Phenobarbital and The Adverse Effects in Cats

Many of you know that Phenobarbital is one of the most effective anticonvulsant drugs (AED) that we use to help control feline seizure disorders. Data we published several years ago suggested that 93% of cats obtained seizure control with serum drug concentrations between 15-40 ug/ml, regardless of the etiology. Remember, control is either a 50% reduction in seizures or 1 or less seizures every 3 months. Despite its high accolades for control, phenobarbital can cause adverse effects in cats. Phenobarbital does undergo hepatic metabolism but, unlike in the dog, it does not result in an increase in ALP. So, what adverse effects can happen?

Clinical Adverse effects
Clinical adverse effects occur in 46.7%of cats in a 2021 study (Marsh et al). These may be described as Type I or Type A adverse effects because they are secondary to the drug properties and often dose dependent. Keep that in mind!  Sedation and ataxia were the most common side effects, but not the only ones. 
Here are the adverse effects, and percent of cats affected, as reported in Marsh's study:
a. Sedation 89%
b. Ataxia 53%
c. Polyphagia 22%
d. Polydipsia 6%
e. Polyuria 6%
f. Anorexia 6%
Perhaps the last 4 are only notable to the observant owner, or in single cat households. Also of note, side effects in cats are reported less often compared with dogs. Interestingly, 26 of the 36 cats with reported adverse effects had transient signs. The majority of these only occurred in the first 4 weeks of treatment and in cats receiving multiple anticonvulsants. Adverse effects were significantly more likely in this population of cats when more than 1 AED was being used.

Biochemical Adverse Effects
A more severe, and concerning type of adverse effect is Type B. These adverse effects were extremely rare in the recent study, as well as in my experience. Bone marrow suppression did occur in 1 cat (as can be seen with dogs) and it resolved with removal of the phenobarbital. Biochemical adverse effects are much rarer in cats than in dogs. If a cat has an elevated ALP, as a general rule, find a reason other than phenobarbital administration. In both the study we published several years ago, and the study by Marsh et al, no cats showed an elevated ALP on laboratory results.
 
Take home message:

• Talk with owners about the common adverse clinical effects in the first 2-4 weeks of treatment. These should resolve but if not, consider reducing the dose.

• Recheck the CBC and biochemistry within 4 weeks of starting phenobarbital to monitor for those rare Type B adverse effects.

• Phenobarbital is useful, but imperfect, so always look at the cat in front of you when making decisions about seizure management. When in doubt -reach out!

Thanks for reading! I hope you have a good week and are appreciating the slow shift to cold pre-winter weather that we’ve been having. I look forward to working with you soon.

Once Daily Phenobarbital for Cats?

A study by Dr. Mojarradi et al, out of Sweden, was recently published in the Journal of Feline Medicine and Surgery reporting on once daily phenobarbital administration for cats with seizures. The reported half-life of phenobarbital in cats is 43-72 hours which could suggest once daily treatment is possible, however based on pharmacokinetic data twice daily dosing has been the standard of care. This retrospective study questioned if this was necessary. 

This study was a retrospective review of 9 cats up to 3 years from enrollment. They tracked the number of seizures before starting phenobarbital (unfortunately for an unknown amount of time) and compared that to the number of seizures after starting phenobarbital. The cats were required to have 2 or more seizures, separated by at least 24 hours, prior to starting phenobarbital however the frequency and duration of the seizure disorder for each cat isn't known. They do comment that 6/9 cats had 1 or more per month prior to starting phenobarbital. Phenobarbital was started at a mean dose of 1.8 mg/kg PO q24h, the mean serum concentration of phenobarbital was 11 ug/ml (range 6-17) at about 1 month (range 19-54 days). All but 1 cat was seizure-free at that first follow-up. The second and third follow-up appointments, roughly 1 year apart, showed a few more seizures in the time range however overall 8/9 cats were considered to be in seizure remission (no seizures for more than 12 months) at the end of the study. Seizure remission, as defined in this study, was less than 1 seizure every 12 months. If they started at 1 seizure/month, and ended at 1 per year that is a pretty remarkable improvement! So remarkable, I wonder if the phenobarbital is responsible for that shift, or not.
My questions:

• Could such a low serum phenobarbital concentration cause such a dramatic response?

