Sedative, Muscle Relaxant, and Narcotic Overdose

CHAPTER 77  SEDATIVE, MUSCLE RELAXANT, AND NARCOTIC OVERDOSE Annie Malouin Wright,

DVM, DACVECC

KEY POINTS • A sedative overdose causes primarily a dose-dependent central nervous system (CNS) depression. • Signs of acute toxicity with muscle relaxants are often an amplification of their main therapeutic effects: muscular flaccidity, CNS and respiratory depression, and anticholinergic syndrome. • Opioid overdose may alter mental status, cause respiratory depression, and produce miosis in dogs and mydriasis in cats. • Sedatives, muscle relaxants, and opioids undergo hepatic biotransformation with primary excretion of their metabolites in the urine. Thus the metabolism of these drugs may be impaired in patients with hepatic disease or renal impairment, increasing the duration and intensity of their pharmacologic action. • Treatment of intoxication with sedatives, muscle relaxants, and opioids is based on general supportive measures. Antidotes are available for only the benzodiazepines, α2 agonists, and opioids.

Dogs and cats may experience toxicity from sedatives, central muscle relaxants, and narcotics, either by iatrogenic overdose by a veterinary health care provider or by consumption of the owner’s or pet’s prescribed medications. All of the agents discussed in this chapter are dispensed only by prescription, and several are not approved for use in veterinary species. Differential diagnoses to consider include the ingestion of other neurotoxins and drugs, as well as primary central nervous system (CNS) disorders. Blood and urine concentration of many of these drugs can be measured. The clinical picture and treatment of overdose for each of these drug categories are discussed separately.

SEDATIVE OVERDOSE Sedatives include a variety of agents that have the capacity to depress the function of the CNS and result in sedation. They also may contain hypnotic (sleep aid), muscle relaxant, anxiolytic, and anticonvulsant properties. Some euthanasia solutions are formulated with highly concentrated barbiturate products, and acute intoxication with these agents may occur after ingestion of meat from an animal recently euthanized (relay toxicosis). However, studies of clinical use or toxicity for several of the drugs discussed in this section have been conducted only in humans.1-4 Therefore it is unknown whether the pharmacokinetics and clinical signs of overdose reported for individual agents apply equally to veterinary species.

Mechanism of Action The sedative agents have various modes of action, which are summarized in Table 77-1.1-4

Pharmacokinetics Table 77-2 describes the pharmacokinetics of the agents listed in Table 77-1.1-8 All of these sedatives undergo hepatic biotransforma400

tion, with excretion of metabolites primarily in the urine. As a result, their metabolism may be impaired in patients with hepatic disease, and their metabolites may accumulate in patients with renal impairment. Benzodiazepines require significant hepatic microsomal enzyme metabolism, and barbiturates stimulate the hepatic microsomal enzyme system.

Clinical Signs For most sedative overdoses, the clinical picture is nonspecific. All of these drugs cause progressive CNS depression in proportion to the quantity of the agent consumed. Also, concurrent administration or ingestion of other CNS depressants (opioids, anesthetics) has compounding effects. CNS signs vary from mental depression, ataxia, stupor, and surgical anesthesia to coma. Finally, death occurs with sufficient depression of medullary neurons to disrupt coordination of cardiovascular function and respiration. Phenothiazines block α-adrenergic receptors and, if given concurrently with epinephrine, the β-activity prevails, causing vasodilation and an increased heart rate. Zolpidem may cause a paradoxic excitation reaction before the sedation phase.9 Clinical signs of overdoses with sedatives and possible interactions with various medications are summarized in Table 77-3.1,3,7,10,11

