Abstract

Neuroleptic drugs have been commonly used in zoo and wildlife medicine for years. Despite potential side effects, there are few reports of adverse reactions to these tranquilizing agents in the veterinary literature and fewer that discuss treatment options in non-domestic species. In the authors’ practice, it is not unusual to observe clinically significant adverse reactions to haloperidol in non-domestic hoofstock. The objective of this article is to review the potential adverse reactions of these neuroleptic drugs and to discuss available treatment options.

Neuroleptic Drugs: Pharmacology and Use in Zoos and Wildlife

Neuroleptic drugs (ND) are used to treat psychosis in man when a tranquilizing effect is desired.¹⁰ Psychosis is defined as a derangement of personality with delusions, loss of contact with reality and deterioration of social functioning. In human psychiatry, the more accurate and preferred term for agents used to treat psychosis are the antipsychotic drugs (APD). The terms ND and APD seem to be used interchangeably. Furthermore, wildlife and zoo veterinarians use the term tranquilizer to describe the purpose and utility of these drugs.

Excellent reviews of the use and pharmacology of long-acting ND in non-domestic species have been written^10,11 and are appropriate for understanding shorter-acting ND, such as haloperidol. Haloperidol and other typical ND act on the D2 subset of dopamine receptors.¹² The D2 receptor is believed to be associated with extrapyramidal symptoms (EPS), the major side effect reported with ND. New generations of APD are becoming more popular in human psychiatry since they exert their effect on a different subset of dopamine receptors or on serotonin receptors, decreasing the potential for EPS. All ND/APD have the potential to cause side effects.¹²

The use of ND has been reported in wildlife medicine for almost 30 yr primarily to tranquilize wild hoofstock intended for relocation in southern Africa.^5,6,11 Their use is now common in zoological settings, as well.^1,3,4,7,9 The clinical use of ND in non-domestic hoofstock is comparable to the use of APD in human psychiatric emergencies of acute anxiety and panic attacks.¹⁰ Anxiety is a state of apprehension, uncertainty and fear resulting from the anticipation of a real or perceived threat and defines the temporary mental state of at least some of our non-domestic hoofstock during our husbandry manipulations. Furthermore, the perceived threat may trigger the innate and classic sympathetic “fight or flight” response. Regardless of the terms or inciting mechanism of anxiety in our animals, ND for tranquilization are available.^3,11

Haloperidol is a butyrophenone derivative with tranquilizer/antipsychotic properties that are effective in the management of hyperactivity, agitation, and anxiety in humans.^5,10 The effective duration of action varies from 10–20 h. It has been used successfully in African hoofstock species during translocation alone or in combination with longer-acting ND.^5,6,11 Haloperidol lactate is likely the most common short-acting ND used in zoological institutions in the United States and has been successfully used in thousands of hoofstock in the author’s practice. This ND has a marked and predictable tendency to cause EPS in man.^10,13 Haloperidol lactate injection (Bedford Laboratories, Bedford, OH, USA) is routinely used at the San Diego Wild Animal Park (SDWAP) when relocating non-domestic hoofstock animals to new enclosures, the hospital or holding facilities. The use of other ND in wildlife species is discussed elsewhere.^1,3,4,6,11 The oral form of haloperidol (Haloperidol hydrochloride USP, 20 mg tablets, Sandoz Inc., Irvine, CA, USA) is used at the SDWAP in non-domestic equids with predictably positive results. The clinical success of oral haloperidol in our ruminant species has been variable but has proven effective by others.⁹ Anxiolytic drugs, such as benzodiazepines, are also used in the treatment of acute agitation and anxiety attacks in man and animals.^10,13 In psychiatric emergencies in humans, the combination of antipsychotic and anxiolytics drugs, such as haloperidol and a benzodiazepine, is often used with synergistic benefits.¹⁰ Common side effects such as EPS and sedation are reduced since decreased amounts of each drug can be provided.

