Adverse extrapyramidal effects in four horse given fluphenazine decanoate

John D. Baird Department of Clinical Studies, Ontario Veterinary College, University of Guelph, Guelph, ON N1G 2W1, Canada.

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Luis G. Arroyo Department of Clinical Studies, Ontario Veterinary College, University of Guelph, Guelph, ON N1G 2W1, Canada.

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Modest Vengust Department of Clinical Studies, Ontario Veterinary College, University of Guelph, Guelph, ON N1G 2W1, Canada.

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M. Kimberly J. McGurrin Department of Clinical Studies, Ontario Veterinary College, University of Guelph, Guelph, ON N1G 2W1, Canada.

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Alexander Rodriguez-Palacios Department of Clinical Studies, Ontario Veterinary College, University of Guelph, Guelph, ON N1G 2W1, Canada.

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Daniel G. Kenney Department of Clinical Studies, Ontario Veterinary College, University of Guelph, Guelph, ON N1G 2W1, Canada.

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Manickam Aravagiri Veterans Administration Greater Los Angeles Healthcare System, Building 210, Room 4, 11301 Wilshire Blvd, Los Angeles, CA 91311.

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George A. Maylin Equine Drug Testing and Research Program, Department of Population Medicine and Diagnostic Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY 14850.

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Abstract

Case Description—4 racehorses were examined because of markedly abnormal behavior following administration of fluphenazine decanoate.

Clinical Findings—Clinical signs included restlessness, agitation, profuse sweating, hypermetria, aimless circling, intense pawing and striking with the thoracic limbs, and rhythmic swinging of the head and neck alternating with episodes of severe stupor. Fluphenazine was detected in serum or plasma from all 4 horses. The dose of fluphenazine decanoate administered to 3 of the 4 horses was within the range (25 to 50 mg) routinely administered to adult humans.

Treatment and Outcome—In 2 horses, there was no response to IV administration of diphenhydramine hydrochloride, but the abnormal behavior in these 2 horses appeared to resolve following administration of benztropine mesylate, and both horses returned to racing. The other 2 horses responded to diphenhydramine administration. One returned to racing. The other was euthanized because of severe neurologic signs, respiratory failure, and acute renal failure.

Clinical Relevance—Findings indicate that adverse extrapyramidal effects may occur in horses given fluphenazine decanoate. These effects appear to be unpredictable and may be severe and life threatening. Use of fluphenazine decanoate as an anxiolytic in performance horses is not permitted in many racing and horse show jurisdictions, and analytic procedures are now available to detect the presence of fluphenazine in serum or plasma.

Abstract

Case Description—4 racehorses were examined because of markedly abnormal behavior following administration of fluphenazine decanoate.

Clinical Findings—Clinical signs included restlessness, agitation, profuse sweating, hypermetria, aimless circling, intense pawing and striking with the thoracic limbs, and rhythmic swinging of the head and neck alternating with episodes of severe stupor. Fluphenazine was detected in serum or plasma from all 4 horses. The dose of fluphenazine decanoate administered to 3 of the 4 horses was within the range (25 to 50 mg) routinely administered to adult humans.

Treatment and Outcome—In 2 horses, there was no response to IV administration of diphenhydramine hydrochloride, but the abnormal behavior in these 2 horses appeared to resolve following administration of benztropine mesylate, and both horses returned to racing. The other 2 horses responded to diphenhydramine administration. One returned to racing. The other was euthanized because of severe neurologic signs, respiratory failure, and acute renal failure.

Clinical Relevance—Findings indicate that adverse extrapyramidal effects may occur in horses given fluphenazine decanoate. These effects appear to be unpredictable and may be severe and life threatening. Use of fluphenazine decanoate as an anxiolytic in performance horses is not permitted in many racing and horse show jurisdictions, and analytic procedures are now available to detect the presence of fluphenazine in serum or plasma.

