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Home , Fluphenazine, Typical antipsychotic

MEDICINE I

Adverse Side Effects in Horses Following the Administration of Decanoate

John D. Baird, BVSc, PhD*; and George A. Maylin, DVM, MS, PhD

Adverse behavioral side effects may occur in some horses after the intramuscular administration of fluphenazine decanoate. In severe cases, these side effects are difficult to manage and may be life-threatening to the horse, stable personnel, and treating veterinarians. The drug is not approved for use in the horse, and testing for fluphenazine is now conducted by various regulatory organizations involved in racing and equestrian competitions. Authors’ addresses: Department of Clinical Stud- ies, Ontario Veterinary College, University of Guelph, Guelph, ON Canada N1G 2W1 (Baird); and Equine Drug Testing and Research Program, New York Drug Testing and Research Program Mor- risville State College, 777 Warren Road, Ithaca, NY 14850 (Maylin); e-mail: jbaird@ovc. uoguelph.ca. *Corresponding author. © 2011 AAEP.

1. Introduction more commonly used clinically than fluphenazine Fluphenazine is a trifluoromethyl enanthate. In humans, the most common dosage of derivative (Fig. 1). The systematic International fluphenazine decanoate is 25 mg (range, 12.5 to 50 Union of Pure and Applied Chemistry (IUPAC) mg), with patients injected once every 2 weeks name of fluphenazine is 2-[4-[3-[2-(trifluoromethyl) (range, 1 to 4 weeks).1,5,6 After the IM of phenothiazin-10-yl]propyl]-piperazin-1-yl]ethanol fluphenazine decanoate, the drug gradually diffuses and it has the following structural formula. from the oily vehicle into the surrounding lymph nodes and tissues. Once the drug enters the tissue, 2. Clinical Pharmacology it is rapidly hydrolyzed by ubiquitous esterases, and Fluphenazine is a highly potent drug the parent compound (fluphenazine) is released. that has been used in human medicine in the main- The hydrolysis of fluphenazine decanoate has been tenance treatment of and other forms shown to be slow at the IM injection sites, probably of psychotic illness since the 1960s.1–3 Long-acting because the oil protects the ester from exposure to intramuscular depot formulations of fluphenazine, esterases. Hydrolysis of fluphenazine decanoate such as fluphenazine decanoate and fluphenazine has also been shown to occur in a variety of tissues enanthate, were developed for use in human pa- including the lymphatic system and blood.1 Anti- tients, who cannot be relied on to take oral antipsy- psychotic drugs are highly lipophilic, highly mem- chotic drugs.1,2,4 The fluphenazine decanoate ester brane-bound or protein-bound, and accumulate in markedly prolongs the duration of action. Flu- the brain, lung, and other tissues with a high blood phenazine decanoate is formulated as a sesame oil- supply. It is virtually impossible (and usually not based intramuscular (IM) and is necessary) to remove antipsychotic agents by dialy-