Treatment Treatment of intoxications with sedatives is based on general supportive measures. Antidotes (reversal agents) are available only for benzodiazepines and α2 agonists (see Chapters 164 and 165). Decontamination is performed as described in Chapter 74 if oral ingestion of a toxic dosage is suspected. Table 77-4 describes the treatment for each class of drugs.1,3,12 In patients with severe mental depression, oxygen is administered and a patent airway maintained to prevent aspiration pneumonia, hypercarbia, or hypoxemia. Mechanical ventilation is initiated when indicated. Continuous electrocardiographic and blood pressure monitoring is required for patients manifesting cardiovascular instability. Administration of intravenous crystalloid fluids promotes diuresis and therefore hastens the elimination of the metabolites of each of these drugs. Hypotension is managed initially with intravenous fluids, followed by vasopressors if required. Seizures are controlled with standard anticonvulsants (see Chapter 166). The patient’s body temperature requires regular monitoring and appropriate measures must be taken to maintain euthermia. Aggressive supportive and nursing care helps prevent complications in recumbent animals.9,13-15

MUSCLE RELAXANT OVERDOSE Muscle relaxants reduce skeletal muscle tension without abolishing voluntary motor control. Most of their effects occur at various levels of the CNS (cortex, brainstem, spinal cord, or all three areas), but some also act directly within the muscle. This clinical grouping of

CHAPTER 77  •  Sedative, Muscle Relaxant, and Narcotic Overdose

Table 77-1  Mechanism of Action of Sedatives1-8,10-14,16-18 Generic Name

Brand Name

Mechanism of Action

Benzodiazepines Alprazolam Clorazepate Chlordiazepoxide Clonazepam Diazepam Estazolam Flurazepam Lorazepam Midazolam Oxazepam Quazepam Temazepam Triazolam

Xanax Tranxene Librium Klonopin Valium ProSom Dalmane Ativan Versed Serax Doral Restoril Halcion

Benzodiazepine receptors are located on the GABAA- receptor complex, a chloride ion channel in the brain and spinal cord. Their activation promotes binding of GABA to its receptor, thereby enhancing chloride currents through these channels (by increasing the frequency of channel openings). The cell membrane becomes hyperpolarized and resistant to excitatory stimuli, explaining the sedative, anticonvulsant, and muscle relaxant effects of benzodiazepines.

Imidazopyridines Zolpidem

Ambien

Potentiates GABA-ergic transmission by selectively modulating certain subunits of the GABAA- receptor complex in the central nervous system (primarily in the cerebellum). This results in the inhibition of neuronal excitation, slowing the activity in the brain to allow sleep (hypnosis) with fewer side effects.

Pyrazolopyrimidines Zaleplon Sonata

Potentiates GABA-ergic transmission by selectively modulating certain subunits of the GABAA- receptor complex in the central nervous system (mostly the brain). This results in the inhibition of neuronal excitation, slowing the activity in the brain to allow sleep (hypnosis) with fewer side effects.

Cyclopyrrolones Eszopiclone

Lunesta

Potentiates GABA-ergic transmission by selectively modulating certain subunits of the GABAA- receptor complex in the central nervous system (mostly the brain). This results in the inhibition of neuronal excitation, slowing the activity in the brain to allow sleep (hypnosis) with fewer side effects.

Phenothiazines Acepromazine

Atravet

Blocks postsynaptic dopamine and α1-adrenergic receptors

α2-Agonists Medetomidine Xylazine

Domitor Rompun

α2-Adrenoreceptor agonists

Barbiturates Phenobarbital Pentobarbital

Luminal Nembutal

Augment GABA responses by promoting the binding of GABA to its receptor GABAA and by increasing the length of time that chloride channels are open and open the chloride channels in the absence of GABA at higher doses

GABA, γ-Aminobutyric acid.

therapeutic agents accommodates a heterogeneous assembly of medications (Table 77-5) that differ in their chemical, pharmacologic, pharmacokinetic, and toxicologic properties. As a result, the type and severity of clinical effects after an overdose may be diverse. A number of agents are used to alleviate musculoskeletal pain and spasms caused by a variety of neurologic conditions in human patients, but little is known about their clinical application in veterinary medicine. Neuromuscular blockers are muscle relaxants as well and are discussed in Chapter 143. Benzodiazepines were discussed in the previous section and are discussed further in Chapter 164).

