Doxepin

Overview

Doxepin (Sinequan®) is a tricyclic antidepressant with potent antihistaminic properties used in dogs and cats primarily for management of pruritus and behavioral disorders with an anxiety component.

Clinically, doxepin is most often used as an adjunctive therapy in cases of atopic dermatitis and psychogenic dermatoses, where both allergic and behavioral factors contribute to clinical signs.

Mechanism of Action (MOA): Doxepin inhibits the reuptake of norepinephrine and serotonin in the central nervous system, increasing their synaptic concentrations. It also has significant antihistaminic (H1, H2), anticholinergic, and alpha-1 adrenergic blocking effects.

Indications

Doxepin is used in dogs and cats primarily as an adjunctive therapy for dermatologic and behavioral conditions, particularly when both pruritic and anxiety-related components are present.

• Atopic dermatitis (adjunctive therapy): May be used to help control pruritus, particularly in mild cases or to reduce frequency of flare-ups, although antihistaminic efficacy may be variable.
• Psychogenic dermatoses: Used in conditions associated with compulsive or anxiety-driven behaviors such as excessive licking, grooming, flank sucking, or psychogenic alopecia.
• Behavior-associated pruritus: Useful when pruritic conditions are exacerbated by stress or behavioral abnormalities.

Dosage (Reference)

Dog

In dogs, doxepin dosing varies depending on the indication. Therapy is typically initiated at the low end of the dosing range and gradually titrated based on clinical response and tolerance.

Cat

In cats, doxepin is used cautiously due to sensitivity to its sedative effects. Dosing should begin at the low end and increased slowly only if well tolerated.

Warnings & Precautions

Doxepin is a tricyclic antidepressant with multiple pharmacologic effects, and its use requires careful patient selection and monitoring, particularly in animals with underlying systemic or neurologic conditions.

• Contraindications: Do not use in patients with known hypersensitivity to tricyclic antidepressants or those receiving monoamine oxidase inhibitors (MAOIs) within the previous 14 days.
• Urinary retention and glaucoma: Use with extreme caution due to anticholinergic effects that may worsen these conditions.
• Cardiovascular disease: Use cautiously or avoid in patients with cardiac disease due to potential effects on heart rhythm and blood pressure.
• Seizure risk: May lower seizure threshold; use with caution in animals with a history of seizures.
• Withdrawal considerations: Gradual tapering is recommended after long-term use to avoid potential withdrawal effects.
• Drug confusion risk: Do not confuse doxepin with similarly named drugs (e.g., digoxin, doxapram, doxycycline).

Drug Interactions

Doxepin may interact with multiple medications through additive CNS depression, anticholinergic effects, or serotonergic and cardiovascular mechanisms. Careful monitoring is recommended when used concurrently with the following drugs.

• Anticholinergic agents (e.g., atropine, oxybutynin): Additive anticholinergic effects may occur; use cautiously.
• Antihistamines (e.g., diphenhydramine, hydroxyzine): Increased sedation may occur.
• Antiplatelet agents (e.g., aspirin, clopidogrel): Increased risk of bleeding.
• Cannabidiol: Additive CNS depression is possible.
• Cimetidine: May inhibit metabolism of doxepin and increase risk of toxicity.
• Hypotensive agents (e.g., amlodipine, enalapril): Additive blood pressure–lowering effects may occur.
• Dextromethorphan: Increased risk of serotonin syndrome.
• Monoamine oxidase inhibitors (MAOIs; e.g., amitraz, selegiline): Concurrent use (within 14 days) is contraindicated due to risk of serotonin syndrome.
• NSAIDs (e.g., carprofen, meloxicam): Increased risk of bleeding.
• Opioids (e.g., morphine, buprenorphine): Additive CNS depression and anticholinergic effects; serotonergic opioids (e.g., tramadol) increase risk of serotonin syndrome.
• Phenobarbital: May reduce doxepin concentrations.
• Prokinetic agents (e.g., metoclopramide): Doxepin may decrease prokinetic effects.
• QT-prolonging drugs (e.g., fluoxetine, ketoconazole, ondansetron): Increased risk of QT prolongation and arrhythmias.
• Serotonergic agents (e.g., fluoxetine, trazodone, mirtazapine): Increased risk of serotonin syndrome.
• Sympathomimetics (e.g., albuterol, phenylpropanolamine): Increased risk of cardiovascular effects such as arrhythmias and hypertension.
• Tramadol: Increased risk of serotonin syndrome.

Side Effects & Overdose

Side Effects

Adverse effects of doxepin in dogs and cats are generally related to its central nervous system and anticholinergic properties. The severity of effects may vary depending on dose and individual sensitivity.

• CNS effects: Hyperexcitability or, more commonly, lethargy may occur.
• Gastrointestinal effects: GI distress such as vomiting or decreased appetite may be observed.
• Anticholinergic effects: Constipation and urinary retention may occur.
• Cardiac effects: Ventricular arrhythmias may occur, particularly in overdose situations.

Overdose

Overdose of doxepin and other tricyclic antidepressants can be rapidly life-threatening and requires immediate medical intervention.

• Cardiovascular effects: Arrhythmias, profound hypotension, and cardiovascular collapse may occur.
• CNS effects: Seizures, coma, and severe depression of consciousness may develop.
• Respiratory compromise: May occur secondary to CNS depression.
• Management: Supportive care is essential, including airway support, antiarrhythmics, and anticonvulsants.
• Decontamination: Activated charcoal may be beneficial; induction of emesis is contraindicated.
• Advanced therapy: Intravenous lipid emulsion (ILE) may be considered in severe toxicity.
• Consultation: Veterinary toxicology consultation is strongly recommended in suspected overdose cases.

Key Notes

Practical clinical points that support effective use of doxepin in dogs and cats:

• Dual therapeutic role: Combines behavioral modification and antipruritic effects, making it useful in cases where dermatologic disease is influenced by stress or anxiety.
• Variable efficacy: Response is inconsistent between patients; some animals show marked improvement while others have minimal benefit.
• Delayed onset of action: Full therapeutic effects, particularly for behavioral conditions, may take several days to weeks to become evident.
• Adjunctive therapy: Best used as part of a multimodal approach rather than as a sole treatment for dermatologic or behavioral disorders.
• Limited evidence base: Clinical dosing recommendations and efficacy data are relatively limited compared with other commonly used agents.
• Central and peripheral effects: Clinical outcomes result from combined CNS neurotransmitter modulation and peripheral antihistaminic activity.