Bromide Therapy

Optimal Bromide Therapy and Monitoring
Lauren A. Trepanier, DVM, PhD, Dip. ACVIM
Madison, WI

    Bromide is a halide element with anticonvulsant properties that is gaining widespread use for the treatment of seizures in dogs. This interesting compound appears to exert its anticonvulsant effects by passing through neuronal chloride channels and hyperpolarizing neurons. Bromide is one of the few drugs that has been shown to be effective in dogs with seizures that are refractory to standard therapeutic serum concentrations of phenobarbital. However, successful control of seizures in these patients is dependent upon appropriate management of bromide therapy. The following guidelines for bromide therapy are based upon the author's clinical experience with the Therapeutic Drug Monitoring program at Cornell over the past five years, as well as results from a retrospective study of 122 epileptic dogs treated with bromide.

When should the addition of bromide to phenobarbital therapy be considered?

    Bromide is indicated in the following situations:

1) for epileptic dogs being treated with either phenobarbital or primidone, that have continued seizures despite therapeutic serum phenobarbital concentrations;

2) for epileptic dogs with or without adequate seizure control, with evidence of hepatotoxicity or other undesirable side effects from barbiturates;

3) for dogs with epilepsy and evidence of pre-existing liver disease (whether or not the liver disease is related to the seizures); and

4) as an option for a first line anticonvulsant in dogs with newly diagnosed epilepsy.

What about using bromide alone as a first-line agent?

    The relative efficacy of bromide alone compared to phenobarbital alone is still not clear. In the handful of epileptic dogs that we have treated with bromide from the time of initial diagnosis, bromide appears to be quite effective as a single agent. Because of the risk of hepatotoxicity with phenobarbital, bromide may be preferable as a first line agent, with smaller doses of phenobarbital added later if additional seizure control is needed. Only further experience with clarify this issue.

What's the best starting dose for potassium bromide?

    Based on dose calculations derived from pharmacokinetic studies in dogs, and clinical experience, the optimal starting dose for bromide in dogs being fed average commercial diets is 30-40 mg/kg once daily. Unless there is nausea associated with a single daily dose, there is no reason to give bromide twice daily. For dogs on high chloride diets (e.g. dry diets with chloride contents greater than 1.0%, such as Eukaneuba Response Formula FP TM, and Hill's h/d, s/d, or i/d), higher starting doses of 50-80 mg/kg/day may be necessary to maintain serum bromide concentrations in the therapeutic range, since high chloride intake increases bromide loss in the urine and lowers serum bromide concentrations. For dogs on bromide alone, 40-50 mg/kg/day is a reasonable starting dose, although higher doses may be necessary to control seizures. Because bromide elimination does vary with chloride intake, all dosages should be optimized by monitoring serum bromide concentrations.

Is a loading dose necessary?

    For dogs already on phenobarbital, a loading dose is probably not necessary and can cause significant sedation in some patients. A loading dose is indicated if bromide is being started alone in a dog with frequent or severe seizures, or if phenobarbital or primidone must be discontinued rapidly in the face of hepatotoxicity. I prefer that dogs be given a loading dose of bromide in the hospital so that they can be monitored, and so that there is no confusion on the part of the owner about continuing the loading dose at home. A dose of 600 mg/kg divided into 4 doses over 24-48 hours achieves therapeutic serum bromide concentrations in most dogs.

How should the dose of phenobarbital be adjusted when bromide is added?

    Seizure breakthrough can occur if the dose of phenobarbital or primidone is tapered too rapidly following the addition of bromide. It is safest to wait until sedation develops to reduce the dose of phenobarbital (usually within the first 4 weeks of therapy), or, if sedation does not occur, to wait until bromide concentrations are within the therapeutic range to begin to taper the dose of phenobarbital. Dose reductions of 10-25% every 4-6 weeks (depending on the patient's seizure interval) work well for most dogs. Because phenytoin and oral diazepam are only minimally effective as anticonvulsants in dogs, the dosages of these drugs can be tapered more rapidly once bromide therapy has been instituted.