Mechanism of Action Spasmolytic agents work by either enhancing the level of inhibition or reducing the level of myocyte excitation. Table 77-5 summarizes the skeletal muscle relaxants of clinical and toxicologic importance and their modes of action.3,16-22

Pharmacokinetics A detailed discussion of muscle relaxant pharmacokinetics is beyond the scope of this chapter. The reader is encouraged to consult suggested references for further information.3,16-23 Limited pharmacokinetic data are available for many of these drugs in veterinary species, and thus elimination in dogs and cats may be unpredictable. In

humans, most muscle relaxants have peak absorption within 1 to 6 hours and are distributed throughout the body. Therefore clinical effects are seen rapidly after oral ingestion. All of the muscle relaxants are metabolized in the liver, and their metabolites are eliminated mostly in the urine.16

Clinical Signs In most cases of muscle relaxant overdose, the clinical features are exaggerations of their main therapeutic effects. Muscular flaccidity, CNS and respiratory depression, adverse cardiovascular effects, and an anticholinergic syndrome from the agents with antimuscarinic effects often are seen in patients with acute toxicity. Additive sedation may occur when given with other CNS depressant agents. In the veterinary literature, only a few reports are available to describe the clinical course seen with muscle relaxant overdose. Table 77-6 summarizes the clinical signs of acute toxicity with muscle relaxants in humans and in veterinary species.*

Treatment Because of the potential for a rapid absorption and onset of clinical signs, decontamination should be attempted without delay. General *References 3, 16, 18-20, 24-27.

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Table 77-2  Pharmacokinetics of Sedatives16,22 Generic Name

Route

Half-Life (hr)

Benzodiazepines Alprazolam Clorazepate Chlordiazepoxide Clonazepam Diazepam Estazolam Flurazepam Lorazepam Midazolam Oxazepam Quazepam Temazepam Triazolam

PO PO PO, IV, IM PO PO, IV, IM, PR PO PO PO, IV, IM IV, IM PO PO PO PO

Imidazopyridines Zolpidem

PO

2.6

—

Pyrazolopyrimidines Zaleplon

PO

1.0

—

Cyclopyrrolones Eszopiclone

PO

5.8

__

Phenothiazines Acepromazine

PO, IV, IM, SC

3

PO: 257 mg/kg IV: 61 mg/kg (mice)

α2-Agonists Medetomidine Xylazine

IV, IM IV, IM, SC

Barbiturates Phenobarbital Pentobarbital

PO, IV PO, IV, IM, PR

12 ± 2 2.0 ± 0.9 10 ± 3.4 23 ± 5 2.5-2.3 10-24 74 ± 24 14 ± 5 1.9 ± 0.6 8.0 ± 2.4 39 11 ± 6 2.9 ± 1.0

0.96 ± 0.25 0.5 48 8

LD50 — — — — >20 mg/kg (dog) — — — IV: 1600 mg/kg — — — —

80 mg/kg (rat) — PO: 150 mg/kg IV: 83 mg/kg (rat) PO: 85 mg/kg IV: 50 mg/kg (dog)

IM, Intramuscular; IV, intravenous; LD50, lethal dose; PO, per os; PR, per rectum; SC, subcutaneous.

Table 77-3  Clinical Signs of Toxicity of Sedatives and Potential Drug Interactions1,3,7,10,11 Drug Class

Clinical Signs of Toxicity

Drug Interactions

Benzodiazepines

Toxicity of these drugs is low CNS depression, ataxia and, uncommonly, respiratory depression and hypotension may occur Cats may develop hepatic failure after oral administration of diazepam

Cimetidine, fluoxetine, erythromycin, isoniazid, ketoconazole, propranolol, metoprolol, valproic acid: may inhibit the metabolism of benzodiazepines and cause excessive sedation

Imidazopyridines

Agitation, sedation, ataxia, anorexia, hypersalivation, vomiting

Pyrazolopyrimidines

Agitation, sedation, ataxia, anorexia, hypersalivation, vomiting

Cyclopyrrolones

Agitation, sedation, ataxia, anorexia, hypersalivation, vomiting

α2-Agonists

CNS depression, bradycardia, atrioventricular blocks, decreased myocardial contractility, decreased cardiac output, initially arterial hypertension followed by hypotension, decreased respiratory rate, apnea, cyanosis, vomiting, recurrence of sedation after initial recovery, occasional spontaneous muscle contractions (twitching), hypothermia, hyperglycemia, death from circulatory failure with severe pulmonary congestion, increased hepatic or renal enzymes