A 4-year-old Thoroughbred mare in race training (horse 1) was referred to the Ontario Veterinary College Veterinary Teaching Hospital in September 2002 with a 4-day history of bizarre behavior and neurologic signs. Four days earlier, the horse had reportedly reacted strangely when bandages were placed on the lower portions of its limbs, and the following day, the referring veterinarian administered flunixin meglumine (1.1 mg/kg [0.5 mg/lb], IV) because of signs of colic. On the morning of referral, the horse was found to be extremely agitated and had pawed at the floor of its stall to such an extent overnight that it had dug large holes in the floor. The horse was repetitively turning its head from side to side and had intermittent episodes of compulsive circling in a counterclockwise direction while in the stall. When tied up, the horse threw itself forcefully against the walls of the stable and had episodes of profuse sweating. Flunixin meglumine (1.1 mg/kg, IV), acepromazine (0.05 mg/kg [0.023 mg/lb], IV), xylazine hydrochloride (0.22 mg/kg [0.1 mg/lb], IV), and dexamethasone (0.05 mg/kg, IM) were administered by the referring veterinarian. Because minimal response was seen, the horse was referred for further evaluation. Three weeks prior to referral, the horse had received a single dose of a West Nile virus vaccine.a

On initial examination at the Veterinary Teaching Hospital, the horse appeared reluctant to move and had a high-stepping gait when made to walk. The horse was sweating profusely, especially on the right side of the neck. Continuous lateral movements of the head and neck were present, and coarse tremors were present in the hind limbs and over the flanks. The abdominal muscles appeared tense, and the posture adopted was consistent with signs associated with abdominal discomfort. Heart rate was 48 beats/min (reference range, 30 to 40 beats/min), respiratory rate was 12 breaths/min (reference range, 8 to 16 breaths/min), and body weight was 454 kg (1,000 lb).

The violent and unpredictable behavior of the horse made it unsafe to determine rectal temperature or conduct a detailed neurologic examination. Because of the neurologic signs and the occurrence of West Nile virus encephalomyelitis in Ontario at the time the horse was admitted,1 serum was submitted for testing with a capture ELISA for IgM against West Nile virus. An indwelling catheter was placed in the right jugular vein with considerable difficulty, and blood samples were collected for a CBC, serum biochemistry profile, determination of plasma fibrinogen concentration, and venous blood gas analysis. The only abnormalities were slightly high serum creatine kinase activity (551 U/L; reference range, 108 to 430 U/L), mild hyperglycemia (10.1 mmol/L; reference range, 3.7 to 6.7 mmol/L), and slightly high serum total bilirubin (85 μmol/L; reference range, 21 to 57 μmol/L) and unconjugated bilirubin (83 μmol/L; reference range, 18 to 55 μmol/L) concentrations. The serum biochemical abnormalities were attributed to muscle trauma, excitement, and inappetence, respectively.

Initial treatment consisted of IV fluid therapy with lactated Ringer's solution (75 mL/kg/d [34 mL/lb/d]) and administration of dexamethasone sodium phosphate (0.05 mg/kg, IV, q 24 h) and flunixin meglumine (1.1 mg/kg, IV, q 12 h). Results of the capture ELISA for IgM against West Nile virus were negative.

During the first 21 hours of hospitalization, the horse became extremely agitated with increasingly frequent episodes of circling, knuckling on the forelimbs, violent pawing with alternate forelimbs, profuse sweating, and rhythmic head tossing. Xylazine hydrochloride (0.33 to 0.66 mg/kg [0.15 to 0.30 mg/lb], IV), butorphanol tartrate (0.04 mg/kg [0.018 mg/lb], IV), diazepam (0.04 mg/kg, IV), dimethyl sulfoxide(1 g/kg [0.45 g/lb] as a 10% solution, IV, q 24 h), morphine (0.013 mg/kg [0.006 mg/lb], IV), detomidine hydrochloride (0.006 to 0.011 mg/kg [0.003 to 0.005 mg/lb], IV), and chloral hydrate (6 mg/kg [2.7 mg/lb], IV) were administered in an attempt to control the horse's violent behavior, but these medications had minimal to no effect. Extreme caution was necessary when administering these medications because of the horse's violent and unpredictable behavior.

On further questioning, the trainer reported that the horse had received fluphenazine decanoateb (50 mg, IM) on 15 occasions during the past 14 months because the horse was highly nervous in a racetrack setting. The last 2 doses had been administered 8 days and 30 hours prior to referral. Because of the history of fluphenazine administration and because behavioral signs were similar to those reported previously for 2 other horses given fluphenazine,2,3 a provisional diagnosis of adverse extrapyramidal effects secondary to fluphenazine administration was made.

