Using clonidine and trazodone for anxiety-based behavior disorders in dogs

The use of psychoactive pharmaceuticals in veterinary behavior medicine has proved invaluable in managing anxiety-based disorders. Without the appropriate and judicious use of these medications, many dogs would be much less likely to respond to behavior modification therapy. Medications such as fluoxetine and sertraline (selective serotonin reuptake inhibitors [SSRIs]) and clomipramine (a tricyclic antidepressant [TCA]) can allow successful therapy for many animals experiencing conditions such as separation anxiety, thunderstorm phobia, and fear-based aggression.

In some cases, however, use of a single pharmaceutical agent does not provide sufficient anti-anxiety effects to achieve a suitable outcome. When a patient fails to respond to monotherapy with an SSRI or a TCA, clinicians have three options:

1. Increase the dose of the medication if the typical maximum dose has not been reached or if the patient has not shown undesirable side effects.

2. Switch to a different drug.

3. Augment the first drug with a second drug.1

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If the first two steps prove ineffective in managing the case, combination drug therapy is a viable alternative. Numerous possible combinations of agents can be used to manage particular cases. In this article, we review the use of clonidine and trazodone in dogs, two medications that are being used more frequently in behavior specialty practices to manage a variety of anxiety-based behavior problems.

CLONIDINE

Clonidine is classified primarily as an alpha-2 agonist. (An example of another alpha-2 agonist used in veterinary medicine is the injectable sedative dexmedetomidine.) Alpha-2 agonists increase alpha-2 adrenoreceptor activity. The increase in alpha-2 adrenoreceptor functioning results in a decrease in norepinephrine release from the locus ceruleus. Through its activation of the hypothalamic-pituitary-adrenal axis, norepinephrine is associated with fear-based responses such as increased vigilance and arousal.2 This can impair a patient's ability to relax in stressful situations, especially when triggering stimuli cannot be avoided or controlled. Common examples of this include meeting unfamiliar people or dogs while on walks or when unfamiliar guests enter a home.

Clonidine is also used as an antihypertensive agent. It has a short half-life (7.7 hours in people2), with its effect reducing over four to six hours. Pharmacokinetic data are lacking for dogs.

Indications and dosage

In veterinary behavior medicine, clonidine is most often used as an add-on agent, combined with an SSRI such as fluoxetine or a TCA such as clomipramine. It is usually dosed on an as-needed basis but can be given up to every eight hours. It needs to be administered one or two hours before exposure to an anticipated stressor.

Clonidine is commonly used to treat noise phobias (including thunderstorms and generalized noise responses), separation anxiety, and fear-based aggression with identifiable triggers. Generally, it is an effective agent when increased arousal or reactivity is a concern. Clonidine has a wide dosing range (0.01 to 0.05 mg/kg). It is available in 0.1-, 0.2-, and 0.3-mg tablets.

Keep in mind that no data support the dose recommendations (e.g. oral bioavailability, half-life); the recommendations are anecdotal as well as extrapolated from human data. Thus, close client communication is vital in determining an effective dose without excessive side effects.

Potential side effects

Side effects from clonidine can include dry mouth, ataxia, constipation, and sedation. Exercise caution when using clonidine in patients with existing cardiac disease.3 Starting at the lower end of the dose range and gradually tapering upward can help minimize the severity of side effects.

Clonidine is metabolized by the liver and excreted by the kidneys, so exercise caution in patients with compromised hepatic or renal function. Also exercise caution when using clonidine in patients with preexisting heart disease as it decreases cardiac output.

Clonidine can produce a dose-dependent biphasic response in blood pressure, with lower doses producing central mediated hypotension, but higher doses producing peripheral mediated vasoconstriction and hypertension (alpha-2-mediated). Use of clonidine in patients also receiving agents that affect atrioventricular node function (e.g. digoxin, calcium channel blockers, or beta blockers) may result in bradycardia or atrioventricular nodal block.4

If clonidine has been used daily for an extended period, consider slow withdrawal to diminish the chance of rebound hypertension.

TRAZODONE

Trazodone is classified as a serotonin receptor antagonist and reuptake inhibitor (SARI). It inhibits activity at the serotonin 5-HT2A postsynaptic receptor and acts as a weak presynaptic serotonin reuptake inhibitor. It is used as an adjunctive agent with TCAs and SSRIs to help manage anxiety-related disorders and facilitate sleep.

Trazodone can also be an alpha-1 antagonist, resulting in hypotension. It is metabolized by the hepatic cytochrome P450 system and reaches its peak plasma concentration at 445 ± 271 minutes; its half-life is 169 ± 53 minutes after a single oral dose.5

Indications and dosage

Trazodone can be administered as needed, daily as often as every eight hours, or by using a combination of the two schedules. Because of the wide range in reaching peak plasma concentration and in its half-life, it is important to recognize that dosing should be adjusted to account for this individual variability. Regular daily dosing is more common with generalized anxiety disorders in which it is difficult to identify a specific trigger, and as-needed dosing is used when those stimuli can be predictably recognized. Therefore, trazodone is used in situations in which there is an identifiable stimulus, such as thunderstorms, or before an owner's departure in separation anxiety cases.6

Trazodone is dosed at 1.7 to 9.5 mg/kg orally every eight to 24 hours. It is recommended to begin dosing at 2 to 3 mg/kg orally every 24 hours and then gradually taper up to effect. Dosing at the lower end of the range should be sufficient when trazodone is used along with a primary agent such as a TCA or an SSRI. Trazodone can also be used as a single agent. Trazodone is available in 50-, 100-, 150-, and 300-mg tablets.

