Foss Trazodone TVTechMayJune2017Foss Trazodone TVTechMayJune2017Foss Trazodone TVTechMayJune2017Foss Trazodone TVTechMayJune2017Foss Trazodone TVTechMayJune2017Foss Trazodone TVTechMayJune2017Foss Trazodone TVTechMayJune2017Foss Trazodone TVTechMayJune2017
TOXICOLOGY
TALK
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TODAY’SVETERINARYTECHNICIAN
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May/June 2017
BACKGROUND
Trazodone is a serotonin 2A antagonist and reuptake inhibitor
that has been used in human medicine as a prescription
therapy for depression, aggression, sleeplessness, and
anxiety since 1981.
1–3
It is available in 50-, 100-, 150-, and
300-mg tablets as well as 150- and 300-mg extended-release
tablets.
1
No products are labeled for veterinary use.
Trazodone selectively blocks serotonin reuptake, which
enhances serotonin’s effects.
4
It is an antagonist of 5-HT
2A
,
H1-histaminic, and α1-adrenergic receptors at low to
moderate doses, resulting in various levels of sedation.
3–6
It
can have hypotensive effects.
4
At higher doses, trazodone
acts as a serotonin agonist, and serotonin syndrome
can develop.
4,6
Trazodone also has anxiolytic properties,
but the exact mechanism of action is unknown.
4
USE IN VETERINARY MEDICINE
In 2008, Gruen and Sherman studied 56 dogs prescribed
trazodone in combination with other primary behavior
therapies and discovered that trazodone seemed to offer
therapeutic benefit with relatively minimal adverse effects.
7
Since then, studies have investigated the benefit of trazodone in
postorthopedic surgery treatment plans involving confinement
to enhance calm behavior and reduce anxiety in hospitalized
dogs. Trazodone has generally been shown to be beneficial
and relatively safe. Adverse events associated with trazodone
can be divided into behavioral and systemic signs. Adverse
Trazodone in
Veterinary Medicine
Trazodone in Veterinary Medicine
Tamara has been with the ASPCA
Animal Poison Control Center
since 2000. She earned her
bachelor’s degree in agriculture
with an emphasis in animal
health technology from Murray
State University in Kentucky.
Tamara especially enjoys the
toxicology-, research-, and
information technology–related
aspects of her position at the
ASPCA. She has a passion for
greyhounds and is an active
volunteer and foster for American
Greyhound. Outside of work,
she loves spending time with her
greyhounds, especially helping
her greyhound Callen have fun
playing running games like lure
coursing and straight racing.
Tamara Foss, CVT
ASPCA Animal Poison
Control Center
Urbana, Illinois
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TOXICOLOGY
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events previously reported in the literature
include drugged or “spacy” behavior,
drowsiness, panting, anxiety/restlessness/
agitation, vomiting/gagging, behavioral
change (counter surfing and trash raiding),
excitation, sedation, increased hunger,
colitis, and aggression (growling).
5,7,8
In veterinary medicine, trazodone is generally
dosed at 1.7 to 19.5 mg/kg/d on a daily or
as-needed basis with immediate action (not
extended-release) tablets and can be given with
food.
1
When administered in combination with
tricyclic antidepressants or selective serotonin
reuptake inhibitors, it is recommended to
begin dosing trazodone at 2 to 5 mg/kg
and increase as needed to a maximum dose
of 14 mg/kg/d.
1
Trazodone should be
administered about an hour before potential
anxiety-inducing stimuli, as its onset of action
is approximately 30 to 60 minutes.
1,5
Gruen
and colleagues reported owner-observed
duration of effect lasting 4 hours or more.
5
The parent compound has an elimination half-
life of approximately 7 hours in immediate-
release tablets.
1
Trazodone undergoes
extensive metabolism in the liver and is
predominately excreted via the kidneys.
1,4
EXPOSURE
Incidence and Clinical Signs
The ASPCA Animal Poison Control Center
reported 417 incidences involving single-
agent trazodone exposures in 379 dogs from
2009 to 2013.
1
In 104 dogs experiencing
adverse effects, sedation and lethargy were
reported in 43% of the dogs. Ataxia was
reported in 16% and vomiting in 14%. Overall,
lethargy, sedation, depression, somnolence,
and subdued behavior are considered
common signs of trazodone exposure.