Diphenhydramine hydrochloride (0.67 mg/kg [0.30 mg/lb], IV) was administered beginning 21 hours after admission of the horse to the Veterinary Teaching Hospital; however, there was no apparent response. Because of the lack of response to sedatives, tranquilizers, and diphenhydramine, a bolus of sodium pentobarbital (2 mg/kg [0.9 mg/lb], IV) was administered. This resulted in strong sedation and abatement of the abnormal behavior, and the horse became mildly responsive. However, approximately 2 to 3 hours after the bolus of pentobarbital was administered, the compulsive circling and rhythmic head tossing recurred. Three additional boluses of pentobarbital (2 mg/kg, IV) were administered with similar results; therefore, a constant rate infusion of pentobarbital was commenced. The dosage of pentobarbital was calculated by taking the amount (2 mg/kg) that had been effective as a bolus and infusing this amount of drug over 120 minutes. Additional doses of diphenhydramine (0.67 mg/kg, IV) were administered 45 and 69 hours after admission, and again, there was no response to this treatment.

On day 3, the horse became tachypneic and appeared to be in respiratory distress. The horse also stumbled and fell, sustaining lacerations above both eyes. The muzzle became swollen as a result of trauma with the forelimbs. During the first 4 days of hospitalization, the violent behavior of the horse was managed by maintaining the horse in a heavily sedated state with a constant rate infusion of sodium pentobarbital. Despite this treatment, there were multiple episodes of maniacal behavior that abated with bolus IV administration of sodium pentobarbital (1 mg/kg).

On day 5, treatment with benztropine mesylatec (0.035 mg/kg [0.016 mg/lb], PO, q 12 h) was commenced. Because an injectable formulation of benztropine was not available at the time, the drug was given orally. Within 5 hours, the horse showed a remarkable improvement and was responsive and alert. In addition, the frequency and severity of episodes of abnormal behavior and ataxia decreased noticeably. The dosage of sodium pentobarbital given as a constant rate infusion was gradually reduced over the next 2 days, as was the dosage of lactated Ringer's solution given IV; fluid therapy was discontinued on day 8. Mild proprioceptive deficits were noticed on day 8, but these deficits gradually abated during the next 24 hours.

By day 9, the horse was considered to be clinically normal. The horse was discharged on day 10. Blood samples were collected throughout the period of hospitalization commencing 29 hours after admission. Serum was separated and stored at −70°C until it could be submitted for determination of serum fluphenazine concentration. Serum fluphenazine concentration was quantitatively determined by use of a highly specific and sensitive liquid chromatography–triple quadrupole tandem mass spectrometer assay. There were marked fluctuations in serum fluphenazine concentrations with the highest serum fluphenazine concentration (39 ng/mL) being recorded 48 hours after admission. At the time of discharge, 12 days after 50 mg of fluphenazine decanoate had been administered IM, the serum fluphenazine concentration was 1.7 ng/mL. Benztropine (0.035 mg/kg, PO, q 12 h) was administered for 7 days after discharge. Following discharge, the horse had no additional episodes of abnormal behavior and successfully returned to racing 25 days after discharge.

A 2-year-old 470-kg (1,034-lb) Thoroughbred filly in race training (horse 2) was referred to the Ontario Veterinary College Veterinary Teaching Hospital in October 2002 with a 12-hour history of colic. Prior to referral, the referring veterinarian had administered 2 doses of flunixin meglumine (1.1 mg/kg, IV), a single dose of xylazine hydrochloride (0.42 mg/kg [0.19 mg/lb], IV), and mineral oil (4.54 L by nasogastric tube).

On initial examination, the horse was agitated, sweating excessively, and mildly dehydrated. Rectal temperature was 38.5°C (101.3°F), pulse rate was 44 beats/min, respiratory rate was 20 breaths/min, visible mucous membranes were hyperemic, and capillary refill time was 2 to 3 seconds. Nephrosplenic ligament entrapment was diagnosed by means of rectal palpation and abdominal ultrasonography. Phenylephrine hydrochloride (3 μg/kg/min [1.36 μg/lb/min], IV) was administered over 15 minutes, and the horse was exercised in a lunging ring for 20 minutes. Rectal palpation and abdominal ultrasonography were repeated, and the nephrosplenic entrapment had resolved. Flunixin meglumine(1.1 mg/kg, IV) was administered, and fluid therapy with lactated Ringer's solution (60 to 80 mL/kg/d [27 to 36 mL/lb/d], IV) was commenced.

During the next 6 hours, the horse remained restless, sweated profusely, and stood with an arched back with its head held low between its forelimbs. The horse circled the stall, pawed constantly, knuckled over on both front forelimbs, and swung its head from side to side. A detailed neurologic examination was performed, but apart from the behavioral signs, no other abnormalities were detected. The horse was not responsive to sedation with 2 doses of romifidine (0.04 mg/kg, IV, q 6 h).