Decrease dosage of general anesthetics Concurrent use of epinephrine may induce ventricular arrhythmias

Barbiturates

Progressive CNS depression: stupor to coma, ataxia, respiratory depression, hypotension, decreased cardiac contractility, noncardiogenic pulmonary edema, aspiration pneumonia, renal failure, hypothermia, decreased GI motility, anemia, hypoglycemia Cats particularly sensitive to respiratory depressant effects

Accelerate the clearance of other drugs metabolized via hepatic microsomal enzymes Chloramphenicol may increase clinical effects

CNS, Central nervous system; GI, gastrointestinal.

CHAPTER 77  •  Sedative, Muscle Relaxant, and Narcotic Overdose

Table 77-4  Treatment of Sedative Overdoses1,3,12,14 Drug

Management

Benzodiazepines Imidazopyridines Pyrazolopyrimidines Cyclopyrrolones

Flumazenil (Romazicon) is a benzodiazepine antagonist binding with high affinity to specific sites on the GABAA-receptor, where it competitively antagonizes benzodiazepines binding and allosteric effects. It also can reverse effects of imidazopyridines, pyrazolopyrimidines, and cyclopyrrolones. Flumazenil has a higher clearance and shorter elimination half-life (1 hr) than all clinically used benzodiazepine agonists. Recurrent benzodiazepine toxicity or resedation is therefore likely once the effects of flumazenil have worn off, and repeated administration may be necessary. Flumazenil is administered only by rapid IV injection because it is highly irritating, and care should be taken to avoid extravasation. Dosage: 0.05 mg/kg IV Elimination is not enhanced by hemodialysis or hemoperfusion.

α2-Agonists

Atipamezole (Antisedan) is an α2-adrenergic antagonist that selectively and competitively inhibits α2-adrenergic receptors, causing sympathetic outflow to be enhanced. It can reverse effects of medetomidine and xylazine. The onset of arousal is apparent usually within 5 to 10 minutes of intramuscular injection, depending on the depth and duration of sedation. Atipamezole also produces a rapid improvement of bradycardia and respiratory depression. Atropine or glycopyrrolate should not be used to prevent or manage bradycardia, because tachycardia and hypertension may result. Atipamezole should be administered intramuscularly regardless of the route used for the α2-agonist. The dosage is calculated based upon body surface area: 1 mg/m2, or give IM an equal volume of atipamezole hydrochloride (Antisedan) and medetomidine (Dormitor) (milliliter per milliliter). Yohimbine or tolazoline also can be used to reverse the effects of xylazine but are less specific antagonists with more side effects than atipamezole.

Barbiturates

Promote diuresis to increase the urinary flow rate. Also, alkalinizing the urine (pH > 7) by intravenous administration of sodium bicarbonate enhances the rate of excretion of unchanged drug in its ionized form. Hemodialysis and hemoperfusion can be used to maximize barbiturate elimination.

GABA, γ-Aminobutyric acid; IV, intravenous.

Table 77-5  Summary of Muscle Relaxants and Their Mechanisms of Action3,16-22 Generic Name

Trade Name

Site of Action

Mechanism of Action

Baclofen

Lioresal

CNS

GABA-agonist

Carisoprodol

Soma

CNS

Indirect GABA-agonist

Cyclobenzaprine

Flexeril

CNS

Tricyclic analog: decreases amplitude of monosynaptic reflex potentials by inhibiting descending serotonergic systems in spinal cord

Chlorzoxazone

Parafon Forte

CNS

Exact mechanism unknown; sedation

Dantrolene

Dantrium

Peripheral

Blocks calcium liberation from sarcoplasmic reticulum of skeletal muscle by binding to ryanodine receptor

