A Retrospective Study on the Use of Acepromazine Maleate in Dogs With Seizures

Introduction

Phenothiazines are commonly used in small animals to reduce anxiety and enhance the effects of sedatives, anesthetics, and analgesics.¹ Phenothiazines are classified as neuroleptic, because they suppress spontaneous movements and complex behavior while leaving spinal reflexes and unconditioned antinociceptive behaviors intact.¹ The central mode of action of phenothiazines is thought to be antidopaminergic.^1,2 On electroencephalography (EEG), neuroleptic drugs slow the frequency and variability of EEG discharge patterns and decrease arousal-induced changes. These effects are reversed by dopaminergic agonists.^1,2

Some phenothiazines, particularly aliphatic phenothiazines with low potency (e.g., chlorpromazine), reduce seizure threshold and induce EEG discharge patterns similar to those seen with epileptic seizure disorders.¹ In dogs with histories of seizures but no underlying metabolic diseases or encephalitis, rapid infusion of chlorpromazine (2.2 mg/kg intravenously [IV]) induced or potentiated EEG alterations in 22 of 43 dogs and precipitated seizures in two of the dogs.³ Because acepromazine is an aliphatic phenothiazine, it is generally avoided as a tranquilizer in dogs with histories of seizures.^4–8 Although seizures after administration of acepromazine have been reported anecdotally, effects of the drug in dogs with prior seizures have not been well documented.^9,10 The purpose of this retrospective study was to evaluate the responses of dogs with seizures to the administration of acepromazine.

Materials and Methods

Medical records from July 1, 1991 through June 30, 2003 were searched for dogs with a diagnosis of seizures. Search terms included epilepsy, epileptic, and seizures. Dogs with hepatic encephalopathy were not included in the study. Records were reviewed for evidence of acepromazine administration. For dogs that received acepromazine, the following were recorded: signalment, age at seizure onset, anticonvulsant medications administered at the time of referral, seizure etiology, indications for and usages of acepromazine, and dosage and effects of acepromazine.

Results

Over the 12-year period, 737 dogs had a diagnosis of seizures. Forty-seven of these dogs had histories of seizures before referral and received acepromazine after seizures were diagnosed and they were included in the study. Affected breeds that received acepromazine included the mixed-breed dog (n=7), Labrador retriever (n=5), American cocker spaniel (n=5), boxer (n=4), pug (n=3), beagle (n=2), Boston terrier (n=2), miniature poodle (n=2), German shepherd dog (n=2), golden retriever (n=1), bichon frise (n=1), border collie (n=1), Cavalier King Charles spaniel (n=1), dachshund (n=1), Doberman pinscher (n=1), English bulldog (n=1), German shorthaired pointer (n=1), miniature schnauzer (n=1), Pekingese (n=1), rottweiler (n=1), shih tzu (n=1), Siberian husky (n=1), Silky terrier (n=1), and Yorkshire terrier (n=1). Ages at presentation ranged from 0.3 to 14 years (median 6 years), with a median age of 3.75 years (range 0.2 to 14 years) at seizure onset. Fourteen dogs were being treated for seizures with oral phenobarbital, and four dogs were being treated with oral potassium bromide at the time of referral.

Etiologies of seizures included brain masses consistent with neoplasia (n=4), brain cyst (n=1), head trauma (n=1), congenital hydrocephalus (n=1), insulinoma (n=1), cerebral thromboembolism secondary to autoimmune hemolytic anemia (n=1), diffuse granulomatous meningoencephalitis (n=1), and Rocky Mountain spotted fever (n=1). Three dogs were diagnosed with idiopathic epilepsy.¹¹