On further questioning, it was disclosed that the horse had received fluphenazine decanoate (50 mg, IM) 3 days prior to referral. Diphenhydramine hydrochloride (0.67 mg/kg, IV) was administered, and over the next 6 hours, the circling and aggressive pawing ceased and the horse became quiet, alert, and responsive. Serum was collected before and 24 hours after administration of diphenhydramine for determination of serum fluphenazine concentration. Serum fluphenazine concentration was 3.34 ng/mL before and 0.94 ng/mL after diphenhydramine administration. The horse was discharged 66 hours after admission.

A 4-year-old 480-kg (1,056-lb) Standardbred gelding (horse 3) in training was referred to the Ontario Veterinary College Veterinary Teaching Hospital in March 2004 with a history of abnormal behavior that had commenced 24 hours after fluphenazine administration. Fluphenazine decanoate (125 mg, IM) had been administered as an anxiolytic because the horse was highly excitable on the racetrack. An additional dose of the drug had been administered 10 days earlier. The horse's behavior was considered normal until 24 hours after the second fluphenazine injection, when the horse was observed by the trainer to be agitated, shaking, and pyrexic (rectal temperature, 40.0°C [104.0°F]). The horse forcefully threw itself against the walls of the stable, exhibited muscle trembling, would kneel on both carpi, and would swing its head repetitively from side to side. Prior to referral, the referring veterinarian had administered diphenhydramine (1 mg/kg, IV) and reported that there had been a slight improvement in the horse's behavior following this treatment. However, the improvement was of a short duration. Five additional doses of diphenhydramine were administered. Subsequently, benztropine mesylate (0.018 mg/kg [0.008 mg/lb], IV, q 12 h) was administered 3 times during the next 36 hours.

On admission, the horse was in good body condition. It was restless, had an anxious expression, and was sweating excessively. Rectal temperature was 38.4°C (101.1°F), heart rate was 64 beats/min, respiratory rate was 12 breaths/min, and the buccal mucous membranes were traumatized and congested. The horse had facial and intermandibular edema and lacerations secondary to repeated head trauma. The dorsal aspects of both carpi and both metacarpophalangeal joints were lacerated and swollen, which was attributed to the kneeling posture the horse adopted prior to referral. No borborygmi were heard during auscultation of the right and left sides of the abdomen. Fluid therapy with lactated Ringer's solution (60 to 80 mL/kg/d, IV) was commenced.

Shortly after admission, the horse started pawing and swinging its head from side to side and had generalized muscle trembling. A bolus of sodium pentobarbital (2 mg/kg, IV) was administered, and a constant rate infusion of sodium pentobarbital (2.5 mg/kg/h [1.14 mg/lb/h], IV) was commenced in an attempt to control the abnormal behavior (circling, pawing). Treatment with benztropine mesylatec (0.018 mg/kg, IV, q 8 h) was begun 2.5 hours after admission, and diphenhydramine (1 mg/kg, IV, q 24 h) was administered 4 hours after admission.

Blood samples were collected 10 hours after admission and submitted for a CBC, serum biochemistry profile, determination of plasma fibrinogen concentration, and venous blood gas analysis. The only abnormalities were high serum creatine kinase (1,357 U/L), mild hyperglycemia (7.3 mmol/L), slightly high serum total bilirubin (91 mmol/L) and unconjugated bilirubin (88 mmol/L) concentrations, and slightly high serum urea nitrogen (10.9 mmol/L; reference range, 4.2 to 8.9 mmol/L) and creatinine (153 mmol/L; reference range, 80 to 130 mmol/L) concentrations. These abnormalities were attributed to muscle trauma, stress, inappetence, and prerenal azotemia.

Approximately 24 hours after admission, the horse was sedated. The horse had appeared to become brighter following initiation of benztropine treatment, and the head tossing and other abnormal behaviors had abated. However, during the first 24 to 36 hours of hospitalization, the edema of the head, face, and lips had progressed to such an extent that respiration was compromised. In addition, the edema was so extensive that it was difficult for the horse to prehend and masticate hay. Flunixin meglumine (1.1 mg/kg, IV, q 12 h for 7 days) and furosemide (0.5 mg/kg [0.23 mg/lb], IV, q 12 h for 48 h) were administered in an attempt to reduce the edema.

During day 2 of hospitalization, the horse had episodes of agitated behavior lasting 2 to 3 hours. Excessive sweating was seen, and the horse circled its stall, repeatedly swinging its head from side to side and mutilating itself by biting at its thorax and flanks. Whenever any attempt was made to reduce the dosage of sodium pentobarbital given as a constant rate infusion, the lateral swinging of the head, profuse sweating, and flank biting would recommence. Boluses of sodium pentobarbital (2 mg/kg, IV) were administered to control these episodes of agitated behavior.

