Treating behavior problems with benzodiazepines (Proceedings)

DEA Class IV, Rapid onset of action, Potential for human abuse, Psychological dependency, Physical dependency, Can be safely used with many other psychoactive medications

Action:

• Facilitates GABA in the CNS by binding to GABAA receptors.

• Behavioral effects due to action on the hypthalamus and limbic system

Uses

• Anxiety and phobias in all species

Aggression

• Evidence in literature is contradictory. Aggression may increase or decrease depending on

• Species, Sex, Type of aggression, Specific benzodiazepine, Specific dose, Single-dose vs. repeated dosing

• Lack a specific anti-aggressive mechanism

• May help with fear-induced aggression

• Use with caution in fear aggression. Learned inhibition of aggression may be lost.

Affiliative Behavior

• May increase, depending on Species, Sex, Type of aggression, Specific benzodiazepine, Specific dose

• Single-dose vs. repeated dosing

Side-effects

• Sedation, Muscle relaxation, Increased appetite, Paradoxical excitation, Increased friendliness, Anxiety, Hallucinations, Muscle spasticity, Insomnia, Idiopathic hepatic necrosis in cats (Diazepam)

Excreted in milk

• Passes through the placenta

• Changes in absorption, distribution, metabolism and excretion occur in various disease states, e.g. impaired hepatic or renal function

Decrease dose in patients that are

• Old, Obese, Impaired renal function, Impaired liver function, Taking other medications that are metabolized by the cytochrome P450 enzyme system

• Do not give to patients with narrow angle glaucoma

Can have an amnestic effect. May or may not interfere with learning

• Wide variation in optimum dose for individual animal

• Tolerance can develop in patients that are on a benzodiazepine for a long period of time, resulting in the need to repeatedly raise the dose to maintain efficacy.

Withdraw gradually

• If patient has been on higher dose daily for several weeks, eventually becomes physically addicted. Gradual withdrawal can avoid side-effects that abrupt withdrawal can cause.

• Gradual reduction allows identification of specific dose that may still be required to control the problem.

• Sudden termination in a patient that has been on continuously for a long period of time can result in rebound, i.e. a resumption of symptoms which may be more intense than prior to treatment. Most likely if has been on a short-acting benzodiazepine.

In case of overdose:

• Supportive

• Cats, give 0.05 mg/kg apomorphine SC or 1 mg/kg xylazine SC to induce vomiting.

• Give activated charcoal

• 3 hours after ingestion, do not induce vomiting or conduct gastric lavage

• Flumazenil (Mazicon) benzodiazepine receptor antagonist

To begin

• Begin when situation for which drug is being used does not exist, e.g. owner home and no storms.

• Test lowest dose to make sure animal is not unusually sensitive (ataxic, sedated) and does not show paradoxical excitement.

• Test in actual situation, e.g. thunderstorm, owner leaves (videotape)

• If sufficient, maintain that dose

• If insufficient, incrementally increase the dose until

• Find effective dose or

• Experience unacceptable side-effects

• Benzodiazepines

• If cannot find effective dose without side-effects, change medication.

Diazepam Alprazolam

Alprazolam Diazepam

• The fact that one medication does not work well does not mean that another will not.

• When discontinuing, common rule of thumb is to decrease dose no faster than 25% each week

• Do more slowly if

• Patient has been on medication a long time (months)

• Particular concerns about relapse

Alprazolam (Xanax and generic)

Dogs 0.02-0.1 mg/kg q4h

Cats 0.0125-0.025 mg/kg q8h

• Alone or as a supplement to another medication with anxiolytic properties such as a TCA or SSRI.

• Short term use in severe cases until a delayed onset of action medication has time to take effect.

• Most effective if given 30-60 minutes BEFORE occurrence of the earliest stimuli that elicit fear responses. Owners must monitor weather conditions closely. If in doubt, medicate.

• If dog is already showing fear, give anyway as may help some, but not as effective

• Dogs given escalating dose over 18 to 26 until achieve a dose of 12 mg/kg q.i.d., then maintained on that dose for three weeks become physically addicted.

• Liver failure? Not yet reported in veterinary patients, but has occurred as a rare event in humans.

Chlordiazepoxide (Librium and generic)

Dogs 2.0-6.5 mg/kg q8h

Cats 0.2-1.0 mg/kg q12h

• Plasma levels peak around 2-5 hours after a single dose of 0.5-0.8 mg/kg

• Plasma levels peak around 7-8 hours after a single dose of 4 or 20 mg/kg.

