John H. Rossmeisl, Jr., DVM, MS, DACVIM, Virginia Tech

ArticleLast Updated March 20153 min readPeer Reviewed
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Phenobarbital is an effective antiepileptic drug used in dogs and cats.1-3


  • Many adverse events associated with phenobarbital (PB) use in dogs and cats are transient; others are acceptably managed with appropriate client education.1,3

  • Hepatotoxicity can develop in dogs treated chronically with PB,3-6 but

    • Is avoidable with diligent therapeutic monitoring

    • May be reversible with prompt drug withdrawal and supportive therapy

  • Early recognition and treatment are key in resolving any complication that may arise.

Adverse Events

  • Adverse events are more commonly observed in dogs than in cats.2,3

  • Common acute and transient adverse behavioral effects include sedation, hyperexcitability, and restlessness.  

    • Signs resolve in most patients within 2 weeks of starting therapy.1,3

      • Improvement may result from induction of PB biotransformation over time.

  • Frequently reported chronic and persistent side effects are polydipsia, polyuria, and polyphagia.

    • Can be intolerable to some owners, requiring changing the antiepileptic drug (AED)1,3

  • In dogs, subacute-to-chronic treatment is often associated with subclinical laboratory abnormalities, including3,7

    • Decreased total and free thyroxine concentrations

    • Mild-to-moderate elevations in ALP and, to a lesser extent, ALT

Toxicities & Severe Reactions

  • Hepatotoxicity

    • Most common clinically significant, severe complication associated with PB3,4,8

    • Risk factors include

      • Chronic PB use

      • Serum PB concentrations >35 μg/mL (151 µmol/L)

      • Concurrent therapy with other hepatotoxic drugs (see Warnings)

    • May result in irreversible and fatal hepatic failure

    • Clinical signs

      • Abdominal effusion

      • Anorexia

      • Icterus and pigmenturia

      • Marked sedation and ataxia

      • Vomiting/diarrhea

    • Laboratory abnormalities

      • Elevated bile acid concentrations

      • Low serum albumin (hypoalbuminemia)

      • Increased serum PB concentration without dose escalation

      • Moderate-to-marked elevations in ALP and ALT

  • Blood dyscrasia3,5

    • Rare idiosyncratic reaction that usually develops within several months of therapy

    • Clinical signs

      • Anorexia

      • Fever

      • Lethargy

      • Splenomegaly

      • Spontaneous hemorrhage

    • Laboratory abnormalities

      •  Neutropenia

      • Thrombocytopenia

      • Anemia

  • Superficial necrolytic dermatitis8

    • Multifocal dermatopathy characterized by erythema and papules that progress to erosions

      • Predilection for footpads, mucocutaneous junctions, and axillary and inguinal regions

    • Can develop with chronic PB administration

    • Often associated with laboratory, ultrasonographic, and histopathologic evidence of hepatic disease

      • Overt clinical hepatic failure is rare.

  • Dyskinesia6

    • Rare reaction defined by abnormal, involuntary, repetitive muscle movements that distort or impair voluntary motions

Treatment Monitoring & Precautionary Measures3-6

  • CBC, serum chemistry panel, and urinalysis should be performed before PB therapy is initiated.

  • After steady-state PB concentrations are confirmed (at approximately 2 weeks), monitor serum PB concentrations, serum chemistry panel findings, and serum bile acids q6mo in patients on chronic PB therapy.

  • Serious hepatotoxicity requires

    • Prompt PB discontinuation

    • Appropriate symptomatic and supportive care

      • Fluids

      • Gastric protectants

      • Dietary and nutraceutical hepatic support

      • Management of hepatic encephalopathy or coagulopathy (if present)

      • Other measures as indicated

    • Acute PB withdrawal may precipitate seizures.

    • Consider loading with additional AED (eg, potassium bromide).

    • Hepatotoxicity, myelosuppression, and dyskinesia may be reversible with prompt recognition and treatment.


  • Avoid PB use in patients with preexisting hepatic disease.

  • Risk for clinically significant liver dysfunction may increase when PB is administered with other hepatotoxic drugs.

  • May potentiate sedative effects of CNS depressants (eg, anti-histamines, benzodiazepines, narcotics)

  • Hepatic or intestinal P450 activities induced by PB may result in drug interactions by increasing drug metabolism, resulting in

    • Reduced blood concentrations and therapeutic efficacy (eg, cyclosporine, doxycycline, zonisamide, mitotane)

    • Increased active metabolites of parent compound, thus potentiating therapeutic effects or causing toxic effects (eg, acetaminophen)