• Could this be the natural regression to the mean (shifts that are unrelated to intervention)?

• Did the retrospective nature of the study include only cats that did well on once daily phenobarbital, otherwise they would have taken twice daily phenobarbital and therefore been excluded from the study? Was this group of cats bound to do well, in other words, and it wasn't due to medication?

Another study by Pakozdy (https://doi.org/10.1177/1098612X12464627) noted that over time, most cats have a natural reduction in seizures while on anticonvulsant drugs. They tracked seizures in cats over a 10 year period and noted that most improved, some were seizure-free and some stopped medication. About 16% of the cats that stopped medication needed to have it restarted due to a return of seizures. 

The data reported in the study from Sweden suggests that we could administer phenobarbital once daily but the results are so remarkable (marked seizure improvement in a short period of time, low serum drug concentrations) that I feel compelled to repeat this study with a different, perhaps large, cohort of cats and make sure this is reliable. My advice: don't switch to once daily just yet!

Thanks for reading! I love managing seizures so please schedule a consult if you have a case that you'd like more assistance with seizure management. I'm happy to help!

Phenobarbital and Cats

It comes as no surprise that I'm a super fan of phenobarbital for seizure control in cats. My research at the University of Wisconsin started with the development of a novel transdermal phenobarbital product, and it ended (so far) with a novel oral formulation (not published yet). Phenobarbital works WELL and for many cats but, alas it isn't perfect.

Misconception vs. TRUTH

1) Phenobarbital causes elevated ALP enzymes in cats.....IT DOES NOT. There was one study that reported a few elevations but NONE of the 77 cats in a recent study, nor any of the cats in a prior study my resident and I conducted had elevated ALP enzymes. Elevated ALP is a dog thing!

2) Phenobarbital does not have observable side effects....FALSE! Side effects occur in 46.7%of cats (Marsh et al). Sedation and ataxia were the most common side effects, but not the only ones.
Here are the side effects (called Type A adverse events), and percent of cats affected, as reported in Marsh's study:
a. Sedation 89%
b. Ataxia 53%
c. Polyphagia 22%
d. Polydipsia 6%
e. Polyuria 6%
f. Anorexia 6%
** Perhaps the last 4 are only notable to the observant owner, or in single cat households. Also of note, side effects in cats are reported less often compared with dogs.
Type B adverse events were extremely rare in the recent study, as well as in my experience. Bone marrow suppression did occur in 1 cat (as can be seen with dogs) and it resolved with removal of the phenobarbital. Lymphadenopathy has been linked to phenobarbital use as well.

3) Phenobarbital side effects happen randomly...FALSE! They are dose dependent and predictable. Higher serum concentrations (above 35 ug/ml) result in a higher odds ratio of developing a side effect. Additionally, 20 of the 36 cats in the study by Marsh had transient signs. The majority of side effects only occured in the first 4 weeks of treatment. This is a terrific point to make when discussing the use of this drug with clients.

What is the Take Away Message?

1) Start phenobarbital at a dosage targeted to reach 20-30 ug/ml. This typically means about 3 mg/kg (or a bit less) q12h.The goal is seizure control without concerning side effects.

2) Counsel clients that side effects occur in about 1/2 of cats, and of those, the majority occur within the first 4 weeks of administration AND resolve without any dose adjustments. If side effects are present beyond 4 weeks, consider a dose reduction.

Happy Rosh Hashana to those celebrating and happy first day of Fall (a few days late)!

Keep those consults coming; I look forward to seeing you soon.

*Marsh O, Corsini G, Van Dijk J, Gutierrez-Quintana R, De Risio L. Prevalence and clinical characteristics of phenobarbitone-associated adverse effects in epileptic cats. Journal of Feline Medicine and Surgery. June 2020. doi:10.1177/1098612X20924925

*Finnerty K, Barnes Heller H, Mercier M, et al. Evaluation of therapeutic phenobarbital concentrations and application of a classification system for seizures in cats: 30 cases (2004 -2013). JAVMA 2014: 244(2):195-199.