Thirty-three dogs had no identifiable diagnosis. Fifteen of these dogs could have been classified as having idiopathic epilepsy based on age at seizure onset (i.e., 1 to 5 years), history (i.e., recurrent seizures without persistent neurological deficits), and normal laboratory test results.¹¹ Four of these 15 dogs underwent advanced diagnostic testing, including computed tomography (CT) scan (n=3) and cere-brospinal fluid (CSF) analysis (n=3), and results were normal in all dogs. Eight additional dogs with no definitive diagnosis and no classification of idiopathic epilepsy underwent advanced diagnostic testing, including CT scan (n=5), CSF analysis (n=7), and measurement of CSF distemper titers (n=1). One of these dogs had diffuse cerebral swelling on CT scan, with a normal CSF. Another dog had inflammatory cells on CSF analysis, but a normal CT scan. Distemper titers, CSF analyses, and CT scans were normal in the remaining dogs. Advanced diagnostic testing was not performed in 10 dogs that did not fit the criteria of idiopathic epilepsy. Hypothyroidism (n=1) and hypoxia secondary to brachycephalic syndrome (n=1) were thought to be contributing factors in two of these dogs.

For dogs that received acepromazine, the following treatment groups were identified: tranquilization for diagnostic testing (n=16); anesthetic premedication (n=15); improvement of postanesthetic recovery (n=6); reduction of excitement or anxiety during hospitalization (n=14); and reduction of frequency or severity of seizures (n=11). Eleven dogs that received multiple doses of acepromazine were included in two or more groups.

Acepromazine maleate^a (0.005 to 0.07 mg/kg IV) in combination with butorphanol^b (0.2 to 0.4 mg/kg IV) was administered once (n=13) or twice (n=3) to 16 dogs with histories of seizures to provide sedation for radiographic, scintigraphic, or electrodiagnostic testing. Fifteen dogs with histories of seizures received acepromazine (0.01 to 0.065 mg/kg IV [n=5], intramuscularly [IM; n=9], or subcutaneously [SC; n=1]) as an anesthetic premedicant in combination with butorphanol (0.2 to 0.4 mg/kg IV or IM; n=12), atropine^c (0.044 mg/kg IV or IM; n=8), glycopyrrolate^d (0.011 mg/kg IV or IM; n=5), diazepam^e (0.4 to 0.66 mg/kg IV; n=4), tiletamine/zolazepam^f (4.4 mg/kg IM; n=1), or morphine^g (0.94 mg/kg SC; n=1) before anesthetic induction with propofol^h (n=6) or isofluraneⁱ (n=6).

Acepromazine (0.006 to 0.025 mg/kg IV) was administered for postanesthetic tranquilization in six dogs with histories of seizures. In a 6-year-old, female, mixed-breed dog, morphine (0.11 mg/kg SC) was administered simultaneously to provide analgesia after wound debridement and closure. In an 8.5-year-old, castrated male boxer with a right frontal lobe mass that underwent a brain CT scan, acepromazine (0.33 mg/kg IV) was administered because of violent postanesthetic thrashing that did not cease with administration of diazepam (0.025 mg/kg IV). After acepromazine administration, the thrashing subsided and the dog became restful. A 14-year-old, female border collie that underwent partial resection of a right cerebral cystic lesion was given acepromazine (0.018 mg/kg IV) eight times over a 24-hour period after surgery, to quiet the dog and reduce anxiety.

In 14 dogs, acepromazine (0.006 to 0.04 mg/kg IV) was administered to reduce anxiety (n=12) or excitement (n=2) during hospitalization. Six dogs received a single dose; five dogs received two doses; and one dog each received three, 11, or 14 doses. No seizures were noted within 16 hours after acepromazine administration in the 36 dogs that received the drug for diagnostic, preanesthetic, or postanesthetic tranquilization, or to reduce excitement or anxiety during hospitalization.

In 11 dogs, acepromazine was prescribed to stop seizures or to reduce their frequency [see Table]. Seizures abated for 1.5 to 8 hours (n=6) or did not recur (n=2) in eight of 10 dogs that were actively seizing when acepromazine was administered. Excitement-induced seizure frequency was temporarily reduced in one dog.