How should serum bromide levels be interpreted?

    We use a therapeutic range for bromide of 1000-2000 ug/mL in our laboratory. This is equivalent to 1-2 mg/mL or 100-200 mg/dL in units used by some other laboratories. Be skeptical of results that are reported as greater than 4 mg/mL; for the gold chloride method, which is the most reliable method for measuring therapeutic serum bromide concentrations, the assay is not accurate (becomes non-linear) above 4000 ug/mL or 4 mg/mL.

What's the optimal therapeutic range?

    In our review of 122 epileptic dogs, dogs on bromide and phenobarbital combination therapy that had improved seizure control (defined as a 50% or greater reduction in seizure frequency following the initiation of bromide) had average serum bromide concentrations of 1600 ug/mL, with a range of 500 to 2900 ug/mL. Only 12% dogs that improved on combination therapy had serum bromide levels less than 1000 ug/mL. Therefore, serum bromide concentrations should generally be targeted to at least 1000 ug/mL for dogs on both bromide and phenobarbital. In addition, about 30% of dogs that showed seizure improvement on both drugs required bromide levels greater than 2000 ug/mL, whereas only about 10% of poor responders (defined as dogs with less than a 50% reduction in seizure frequency following bromide initiation) reach bromide levels this high. Thus, for dogs that have continued poor seizure control on bromide, serum bromide concentrations of 2000 ug/mL or greater may be necessary to improve seizure control. We have set our bromide therapeutic range for dogs on combination therapy to 1500-2500 ug/mL.

What about serum bromide concentrations for dogs on bromide alone?

    For dogs treated with bromide alone, serum bromide concentrations associated with seizure control spanned a wide range in our survey (830-3410 ug/mL), but tend to be higher than comparable bromide levels for dogs on combination therapy, with an average of 1900 ug/mL. In addition, about 50% of dogs that responded to bromide monotherapy require bromide levels greater than 2000 ug/mL, while 10% of these dogs maintained levels even greater than 3000 ug/mL. Thus, the upper end of the therapeutic range for dogs on bromide alone should probably be extended to approximately 2500-3000 ug/mL, with careful monitoring for side effects (see below).

How should serum phenobarbital levels be interpreted in dogs that are also on bromide?

     The therapeutic range for serum phenobarbital concentrations (15-45 ug/mL) was established for dogs on phenobarbital monotherapy. The range of phenobarbital concentrations associated with seizure control in dogs on bromide as well as phenobarbital is wider (4-56 ug/mL) than the established therapeutic range. In our group of dogs on bromide, those that show improved seizure control have serum phenobarbital concentrations (mean 23 ug/mL) that are significantly lower than those historically established for dogs on phenobarbital alone (mean approximately 27 ug/mL), with about 45% of bromide-treated dogs showing continued seizure control at phenobarbital levels less than 20 ug/mL. Therefore, the established therapeutic range for serum phenobarbital concentrations should not be strictly applied to dogs that are also being treated with bromide, and "subtherapeutic" phenobarbital concentrations should not be used to justify increases in the dose of phenobarbital in these patients. Since some dogs on bromide can be taken off of phenobarbital, there is no real lower end of the therapeutic range for phenobarbital in bromide-treated dogs. Phenobarbital dose reductions should instead be guided by clinical response, with the goal being to use the lowest dose of phenobarbital that continues to control seizures in combination with bromide.

Can most epileptic dogs on bromide be taken off phenobarbital?

     In the 113 dogs in our group for which bromide therapy was initially added to barbiturates, phenobarbital and/or primidone therapy has been discontinued successfully in 19% of cases. An additional 35% of dogs that were started on bromide have been able to have the dose of phenobarbital reduced while still maintaining seizure control, with an average 47% reduction in the dose of phenobarbital (range 6 - 84%). Altogether, 53% of all dogs started on bromide that we have followed have had a dose reduction or elimination of barbiturate therapy with continued or improved seizure control compared to the period prior to bromide initiation.