NOTES

AAEP PROCEEDINGS ր Vol. 57 ր 2011 57 MEDICINE I sequence of medications, the symptoms may be la- beled as .15 Neuroleptic- induced movement disorders or EPS are commonly encountered in humans after treatment with the typical .2,12 The signs of EPS include (i.e., , rigidity), bradykinesia (abnormal slowness of movement), akinesia (diffi- culty in initiating and maintaining movement), (i.e., abrupt onset, sometimes bizarre mus- cular spasms affecting mainly the musculature of the head and neck), and (inner restless- ness, compulsion to move).12,16,18 Fig. 1. Chemical structure of fluphenazine. Typical antipsychotics, such as fluphenazine, have a higher affinity for D2 receptors than dopa- mine and as a consequence more frequently elicit Parkinsonism than the newer atypical antipsychot- 5 sis. Studies in laboratory rats showed that flu- ics that bind more loosely to the dopamine D2 recep- 14,17 phenazine is 10-fold to 27-fold higher in brain tors. The incidence of acute EPS associated regions than is plasma.7 Fluphenazine may also with antipsychotics varies; however, most medical enter the fetal circulation and breast milk.5 researchers agree that neuroleptic-induced EPS oc- After a single injection of fluphenazine decanoate curs in 50% to 75% of patients who take typical in humans, an early high peak of the drug occurs antipsychotics.12,16 Most typical antipsychotics during the first day and then declines, with a half- have a narrow therapeutic index, which means that life ranging from 6.8 to 9.6 days. After multiple the separation between the dose that produces effi- injections of fluphenazine decanoate, however, the cacy and the one that produces EPS and other ad- mean apparent half-life increases to 14.3 days.8 verse effects is narrow.12 The individual response to treatment with antipsy- Dopamine D receptor antagonists, such as flu- 6,9 2 chotics is highly variable in humans. Patients phenazine, have also been shown to cause hyperp- must be monitored closely to find a dose that is both 19 6 rolactinemia. Hyperprolactinemia is commonly safe and effective. Humans treated with 25 mg observed in women administered therapeutic doses fluphenazine decanoate require 3 months to reach a 6 of typical antipsychotics resulting in , steady-state plasma level. Substantial evidence , , and infertility.15,16,19,20 exists that there is also a sex difference in antipsy- Studies in humans taking long-term antipsychotic chotic dosing, in that women require lower doses medications have also shown that they are at high given at longer intervals.10 risk of developing reduced bone mineral density Antipsychotic agents are also referred to as neu- as a consequence of hyperprolactinemia-induced roleptics and are categorized as either typical (also 19,20 known as first generation) or atypical (also known as hypogonadism. second generation).11 Fluphenazine is classified as a , which refers to the fact that 4. Fluphenazine in Horses when used in clinically effective dosages, they typi- Long-acting depot preparations of fluphenazine, cally induce extrapyramidal side effects (EPS) and such as fluphenazine decanoate and fluphenazine symptoms.12 Typical antipsychotics have also been 9 13,14 enanthate, have been administered off-label to referred to as classic, traditional, or conven- 21,22 12,15 horses for a long-lasting effect and as tional antipsychotics. The typical antipsychot- an and behavior modifier for horses in ics are associated with adverse side effects in training and competition.21–24 It also been used in humans that can affect every system of the body.16 horses undergoing stall rest after surgery,25 in man- 24 3. Mode of Action aging the behavior of young horses, and for the 26 The primary site of action for all antipsychotics is treatment of fescue toxicosis in pregnant mares. 17 There are also anecdotal reports of its use for aga- the dopamine D2 receptor. Dopamine transmis- sion has been found to play an important role in four lactia, head-shaking, and shivers. major pathways: nigrostriatal, mesolimbic, tu- Dowling (2004) stated that “before prescribing any beroinfundibular, and mesocortical. The nigrostri- drug for problem behavior in horses, the clinician atal circuit, originating from A8 and A9 groups of should have (1) a reasonable diagnosis; (2) an appre- dopamine cells, is well known from the impact of ciation for the mechanism of action of the drug; (3) a deficiencies. When these deficiencies occur natu- clear understanding of the potential side effects; (4) rally in the , Parkinson disease of- an understanding of how the drug will specifically ten develops with concomitant movement disorders, alter the problem behavior; and (5) an understand- rigidity, and so forth, and when they occur as con- ing of the potential for abuse (unethical use).22

