen- action, clomipramine was administered cy of each of the four monitored behaviors

92 Vol. 2, No. 2, 2004 • Intern J Appl Res Vet Med was averaged for each hour for all control periods combined. Since the data were not normally distributed and the sample size was small, a nonparametric test for paired data (Wilcoxon signed rank test) was used to compare the frequency of behaviors at each time period in the control period after each drug was administered. Significance was determined at P ≤ .05 level.

RESULTS None of the horses had any clinically rele- vant medical findings on physical, hemato- logic, or biochemical analysis. Based on the failure to identify any medical cause for the behavior exhibited by the horses and the presence of characteristic clinical signs, ESMS was the confirmed diagnosis for each horse enrolled in the study. Gross inspection of the results indicated that of the four behaviors that were easily monitored, only self-mutilative attempts (including flank-biting) and hemiballismus occurred with sufficient frequency for mean- ingful analysis. Each of the remaining behav- iors occurred less than three times per hour. The relative frequency of self-mutilative attempts and hemiballismus varied among the horses during the control periods, and neither activity was more representative than the other of the syndrome. Thus, to obtain a sin- gle stable indicator of ESMS behavior, the numbers of self-mutilative attempts and kicks were summed for each horse at each time. The total hourly frequency of these signs at baseline was used as the criterion to evaluate the response to drug treatments. Because horses were affected to different degrees, median frequencies of the behaviors were used, rather than the mean. The same control eatments Administered to Horseseatments with Equine Self-Mutilation Syndrome

values were used for comparison in all trials Tr

(Figure 1). Detomidine Detomidine Detomidine Detomidine Detomidine Detomidine Detomidine Manipulation of the Dopaminergic System Dopamine Blockade

Acepromazine produced a significant (P < Sequence of .05) reduction in the frequency of signs for 3 hours following IV injection. However, it able 3. T Sequence of Drugs Given to Each Horse PSTDetomidine M DR RV MD NP B PB also produced generalized and an NaltrexoneMorphineAcepromazine NaltrexoneCocaineApomorphine Cocaine MorphineAmphetamine Apomorphine NaltrexoneClomipramine Acepromazine AmphetamineNo treatment Acepromazine MorphineHaloperidol Buspirone Apomorphine Naltrexone Amphetamine Clomipramine Cocaine Cocaine Apomorphine Haloperidol Amphetamine Morphine No treatment Naltrexone Buspirone Acepromazine Apomorphine Acepromazine Amphetamine Clomipramine No treatment Haloperidol Naltrexone Acepromazine Morphine Haloperidol Buspirone Haloperidol Buspirone Buspirone Haloperidol Acepromazine Morphine Cocaine Acepromazine Cocaine Morphine Buspirone Amphetamine Clomipramine Amphetamine Haloperidol Apomorphine Apomorphine Naltrexone Clomipramine Amphetamine Morphine No treatment Buspirone Apomorphine Cocaine Naltrexone Clomipramine Cocaine

Intern J Appl Res Vet Med • Vol. 2, No. 2, 2004 93 P=.012 P=.018 P=.036 P=.08 P=.33 P=.043 P=.068 P=.012 40 40 Baseline 30 30 Baseline Acepromazine Cocaine 20 20 10 10 No. of Events No. of Events 0 0 12 34 12 34 Time (hr) Time (hr)

P=.75 P=.08 P=.46 P=.14 P=.86 P=.05 P=.09 P=.035 40 40 Baseline Baseline 30 Haloperidol 30 Naltrexone 20 20 10 10 No. of Events No. of Events 0 0 12 34 12 34 Time (hr) Time (hr)

P=.55 P=.29 P=.12 P=.028 P=.042 P=.33 40 40 Baseline Baseline 30 Apomorphine 30 Morphine 20 20 10 10 No. of Events No. of Events 0 0 12 34 12 34 Time (hr) Time (hr)

P=.012 P=.09 P=.16 P=.48 P=.16 P=.028 P=.042 P=.33 40 40 Baseline Baseline 30 Detomidine 30 Buspirone 20 20 10 10 No. of Events No. of Events 0 0 12 34 12 34 Time (hr) Time (hr)

P=.89 P=.40 P=.22 P=.50 P=.46 P=.17 P=.60 P=.50 40 40 Baseline Baseline 30 Amphetamine 30 Clomipramine 20 20 10 10 No. of Events No. of Events 0 0 12 34 12 34 Time (hr) Time (hr)

Figure 1. The median number of kicks and self-mutilating attempts for horses before and after drug administration. P values refer to comparisons of treatment versus control values by the Wilcoxon signed rank test.