How can I optimize the chances of a patient getting off of phenobarbital while maintaining seizure control?

    If discontinuation of phenobarbital is the goal in a particular patient, serum bromide concentrations should be targeted to greater than 2000 ug/mL, since dogs that are able to have phenobarbital discontinued have significantly higher serum bromide concentrations (mean 2040 ug/mL) than do dogs for which no change in the dose of phenobarbital is achieved (mean bromide level, 1470 ug/mL), or dogs for which phenobarbital dosage is only reduced but not eliminated (mean bromide level 1660 ug/mL).

What are the chances that a refractory epileptic patient will improve on bromide?

    Most dogs with epilepsy show improvement when bromide therapy is added. Podell & Fenner reported in 1993 that 83% of their canine epileptic patients with refractory epilepsy had a reduction in seizures following the initiation of bromide, with 26% of dogs becoming seizure-free. We have since noted that serum bromide levels greater than 2000 ug/mL tend to be associated with improved seizure control. This is borne out by the finding that a full 90% of the dogs in our study that were treated with both phenobarbital and bromide and reached serum bromide concentrations greater than 2000 ug/mL, showed significant seizure improvement (a 50% or greater reduction in seizure frequency compared to the period prior to bromide initiation).

What side effects of bromide are most common and how should they be managed?

    Lethargy, sedation, ataxia, and hindlimb weakness are quite common with bromide and phenobarbital in combination. These side effects are dose-dependent and usually respond within several days to a 10-25% reduction in the dose of phenobarbital. Although a reduction instead in the dose of bromide can also be considered, the goal in most patients is to reach therapeutic serum bromide concentrations and to reduce the dose of phenobarbital over time, so that a dose reduction in phenobarbital is preferred. If lethargy and sedation do not respond within 5 to 7 days to a reduction in the dose of phenobarbital, serum bromide levels should be evaluated. Other side effects of bromide with or without phenobarbital include polyuria, polydipsia, polyphagia with weight gain, and behavior changes. These side effects are a nuisance but are rarely significant enough to require drug discontinuation.

Is bromide safer than phenobarbital for long term use?

    We don't know. Phenobarbital has been used in dogs for decades and has always been considered a relatively safe drug. Only in the last five to ten years has it been recognized that some dogs develop hepatotoxicity when treated with phenobarbital alone. Neither the incidence nor the underlying mechanism of this adverse reaction is known, but it appears likely that hepatotoxicity is related to chronic and/or high doses of phenobarbital. However, other modulating risk factors are also likely to be present, since not all dogs on long-term phenobarbital therapy develop this syndrome. Although we don't yet have decades of experience with the use of bromide in dogs with epilepsy, it does appear so far that bromide is relatively safe in dogs when used over months to years and monitored appropriately.

SUMMARY

    For dogs treated with both bromide and phenobarbital, an estimated 53% will be able to have a reduction or discontinuation of phenobarbital even while showing an improvement in seizure control. The therapeutic range for phenobarbital in dogs also treated with bromide is lower than the standard range established for phenobarbital monotherapy. Higher serum concentrations of bromide (above 2000 mg/mL) may be necessary if eventual discontinuation of phenobarbital is desired, or if bromide monotherapy is elected.

Additional references:

Dayrell-Hart B, Steinberg SA, VanWinkle TJ, Farnbach GC. Hepatotoxicity of phenobarbital in dogs: 18 cases (1985-1989). JAVMA 1991; 199: 1060-1066.

Podell M, Fenner WR. Bromide therapy in refractory canine idiopathic epilepsy. J Vet Intern Med 1993; 7: 318-327.

Trepanier LA. Use of bromide as an anticonvulsant for dogs with epilepsy. JAVMA 1995; 207: 163-166.

VIN General Veterinary Library, 1998
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