During the 12-year period of this study, only one dog had seizures after acepromazine administration. A 5-year-old golden retriever that was presented with rear-limb lameness and back pain had a generalized tonic-clonic seizure 1 minute after administration of acepromazine (0.04 mg/kg IM) combined with butorphanol (0.2 mg/kg IM) and atropine (0.04 mg/kg IM). The dog had no prior history of seizures, and the same drug regimen had been administered at a previous examination without negative side effects. The seizure stopped without treatment. The dog seized again 20 minutes later, and diazepam was administered IV to effect (dose not recorded). The dog developed respiratory arrest and was intubated and ventilated until spontaneous respirations returned. The dog recovered, and further seizures were not noted during the hospitalization. The final diagnosis in this dog was discospondylitis secondary to brucellosis.

Discussion

Early veterinary textbooks note the anticonvulsant properties of acepromazine.^12,13 More recently, authors have cautioned against its administration to animals at risk for seizures, although references for this warning are usually lacking.^4–8 The effects of chlorpromazine on the seizure threshold are well documented in dogs; however, studies on the effects of acepromazine are less common.^3,14 In one experimental report, the postanesthetic seizure rate for healthy beagles undergoing subarachnoid injection of metrizamide was 40% in those anesthetized with atropine, sodium thiopental, and methoxyflurane; in beagles sedated with atropine, acepromazine, and oxymorphone, the postanesthetic seizure rate was 100%.¹⁵ The dosage of acepromazine was not noted in that study. Because anesthetic protocols differed for the two groups, it was unknown whether acepromazine increased the risk of seizures. Anesthesia with sodium thiopental may have reduced seizure activity in dogs not receiving acepromazine.

Acepromazine has also been shown to prolong seizure activity in some rats with experimentally induced disorders of neuronal migration.¹⁶ Acepromazine may, however, have some anticonvulsant effects as well. Alone or in combination with other drugs, it has been used to reduce or eliminate seizures in dogs with bromocyclen, cyclonite, or metaldehyde toxicity.^17–19 Acepromazine also improved survival rates and reduced neuronal damage in rats with status epilepticus initiated by systemic injection of lithium and pilocarpine, although it did not completely eliminate overt signs of status epilepticus.²⁰

The risk of seizure activity from administration of psychotropic medications is related to the specific drug, drug dosage, metabolic factors, concurrent use of other drugs that decrease seizure threshold or alter pharmacokinetics, and the patient’s history of seizure activity.^21,22 Of the phenothiazines, chlorpromazine has the greatest risk of seizure provocation in people.²³ Increased epileptic potential in humans is also seen with other phenothiazines such as chlorperazine, thioproperazine, and acetylperphenzine; however, butaperazine, trifluoperazine, perphenazine, and thioproperazine do not carry the same risk.²² Incidence of seizures in people treated with phenothiazine drugs is 1.2%, compared to a 0.07% to 0.09% incidence of unprovoked seizures in the general population; seizure rates are also affected by the underlying disease process and the drug dosage.^21–23 For people treated with phenothiazines, seizure rates are 2% in those with organic brain disease and 0.9% in those with functional psychoses.²¹ With low or moderate doses of phenothiazines, seizure rates in people are 0.3% and 0.7%, respectively. With high doses, seizure rates increase to 9%.²¹ Seizure rates after overdosage of phenothiazines range from 4.4% to 60%.²¹

In the study reported here, no seizures occurred in acepromazine-treated dogs with a history of seizures. Seizure rate after chlorpromazine administration has been reported as 4.7% in dogs with a history of seizures; but seizure rates in dogs after acepromazine administration have not been thoroughly evaluated.^3,10 If the incidence of seizures in dogs is similar to the incidence in people treated with any phenothiazine (i.e., 1.2%), then the effect of acepromazine may not be apparent in the 47 dogs reported here.^21–23 Seizure rates after acepromazine administration may also be low in this population of dogs because of the dosage used. Previously, recommended doses of acepromazine ranged from 0.025 to 1 mg/kg IV, IM, or SC, with a maximum total dose of 3 mg IV.^2,6,24 Most dogs treated at the study institution received an initial total dose of 0.1 to 0.25 mg; thus, dosages for tranquilization or as a preanesthetic medication varied from 0.005 to 0.07 mg/kg.