Methocarbamol

Robaxin

CNS

Unknown; structurally related to guaifenesin

Metaxalone

Skelaxin

CNS

Not established; thought to be related to its sedative properties

Orphenadrine

Norflex

CNS

Directly causes dopamine release; NMDA receptor antagonist; blocks norepinephrine uptake; peripheral antimuscarinic action

Tizanidine

Zanaflex

CNS

Central α2-adrenergic agonist

CNS, Central nervous system; GABA, γ-aminobutyric acid; NMDA, N-methyl-D-aspartic acid.

guidelines for decontamination can be found in Chapter 74. For patients that ingest baclofen or carisoprodol, only one dose of activated charcoal with a cathartic is necessary because these drugs do not undergo enterohepatic circulation. For the remaining muscle relaxants, efficacy of multidose activated charcoal regimens has not been established.16 Gastric lavage should be performed in cases of large ingestions, and the anesthetic protocol used must not compound the CNS depression. A short-acting induction agent such as propofol, followed by inhalant anesthesia, is recommended. The airway must be protected at all times with a cuffed endotracheal tube. Because no antidote exists for centrally acting muscle relaxant overdose, aggressive supportive care and intensive monitoring are imperative. The patient’s ventilation and oxygenation should be

monitored closely. Endotracheal intubation and positive-pressure ventilation should be considered in select patients (see Chapter 30). Animals manifesting cardiovascular instability require continuous electrocardiographic and blood pressure monitoring. Bradycardia from baclofen toxicity is responsive to atropine in human patients.24,28 Hypotension should be treated initially with intravenous crystalloid or colloid fluids (see Chapter 60), followed by vasopressors if needed (see Chapters 157 and 158). Hypertension should be treated with vasodilators (e.g., nitroprusside, amlodipine) if necessary (see Chapter 159). Baclofen and carisoprodol are excreted by the kidneys; therefore adequate diuresis is important to prevent acute kidney injury and enhance elimination of the drugs. In addition, hemodialysis or hemoperfusion can be used to reduce the

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Table 77-6  Clinical Signs of Acute Muscle Relaxant Toxicity3,6,16,18-20,24-30

Table 77-7  Functions or Side Effects of Opioid Receptors

Drug

Clinical Signs

Opiate Receptor

Function

Baclofen

Vomiting, salivation, sedation, ataxia, vocalization, hypotension or hypertension, bradycardia, tachycardia, cardiac conduction abnormalities, coma, dyspnea, respiratory arrest Deaths in dogs have occurred at doses between 8 and 16 mg/kg18

Mu

Carisoprodol

Coma, hypotension, seizure, shock, respiratory depression, pulmonary edema, respiratory arrest and eventually cardiac arrest, nystagmus, vomiting, urticaria, pruritus, ataxia, tremors, agitation, myoclonus, tachycardia

Analgesia Respiratory depression Euphoria Bradycardia Constipation Vomiting Physical dependence Temperature change (hypothermia in dogs, hyperthermia in cats)

Delta

Analgesia

Sigma

Autonomic stimulation Dysphoria Hallucinations

Kappa

Analgesia Sedation

Epsilon

Analgesia

Cyclobenzaprine

Anticholinergic toxidrome, lethargy, sinus tachycardia, agitation, hypertension or hypotension

Chlorzoxazone

CNS depression, GI upset, hypotonia, areflexia, hypotension, hepatotoxicity

Dantrolene

Hypotonia, sedation, hepatotoxicity

Methocarbamol

Sedation, lethargy, weakness, ataxia, salivation, emesis

Metaxalone

Sedation, GI upset, hepatotoxicity, nephrotoxicity

Orphenadrine

Anticholinergic toxidrome, mydriasis, tachycardia, coma, seizures, hypothermia, shock, cardiac arrest

CNS, Central nervous system; GABA, γ-aminobutyric acid; GI, gastrointestinal.

elimination half-life of baclofen and carisoprodol.16,24 Administration of intravenous lipid emulsion is another emerging therapy for animals with lipid-soluble drug toxicities.29,30 Agitation can be treated with benzodiazepines. Seizures require prompt treatment with standard anticonvulsants. However, if carisoprodol has been ingested, barbiturates are not recommended for seizure control because they may compound the CNS depression. Diazepam, despite also being a γ-aminobutyric acid agonist, is the drug of choice for baclofen- and carisoprodol-induced seizures.18-20,24 Flumazenil and physostigmine have been used to help reverse comatose states in cases of baclofen toxicosis in humans.24,31 Flumazenil had varied results because it may be a proconvulsant when combined with a potential γ-aminobutyric acid antagonist such as baclofen.24 Temperature regulation may be deranged in recumbent or comatose patients; therefore close monitoring and heat support (or cooling measures), if necessary, are recommended.

