Pharmacologic Treatment of Equine Self-Mutilation Syndrome
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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 Pharmacology, 136 Harrison Avenue, Boston, MA 02111 KEY WORDS: horse self-mutilation, sero- opioid-receptor antagonist naltrexone and tonin, dopamine, opioid, norepinephrine, the serotonin agonist buspirone. 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 aggression,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 geldings 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to the were reported to be affected (U. A. Leuscher horses in a saline-controlled behavioral and D. B. McKeown, unpublished data).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, Acepromazine, 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 hemiballismus. Detomidine, an α-2 precipitation by trauma.4–7 antagonist, also produced a significant (P < .05) reduction in these behaviors, as did the Endorphins and enkephalins 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 Opioids 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 Gelding Quarter horse 13 dopamine antagonists (e.g., haloperidol) and RV Stallion Arabian 12 agonists (e.g., apomorphine 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 serotonergic 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 dopamine antagonist and a case analysis. Finally, at least 48 hours after report describing the suppression of ESMS admission to the clinic, horses were tics with nalmefene, an opioid antagonist.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 mechanism of action. 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, morphine, acepromazine, cocaine, gastric endoscopy, retinal examination, apomorphine, amphetamine, clomipramine, 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 dopaminergic and noradrenergic activity Apomorphine 0.06 IV Increases dopaminergic activity Buspirone 0.5 (2 hours PO Partial agonist for serotonin receptors prior to taping) Clomipramine 1–2 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 0.5–1.0 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 pharmacodynamics 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 injection 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