Adverse Reactions

Many psychotic conditions are caused by overactivity of dopamine in the brain, specifically the limbic system.⁸ The limbic system regulates thoughts and perceptions, therefore abnormally elevated levels of dopamine can cause psychosis. Dopamine is blocked by APD in the limbic system but also causes similar action in the extrapyramidal system, which controls muscle activity. Muscle tone is a balance between the levels of dopamine and acetylcholine (ACH) in the extrapyramidal system. If dopamine is blocked or reduced, more ACH is released in the muscle resulting in increased muscle tension and EPS. The frequent side effects of ND are well described in the human literature,^10,13 but only a few reports are described in domestic animals² or in wildlife species⁷.

The three classic categories of EPS include acute dystonia, akathisia and pseudo-parkinsonism.¹³ Adverse reactions can also be categorized as “acute” (dystonia, akathisia and parkinsonism) and “tardive,” which means having symptoms that develop slowly or appear long after inception. Haloperidol is well known to cause tardive dyskinesia in humans following long-term use but may also be triggered by acute high dose.¹² Tardive dyskinesia causes repetitive muscular movements of the face, mouth, limbs or trunk. Acute dystonia consists of abnormal muscle spasms and postures of the head, neck and face. Akathisia is an extrapyramidal disorder consisting of restlessness, anxiety and inability to stand still. Drug-induced pseudo-parkinsonism is characterized by muscle rigidity, tremors, diminished facial expressions and shuffling/stiff gait. At the SDWAP, adverse effects have only been noted following injectable haloperidol and can be characterized by one or more of the three classic categories of EPS and possibly tardive dyskinesia. Four case reports are described below.

Treatment Options for Adverse Reactions

Since adverse reactions to ND in non-domestic hoofstock are typically medical emergencies, treatment options must be understood. Treatment includes discontinuing or lowering the dose of the inciting ND, controlling excitatory signs with sedatives/hypnotics, and providing an anticholinergic drug.^2,11,13 Other medications such as beta-adrenergic blockers (propranolol) are used to treat akathisia in humans.¹³

As stated above, ND block dopamine in the extrapyramidal system causing an increase in ACH and increased muscle tension. Anticholinergic drugs block the neurotransmitter ACH in the brain and are a common treatment for EPS to relax muscle tension. These include diphenhydramine, benztropine, biperiden, ethopropazine, orphenadrine, procyclidine and trihexyphenidyl.¹³ Intravenous or IM anticholinergic drugs provide rapid treatment of acute dystonia and drug-induced parkinsonism in EPS. Since the ND we use may have long duration of action, the anticholinergics may be metabolized after several hours, so additional doses may be necessary.¹³

New Antipsychotic Drugs

The use of the so-called atypical or second-generation APD, is growing in human medicine due to their reported clinical efficacy and decreased tendency to cause EPS.¹⁰ However, this claim is challenged by some due to a separate list of side effects.¹² Reference to the use of these drugs could not be found in the zoo and wildlife literature.

Clozapine is the prototype atypical APD and was the first to be released for use in human psychiatry. Clozapine is preferentially more active at limbic dopamine receptors and may explain reduced EPS.¹⁰ It is known to cause agranulocytosis, so it is reserved for patients with unresponsive schizophrenia or severe EPS. Risperidone is a potent serotonin and moderate dopamine antagonist, thereby reducing the potential for EPS.¹⁰ Side effects include sedation, insomnia, constipation and weight gain. An IM preparation is useful for emergency treatment of acute agitation and schizophrenia. Olanzapine is chemically similar to clozapine but does not cause agranulocytosis.¹⁰ Side effects include significant weight gain and sedation. Since an IM preparation is available, its use in acute agitation is similar to risperidone. Quetiapine is another new APD with a high serotonin/dopamine receptor binding ratio responsible for its antipsychotic effect and low incidence of EPS.¹⁰ It can cause sedation, hypotension and dizziness. Ziprasidone is a new atypical APD similar to risperidone.¹⁰ This drug has great clinical potential and since an IM preparation is available it may replace haloperidol as the agent of choice in acute psychotic patients. Side effects are similar to risperidone.