During day 3 of hospitalization, the edema of face and nostrils became so severe that an emergency tracheotomy was performed. Following the tracheotomy, sodium penicillin (30,000 U/kg [13,636 mg/lb], IV, q 6 h) and gentamicin (6.6 mg/kg [3 mg/lb], IV, q 24 h) were administered for 7 days. The edema of the head and face gradually resolved over the next 24 hours, and the horse was gradually able to eat increased amounts of feed. During the next 5 days of hospitalization, the frequency and severity of episodes of abnormal behavior decreased. The dosage of sodium pentobarbital was gradually reduced over a 48-hour period, and administration was discontinued on day 8. Intravenous fluid therapy was discontinued on day 9.

Fluphenazine was detected in all serum samples obtained up to the time of discharge, 12 days after the last dose of fluphenazine decanoate had been administered. The highest serum fluphenazine concentration (33 ng/mL) was recorded on day 2 of hospitalization, and serum fluphenazine concentration at the time of discharge was 1.3 ng/mL. The horse was discharged after 10 days of hospitalization and returned to racing after 2 months.

A 2-year-old Standardbred filly (horse 4) that was about to commence training was administered fluphenazine decanoated (40 mg, IV) by the farm veterinarian because of erratic behavior that made the filly difficult to train. According to the trainer, this was the first time fluphenazine had been administered. The horse appeared to be behaving normally until 36 hours after fluphenazine administration, when it was found standing in the paddock with its head and neck bent ventrally and a constant oscillatory rotation of the head. The horse adopted a very strange posture with both forelimbs extended and the poll of the head resting on the ground, so that the horse was looking at its abdomen. The horse could not walk forwards but was able to move backwards.

Approximately 48 hours after the fluphenazine injection, the horse became laterally recumbent and had a markedly reduced respiratory rate and effort. The oscillatory head movement continued during this time, resulting in head trauma, especially around the right orbit. The horse remained in lateral recumbency for approximately 8 hours and did not eat or drink during this time. Treatment consisted of oral administration of 20 L of an electrolytes solutione and IV administration of flunixin meglumine(1.1 mg/kg). Edema of the muzzle developed 60 hours after fluphenazine decanoate administration.

When examined on the farm by 2 of the authors (JDB, LGA) 72 hours after fluphenazine administration, the horse had signs of extreme depression and was standing with its head held just above the ground so that from a distance it appeared as though the horse was grazing. The horse could not raise its head and had a continuous, rapid, oscillatory rotary motion of the head. Muscle fasciculations involving the triceps muscle group bilaterally were present. Blood was collected for a serum biochemistry profile. The only important abnormalities were severe azotemia (serum urea, 31.6 mmol/L; serum creatinine, 756 mmol/L), hypernatremia (158 mmol/L; reference range, 136 to 144 mmol/L), hypercholesterolemia (4.68 mmol/L; reference range, 1.7 to 2.7 mmol/L), hyperproteinemia (84 g/L; reference range, 58 to 75 g/L), and hyperalbuminemia (45 g/L; reference range, 30 to 37 g/L). Serum creatine kinase (5,516 U/L), aspartate aminotransferase (1,926 U/L), and alkaline phosphatase (760 U/L; reference range, 119 to 329 U/L) activities were also high.

Diphenhydramine hydrochloride (1.5 mg/kg [0.68 mg/lb], IV) was administered as a slow IV bolus. Within 1 minute, the horse became brighter, more alert, and more responsive and stood with 1 forelimb raised in the air. The oscillatory rotary head motion ceased, and the horse was able to lift its head into a normal position and vocalized. The horse had sustained considerable trauma to the right eye and orbit and buccal mucosa. A second dose of diphenhydramine (1.5 mg/kg, IV) was given 4 hours later, and treatment with benztropine mesylate (0.035 mg/kg, PO, q 12 h) was commenced.

Blood was collected 72, 76, and 88 hours after fluphenazine decanoate administration and submitted for determination of serum fluphenazine concentration. Serum fluphenazine concentrations were 1.5, 0.9, and 0.57 ng/mL 72, 76, and 88 hours, respectively, after fluphenazine decanoate administration.

Approximately 92 hours after fluphenazine administration, the horse suddenly developed severe respiratory distress and edema of the nasal mucous membranes. Oxygen (10 L/min) was administered through an intranasal catheter, but the horse became recumbent and started paddling. The horse was euthanized 93 hours after fluphenazine decanoate administration; a necropsy was not performed.