Prognosis Asymptomatic patients having ingested any of these drugs should be observed for a minimum of 24 hours. The prognosis for toxicity with most of these muscle relaxants in veterinary medicine is unknown. For symptomatic patients with baclofen toxicity, resolution of clinical signs may take several days in severe cases, but if adequate supportive care and monitoring are available, the prognosis is generally good.18 The vast majority of human patients recover after prompt recognition of the toxic condition and rapid institution of supportive care.32

NARCOTIC OVERDOSE Narcotics (opioids) have been the mainstay of pain management for thousands of years, and they remain so today in human and veteri-

nary medicine. These drugs derived from opium, and they include the natural products morphine and codeine, as well as many synthetic derivatives such as fentanyl, methadone, hydrocodone, hydromorphone, and heroin.33

Mechanism of Action Opioids produce their effects by interacting with specific receptors distributed throughout the central and peripheral nervous systems, the gastrointestinal (GI) tract, the urinary tract, and other smooth muscles.33 Five receptors have been identified: mu (µ), kappa (κ), delta (δ), sigma (σ), and epsilon (ε), and each is associated with certain clinical effects, as described in Table 77-7.3 Opioid receptor activation results in inhibition of adenyl cyclase activity, activation of receptor-operated potassium currents, and suppression of voltagegated calcium currents. These effects cause hyperpolarization of the cell membrane, decreased neurotransmitter release, and reduced pain transmission.33 Functionally, opioids can be classified into four groups: morphinelike opioid agonists, opioid antagonists, mixed agonist-antagonists, and partial agonists (see Chapter 163).

Pharmacokinetics An in-depth discussion of opioid pharmacokinetics is beyond the scope of this chapter (see Chapter 163).3,33,34 However, several points require emphasis. Morphine, oxymorphone, hydromorphone, butorphanol, and buprenorphine are well absorbed after intravenous, intramuscular, subcutaneous, oral, and rectal administration. However, first-pass metabolism is significant and results in low bioavailability and a less predictable effect after oral ingestion. Distribution of opioids from the blood to the CNS is variable. Generally, with the highly lipid-soluble drugs (e.g., codeine, fentanyl, and heroin), onset of action occurs more rapidly, and the pharmacologic effects resolve earlier. Drugs that are less lipid soluble, such as morphine, move less rapidly and therefore take longer to be effective and may have a longer duration of action. The clinical effects of most opioids persist for 2 to 8 hours; exceptions are fentanyl, which lasts for 15 minutes.3,33-35 All opioids are metabolized primarily in the liver via glucuronidation. Cats are deficient in this metabolic pathway, and therefore the half-life of certain drugs may be prolonged. Elimination is primarily renal.3 Patients with severe hepatic and/or renal