It is unknown whether acepromazine initiated the seizures in the golden retriever that was diagnosed with brucellosis. High brain concentrations of acepromazine are unlikely 1 minute after IM administration; however, an intra-arterial injection can result in convulsions.^25–27

The incidence of seizures potentially induced by acepromazine in the general dog population could not be calculated in the study reported here, because the total number of dogs that received acepromazine for tranquilization or as an anesthetic premedicant was not available. Seizures may not be evident in dogs once they are under anesthesia; however, premedications are routinely administered 30 to 45 minutes before anesthetic induction, which would allow ample time for drug absorption and distribution to the central nervous system. It is possible that seizures in the general population may have been missed in the records search from lack of recording of the diagnosis. A prospective study may be necessary to determine the true incidence of seizures after acepromazine administration in the general clinical population.

Acepromazine was administered in an attempt to decrease seizure activity in 11 dogs in this study. Acepromazine has been used in combination with other medications to reduce or eliminate seizures in dogs with toxicities; however, the use of acepromazine to control seizures resulting from idiopathic epilepsy and other non-toxic etiologies has not been reported.^17–19 In one study, chlorpromazine (2 to 4 mg/kg per os [PO] q 8 to 12 hours) was administered to reduce or control seizures in dogs that were also receiving oral phenobarbital or potassium bromide.²⁸ Seizure activity was reduced in nine of 10 dogs, but information regarding the etiology of seizures or final outcomes of the dogs was not available in that report.²⁸ In the study reported here, acepromazine was believed to have some beneficial effects in nine of 11 dogs, although most of these dogs were receiving other anticonvulsant medications at the same time. Interestingly, four of these 11 dogs received IV dosages higher than those normally used for tranquilization or anesthetic premedication, and seizures stopped for at least 1.5 hours in three of the dogs. Because of the limitations of a retrospective study, it was not possible to determine whether the dogs were having true seizures. It is also possible that cessation of the seizures was coincidental with acepromazine administration, or that acepromazine abolished motor activity but did not stop abnormal electrical activity in the brain.

Some clinicians may avoid using phenothiazines in animals with intracranial swelling or compression because of potential vasodilatory effects that could result in increased cerebral blood volume and intracranial pressure.^29,30 In one experimental study, pretreatment of healthy dogs with acepromazine (0.1 mg/kg IM) caused a significant increase in estimated cerebral blood volume based on results of T2-weighted, echo planar magnetic resonance imaging with rapid contrast infusion.³¹ Intracranial pressure was not monitored in that study. In another study, dogs given chlorpromazine experienced an initial spike in intracranial pressure that was attributed to expansion of the intracranial arterial bed, since the increase in intracranial pressure coincided with a fall in the systemic arterial pressure.³² Intracranial pressure subsequently decreased in eight of 11 dogs evaluated. In the remaining three dogs, a steady increase in intracranial pressure was noticed, which was attributed to hypoventilation in two dogs.³² To the authors’ knowledge, the effects of phenothiazines on intracranial pressure in dogs with reduced intracranial compliance have not been evaluated.

Conclusion

In this study, no evidence was found that acepromazine increased the risk of seizure occurrence in dogs with a history of seizures. In several dogs, seizures stopped with administration of acepromazine. Evaluation of the effects of acepromazine in dogs with a history of seizures was confounded by several factors, including variations in disease etiology and drug dosage; concurrent administration of sedatives, anesthetics, or anticonvulsant medications in many animals; and the retrospective nature of the study. A controlled prospective study is needed to determine the incidence of seizures after acepromazine administration in dogs with a history of seizures and in the general canine population.