Discussion

Fluphenazine is a highly potent phenothiazine neuroleptic4,5 that is widely used in human medicine for maintenance treatment of schizophrenia and other forms of psychotic illness.6–8 Long-acting or IM depot formulations of fluphenazine such as fluphenazine decanoate are typically used in human patients who can not be relied on to take antipsychotic drugs orally.8–10 In horses, depot formulations of fluphenazine have been used to provide a long-lasting sedative effect.11 Because plasma and urine concentrations rapidly fall below the limits of detection for available assays, abuse may result.11 To the authors' knowledge, only 2 reports2,3 have been published previously describing adverse extrapyramidal effects and Parkinsonism in horses following administration of long-acting forms of fluphenazine.

The present report describes severe behavioral abnormalities that were observed in 4 racehorses 24 to 36 hours after administration of fluphenazine decanoate. The clinical signs that were observed were consistent with previous reports of adverse extrapyramidal effects and Parkinsonism in horses2,3,12 and included agitation, profuse sweating, hypermetria, aimless circling, intense pawing and striking with the thoracic limbs, and rhythmic swinging of the head and neck alternating with episodes of severe stupor.

Three of the horses described in the present report had received fluphenazine decanoate by IM injection, and 1 had received the drug by IV injection. Fluphenazine was detected in the serum samples obtained from all 4 horses during hospitalization and at the time of discharge. Three horses recovered following intensive care and returned to racing, but the remaining horse was euthanized because of severe neurologic signs and respiratory failure. This horse also had serum biochemical abnormalities compatible with acute renal failure.

Antipsychotic agents, also referred to as neuroleptics, are categorized as typical or atypical. The term typical antipsychotics refers to those antipsychotics that when used in clinically effective dosages typically induce extrapyramidal effects.13 The discovery of the dopamine D2 receptor has led to the confirmation that this receptor is the primary site of action for all antipsychotics.14,15 Typical antipsychotic such as fluphenazine have a higher affinity for dopamine D2 receptors in the brain than does dopamine itself, whereas the newer atypical antipsychotics, which elicit little or no Parkinsonism, bind more loosely than dopamine to dopamine D2 receptors.14 Fluphenazine dissociates slowly from these dopamine D2 receptors, and this slow dissociation is associated with a greater risk that adverse extrapyramidal signs will be induced.5,14

When dopamine transmission deficiencies occur naturally in the substantia nigra, Parkinson's disease often develops with concomitant movements disorders, such as rigidity, among others. When these deficiencies occur as a consequence of medications, the signs are considered adverse extrapyramidal signs.16 Neurolepticinduced movement disorders or adverse extrapyramidal signs are commonly encountered in humans following treatment with typical antipsychotics.8,13,17 These adverse signs include Parkinsonism, akinesia, bradykinesia, dystonia, and akathisia13,17 and can develop within a few days after the start of or after months of antipsychotic treatment.

Most typical antipsychotics have a narrow therapeutic index,13 and in humans, the individual response to treatment with antipsychotics is variable.18 Although antipsychotic potency and antipsychotic dose are unequivocal risk factors for drug-induced Parkinsonism, the development of this adverse effect is notoriously unpredictable.19 The typical antipsychotics, such as fluphenazine, are associated with adverse effects involving every system of the body.17

Fluphenazine is available in formulations for oral and IM administration.7,8 The 2 long-acting depot formulations for IM administration are fluphenazine decanoate and fluphenazine enanthate.8 Fluphenazine decanoate is formulated in a sesame seed oil base and, in human patients, is typically given by IM injection every 2 to 3 weeks.10 The fluphenazine decanoate dosage for adult humans ranges from 25 to 50 mg, IM, every 2 weeks20–22 to 12.5 to 100 mg, IM, every 6 weeks.8,22 To the authors' knowledge, no studies of the pharmacokinetics of fluphenazine decanoate in horses have been published, and the only published dosage for fluphenazine in horses is 0.05 to 0.08 mg/kg (0.023 to 0.036 mg/lb), IM, every 2 weeks, with a warning to beware of idiosyncratic reactions.23