CHAPTER 77  •  Sedative, Muscle Relaxant, and Narcotic Overdose

insufficiency are theoretically at increased risk of toxicity because of the accumulation of active metabolites. In normal dogs, the lethal dose for morphine is 100 mg/kg.3 Opiate administration may obscure the clinical course and physical examination findings in some animals and therefore should be used cautiously in patients with intracranial disease, increased intracranial pressure, acute respiratory dysfunction, and acute conditions of the abdomen. Opioids may lead to hypoventilation and hypercapnia, which cause cerebral vasodilation and increased intracranial pressure. In patients with respiratory dysfunction and decreased carbon dioxide sensitivity, opioid drug administration may exacerbate the hypercapnia, necessitating endotracheal intubation and mechanical ventilation. Neonatal and geriatric patients are more susceptible to the effects of opioids and require lower dosages. In the developing fetus, opiates pass more easily into the CNS because the blood-brain barrier is not fully developed. Therefore a fetus may suffer severe depression, although the mother has no evidence of side effects. Small amounts of opioids also are distributed into the milk of nursing mothers.33,34 Opioids can interact with many drugs that may potentiate their effects. Morphine is contraindicated in human patients receiving monoamine oxidase inhibitors (MAOIs) because they may exhibit signs of opiate overdose after receiving therapeutic doses of morphine while taking MAOIs.3,36 Also, fentanyl, meperidine, tramadol, methadone, and dextromethorphan are weak serotonin reuptake inhibitors and have been involved in serotonin toxicity reactions with MAOIs.36 Interactions between other opioids and MAOIs have not been shown in dogs37 (see Chapter 79). Phenothiazines potentiate opioids, possibly by interfering with their metabolism.33 Cimetidine may increase opioid effects by increasing the duration of action. Erythromycin also may enhance opioid effects.38

Clinical Signs The clinical signs seen with opioid overdose are caused by an amplification of their action at the receptors discussed earlier. The µ receptor, which mediates many of the life-threatening effects, including respiratory depression, principally is affected. There is a classic triad seen with opioid toxicity: CNS depression, respiratory depression, and miosis in dogs. Cats typically develop mydriasis. Multiple organ systems also can be affected. Patients may be hyporeflexic, hypothermic, hypotensive, and have decreased borborygmi. These toxic effects are mediated primarily through stimulation of the µ, κ, and δ receptors.3,33,34 The miosis in dogs results from µ-related stimulation of the visceral nuclei of the oculomotor nuclear complex and the parasympathetic nerve that innervates the pupil.39 The patient’s level of consciousness can vary from excitement to dysphoria and from mild sedation to coma.40,41 Profound CNS depression, impaired gag response, cough suppression, and centrally mediated nausea and vomiting place the animal at high risk for pulmonary aspiration of gastric contents.3 Seizures can occur with high doses of agonist opioids. This is well recognized in humans33; however, its occurrence in small animals is unknown. Intrathecal administration of morphine can cause myoclonus.42 Opioids may alter the thermoregulatory response. Hypothermia is seen commonly in dogs, whereas hyperthermia may occur in cats.43 The most significant adverse side effect of opioids is respiratory depression. It is caused by a reduction in responsiveness to carbon dioxide in the brainstem respiratory center, as well as the centers that regulate respiratory rhythm. Areas of the medulla oblongata that control ventilation (nucleus tractus solitarius and nucleus ambiguus) have many opioid binding sites, and these respiratory neurons are inhibited by opioid receptor agonists. Attenuation of normal chemoreceptor-mediated ventilatory responses to hypercapnia and

hypoxia by opioids also may lead to ventilatory depression. Dogs and cats seem to be less sensitive than humans, in whom respiratory arrest is responsible for most opioid-related deaths.3,33 Initially, respiratory depression may be subtle in some patients because small decreases in tidal volume may occur before the respiratory rate declines. With further progression, the rate, tidal volume, and minute volume decrease. Therefore the rate alone can be an unreliable measure of ventilation. Because hypoventilation is defined as an inability of the respiratory system to eliminate metabolically produced carbon dioxide, the finding of hypercarbia on arterial (or venous) blood gas analysis is the most objective determinant of the presence and degree of respiratory depression. Opioids also may induce panting indirectly in dogs by resetting the thermoregulatory center, so the animal attempts to lose heat by increasing the respiratory rate, despite a normal to low body temperature. The effects of opioids on the cardiovascular system are minimal at therapeutic or toxic doses. Pure opioid agonist interactions with µ receptors may result in bradycardia and cardiac conduction abnormalities. The systemic vascular resistance remains relatively stable after opioid administration, although morphine may decrease peripheral vascular tone.44 Morphine and meperidine, when given intravenously, may cause histamine release leading to peripheral dilation (arterial and venous) and bradycardia; this drug should be avoided in animals with suspected or confirmed mast cell disease or after envenomation. Cutaneous signs include itching, warmth, and urticaria.34 Opioids cause a variety of direct gastrointestinal (GI) effects. They decrease the tone of the lower esophageal sphincter. Intestinal tone is increased while propulsive activity is reduced. Opioids also lower small intestinal secretions (pancreatic, biliary, and electrolytes and fluid) and enhance intestinal fluid absorption. These actions may result in constipation. Morphine has been associated with spasm of the sphincter of Oddi; therefore it is not used in people suffering from obstructive biliary or pancreatic diseases. In addition, opioids can directly stimulate the chemoreceptor triggering zone and thus may cause nausea and vomiting.33 At high doses, opioids may increase ureteral tone, bladder tone, and external sphincter tone, leading to urinary retention. Morphine, as well as other µ-agonist drugs, is reported to increase antidiuretic hormone release and thus reduce urine production and cause an increase in specific gravity.34

