Tried & True: Why Phenobarbital Remains ACVIM’s First-Line Antiepileptic Drug

Sponsored by Mizner

A variety of seizure management strategies exist among practitioners,^1-3 potentially generating a fair bit of confusion regarding best practices for antiepileptic drug (AED) selection and monitoring. The American College of Veterinary Internal Medicine (ACVIM) convened a panel of expert leaders in neurology and internal medicine to clear up this confusion by providing a reference for seizure management best practices. Key points are summarized and discussed below to aid the busy general practitioner in evidence-based clinical decision-making.

Initiating Treatment

Knowing when to start AED treatment can be tricky due to variation in disease and to the many factors that should be taken into consideration (eg, seizure etiology, risk for recurrence, seizure types).^1,2 Although there appears to be no benefit to initiating AED treatment after 1 unprovoked seizure, starting seizure control early in the disease process may lead to better outcomes.^1,2,4 The ACVIM panel recommends initiating seizure control in the following situations¹:

• Presence of structural lesion or known brain disease

• Acute repetitive seizures or status epilepticus (ie, seizure lasting ≥5 minutes or ≥3 generalized seizures in a 24-hour period)

• ≥2 seizures in a 6-month period

• Prolonged, severe, and/or unusual postictal periods

Selecting a First-Line Monotherapy

Although several AED options exist, relatively few strong evidence-based clinical studies evaluating their efficacy as monotherapy are available, contributing to confusion among practitioners regarding which should be chosen first.^1,2 Based on evaluation of the available published data, as well as expert opinion of clinical performance, the ACVIM panel categorized AEDs into 4 tiers of recommendation¹:

• Grade A (high recommendation and likely to be effective): Phenobarbital, imepitoin (not currently available in the United States)

• Grade B (moderate recommendation and most likely to be effective): Potassium bromide

• Grade C (low recommendation and may not be effective): Levetiracetam, zonisamide

• Grade D (not recommended for treatment and may be ineffective and/or dangerous to the patient): Primidone

Phenobarbital is the only drug available in the United States that has received a grade A recommendation.¹ Its long history of use and strong clinical evidence of monotherapy efficacy, demonstrating a cumulative success rate of 82% and reducing seizures by >50% across several studies, contributed to its recommendation.^1,5-12 Comparatively, potassium bromide has only been evaluated as a monotherapy by clinical trial once; zonisamide is supported by a few small case series rather than blinded, randomized clinical trials; and levetiracetam as a first-line treatment is backed by expert opinion only, leading to lower recommendations for each.^1,10,12-14

These recommendations serve as helpful reminders that, although clinicians may gravitate to newer drugs such as levetiracetam, drug selection should remain firmly grounded in scientific evidence of efficacy.

Improving Outcomes

Case outcome is influenced not only by treatment success but also by perceived patient quality of life and the burden treatment places on the household.^1,15,16 Emotional, social, and financial burdens may lead to euthanasia and should be taken into consideration when selecting an AED.^1,16 This is important to keep in mind when choosing more difficult to dose or more expensive medications, which may place an undue burden on owners. Phenobarbital’s relatively low cost, good tolerability when used appropriately, and simple twice-daily dosing may also help it perform favorably as a first-line AED in this regard.¹

Focusing on the Front-Runner: Phenobarbital Management Pearls

Phenobarbital should be started at a dosage of 2.5 mg/kg PO every 12 hours.¹ The use of phenobarbital in animals is currently extra-label in the United States; since the writing of the ACVIM consensus statement, however, a new FDA-approved beef-flavored phenobarbital option made specifically for dogs is on the horizon.

Phenobarbital’s well-known profile of adverse effects should be discussed with owners before initiating treatment to manage owner expectations and improve perceived patient outcomes. For example, owners can be advised that initial behavioral changes (ie, hyperexcitability, restlessness, sedation) are transient and usually resolve in 1 to 2 weeks; owners can also be given tips for handling polyphagia and polydipsia to avoid weight gain and urinary accidents in the house.¹ The more serious and rare adverse effects, including hepatotoxicity, blood dyscrasias, and necrolytic dermatitis, should be monitored for with regular blood work.^1,2 Cumulative hepatotoxicity may potentially be prevented by maintaining trough plasma concentrations within the recommended limits.¹

The ACVIM panel recommends that the therapeutic trough phenobarbital serum concentration remain in the 15 to 35 µg/mL range and be monitored routinely at the following occasions¹:

• 2 weeks after initiating treatment or after any dosage change (when the drug has reached steady state)

• 6 weeks after initiating treatment (when increased hepatic clearance may occur)

• Every 6 months long-term

• Whenever >2 seizure events occur between routine monitoring

However, dosing decisions should ultimately be guided by patient response to treatment.^1,2

Conclusion

Phenobarbital remains the tried-and-true AED for initiating seizure monotherapy management, recommended by ACVIM as a first-line treatment. Further scientific studies are necessary to evaluate the efficacy and predictability of other drugs before those can join phenobarbital as recommended first-line medications.