In an effort to decrease side effects and improve control of our anxious and agitated patients, zoo and wildlife veterinarians are encouraged to expand the use of the new APD. In the author’s practice, all of the documented adverse reactions have been to haloperidol, a short-acting ND that has been used for over 25 yr in zoo and wildlife species. It seems prudent to explore alternatives with less potential for dangerous side effects. Risperidone, olanzapine, ziprasidone, olanzapine are available in injectable form and human doses should be a reasonable starting point for our non-domestic hoofstock. Further evaluation of these drugs with controlled studies and documentation of adverse reactions in zoo and wildlife settings are necessary as we search for ideal ND.

Case Descriptions

Case One

A 5-yr-old, female, 1650 kg (est.), southern white rhinoceros (Ceratotherium simum) was received into quarantine at the SDWAP. Due to persistent anxiety, inappetance and injurious behavior, 160 mg of IM haloperidol (Haloperidol USP, 20 mg/ml, Kyron Laboratories, Benrose, RSA) was provided. Four hr later, the animal was found thrashing on the ground unable to stand with opisthotonus and disorientation. Diphenhydramine hydrochloride (Baxter Health Care, Deerfield, IL, USA) 500 mg was provided IV. By 18 min, the muscle tone of the animal’s face, neck and back were normal and she was standing and resting calmly by 47 min. The next morning, the rhinoceros was found in lateral recumbency with signs of another haloperidol reaction (deep excavation of dirt in immediate area). She stood up when approached, remained lethargic throughout the day but was normal at 48 h PHA. Signs of EPS were noted. Stock sufficient emergency diphenhydramine if providing ND to large patients. The amount provided in this case was likely insufficient as relapse of EPS was highly suspected. Diphenhydramine is used to treat EPS in our practice due to its positive response, safety and varied clinical indications (antihistaminic activity).

Case Two

A 7-yr-old, female, 52 kg, blesbok (Damaliscus pygargus phillipsi) was anesthetized with 1.5 mg carfentanil citrate (Wildlife Pharmaceuticals, Inc., Fort Collins, CO, USA) IM, given 10 mg haloperidol lactate (Haldol, Ortho McNeil Pharmaceuticals, Inc., Titusville, NJ, USA) IM and reversed with 150 mg IV naltrexone hydrochloride (Wildlife Pharmaceuticals, Inc.). The blesbok was found on the ground 60 min later with obvious opisthotonus, facial tics and redundant head movements. Renarcotization was ruled out by no response to supplemental naltrexone. Diphenhydramine (Baxter Health Care), 75 mg IM was provided and the animal was normal in 15 min. Typical EPS were noted and quickly reversed with diphenhydramine. Side effects of ND may be misdiagnosed due to similarity with other disease states.

Case Three

An 8-yr-old, male, 58 kg, Kenyan impala (Aepyceros melampus) became hyperthermic during anesthesia induction and was hospitalized for IV support. Haloperidol lactate (Bedford Laboratories) 7.5 mg and haloperidol decanoate (Sicor Pharmaceuticals, Irvine, CA, USA) 75 mg were given IM prior to entering the hospital. For two days, the animal was calm but then became anxious so 15 mg of haloperidol lactate was provided IV and then repeated 5 hr later. Two hr later the animal was found disoriented, with facial tics and redundant head movements. Diphenhydramine (Baxter Health Care) 150 mg was given IM and by 30 min all EPS disappeared. Two IV doses of haloperidol caused acute dystonia, pseudo-parkinsonism and tardive dyskinesia since high doses of ND may trigger this adverse reaction.¹² Diphenhydramine offered rapid and effective reversal of EPS.

Case Four

A 1-yr-old, female, 23 kg, hog deer (Axis procinus) was anesthetized for shipment and given 5 mg of haloperidol lactate (Ortho McNeil Pharmaceuticals, Inc.) IM prior to relocation to a holding facility. One hr later, it was found with thrashing on the ground with opisthotonus. The animal was given 6 mg of benztropine mesylate (Cogentin, 2 mg/ml, Merck & Co., Inc., Whitehouse Station, NJ, USA) IV and was noted to be normal within 1.5 hr. In our practice, hog deer seem extremely sensitive to haloperidol-induced EPS, so this ND is avoided in this species. Benztropine mesylate is a valid option for treatment of EPS.²

Acknowledgments

The authors acknowledge the insight and input from the veterinarians, veterinary technicians and mammal department at the San Diego Wild Animal Park.

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