58 2011 ր Vol. 57 ր AAEP PROCEEDINGS MEDICINE I 5. Reports of Adverse Reactions in Horses Extrapyramidal side effects after the intramuscular administration of fluphenazine decanoate, as re- ported in humans,5 have also been reported in the horse.21,23–25 The doses of fluphenazine decanoate administered to those horses that have shown EPS have ranged from 25 mg25 to 50 mg21,23 to 125 mg.23 Extrapyramidal signs are usually observed between 24 and 36 hours after fluphenazine decanoate ad- ministration.21,23,25 A case has been reported in which EPS signs were noticed 14 hours after the intramuscular administration of 37.5 mg of flu- phenazine enanthate24; another report described signs that developed 72 hours after the administra- tion of 50 mg fluphenazine decanoate.23 It is surprising that such severe and dramatic Fig. 2. Horse exhibiting abnormal posture and swinging of head EPS occur in horses (body weight, 400 to 450 kg) and neck after fluphenazine decanoate administration. after the administration of amounts of fluphenazine decanoate that are within the standard dose of 25 to 50 mg administered to adult humans (body weight, approximately 70 kg).1,23,24,27,28 Given this large behavior.21,23,24 Horses may become laterally re- body weight difference, it would appear that the cumbent21,25,31 and may paddle while recumbent.25 horse may be very susceptible to adverse side effects There are reports of seizures,21 jaw champing,25 and of fluphenazine decanoate.23,24 It has been pro- flank biting.23 posed that horses might be more susceptible to flu- Abnormal neurological signs have been observed phenazine-induced EPS because they may have a in neonatal foals nursing dams that have been ad- more extensive extrapyramidal system than that in ministered fluphenazine decanoate. Fluphenazine humans.25 To the author’s knowledge, there are no has been detected in the dam’s milk and serum of published studies on the of flu- the dam and her foal. phenazine decanoate in the horse. 7. Diagnosis 6. Clinical Signs Determination of serum or plasma fluphenazine Horses exhibiting extrapyramidal signs can be ex- concentrations can only be performed by a small tremely dangerous to humans.22–25,29 The violent number of equine analytical laboratories in North behavior of these horses presents considerable diag- America and throughout the world. Unfortunately nostic and therapeutic challenges. results are usually available after a minimum of 2–3 The clinical signs result from a dopamine-acetyl- weeks. This is not of great value when a veterinar- imbalance in the extrapyramidal motor sys- ian is confronted with a case of a horse exhibiting tem. The signs of EPS in horses are characterized extrapyramidal signs due to fluphenazine. However, by episodes of severe and somnolence determination of fluphenazine in serum or plasma is and the adoption of abnormal postures with inter- the “gold standard” and retrospectively is of value in vals of extremely frantic, repetitive, compulsive, manic movements.21,24,29,30 They may be reluctant to move forward, and when they do, some have a hypermetric gait.23,24,29 Muscle fasciculation has been noted.23–25 When placed in a stall, they ap- pear agitated and restless and may compulsively circle the stall.21,23–25,29,31 Episodes of repetitive and rhythmic neck flexion and head-tossing may occur.23–25,29 Horses may show a rhythmic side-to- side swaying of the head and neck23,25 (Fig. 2). Af- fected horses adopt abnormal postures and often stand with their forelimbs extended forward and may flex their head and neck ventrally and look backward between their forelimbs.21 Horses affected with EPS may have intermittent episodes of pawing that may become more frantic and violent.21,23–25 These pawing episodes may last for up to 1 to 2 minutes (Fig. 3). Horses have 24,25 25 also been reported to strike and rear. Pro- Fig. 3. Horse exhibiting frantic pawing after fluphenazine de- fuse sweating may occur as a result of this abnormal canoate administration.