9
Additional information on signs reportedly
exhibited by dogs exposed to trazodone
alone from January 2003 to November
2016 and the lowest dose at which each
sign was seen is provided in TABLE 1.
Management
Decontamination measures are an important
component of exposure management.
Induction of emesis within 1 hour of exposure
is recommended in asymptomatic patients
if no contraindications to emesis exist.
9
Activated charcoal with sorbitol may be
recommended in large exposures only.
9
Peer Reviewed
|
todaysveterinarytechnician.com
Studies have
investigated the
benefit of trazodone
to enhance calm
behavior and
reduce anxiety in
hospitalized dogs.
shutterstock.com/Gabriel Scott
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May/June 2017
PEER
REVIEWED
Treatment of trazodone overdose generally
consists of symptomatic and supportive
care. Although adverse effects are often
reported, relatively few cases have involved
serious signs and no deaths are attributed to
trazodone exposure to date.
9
Special attention
should be given to ensuring maintenance
of cardiac output and being attentive to
signs of hyperthermia or hypothermia and
correcting as needed.
9,11
IV fluid therapy may
be needed to maintain blood pressure.
6,9
Diazepam is the drug of choice for managing
tremors or seizures, and atropine is
suggested for treatment of bradycardia.
6,9
Being aware of signs associated with
serotonin syndrome is important as this can
be a serious and potentially life-threatening
condition to manage. Serotonin syndrome
develops as a result of an overabundance of
serotonin in the central nervous system.
6
It can
be a risk in cases of exposure to high doses
of trazodone.
1,4
Clinical signs of serotonin
syndrome in dogs, in order of most to least
common, include vomiting, diarrhea, seizures,
hyperthermia, hyperesthesia, depression,
mydriasis, vocalization, death, blindness,
hypersalivation, dyspnea, ataxia/paresis,
disorientation, hyperreflexia, and coma.
1
Cyproheptadine, a serotonin antagonist,
helps combat serotonin syndrome signs.
6,11
Phenothiazines should be used cautiously
because of potential hypotensive effects.
6
Interaction With Other Drugs
Trazodone interacts with numerous drugs,
and some of these interactions may have
clinically significant effects. Of special
interest are medications that may be
strong inhibitors or inducers of cytochrome
P450 3A4 (CYP3A4) isoenzyme, which is
involved in trazodone metabolism.
4
Azole
antifungals (eg, ketoconazole, itraconazole,
fluconazole) and macrolide antibiotics (eg,
erythromycin, telithromycin, clarithromycin)
are CYP3A4 inhibitors and thus may enhance
the effect of trazodone.
1,4
Carbamazepine,
phenobarbital, phenytoin, rifampicin, and
modafinil, which are CYP3A4 inducers, may
decrease the effect of trazodone.
1,4,9
Extreme caution should be used with
concomitant trazodone and fluoxetine use and/
or exposure as it is believed that fluoxetine
may inhibit metabolism of trazodone.
1,4
Additionally, fluoxetine and other serotonergic
medications (eg, paroxetine, sertraline,
amitriptyline, clomipramine, amphetamines,
dextromethorphan) as well as monoamine
oxidase inhibitors (eg, phenelzine, amitraz,
selegiline), metoclopramide, and tramadol,
could heighten the risk of serotonin syndrome
when combined with trazodone.
1,4,6,8
Serotonin syndrome patients with severe
cardiac disease or renal and/or hepatic function
deficits should be monitored very closely and
may merit additional treatment measures.
1
Prognosis
The prognosis for patients exposed to
trazodone is generally good, especially when
serotonin syndrome has not developed.
Signs generally resolve in 12 to 24 hours.
6
Trazodone in Veterinary Medicine
TABLE 1 Signs Associated With
Trazodone Exposure in Dogs
10
SIGN LOWEST DOSE (MG/KG)
AT WHICH SIGN
WAS SEEN
Lethargy 0.55
Depression/vomiting 1.35
Ataxia 1.7
Diarrhea 2.82
Hyperactivity 3.8
Hypotension 5.94
Hyperesthesia 6.06
Vocalization 6.6
Tremors 8.17
Disorientation 8.28
Tachycardia/hypertension 8.83
Hyperthermia 11.8
Collapse 12.99
Mydriasis/bradycardia 16.23
Seizure 78.7
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