Following IM injection of fluphenazine decanoate, the drug gradually diffuses into the surrounding tissues. Enzyme-mediated hydrolysis of fluphenazine decanoate occurs in various parts of the body, including the injection site, lymphatic system, and blood.10 Antipsychotic drugs are highly lipophilic and highly membrane or protein bound, and they accumulate in the brain, lungs, and other tissues with a high blood supply.5 They also enter the fetal circulation and breast milk.5 In humans, IM administration of fluphenazine decanoate rapidly results in a high plasma concentration of fluphenazine, with time to peak plasma concentration being 8 to 10 hours, followed by a sustained plateau in concentration.8 The elimination half-life of fluphenazine decanoate in humans is 14.3 days.8 The onset of action is usually 1 to 3 days, with clinically apparent effects on psychosis typically evident within 2 to 4 days. Patients who have received multiple depot fluphenazine injections continually absorb the drug from the multiple injection sites. Horses 1 and 3 in the present report were given multiple doses of fluphenazine decanoate within a shorter period of time than is recommended for human patients with schizophrenia, and the adverse extrapyramidal signs may have developed because of continued absorption of fluphenazine from multiple depots. The time to reach a stable state in human patients receiving long-acting antipsychotics can range from 4 to 6 weeks8 to 3 to 6 months.23 A major disadvantage of using long-acting depot formulations of antipsychotics is that the drug can not be rapidly withdrawn if adverse effects occur.8 It is virtually impossible to remove antipsychotic drugs by dialysis.5

In 1997, a highly sensitive and specific high-performance liquid chromatographic assay with coulometric detection was developed for the simultaneous assay of fluphenazine decanoate and fluphenazine concentrations in plasma.20 The detection limit of this assay, for both fluphenazine decanoate and fluphenazine, is 0.1 ng/mL of plasma.20 For all 4 horses described in the present report, this assay was used to measure serum fluphenazine concentrations. However, these concentrations should be interpreted with caution because although effective plasma concentrations have been established for some antipsychotics in humans, considerable interpatient variation9 occurs and variability in dosage requirements for antipsychotic drugs is well recognized.24 In people, high plasma concentrations of fluphenazine can be detected months after treatment has been discontinued.7

In 2 previous reports2,3 of horses with adverse effects associated with fluphenazine administration, abnormal behaviors developed 14 hours after IM administration of 50 mg of fluphenazine decanoate2 and 16 hours after IM administration of 37.5 mg of fluphenazine enanthate.3 In the horses described in the present report, the dose of fluphenazine decanoate ranged from 40 mg (horse 4) to 50 mg (horses 1 and 2) to 125 mg (horse 3). As mentioned in a previous report,3 it is surprising, given the body weight difference, that such severe and dramatic extrapyramidal signs would develop in horses given doses of fluphenazine decanoate similar to those administered to adult humans with schizophrenia.8,20,21,25 This at least suggests that horses may be more susceptible to the adverse effects of fluphenazine decanoate. In our experience, some veterinarians consider severe adverse effects following fluphenazine decanoate administration to be uncommon. However, because the drug is not labeled for use in horses, it is not possible to obtain accurate or reliable data on the frequency of these effects. The severity of the extrapyramidal signs that were seen in the horses described in the present report posed considerable safety risks for veterinarians and hospital staff treating these horses, and it is possible that other horses that developed similar signs following fluphenazine administration were simply euthanized without any recognition of the fact that these signs were secondary to fluphenazine administration. The authors are aware of horses that have been euthanized on farms or at referral hospitals because the horse became maniacal, extremely dangerous, and unmanageable following administration of fluphenazine decanoate.

The principal treatment for neuroleptic-induced dystonic reactions is based on the cholinergic-dopaminergic transmitter model.26 Under normal conditions, the cholinergic-dopaminergic system maintains physiologic balance, resulting in coordinated neuromuscular activity.26 Treatment, therefore, consists of either restoring dopaminergic function by discontinuing antipsychotic drug administration, enhancing cholinergic function by administering anticholinergic medications, or both.26 In humans, parenteral administration of anticholinergics such as benztropine mesylate or diphenhydramine hydrochloride, which has antihistaminic and anticholinergic effects, has been successfully used to treat druginduced dystonic reactions.16,26,27 Benztropine mesylate is a synthetic compound containing the tropine portion of atropine and the benzohydryl portion of diphenhydramine hydrochloride26; it has both anticholinergic and antihistaminic effects.26,27 Acute dystonic reactions in humans generally respond rapidly to benztropine mesylate (0.02 mg/kg [0.009 mg/lb], IV or IM) administration.17,27–29 A response is typically seen within 20 minutes after benztropine administration, although administration of a second dose may be necessary after 30 minutes in particularly severe cases,27–29 and treatment with anticholinergic drugs is usually continued for 4 to 7 days to prevent a recurrence.4 If there is no response to initial treatment, an alternative anti-Parkinsonian agent, such as diphenhydramine hydrochloride, may be given.28 Theoretically, benztropine mesylate should have stronger anti-Parkinsonian and anticholinergic effects than diphenhydramine hydrochloride alone.26