94 Vol. 2, No. 2, 2004 • Intern J Appl Res Vet Med associated decrease in all motor activities. Manipulation of the Opioid System Haloperidol also produced sedation, which Opioid Blockade was most pronounced during the first 2 Following an initial period of increased activ- hours following administration. The appar- ity lasting approximately 15 minutes, horses ent reduction in ESMS behavior following treated with naltrexone showed a significant haloperidol approached significance during (P < .05) reduction in the frequency of the second hour after treatment (Figure 1). ESMS events in the second and fourth hours Dopamine Activation following treatment. There was a reduction in Ten to 15 minutes after IV injection of apo- frequency of activities that approached sig- morphine, the horses began to exhibit loud, nificance during the third hour. During the stertorous breathing and circling in the stall. entire period after treatment, the horses Apomorphine reduced the frequency of signs showed mild sedation similar to that pro- 15 of ESMS, but the reduction did not the duced by nalmefene (Figure 1). level of significance when the hourly rate of Opioid Activation ESMS behavior was computed and compared Morphine produced a significant (P < .05) with that for the control measurements. decrease in ESMS behavior in the second Manipulation of and third hours following IV injection. Inhibition of Norepinephrine Release Increased motor activity was apparent toward the end of the first hour, possibly contribut- Detomidine, an α-2 blocker, produced a sig- ing to the decrease in ESMS behavior nificant (P < .05) reduction in the ESMS (Figure 1). score for the first hour after IV injection. The reduction approached significance dur- Manipulation of the Serotonergic System ing the second hour. As with acepromazine Buspirone, a serotonin agonist, produced a and apomorphine, the reduction in the fre- significant (P < .05) decrease in ESMS quency of ESMS behavior was associated activities in the second hour following oral with marked sedation (Figure 1). administration. The horses appeared alert Stimulation of Norepinephrine/Dopamine during the entire observation period, Systems although they exhibited considerable pacing in the stall. Clomipramine, administered Amphetamine and cocaine stimulate norepi- daily (PO) for 3 weeks did not provide any nephrine release and increase activity in observable affect on ESMS behavior in dopamine systems. Amphetamine did not these horses. significantly alter the frequency of ESMS events during the 4-hour test period. Treated DISCUSSION horses appeared anxious and spent most of The results support the contention that the time walking around the stall. They ESMS resembles human TS.3 The decrease became noticeably engaged in head bobbing in ESMS–related behavior produced by ace- and blinking. Cocaine produced a signifi- indicates that dopamine plays a cant (P < .05) reduction in ESMS activity in facilitatory role in ESMS as it does in the second and fourth hours following injec- TS.8,9,17,18 The duration of the effect of ace- tion. The reduction approached significance promazine was relatively prolonged, as during the third hour after drug administra- would be expected from a drug with a half- tion. Some horses became extremely tense life of 50 to 150 minutes and a prolonged and “frozen” in posture and showed con- pharmcodynamic action in horses.19 Also, stant twitching of their ears following the reduction in the frequency of ESMS administration of cocaine. Others engaged behavior observed for apomorphine, in head bowing, pawing, or biting at the although failing to achieve significance, is padding inside the stall (Figure 1). similar to what has been reported for this

Intern J Appl Res Vet Med • Vol. 2, No. 2, 2004 95 drug in the treatment of TS.17 The lack of administered to the horses every 30 minutes, significance may be attributable to apomor- the sustained (4-hour period) clinical effects phine’s short (<30 minutes) action in horses were an expected finding.26 after IV injection.15 It is also possible that 1- The suppression of ESMS activities with hour time blocks are too long for quantita- buspirone suggests a role for serotonergic tion of clinical response in this study. The modulation of the behavior. With TS, drugs apparent paradoxical response to dopamine that activate serotonergic systems have an receptor blockade and agonism in ESMS inhibitory effect on symptoms.9,27 Buspirone and TS may be a dose-related phenomenon, appeared to have 2 to 3 hours of activity at the result of selective presynaptic striatal the dosage used in this study (0.5 mg/kg). effects of dopamine agonists, or due to This duration of action is consistent with direct/indirect effects on sensory gating or earlier unpublished observations and with motor-output channels via postsynaptic, cor- published data on the of 12 tical dopamine receptors. buspirone in horses.28 The observation of a significant (P < Curiously, clomipramine, a preferential .05) decrease in ESMS behavior with deto- serotonin reuptake blocker, did not produce midine, an α-2 agonist, is in accord with to any significant effect on ESMS behavior in the response of humans with TS to cloni- the horses in this study. The lack of effect dine, a drug with a similar action.20,21 This may have been related to the short duration finding suggests a role for norepinephrine in of administration (3 weeks) or to the rela- facilitating both conditions. The duration of tively low dose employed. In humans, sero- detomidine’s clinical effect was in agreement tonin reuptake inhibitors are drugs of choice with what is known about its pharmacokinet- for the treatment of many aspects of TS, ics. Detomidine has a half-life of 1.78 hours although tics may be better controlled with following IV injection in horses.22 dopamine antagonists.9 A pronounced decrease in ESMS behav- Cocaine produced a significant (P < .05) ior was produced by the opioid antagonist, decrease in ESMS behavior in these horses, naltrexone. This finding is in agreement with which was not an expected finding, consid- an earlier report for another antago- ering that cocaine may induce tics in nist (nalmefene) used as a treatment for humans with TS.29 However, as with mor- ESMS.4 The results are also similar to find- phine, the ancillary actions of cocaine may ings reported for humans suffering from TS.23 have overshadowed its primary pharmaco- Both morphine and naltrexone caused a logic effect. Additionally, the actions of significant (P < .05) decrease in ESMS cocaine are difficult to identify because it behavior. The decreases observed after mor- blocks the reuptake of several monoamines, phine may have been secondary to increased and resulting stimulation of presynaptic motor activity, or they could be explained by receptors for these neurotransmitters may repletion of an otherwise deficient reward cause decreased motor activity. Thus, system, as hypothesized for various impul- cocaine’s effects may be somewhat ambiva- sive, addictive, and compulsive behaviors in lent and perhaps species and dose depend- humans.24 The response to these drugs might ent. Amphetamine produced no significant also be explained by their common action as decrease in ESMS behavior, perhaps N-methyl-D-aspartate–receptor antagonists.25 because the behavioral effects were over- Morphine’s effects only became apparent shadowed by the horses’ continuous walk- toward the end of the first hour following ing. In humans with TS, tend to administration of an “ dose” (0.1 exacerbate the symptoms.30 mg/kg) at the 30-minute mark. Considering The present study indicates that some morphine’s half-life in horses (87.9 minutes) manipulations of , dopamin- and with increasing doses of morphine being ergic, and systems in horses with

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