AAEP PROCEEDINGS ր Vol. 57 ր 2011 59 MEDICINE I confirming the diagnosis. For most veterinarians, inhibitory transmitter. Under normal conditions, the history of fluphenazine administration within the - system maintains the last 72 hours, as well as clinical signs of rest- physiologic balance, resulting in coordinated neuro- lessness, agitation, bizarre behavior, violent and muscular activity.32 After the administration of frantic pawing, and abnormal movements of the fluphenazine, blockage of the dopamine D2 receptors head and neck, are supportive of a diagnosis of EPS. occurs, especially in the nigrostriatal system. The There have been wide variations in serum flu- neurotransmitters become dominant phenazine concentrations in horses with EPS.23–25 and overactive after the sudden withdrawal of dopa- In severe EPS, fluphenazine concentrations as high minergic inhibition, leading to an acute extrapyra- as 20.3 ng/mL24 and 39 ng/mL23 have been recorded, midal reaction.17 but there are also cases with marked signs with Centrally acting drugs that re- values of 3 to 4 ng/mL.23,25 Wide and highly fluc- store an appropriate dopamine-acetylcholine bal- tuating variations in serum or plasma fluphenazine ance, such as benztropine and concentrations have also been observed in humans.6 hydrochloride, may be used to treat the extrapyra- Plasma fluphenazine concentrations in the range of midal signs. Both drugs have been used in the 0.25 to 0.80 ng/mL have been considered to be prob- treatment of fluphenazine-induced EPS in the ably adequate for maintenance therapy.6 Asare- horse.21,22–25,29,31 sult of the highly lipophilic nature of fluphenazine, Diphenhydramine hydrochloride (0.67 to 1.0 the tissue levels may be more important than mg/kg IV) administered as a bolus or over 20 min- plasma or serum fluphenazine values. The author utes is the most widely used drug in the treatment of is not aware of any studies on tissue levels after EPS in the horse.23–25,31 If there is no response, a fluphenazine decanoate administration to the horse. second dose after an interval of approximately 15 minutes should be given.23,24 If there is still no 8. Differential Diagnoses response, benztropine mesylate (0.018 mg/kg IV q Differential diagnoses should include any disease 12 h or 0.04 mg/kg PO q 12 h) should be given.23 producing cerebrocortical dysfunction.28 The pri- Benztropine mesylate is a synthetic compound con- mary diagnostic rule-outs for fluphenazine-induced taining the tropine portion of and the EPS in a horse include rabies, equine herpes virus benzohydryl portion of diphenhydramine.32 Theo- (EHV)-1 myeloencephalopathy, equine protozoal retically, benztropine mesylate should have stronger myeloencephalitis (EPM), Eastern equine encepha- antiparkinsonic and anticholinergic effects than litis (EEE), Western equine encephalitis (WEE), diphenhydramine.5,32 Benztropine mesylate has West Nile virus (WNV), and fumonisin toxicity (i.e., both anticholinergic and antihistaminic effects.32 equine leukoencephalomalacia).23,25,28 Because In horses, it has been recommended that treatment many of the horses appear restless, agitated, with with benztropine mesylate (0.035 mg/kg PO q 12 h) constant walking and episodes of pawing, colic may should be continued for 7 to 10 days to prevent a also be a diagnostic possibility. In the western recurrence. In humans, a more rapid response has United States, nigropallidal encephalomalacia from been observed with antipsychotic-induced dystonic the chronic ingestion of yellow star thistle (Centau- reactions after treatment with benztropine mesylate rea solstitialis) or Russian knapweed (Centaurea than with diphenhydramine.13,16,32 repens) may also be considered as a possible diagno- In some horses with EPS, neither diphenhyd- sis.24,30 However, many of these diseases may not ramine hydrochloride23,25 or benztropine mesylate be considered primary rule-outs when the vaccina- is effective.23 In these refractory cases, supportive tion history and seasonal, environmental, and geo- therapy may be necessary. Intravenous graphic conditions are taken into account. If the and has been found to severe signs exhibited by some horses are not recog- be useful in managing the maniacal behavior of nized as being secondary to antipsychotic adminis- these horses.21,23,25,31 The ability to provide long- tration, it may lead to inappropriate euthanasia.29 term sedation and control of fluphenazine-induced central nervous system excitement without inducing 9. Treatment recumbency or anesthesia has been shown to be very Horses with EPS are often refractory to conven- beneficial in managing these severe cases.21 Intra- tional tranquilizers such as , , venous boluses or continuous-rate infusion of so- or romifidine or they may result in a variable and dium pentobarbital (2.6 to 5.5 mg/kg IV) have been transient effect.23–25,31 An intravenous catheter given to provide rapid sedation.21,23 In some should be placed whenever possible to allow easy horses, continuous-rate infusion of phenobarbital af- venous access for repeated sedation and fluid ter a loading dose of 12 mg/kg administered in 1 L administration. over 20 to 30 minutes21,25 and oral phenobarbital The principal treatment of fluphenazine-induced (10.6 mg/kg) has been used to manage these cases.25 EPS is based on the cholinergic-dopaminergic trans- While receiving , horses with EPS need mitter model.23–25,32 In the extrapyramidal sys- close monitoring for a period of 5 to 10 days, and, tem, especially in the basal ganglia, acetylcholine is ideally, serum phenobarbital levels should be mon- an excitatory transmitter, whereas dopamine is an itored to maintain the recommended therapeutic

60 2011 ր Vol. 57 ր AAEP PROCEEDINGS MEDICINE I range of 20 to 40 ␮g/mL.25 With improvement of for fluphenazine and . The New York the horse’s mental status and behavior, the admin- Racing and Wagering Board Rules of Racing that istration of phenobarbital may be gradually re- pertain to these drugs for Thoroughbreds is Rule duced.23,25 Intravenous may be 4043.7 and for Harness horses is Rule 4120.11. used in place of barbiturates.31 These rules state: “(a) Notwithstanding any incon- Balanced electrolyte solutions, such as lactated sistent provision of this part, a finding by the labo- Ringer’s solution, should be given IV during hospi- ratory that the drug reserpine or the drug talization to provide renal diuresis.21,23,25 Obser- fluphenazine was present in the sample taken from vation of a response to anticholinergic treatments a horse shall result in the disqualification of the (diphenhydramine, benztropine mesylate) for EPS horse from the race and from any share of the purse may place the viral encephalitides lower on the dif- in the race; and (b) The trainer of a horse which has ferential diagnostic list. been the subject of a finding by the laboratory that the drug reserpine or the drug fluphenazine was 10. Prognosis present in the sample taken from that horse shall The prognosis for the recovery of affected horses not be subject to application of trainer’s responsibil- tends to be good, and recovery is typically com- ity based solely upon the finding by the laboratory 28 plete. The prognosis may depend on the dosage, that the drug reserpine or the drug fluphenazine route of administration, frequency of administra- was present in the sample.” tion, and interval(s) between doses. Considerable The Fe´de´ration Equestre Internationale classifies difficulty may be involved in the treatment of these fluphenazine as a prohibited substance, which horses. Transportation to a referral hospital is means a substance that has been deemed by the recommended, but that may be difficult and hazard- Fe´de´ration Equestre Internationale to have no com- 23,25 ous. There are reports of horses being eutha- mon legitimate use in equine medicine and/or have a nized because of the severity of the behavioral high potential for abuse. Positive drug tests have abnormalities and the lack of response to conven- been reported. tional tranquilizers and (diphenhy- 23 Equine veterinarians who are involved in pre- dramine, benztropine mesylate). There are no purchase examinations may now request drug screen- reports of the long-term continuation of EPS in the ing tests that include detection of fluphenazine. horse, as reported in humans.12,16,25