Potential side effects

Side effects commonly include gastrointestinal effects (vomiting and diarrhea), sedation, ataxia, hypotension, excitement or agitation, and panting. Priapism is a rare side effect in people, so exercise caution when using trazodone in breeding male dogs.

When combined with an SSRI or a TCA, trazodone may increase the risk of seizures due to an unknown etiology, but consider that it could be a consequence of serotonin syndrome (see the sidebar "Serotonin syndrome: Be on the lookout"). SSRIs and TCAs may also increase plasma concentrations of trazodone. In addition, plasma concentrations of digoxin may be increased with trazodone administration.4,7

Serotonin syndrome: Be on the lookout

Most side effects diminish with time, so often waiting is the best response to the appearance of mild to moderate side effects. It is best to begin at the lower end of the dosage range to limit side effects. Administer a dose at the lower levels for three days and then gradually taper up as needed.8

MULTIPLE DRUG DOSING CONSIDERATIONS

The side effects mentioned previously and in this section are typically transient and mild. In some cases, however, these effects can be more prolonged and serious. Be sure to educate clients about the possible side effects and tell them to contact you or another veterinarian immediately with any concerns.

If you encounter adverse effects, you can decrease the dose (50% reduction is common) or, in more severe cases, discontinue the medication completely. Compounds with longer half-lives, such as SSRIs, can be discontinued abruptly, if necessary. But with shorter-acting compounds, such as TCAs, the dose should be gradually tapered to minimize withdrawal signs. Likewise, trazodone and clonidine should be slowly withdrawn if they have been administered two or three times daily for a prolonged period. Gradual withdrawal is helpful in all cases when there is a need to determine the lowest effective dose.

Dose adjustments for SSRIs should be made in four- to six-week increments, while shorter-acting compounds can be adjusted every one or two weeks. There is no need to withdraw these medications before anesthesia, but consider reducing premedication sedation to minimize interactions.

Other factors to consider when administering psychoactive pharmaceuticals include the following:

• Serotonergic agents (SSRIs, TCAs, and SARIs) may decrease triiodothyronine and thyroxine concentrations.

• Serotonergic medications such as SSRIs, TCAs, and SARIs should not be combined with monoamine oxidase inhibitors (MAOIs). MAOIs commonly used in veterinary medicine include selegiline and amitraz. These medications may precipitate a condition called serotonin syndrome when used in combination (see the sidebar "Serotonin syndrome: Be on the lookout"). Combining serotonergic agents with tramadol may have similar effects.

• Perform baseline premedication database testing including a complete blood count, serum chemistry profile, and urinalysis. Repeat this testing within one or two months after starting medication and then again every six to 12 months.

• For patients with a history of heart disease, consider performing a baseline electrocardiogram when prescribing serotonergic medications such as SSRIs, TCAs, and SARIs, particularly if a combination therapy is being used.

• Consider giving clients a handout outlining the possible effects of clonidine and trazodone to educate them about when they should contact their veterinarian.9 (Download a client handout at dvm360.com/PsychopharmEffects.)

• Any serotonergic medication (TCAs, SSRIs, and SARIs such as trazodone) may aggravate seizures in patients with a history of epileptic seizures and should also not be used in pregnant or breeding animals.10

• Because of their propensity to inhibit cytochrome P450 hepatic enzyme activity, SSRIs and TCAs should be used cautiously with drugs that rely on the same metabolic system. These include narcotics, tramadol, benzodiazepines, ketoconazole, and carbamazepine.3

• Phenobarbital may lower plasma concentrations of SSRIs and TCAs because of its induction effect on the cytochrome P450 system, thus increasing hepatic metabolism of medications in these two classifications.9 Similarly, because SSRIs and TCAs can suppress cytochrome P450 activity, there is a potential for these compounds to result in increased concentrations of phenobarbital and other medications that depend on the cytochrome P450 system for their metabolism.

SUMMARY

Adjunctive therapy for anxiety-based behavioral disorders in veterinary medicine can greatly increase the likelihood of a beneficial outcome. Clonidine and trazodone are two agents that are being used more frequently in veterinary behavior medicine and can be used in combination with more traditional serotonergic medications to help implement a behavior modification plan. Care in dosing and diligent client communication can minimize side effects and increase client satisfaction when these drugs are prescribed for their dogs.

John J. Ciribassi, DVM, DACVB, and Kelly Ballantyne, DVM, Chicagoland Veterinary Behavior Consultants, 1042 Mountain Glen Way, Carol Stream, IL 60188.

Editors' note: Dr. Ciribassi is a coauthor of the recently available Decoding Your Dog: The Ultimate Experts Explain Common Dog Behaviors and Reveal How to Prevent or Change Unwanted Ones (Houghton Mifflin Harcourt), the first behavior book for pet owners from the American College of Veterinary Behaviorists.

To view the references for this article, visit dvm360.com/PsychopharmRefs.