Treatment The mainstays of therapy for opioid overdose include providing a means for adequate ventilation and the administration of naloxone, an opioid antagonist (see Chapter 163). Patients whose respiratory status is compromised sufficiently should be intubated and supported with 100% oxygen and positive-pressure ventilation while naloxone is administered. Mechanical ventilation with positive endexpiratory pressure may be required if there is no response to the naloxone or if adequate oxygenation and ventilation cannot be achieved (see Chapter 30). Intubation and cuff inflation provides optimal airway control, decreases the risk of aspiration if vomiting or regurgitation occurs, allows access for airway suctioning and institution of positive pressure ventilation, and enables the administration of naloxone via the endotracheal route if intravenous access cannot be obtained. GI decontamination should be considered in patients that have had oral exposure to opioids, particularly those drugs that can have delayed absorption such as loperamide and sustained-release morphine products. Concomitant use of naloxone may facilitate GI decontamination by decreasing GI atony (increasing GI tone). Although they occur rarely, seizures, hypotension, and cardiac arrhythmias should be treated with standard therapies. Body temperature should be monitored and euthermia maintained.

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Naloxone is a synthetic derivative of oxymorphone (see Chapter 163). It is the opioid antagonist of choice because it competitively binds opioid receptors κ, δ, and, particularly, µ. It has a greater affinity for receptors than do the agonists. It is highly lipophilic and moves rapidly into the CNS. Naloxone usually has an onset of action of 1 to 2 minutes when given intravenously. The duration of action typically persists from 45 to 90 minutes. The dosage of naloxone for dogs and cats to reverse adverse opioid effects is 0.01 to 0.04 mg/kg. It may be given by the intravenous, intramuscular, intraosseous, subcutaneous, or endotracheal routes. Naloxone administration is generally safe in patients with opioid overdose, but very high dosages can initiate seizure activity. In animals with no initial response, repeat doses should be administered and titrated to each patient’s response.3,45 Naloxone may have a shorter duration of action than most opioids, and repeated doses or a continuous infusion may be necessary. A continuous infusion is administered by determining the amount of naloxone required to reverse respiratory depression, then administering two thirds of this dose every hour as a continuous infusion. Half of the loading dose should be administered 15 minutes after the initial dose because of a transient decline in the naloxone level 20 to 30 minutes after the initial bolus. The rate of the infusion should be titrated to maintain adequate ventilation. Naloxone can be mixed in most intravenous fluids in varying concentrations.44 The infusion is continued for the typical duration of effect of the involved opioid then gradually reduced while the patient’s respiratory and mental status are monitored closely. Continuous infusions have been used safely in adults and children.46,47 Larger-than-customary doses may be required to reverse the effects of codeine, methadone, propoxyphene, pentazocine, butorphanol, buprenorphine, and nalbuphine.48

PROGNOSIS Asymptomatic patients overdosed with any of these drugs should be observed for a minimum of 24 hours. The prognosis for toxicity with most of these drugs is unknown, but as with other intoxications, the outcome depends on the quantity of drug ingested and the severity of clinical signs demonstrated on admission. Early decontamination and good supportive care can prevent serious CNS, respiratory, and cardiovascular depression or complications.

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