11. Testing for Fluphenazine References In 1997, a highly sensitive and specific high-perfor- 1. Luo J-P, Hubbard JW, Midha KK. Sensitive method for the mance liquid chromatographic method with coulo- simultaneous measurement of fluphenazine decanoate and metric detection was developed for the simultaneous fluphenazine in plasma by high-performance liquid chroma- tography with coulometric detection. J Chromatogr B 1997; assay of fluphenazine and its metabolites in plasma. 688:303–308. The lower limit of quantification and detection of 2. Altamura AC, Sassella F, Santini A, et al. Intramuscular fluphenazine and its metabolites in equine plasma is preparations of antipsychotics: uses and relevance in clini- 0.1 ng/mL.1 cal practice. Drugs 2003;63:493–512. The United States Equestrian Federation (USEF) 3. Preskorn SH. CNS Drug Development, part I: the early period of CNS drugs. J Psychiatr Pract 2010;16:334–339. classifies fluphenazine as a forbidden substance and 4. Miller RS, Peterson GM, McLean S, et al. Monitoring warns that it is possible that long-acting forms of plasma levels of fluphenazine during chronic therapy with fluphenazine or its metabolites may remain detect- fluphenazine decanoate. J Clin Pharm Ther 1995;20:55–62. able in blood for long periods of time. For this 5. Baldessarini RJ, Tarazi FI. Drugs and the treatment of psy- reason, a 90-day withdrawal time is recommended chiatric disorders and mania. In: Hardman JG, Limbird LE, ed. Goodman & Gilman’s The Pharmacological to avoid inadvertent positive findings. Detection Basis of Therapeutics. 10th edition. New York: McGraw- depends on the formulation of the drug, dose or Hill, 2001:485–520. doses administered, frequency of administration, 6. Marder SR, Aravagiri M, Wirshing WC, et al. Fluphenazine route of administration, weight of the horse or pony, plasma level monitoring for patients receiving fluphenazine decanoate. Schizophrenia Res 2002;53:25–30. and health condition of the animal. Fluphenazine 7. Aravagiri M, Marder SR, Yuwiler A, et al. Distribution of testing was instituted by the USEF in 2003, and up fluphenazine and its metabolites in brain regions and other until 2010 there have been 48 positive tests in com- tissues of the rat. Neuropsychopharmacology 1995;13:235– petition horses under the USEF jurisdiction. The 247. penalties imposed for a positive fluphenazine test 8. Jann MW, Ereshefsky L, Saklad SR. Clinical pharmacoki- netics of the depot antipsychotics. Clin Pharmacokinet have ranged from $3000 to $6000 as well as suspen- 1985;10:315–333. sion from competing or taking any part whatsoever 9. Farde L, Wiesel F-A, Halldin C, et al. Central D2-dopamine in recognized competitions as an exhibitor, partici- receptor occupancy in schizophrenic patients treated with pant, or spectator for periods of 3 to 6 months. antipsychotic drugs. Arch Gen Psychiatry 1988;45:71–76. Any trophies, prizes, ribbons, and monies won by 10. Seeman MV. Gender differences in the prescribing of anti- psychotic drugs. Am J Psychiatry 2004;161:1324–1333. these horses must also be returned. 11. Leucht S, Corves C, Arbter D, et al. Second-generation ver- From November 1, 2003, the New York Racing sus first-generation antipsychotic drugs for schizophrenia: and Wagering Board commenced post-race testing a meta-analysis. Lancet 2009;373:37–41.

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