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Treating behavior problems with benzodiazepines (Proceedings)
Benzodiazepines facilitate GABA in the CNS by binding to GABA-A receptors.
DEA Class IV, Rapid onset of action, Potential for human abuse, Psychological dependency, Physical dependency, Can be safely used with many other psychoactive medications
- Facilitates GABA in the CNS by binding to GABAA receptors.
- Behavioral effects due to action on the hypthalamus and limbic system
- Anxiety and phobias in all species
- 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.
- May increase, depending on Species, Sex, Type of aggression, Specific benzodiazepine, Specific dose
- Single-dose vs. repeated dosing
- 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.
- 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:
- 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
- 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
- If cannot find effective dose without side-effects, change medication.
- 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.
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
- 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.
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