In a previous report,3 a yearling Thoroughbred filly that developed adverse effects after being given fluphenazine was successfully treated with diphenhydramine hydrochloride. The abnormal behavior resolved within 3 minutes; however, signs returned 18 hours later, and a second treatment with diphenhydramine hydrochloride was required. No further treatment was necessary.3 In contrast, IV administration of diphenhydramine hydrochloride resulted in complete recovery in only 1 of the 4 horses (horse 2) described in the present report. Temporary improvement was seen in a second horse (horse 4), but no observable clinical response was noticed following diphenhydramine administration in the remaining 2 horses.

To the authors' knowledge, this is the first published report in which benztropine mesylate has been used in treating adverse extrapyramidal signs that developed following administration of fluphenazine decanoate in horses, although 2 previous reports30,31 describe the successful use of benztropine mesylate (8 mg, IV) to treat priapism in 2 mature horses. In horse 1, it is not known whether the rapid improvement in behavior and neurologic status could be attributed solely to oral administration of benztropine mesylate. Tranquilizers had little or no effect in controlling the maniacal behavior in this horse or in the other 3 horses. However, intravenous administration of sodium pentobarbital was successfully used in 2 horses (horses 1 and 3) to provide long-term sedation and control of maniacal behavior without inducing recumbency or anesthesia.

Fluphenazine was detected in serum from all 4 horses in the present report, with concentrations as high as 39 ng/mL. To our knowledge, only a single previous report3 describes measurement of serum fluphenazine concentration in a horse, but the assay method used was not stated. Plasma fluphenazine and fluphenazine decanoate concentrations have been found to be stable in samples stored for up to 1 month at −20°C.20

The clinical signs and laboratory findings in 3 (horses 1, 3, and 4) of the 4 horses in the present report bear many similarities to a syndrome described in human medicine as neuroleptic malignant syndrome.17,32–36 Neuroleptic malignant syndrome is an infrequent but potentially life-threatening neurologic emergency most commonly associated with neuroleptic drug administration.17 Long-acting depot preparations of fluphenazine have been and continue to be used in an extralabel manner in racehorses and horses used in other equestrian sports because of their anxiolytic and sedative effects. Anecdotally, fluphenazine has been used to facilitate handling of wild or feral horses and to improve concentration and rider responsiveness and enhance performance during competitive situations in trained horses with high-strung personalities.37 Before prescribing any drug for behavior problems in horses, veterinarians should have an appreciation for the mechanism of action of the drug as well as a clear understanding of the potential adverse effects and potential for abuse.11 The United States Equestrian Federation lists fluphenazine as a forbidden substance and strongly recommends that fluphenazine not be administered to a horse or pony for at least 90 days prior to competition. The Federation suspended 30 trainers between 2003 and 2005 for exhibiting horses that had been given fluphenazine or that tested positive for fluphenazine. In November 2003, the New York Racing and Wagering Board began postrace testing for fluphenazine, and in the first 2 years of fluphenazine testing, initiated 19 prosecutions because of positive postrace fluphenazine test results in Thoroughbreds and harness racehorses.

In describing these 4 cases, the authors wish to convey to veterinarians that development of adverse extrapyramidal signs following administration of fluphenazine decanoate in horses, as in humans, is unpredictable. Affected horses are extremely difficult to treat because of their maniacal and violent behavior, and the clinical and behavioral signs may be similar to those associated with colic and various inflammatory neurologic diseases. The diagnosis of drug-induced adverse extrapyramidal signs may be hindered by the fact that owners and trainers may not be forthcoming in informing their veterinarians that horse have received an illegal antipsychotic medication, which may delay institution of appropriate treatment or result in inappropriate euthanasia.12 Information regarding recently administered medications is critical for the management of these cases.

a.

West Nile virus vaccine, Fort Dodge Animal Health, Fort Dodge, Iowa.

b.

pms-Fluphenazine decanoate, Pharmascience Inc, Montréal, QC, Canada.

c.

pms-Benztropine, Pharmascience Inc, Montréal, QC, Canada.

d.

Fluphenazine Omega, Omega Laboratories Ltd, Montréal, QC, Canada.

e.

Electrolytes concentrated, Vétoquinol NA Inc, Lavaltrie, QC, Canada.

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