• Doses of 2.5-20 mg/kg stimulate appetite

• Doses of 10-40 mg/kg cause ataxia

• Given doses up to 50 mg/kg PO for 6 months have not shown adverse effects.

• Nervous/timid dogs become less timid at 3.5 mg/kg daily in the morning

• Used to tame zoo animals for handling

Clonazepam (Klonopin and generic)

Extensive metabolism in the liver to various inactive metabolites.

Dogs given 0.5 mg/kg q12h

Week 1; half-life 2 hours

Week 3; half-life 8 hours

Dogs given clonazepam q12h for three or more weeks, then acutely withdrawn, exhibit anorexia, hyperthermia and weight loss

Cats given 1000 mg/kg survived

Clorazepate dipotassium (Tranxene® & generic)

DOGS 0.5-2.0 mg/kg q4h

CATS 0.5-2.0 mg/kg q12h

• Dogs given a single dose of 2 mg/kg PO have peak plasma concentrations of nordiazepam at 1-3 hours.

• Mean elimination half-life of nordiazepam is 284 minutes (almost 5 hours) after a single dose and 355 minutes (almost 6 hours) after multiple doses given q12h.

Diazepam (Valium® & generic)

Dogs 0.5-2.0 mg/kg q4h

Cats 0.1-1.0 mg/kg q4h

Blood concentrations are proportional to dose given.

Half-life

Dog 2.5-3.2 hours

Cat 5.5 hours

Multiple metabolites: nordiazepam, oxazepam, temazepam

Half-life of nordiazepam

Dog 3-5.7 hours

Cat 21.3 hours

Half-life of oxazepam

Dog 3-5.7 hours

Cats: 500 mg/kg PO is fatal within 1 day

• Acute withdrawal of diazepam dependent dogs by administration of flumazenil.

• Tremors, twitches, jerks, seizures

• Martin et al. 1990

• Reports of death due to acute hepatic necrosis reported in cats beginning in 1994.

• Clinical signs as soon as 5 days after beginning daily administration.

• Death within 24 hours in spite of aggressive supportive treatment.

• Some do survive, Various brands

• No conclusive evidence as to why diazepam caused fatal hepatic necrosis.

• Take baseline blood chemistry before start, Check at 3-5 days.

• If elevated Alanine Transaminase (ALT) or Aspartate Transaminase (AST), discontinue.

• While there is a real risk of fatal liver disease when using diazepam, it is RARE.

Flurazepam (Dalmane and generic)

Dogs 0.1-0.5 mg/kg q12h

Cats 0.1-0.2 mg/kg q12h

• Major metabolite is N1-desalkyl-flurazepam, which has a half-life of 47-100 hours

• More effective on second and third nights of consecutive use than on first night, probably due to metabolite.

• May be preferred benzodiazepine for pets that wake at night, but no research or clinical reports on this or other uses of flurazepam.

Lorazepam (Ativan and generic)

Uses in humans

• Short-term relief of symptoms of anxiety and management of anxiety disorders

• Lorazepam

• Major metabolite is lorazepam glucuronide, which has no significant CNS activity.

Formation of lorazepam glucuronide is much faster in dogs than in humans. Peak plasma levels of unchanged lorazepam are almost identical in humans and dogs if dogs are given a dose 30X higher than humans on a per kg basis.

Cats do glucuronidate lorazepam!

Peak plasma concentration

Dog 0.5 hours at 1 mg/kg PO

Cat 12 hours at 20 mg/kg PO

Good separation between anxiety-reducing doses and sedative-hypnotic doses

Oxazepam (Serax and generic)

Dog 0.04-1.0 mg/kg q6h

Cat 0.2-1.0 mg/kg q12h

No active intermediate metabolites

Main metabolite is an inactive glucuronide conjugation of oxazepam.

• May be best benzodiazepine for geriatric patients and patients with liver disease or obesity.

• Dogs given 5-10 mg/kg oxazepam PO exhibit peak plasma levels in 4-6 hours.

• Wide separation of clinically effective doses and doses that produce side-effects

• Has a larger spread between clinically effective dose and dose that produces side-effects than chlordiazepoxide or diazepam.

Cats: Good appetite stimulant with longer duration of action than diazepam. No reported incidents of liver failure. If liver failure is due to problems of metabolism in some individuals, oxazepam is probably unlikely to cause this problem.

Crowell-Davis SL and Murray T 2006 Veterinary Psychopharmacology, Blackwell Publishing.